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Transcript of Sin título
Uxue Murgoitio Esandi
Story of an indication
Pharmacology matters: Immunosuppression
Complications: never late
I. Absolute indications
Hemodinamic disrepair due to heart failure
Refractory cardiogenic shock
Inotrope-dependent for correct perfusion
VO2 max < 10ml/Kg/min after reaching the anaerobic threshold
Severe activity limited myocardial ischemia without possible revascularization (PCI or CABG)
Symptomatic resistant ventricular arrithmias
II. Relative indications
VO2 max 11-14 ml/Kg/min with important limitation of the functional capacity
Recurrent and unstable ischemia without any possible intervention
Recurrent instability of the water equilibrium/renal function not due to therapeutic failure
III. Insufficient indications
Low left ventricle ejection fraction
Previous NYHA II or III functional class
Previous ventricular arrithmias
VO2 max > 15 ml/Kg/min without other indications
Age >70 (biological and chronological age)
Malignant tumors with a high probability of recurrence after immunosuppression
Diabetes Mellitus with severe target organ damage
Smoking, alcoholism and drug addiction
Unfavourable phsychosocial environment that could keep from treatment adherence
Severe damage of renal or hepatic function if combined transplant is not possible
Fixed severe pulmonary hypertension
Obesity. Severe peripheral and cerebral vasculopathy
Peptic ulcer or active diverticulitis
Other systemic diseases with poor prognosis
Drugs acting on immunophilins
Graft Vascular Disease
It was developed as an alternative to CsA
Some shared adverse efects; many avoided.
Better bioavailability: more soluble and less need of bile production
Mechanism of action: it needs to form complexes with immunophilins, the FKBP-12 cytoplasmic protein in this case, in order to inhibit calcineurin. Therefore, IL-2, TNF-a, INF-y and IL-10 should also be inhibited.
Pharmacokinetics: poor oral bioavailability (25%) due to erratic gastrointestinal absorption. Coadministration of Tac with Mycophenolate mofetil (MMT) increases the bioavailability of its active metabolite, the Mycophenolic acid.
Main adverse efects: renal toxicity, less hypertension and hyperlipidemia, Diabetes Mellitus, (not gingival hyperplasia, hypertrichosis, but alopecia), neurotoxicity, hypomagnesemia, hyperkalemia and hyperuricemia.
Initial dose: orally 0,075 mg/kg/day in two dosis or continuous perfusion 0,01-0,02 mg/Kg/day
Mycophenolate Mofetil (MMF)
Mechanism of action: The MMF is rapidly hydrolyzed, becoming mycophenolic acid (MPA), and blocks the
synthesis of purines by the reversible and non-competitive inhibition of the Inosine-5-monophosphate dehydrogenase. This one is the only pathway through which the lymphocytes can synthesize DNA.
The MMF inhibits selectively the T and B lymphocyte proliferation in cases of allogenic stimulation.
IL-2 production is not blocked, as with CNI.
Pharmacokinetics: the MMF depends on the gastric and hepatic hydrolyzation to become MPA, then, the bioavailability reaches the 90%. After having his job done, the MPA is conjugated to a bile inactive metabolite for its excretion.
The MMF dose is 2-3 g/day, making it twice a day adjusted by secondary effects, mainly myelotoxicity and gastrointestinal intolerance.
The Mycophenolate Sodium, recently developed, happens to have a similar security and efficacy profile.
Glucocorticoids are a regular component in the induction, maintenance and rejection treatment after heart transplant.
Example of an induction and maintenance treatment protocol:
Two 500 mg doses of methylprednisolone before and after surgery
Three 125 mg doses every 8 hours after the intervention
Initially, one dose of 1 mg/Kg/day of prednisone which will go decreasing in 0,1 mg/Kg every 48 hours until the 0,2 mg/Kg/day dose is reached.
The 0,2 mg/Kg/day dose will be reduced to 0,1 mg/Kg/day about the 6th month after transplant
Many adverse effects: hypertension, emotional lability, cataracts, peptic ulcer, delayed wound healing or proximal myopathy as well as hyperlipidemia, salt and water retention, Diabetes Mellitus, osteopenia or estaturoponderal delay.
The regularly performed endomyocardial biopsies would lead to a glucocorticoid dose reduction if negative, yet the total removal is still controversial. Nowadays, the rate of corticoid withdrawal is 23% the first year, and 39%, the fifth.
Acute cellular rejection:
first 6 months after the transplant.
It is based on a T cell response, the myocardial infiltration leads to cell death and diastolic dysfunction of the graft, the lack of early treatment enables systolic dysfunction and graft failure.
- Inespecific (asthenia, dizziness, nausea or febricula)
- Left and right congestive symptoms
- Low output symptoms
- Rhythm disorders
Under suspicion of acute cellular rejection:
Start urgent treatment
Nevertheless, many of the rejection episodes are asymptomatic:
- Endomyocardial biopsy (EMB)
the B cell response.
Graft dysfunction with few or no signs of cellular rejection.
Etiology unclear: multifactorial hypotheses
Normally, heart failure or sudden death are the first clinical manifestations.
Prevention and diagnosis:
Primary prevention: close follow-up of the cardiovascular risk factors
Coronary angiographies are recommended once a year or every two years (level C of evidence).
Treatment is reduced and has a poor efficacy:
- Immunosuppressive drugs' replacement
- Revascularization: firstly, PCI; secondly, CABG (surgical)
Diffuse, concentric and longitudinal thickness of the intima of the vascular tree, affecting from the big epicardial coronary arteries to the microvasculature and leading to ischemic cardiomyopathy.
When acute heart failure, differential diagnosis between GVD and acute rejection
Main cause of late death after transplant
- Lymphoproliferative syndromes
- Screening for breast, colon and prostate cancers
- Close follow-up of cutaneous tumors
- Minimization of chronic immunosuppression
- Similar to general population
Infection etiology or frequency depends on the time after transplant:
- First month
- Between the 2nd and 6th month
- 6th month forward
- Early and specific diagnosis
- Poor clinical presentation
- Microbiological or histological diagnosis
- Opportunistic infections
- Interactions and toxicity of the antibiotics
- Utility of the reduction of immunosuppression
- Graft implantation moment
- Preformed antibodies
- Inflammation, ischemia and generalized myocardial necrosis: fulminant clinical course.
Treatment: diminish the antibody count
Glucocorticoids, plasmapheresis, monoclonal antibodies...
Drugs acting on immunophilins
Immunosuppressive drug: transplants and autoimmune diseases
Mechanism of action: it needs to form complexes with immunophilins, cyclophilins in this case, in order to inhibit calcineurin. Therefore, IL-2, TNF-a, INF-y and IL-10 should also be inhibited.
Pharmacokinetics: lipophilicity makes its bioavailability unpredicable: Neoral.
CsA is metabolized by CYP3A4 in the liver and then excreted by the kidneys and intestines.
Main adverse efects:
- Renal toxicity - Hypertension
- GI disorders - Transient hepatotoxicity
- Gingival hyperplasia - Hypertrichosis/hirsutism
- Angioedema - Neurotoxicity
- Hypomagnesemia - Hyperkalemia
Monitor the hepatic and renal functions: control the cyclosporine blood levels!
Maintenance dose: 2-6 mg/kg/day divided in two dosis
Mechanism of action: Azathioprine - 6-mercaptopurine - tioiosine monophosphate (TIMP)
The purine analog gets in the DNA and inhibits its synthesis.
Suppressed T and B lymphocyte proliferation; tumor development.
Pharmacokinetics: Good intestinal absorption and prolonged effect (12-24h). Azathioprine is metabolized in the liver and excreted through urine.
The catabolism depends on oxidase xanthines: alopurinol!
The AZA dose is 1-2 mg/kg/day, if combined with CNI and with possible dose reduction if leukocytes<3000mL, platelets<100000mL and Ht<30%. Aza blood levels are not monitored.
- Myelosuppression: anemia, thrombocytopenia and leukopenia.
"...Once the donor's heart is on the operating table, we proceed to remove the diseased heart. The first incision is made through the interatrial groove to the base of the mitral annulus and the base of the LAA. Then, the superior and inferior cava veins are sectioned and the left atrium gets finally sectioned too. Subsequently, two other sections are performed a few millimeters from the aortic and pulmonary valves and, therefore, the receptor's heart is completely removed. The vascular structures are then adjusted and improved to proceed with the donor's heart's anastomosis. The first anastomosis is going to be the left atrium with a 3/0 Prolene...
...While the patient gets heated the pulmonary artery's anastomosis is done with a 4/0 Prolene. From 5 to 10 minutes later the heart starts beating spontaneously in sinus rhythm with satisfactory ventricular contractions which leads to a soon disconnection of the CPB pump because of good systolic pressures. The
total donor ischemic time
has been 3 hours and 30 minutes and after an approximately 25 minute assistance the CPB pump is disconnected with a total ECC of 2 hours and 15 minutes..."
Myocardial ischemia and preservation
- No myocardial preservation techniques
- Principal of hypothermia
- Cardioplegic principle
- Reperfusion and reoxygenation damage
Cold static preservation
Continuous perfusion for cardiac preservation
Monday, 9th of June 1997
"60 year old patient. Male.
History of anterior myocardial infarction in December 1989,
in January 1990 operated on of septoapical aneurysmectomy and triple aortocoronary bypass.
The patient was periodically followed being in a NYHA class II.
The 24th of November 1995, though good physical appearance, a 5 second pause was found due to carotid sinus massage, syncope also happened. The electrocardiogram showed a trifascicular block, a pacemaker was implanted.
The patient evolved successfully until April 1996, when he presented with major cold symptoms. It was treated with antibiotics and theophyllines. As a consequence of the bronchodilator therapy, the patient has presented malaise and precordial oppression with progressive dyspnea ever since.
Nowadays, the patient has an important orthopnea, PND and generalized edema.
The patient enters the waiting list for heart transplantation."
Saturday, 4th of May 1996
Cyclosporine 175 mg/12 hours, orally at 9am and 9pm
Azathioprine 200 mg/day, orally at 4pm
Prednisone 5 mg/day, orally at 8am
Cyclosporine 150 mg/12 hours, orally at 9am and 9pm
Azathioprine 150 mg/day, orally at 4pm
Cyclosporine 125 mg/12 hours, orally at 9am and 9pm
Mycophenolate Mofetil 500 mg/12 hours, orally at 9am and 9pm
Cyclosporine 75 mg/12 hours, orally at 9am and 9pm
Mycophenolate Mofetil 750 mg/12 hours, orally at 9am and 9pm
Cyclosporine 25 mg/12 hours, orally at 9am and 9pm
Mycophenolate Mofetil 500 mg/8 hours
Cyclosporine 25 mg/day, orally at 2pm
Mycophenolate Mofetil 750 mg/12 hours
Prednisone 5 mg/day
Screening for acute rejection
- Every 15 days during the first 3 months
- Sixth month
- Once a year
Monitorization of the immnosuppressants' blood level
"The 28th of May 1998, under local anesthesia and via femoral, the right ventricle's emdomyocardial biopsy was performed.
The pathological study revealed a IA acute rejection,
light and focal"
Mycotic pseudoaneurysm of the ascending aorta is a rare but potentially life-threatening
complication after orthotopic heart transplantation.
CUN: once a year
hemodynamic study, coronary angiography...
"Exercise Stress Echo Test (26/07/01):
Treadmill: Stress44 Time: 11:00
Left Ventricle: Concentric hypertrophy
TDD(mm): 46 TSD(mm):30 EF(%): 66 VS:62 TDV(ml): 96 TSV(ml): 33 DS(mm): 11
FS(%): 35 SS(mm): 14 SPP(mm): 16
Contractility: septal normal, anterior normal, apical normal, inferior normal, posterior normal, lateral normal
Right Ventricle: normal
Atria: dilated left atrium, dilated right atrium
LA-length(cm): 6.7 LA-Trans(cm):4 LA-antero-post(cm): 6.3 RA-length(cm): 4.8 RA-Trans(cm):3.7
Mitral Valve: Normal
E(cm/s):84 A(cm/s):43 E/A:2 THP(m/s):66 DT(ms):210
Aortic Valve: Normal
Pulmonary Valve: Normal
Tricuspid Valve: Normal
ECG: Sinus rhythm, no alterations
Basal Echo: Orthotopic heart transplant. Hypertrophic left ventricle with normal global systolic function (EF=0.65). Dilated left atrium. Typical transplanted heart filling pattern, DT of 210 ms, IVRT of 60ms and WMSI of 1.
Dobutamine echo: Infusions of dobutamine were performed at doses of 5, 10, 20, 30 and 40 µg/Kg/min with a three minute gap for each dose. The Optison 3 mg echocardiographic contrast was previously administered for cavity opacification. Heart rate reached 145 bpm (93% of his MHR). Blood pressure reached 164/100 mmHg. The maximum double product was 23780. Clinically asymptomatic. No electrocardiographic changes. Regional motility alterations were not observed. WMSI of 1.
Conclusions: Negative study for ischemia."
2009: Prostate adenocarcinoma
2010: NHL - postransplant follicular lymphoma grade II, stage IV-A
2011: seborrheic keratosis
2013: Lung nodule compatible with adenocarcinoma
Multiple episodes of urinary tract infections, herpes virus and CMV infections, complicated cholelithiasis...
"A heart transplant patient comes to the ER with respiratory distress. He started with fever (39ºC) and malaise five days ago. After talking to Dr Rabago on the phone, he started taking Tavanic. The fever improved but the dyspnea didn´t.
When hospitalized, empirical antibiotic therapy is started with Piperacilin/Tazobactam and Levofloxacin intravenously, adjusted by renal function. Clinical improvement is observed the next days, the patient remains apyretic and without any need of oxygen. At the time of discharge, the patient has reached 8 days of intravenous antibiotic therapy.
Diagnosis: Left pneumonia without microbiological isolation.
The patient is hospitalized for asthenia and a mainly morning febricula which subsides with paracetamol. The cultures were negative.
On the CT performed the 21st of September an 8 cm mycotic pseudoaneurysm was found. Therefore, a preferred surgery is scheduled for the 25th of September.
Under general anesthesia and CPB pump the replacement of the ascending aorta is performed using a 28 mm Hemashield Gold graft. An important recessed mycotic aneurysm is found with an infected thrombus in it (sent to microbiology). Severe adherences were also found and were difficult to dissect.
On the first days after surgery, the patient presented with bilateral effusion and atelectasis with air leak. Once diuresis was forced, the patient progressively improved and was moved to the ward, where positively evolved.
The cultures of the aortic tissue were positive for
. The patient was treated, first, with intravenous Ceftriaxone during 2 weeks and, after, with Levofloxacino 4 more weeks."