Heart transplantation

Heart transplantation is an opportunity for patients with end-stage heart failure, coronary artery disease, arrhythmias, hypertrophic cardiomyopathy or congenital heart disease, who have a high risk of death and symptoms so severe that they preclude the optimal use of drugs and medical equipment.

Heart transplantation may be indicated in patients who cannot be weaned off temporary cardiac support devices after myocardial infarction or after nontransplant cardiac surgery, or in patients with cardiac complications due to pulmonary disorders requiring lung transplantation. An absolute contraindication is pulmonary hypertension; relative contraindications include organ failure (pulmonary, renal, hepatic) and local or systemic infiltrative disorders (cardiac sarcoma, amyloidosis).

All organs are collected from brain-dead cadaveric donors who must be under 60 years of age, have normal heart and lung function, and have no history of coronary heart disease or other heart disease. The donor and recipient must have matching blood types and heart sizes. About 25% of recipients die before a suitable donor organ is found. Ventilators and artificial hearts provide temporary hemodynamics for patients awaiting a transplant. However, if these devices are left in place for long periods, there is a risk of sepsis, device failure, and thromboembolism.

Worldwide statistics show that after a rapid increase in the mid-1980s, the annual number of heart transplants has reached an average of about 3000 and has not changed significantly since due to the limited availability of donor organs. The increase in the number of heart transplants has been accompanied by a natural accumulation of experience in performing the operations and an increase in the survival of recipients. Before the introduction of cyclosporine, the one-year survival was approximately 40%. The introduction of cyclosporine into widespread clinical practice, together with intensive immunological monitoring by endomyocardial biopsy and active treatment of rejection with lymphospecific monoclonal antibodies, has increased the survival of recipients to 80% at one year and more than 70% at 5 years of follow-up. Some centers have reported that the 4-year survival rate reaches 90%. Other conditional results, such as the assessment of the quality of life of patients, are also considered very encouraging.

Anesthesia during orthotopic heart transplantation has certain features associated with the initial severity of the patient's condition, the need to stop the recipient's heart, connect it to the heart-lung machine, the specific effect of drugs on the denervated heart, etc.

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Pathophysiological changes in terminal heart failure

Most patients who are included in the waiting list for a heart transplant are in the terminal stage of heart failure, which is practically not amenable to therapeutic treatment methods against the background of exhausted compensatory capabilities. The terminal stage of the disease may be a consequence of congenital or acquired diseases of the heart or vascular system. The leading causes are ischemic and valvular heart disease, as well as primary cardiomyopathy. Depending on the cause, the onset of decompensation is preceded by periods of physiological adaptation of varying duration, which usually ends with the manifestation of congestive heart failure. From the moment this syndrome manifests itself, the prognosis for 5-year survival becomes less than 50%, and in patients with rapid progression of symptoms this figure is even lower.

The occurrence of rhythm disturbances and data indicating pump failure (e.g. low ejection fraction) are extremely unfavorable prognostically. In LV lesions, the main compensatory mechanism is an increase in the LV end-diastolic volume, which increases the resting period of myocardial fibers and stimulates their more effective contraction. Such changes restore stroke volume at the cost of increased LA pressure and increased pulmonary venous overload. Other compensatory mechanisms include increased catecholamine levels and increased renin production, leading to salt and water retention in the body.

The progression of these pathophysiological mechanisms eventually reduces the strength and effectiveness of cardiac arrest and leads to severe congestive heart failure, refractory to conventional pharmacotherapy. At this point, some patients can still be treated on an outpatient basis, having small functional reserves, while others cannot be treated on an outpatient basis due to severe dyspnea or dependence on intravenous inotropic drugs, mechanical circulatory support, and/or mechanical ventilation.

Prolonged periods of low CO compromise other vital organ functions, causing passive liver overload and prerenal azotemia. Gradual progression of inadequate perfusion of the heart itself culminates in irreversible decline in cardiac function. Heart transplantation may be indicated at any of these stages and even after mechanical circulatory support has become necessary. Survival rates have been shown to be relatively high even in patients requiring mechanical circulatory support as a temporary measure prior to transplantation, as well as in those receiving a temporary artificial heart.

Typical diagnoses for transplantation are ischemic cardiomyopathy with LVEF less than 20%, idiopathic and viral cardiomyopathy, and some congenital defects. An indication for heart transplantation is a patient's condition corresponding to New York Heart Association class IV (extremely severe) and an unfavorable prognosis that persists despite intensive drug therapy.

Severe pulmonary hypertension with mean PAP values above 50 mm Hg is considered a contraindication for heart transplantation, and moderate increase in pulmonary pressure is a factor predisposing to dysfunction of the donor heart. Absolute contraindications include severe pulmonary hypertension, since the RV of a normal donor heart is unable to quickly cope with the sharply increased, established resistance of the pulmonary vessels and quickly decompensates.

In such patients, the chance of survival is a heart-lung transplant or a heart-lung complex transplant.

Heart or heart-lung complex transplantation is the method of choice for patients with end-stage lung diseases complicated by right ventricular failure, or in the end-stage of congenital heart disease with secondary involvement of the pulmonary vessels - Eisenmenger syndrome. The specific pathological symptom complex in potential recipients includes primary pulmonary hypertension, emphysema, multiple pulmonary embolism, cystic fibrosis, granulomatous and fibrotic lung diseases. Suitable donor organs contain the heart and lungs, including a tracheal segment of sufficient length.

The selection of potential donors may present certain difficulties related to possible infection, injury, neurotoxic pulmonary edema and aspiration of gastric contents. For optimal preservation of the lungs, hyperoxia should be avoided - FiO2 should not be higher than 0.4-0.5, blood oxygen saturation should be 90-100%. Excessive infusion of crystalloids is dangerous, since it is important to avoid fluid accumulation in the lungs.

Preoperative preparation

Despite the fact that candidates for heart transplantation receive intensive drug therapy in the preoperative period, most of them have signs of dysfunction of various body systems. Low CO can lead to chronic passive liver overload, hepatomegaly, and the presence of ascites in the abdominal cavity. On the part of the lungs, pulmonary venous overload and interstitial edema are observed. Signs of venous congestion are aggravated by the development of oliguria and prerenal azotemia, an increase in the level of renin and plasma catecholamines. Periodic disturbances of consciousness as a result of low CO are not uncommon.

Candidates for a procedure such as heart transplantation usually receive oral or intravenous inotropic drugs (eg, digoxin, amrinone), vasodilators (captopril), diuretics, and, if necessary, antiarrhythmics. Patients with a large, dilated heart and low cardiac output are prone to intracardiac thrombus formation and therefore require anticoagulants (warfarin, LMWH). Particular attention should be paid to the prevention of infectious complications, since they account for almost half of the deaths after transplantation and are even more risky than transplant rejection syndrome.

Premedication

Diazepam IM 10-20 mg, once 25-30 minutes before the patient is brought into the operating room or Midazolam IM 7.5-10 mg, once 25-30 minutes before the patient is brought into the operating room

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Diphenhydramine 50-100 mg, once 25-30 minutes before the patient is taken to the operating room or Chloropyramine IM 20 mg, once 25-30 minutes before the patient is taken to the operating room

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Cimetidine IM 200 mg, once 25-30 minutes before the patient is taken to the operating room

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Betamethasone IM 4 mg, once 25-30 minutes before the patient is taken to the operating room.

Basic methods of anesthesia

Induction of anesthesia:

Diazepam IV 0.15-0.2 mg/kg, single dose or Midazolam IV 0.2-0.25 mg/kg, single dose or Flunitrazepam IV 0.02-0.025 mg/kg, single dose

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Fentanyl IV 4-5 mcg/kg, single dose

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Atracurium besylate IV 25-50 mg (0.4-0.7 mg/kg), single dose or Pipecuronium bromide IV 4-6 mg, single dose or Cisatracurium besylate IV 10-15 mg (0.15-0.3 mg/kg), single dose

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Ketamine intravenously 1.5-1.1 mg/kg, once.

Candidates for heart transplantation are often on the waiting list for a long period of time. When choosing drugs for premedication and induction, it is necessary to take into account the degree of asthenia and mental stability of these patients, the presence of signs of encephalopathy. Therefore, when prescribing premedication, preoperative sedation should be used with caution, especially since the ineffective work of the heart of patients in the terminal stage of heart failure largely depends on the increased level of endogenous catecholamines. These patients are extremely sensitive to drugs that depress the activity of the central nervous system, due to a relative decrease in the volume of distribution, poor peripheral circulation and high concentration of drugs in well-perfused organs and tissues.

Whether the patient has been in hospital for a long time or has just been admitted as an emergency, it turns out that most of these patients have recently eaten, and the situation of receiving a donor heart requires that the operation be started quickly. Gastric emptying through a tube is necessary, but the moment of possible oral cyclosporine administration, prescribed before the operation, should be taken into account.

During induction, reduced bolus doses of drugs are used. A number of studies indicate the advisability of slow infusion of induction drugs and their titration methods. The main agents for induction are intravenous anesthetics (ketamine, etomidate), analgesics (fentanyl), non-depolarizing muscle relaxants (pipecuronium bromide, cisatracurium besylate, etc.). Various types of ataralgesia (diazepam 0.15-0.2 mg/kg, midazolam 0.2-0.25 mg/kg, flunitrazepam 0.02-0.025 mg/kg) in combination with the analgesic fentanyl (4-5 mcg/kg) and/or ketamine (1.7-1.9 mg/kg) are successfully used to induce anesthesia before heart transplantation. Maintenance of anesthesia: (isoflurane-based general balanced anesthesia)

Isoflurane inhalation 0.6-2 MAC (in minimal-flow mode)

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Dinitrogen oxide with oxygen by inhalation 1:1 (0.25:0.25 l/min)

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Fentanyl intravenously bolus 0.1-0.2 mg, frequency of administration is determined by clinical appropriateness

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Midazolam intravenously bolus 0.5-1 mg, frequency of administration is determined by clinical appropriateness or

Ketamine IV 1.1-1.2 mg/kg/h, frequency of administration is determined by clinical appropriateness

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Diazepam IV 0.08-0.13 mg/kg/h, frequency of administration is determined by clinical appropriateness

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Fentangsh 4-7 mcg/kg/h, the frequency of administration is determined by clinical appropriateness.

Muscle relaxation:

Atracurium besylate IV 1-1.5 mg/kg/h or Pipecuronium bromide IV 0.03-0.04 mg/kg/h or Cisatracurium besylate IV 0.5-0.75 mg/kg/h. During orthotopic transplantation at the stage before connecting the artificial heart pump, all manipulations with the heart should be minimal to avoid displacement of intracardiac thrombi. The main task of the anesthesiologist is to maintain hemodynamic stability and exclude the use of large doses of inotropic drugs, intra-aortic balloon pump, artificial LV and emergency start of artificial heart pump. It is possible to avoid circulatory depression when achieving deep anesthesia if you avoid the use of anesthetics with cardiodepressant and pronounced vasodilatory properties, giving preference to fentanyl or small doses of ketamine. The calculated doses of drugs administered using a perfusor are 1.1-1.2 mg/kg/h of ketamine, 0.08-0.13 mg/kg/h of diazepam, 4-7 mcg/kg/h of fentanyl, and 0.03-0.04 mg/kg/h of pipecuronium bromide. Most researchers draw attention to the need for a very cautious attitude to reducing afterload in patients with primary pulmonary hypertension and hypertrophic cardiomyopathy, since the heart of these patients is not able to increase productivity in response to vasodilation.

After sequential cannulation of the vena cava and aorta, extrapulmonary cardiopulmonary bypass is started, and patients are cooled as in routine cardiac surgery to 26-28°C. The volumetric perfusion rate is 2.4-2.6 L/min. In recipients with severe metabolic acidosis and high oxygen debt, it may be necessary to perfuse at a higher rate until these parameters are normalized. During the hypothermia period, the diseased heart is removed. Surgical anastomoses are then performed between the atrial walls of the donor heart and the atrial stump of the recipient. Particular care must be taken to keep the anterior wall of the donor heart cold even during anastomosis of the posterior wall, since premature warming may subsequently cause insufficient RV function. The heart is filled with cold saline to expel most of the air, an aortic anastomosis is performed, and after repeated air removal, the clamps are released (ending ischemia time). Quite often, electromechanical activity is restored spontaneously, and the final part of the procedure is the pulmonary artery anastomosis.

Many patients with end-stage heart disease receive maintenance therapy with diuretics - mannitol or furosemide.

Intraoperatively, they may need to maintain adequate diuresis, so in some cases it is necessary to connect hemofiltration or plasmapheresis. In this case, it is important to constantly monitor the electrolyte balance, taking into account the special sensitivity of the transplanted heart to the level of potassium in the blood plasma. It is necessary to maintain potassium levels in the plasma at least 4.5 mmol / l for effective prevention and reduction of the frequency of cardiac arrhythmias.

In many centers, 500 mg of methylprednisolone is administered intravenously immediately before removing the arterial clamp to prevent a “hyperacute” immune reaction:

Methylprednisolone intravenously 500 mg, single dose.

Immediately after release of the arterial clamp, a slow atrioventricular rhythm or AV block is usually observed. At this point, an infusion of isoproterenol or another catecholamine with a positive chronotropic effect is often started to temporarily maintain the heart rate. Most arrhythmias resolve, but in some cases they persist stubbornly even in the absence of a rejection reaction. Ultimately, approximately 5% of recipients require implantation of a permanent pacemaker. If the heart rate is less than 60-70 bpm, epicardial leads are placed and pacing is started.

Immediately after transplantation, the heart is often suboptimal, and many transplant centers routinely use continuous infusion of inotropic drugs. Responses to catecholamine infusion are generally similar to those seen in other cardiac surgery patients.

A markedly elevated PVR is a contraindication to orthotopic transplantation. However, transient pulmonary vasospasm may occur at the time of weaning from CPB even in patients with initially normal PAP, causing life-threatening right heart failure. Infusion of alprostadil, a synthetic PG E1, at a rate of 0.025-0.2 mg/kg/min may be effective in unloading the right heart. However, in order to maintain systemic vascular resistance, simultaneous infusion of alprostadil and norepinephrine is sometimes required:

Alprostadgsh IV 0.025-0.2 mg/kg/min

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Norepinephrine IV 10-20 ng/kg/min.

Increased PVR during surgery often decreases, allowing discontinuation of alprostadil infusion. In critical cases, mechanical support methods can be used, which are successfully used at different stages of the operation.

Monitoring and induction of anaesthesia for a procedure such as cardiac or heart-lung transplantation are generally the same as for cardiac transplantation, but it is important to remember that complete cessation of ventilation during the procedure and pulmonary hypertension are additional factors that can lead to haemodynamic instability. CPB should be prepared to begin at any time. Difficulties in gas exchange during induction may lead to hypercarbia or hypoxia and increase PVR. Patients with CHD may have bidirectional intracardiac shunts, predominantly right-to-left, leading to severe hypoxemia. Such shunts may also cause paradoxical air embolism, so care must be taken to avoid bubbles in the infusion lines. Chronically cyanotic patients often have marked polycythemia (haematocrit > 60%) and exhibit coagulation disorders. Large endotracheal tubes are preferred for all recipients to facilitate therapeutic bronchoscopies. Special attention should be paid to measures to prevent damage to the tracheal mucosa, to insert the endotracheal tube to a minimum depth, and to position the inflatable cuff above the tracheal anastomosis.

In the pre-CPB period, surgical manipulations may be complicated by multiple pleural adhesions and possible bleeding. During CPB, the heart-lung block is implanted, which is relatively simple and is performed by sequential tracheal, right atrial, and aortic anastomoses. Performing the tracheal anastomosis involves a certain technique to prevent suture divergence, such as wrapping the suture line with vascularized omentum. In order to reduce the risk of damage to the anastomotic sutures, the pressure in the tracheobronchial tree is reduced by decreasing the tidal volume with an increase in the respiratory rate. In addition, the oxygen fraction in the gas anesthetic mixture is reduced, reducing the partial pressure of oxygen in the lungs.

During surgery, pulmonary compliance and gas exchange may deteriorate due to pulmonary hemorrhage or inadequate protection, so PEEP is often required. Bronchoscopy is used to inflate the transplanted lungs to relieve mechanical secretion obstruction. Postoperative bronchospasm may require intensive therapy with bronchodilators, including beta-adrenergic agonists, aminophylline, and halothane.

The peculiarities of surgical intervention include the fact that the phrenic, vagus and recurrent laryngeal nerves can be damaged by both transection and local cooling. Due to extensive dissection of the mediastinum and pleura, the early period after CPB may be complicated by bleeding, leading to coagulopathy.

Immediately from the moment of restoration of blood circulation through the transplanted heart-lung complex, inotropic support with catecholamines (isoproterenol, dobutamine, dopamine, etc.) begins, which continues in the postoperative period for several days. To prevent pulmonary edema, a negative fluid balance is maintained.

Adjuvant therapy

They correspond to those in other organ transplant operations and in heart operations.

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Heart transplantation in children

In the mid-1990s, the number of heart transplants for CHD exceeded those for dilated cardiomyopathy, which was a clear indicator of the priority use of this procedure in children, since most recipients were under 5 years of age. However, the overall mortality of young children remains higher than that of adolescents and adults (1-year survival is 76% versus 81%). Most early deaths are due to cardiac complications - they occur in the presence of complex vascular anatomy, with increased PVR, and with previous cardiac surgery. Pulmonary hypertension is a well-recognized contraindication to heart transplantation in adults, but it is often difficult to accurately quantify the magnitude of hypertension in children. If PVR values are high, the RV of a normal graft is unable to quickly adapt to the afterload, and refractory right heart failure develops. Long-term survival may be limited by the accelerated form of coronary atherosclerosis, as in adults.

In contrast to the usual practice for other transplantable organs, neonates have generally accepted indications for a procedure such as cardiac transplantation, defined by arterial atresia and hypoplastic left heart syndrome. If reconstruction of the aortic arch is required, profound hypothermia and circulatory arrest are usually necessary. Positional mismatch or disproportion of the great vessels and abnormal placement of the systemic and/or pulmonary veins can complicate this procedure, and these factors prevent the 1-year survival of neonates undergoing surgery from exceeding 66%.

Heart transplant procedure

The donor heart is stored under hypothermia. It must be transplanted within 4-6 hours. The recipient is placed on a heart-lung machine; the recipient's heart is removed, preserving the posterior wall of the right atrium in situ. The donor heart is then transplanted orthotopically with the formation of aortic, pulmonary artery and vein anastomoses; a simple anastomosis connects the remaining posterior wall of the atrium to the donor organ.

Immunosuppressive regimens vary but are similar to those used in renal and liver transplantation (eg, anti-IL-2 receptor monoclonal antibodies, calcineurin inhibitors, glucocorticoids). At least one rejection episode (average 2 or 3) occurs in 50–80% of patients; most are asymptomatic, but 5% develop pulmonary ventilation dysfunction or atrial arrhythmias. The incidence of acute rejection peaks in the first month, declines over the next 5 months, and plateaus by 1 year. Factors that increase the risk of rejection include young age, female recipient and donor gender, black donor race, and HLA mismatch. Cytomegalovirus infection also increases the risk of rejection.

Because graft injury may be irreversible and catastrophic, endomyocardial biopsy is performed annually to evaluate the extent and distribution of mononuclear cell infiltrates and the presence of damaged myocytes. The differential diagnosis includes perioperative ischemia, cytomegalovirus infection, and idiopathic B-cell infiltration (Quilty changes). Mild rejection (stage 1) without significant clinical manifestations requires no treatment; moderate to severe rejection (stages 2 to 4) or mild rejection with clinical manifestations is treated with glucocorticoids and antithymocyte globulin or, if necessary, OTZ.

The main complication is vascular lesion of the cardiac allograft, a form of atherosclerosis in which diffuse narrowing or obliteration of the vascular lumen occurs (in 25% of patients). It is a polyetiological disease, and its development depends on the age of the donor, cold or reperfusion ischemia, dyslipidemia, the use of immunosuppressants, chronic rejection, and viral infection (adenovirus in children, cytomegalovirus in adults). For early diagnosis, a stress test or coronary angiography with or without intravascular ultrasound is often performed during endomyocardial biopsy. Treatment consists of aggressive lipid reduction, diltiazem, and everolimus 1.5 mg orally twice a day can be used as a prophylactic measure.

What is the prognosis for a heart transplant?

The 1-year survival rate is 85%, and the annual mortality thereafter is about 4%. Pretransplant predictors of 1-year mortality include the need for preoperative ventilation or ALV, cachexia, female recipient or donor sex, and diseases other than heart failure or coronary artery disease. Posttransplant predictors include elevated CRP and troponin levels. The most common causes of death in the first year are acute rejection and infection; causes of death after the first year are cardiac allograft vasculopathy or lymphoproliferative disorders. The prognosis for recipients surviving beyond 1 year is excellent; exercise capacity is lower than normal but sufficient for daily activities and may increase over time due to sympathetic reinnervation. More than 95% of patients achieve New York Heart Association (NYHA) functional class I, and more than 70% return to full-time work.

Evaluation of the patient's condition after heart transplantation

The early postoperative period is the most difficult and critical in the adaptation of the donor heart to new operating conditions. The outcome of the operation is largely determined by the occurrence of right ventricular failure, the incidence of which at this stage reaches 70%. Despite the apparent effectiveness and power of the transplanted organ, the anesthesiologist should avoid the temptation to quickly stop isoproterenol infusion in the postperfusion or early postoperative period. When inotropic support is turned off, bradyarrhythmia or atrioventricular block may be observed and temporary cardiac stimulation may be required. Almost all patients in the postoperative period are found to have rhythm disturbances (in 81.2% - supraventricular, in 87.5% - ventricular). Along with rhythm disturbances of the donor heart, patients quite often have arrhythmias of the remaining atria of the recipient, sinus node weakness syndrome. Some patients require implantation of permanent pacemakers. The presence of persistently low CO may be the result of rejection or reperfusion injury. The only definitive method of establishing the diagnosis in this case is endomyocardial biopsy.

Causes of RV dysfunction, which is a typical complication of the early post-transplant period, may include isolated right ventricular failure with elevated and normal PVR and right ventricular failure combined with LV failure. Isolated right ventricular failure can be successfully treated with sympathomimetics in combination with vasodilators.

The most unfavorable is the combination of right and left ventricular failure, which may be a consequence of the discrepancy between the sizes of the donor and recipient hearts, as well as myocardial contusion and hypoxic and metabolic damage to the heart at the donor stage of transplantation. Intensive care in such patients requires the use of large doses of inotropic drugs and is accompanied by high mortality.

Cardiac function usually returns to normal values in 3-4 days. Inotropic drug therapy is discontinued after stable stabilization of cardiac output. IV drugs are gradually replaced by oral ones. In the first days after transplantation, the required heart rate to maintain optimal cardiac output is 90-120/min. A distinctive feature of a transplanted heart is the denervation symptom complex. This includes the absence of pain in the heart even in the presence of coronary insufficiency, moderate tachycardia at rest, no response to atropine or the Valsalva maneuver, the presence of two P waves, no reflex changes in heart rate during breathing, pressure on the carotid sinus, and sudden changes in body position. The causes of these changes are the lack of regulation of cardiac activity by the central nervous system, in particular the parasympathetic system.

Patients who have previously undergone cardiac surgery and have been treated with conventional methods may develop significant mediastinal bleeding and coagulopathy. With continuous maintenance of hemodynamic stability, moderate preoperative organ dysfunctions gradually disappear. However, if the transplanted heart function is poor, the function of organs with preoperative dysfunctions may rapidly decompensate. Since the risk of infectious complications is high, active prevention and identification of possible sources of fever are necessary.

Most patients receive a triple immunosuppressive regimen (cyclosporine, azathioprine, prednisolone), and in some centers, muromonab-CDS. In the early postoperative period, bacterial pneumonia with typical hospital strains is more common. Later, opportunistic infection with CMV, pneumocystis, or legionella may occur.

In the postoperative period, after such procedures as heart or heart-lung transplantation, episodes of rejection occur quite frequently, which are accompanied by infiltrates, fever, and deterioration of gas exchange. Lung grafts can be rejected without significant abnormalities in endomyocardial biopsy specimens, so that low CO is not necessarily a sign of rejection. Recipients are also highly susceptible to bacterial pneumonia, which has a clinical picture of rejection, so bronchoalveolar lavage or transbronchial biopsy may be necessary to establish an accurate diagnosis. A serious problem soon after heart-lung transplantation is tracheal suture line failure, which can lead to fatal mediastinitis. Later, a significant number of survivors develop obliterating bronchiolitis. Its etiology is still unknown, but it is clearly associated with a progressive decrease in exercise tolerance.

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