Heart transplantation

Heart transplantation is a chance for patients at terminal stage of heart failure, with coronary artery disease, arrhythmias, hypertrophic cardiomyopathy or congenital heart diseases, with a high risk of death and so serious symptoms that exclude optimal use of drugs and medical equipment.

Heart transplantation can be indicated to patients who can not be disconnected from temporary cardiac support devices after myocardial infarction or after heart surgery not associated with transplantation or patients with heart complications with pulmonary disorders requiring pulmonary transplantation. Absolute contraindication is pulmonary hypertension; relative contraindications include organ failure (pulmonary, renal, hepatic) and local or systemic infiltrative disorders (heart sarcoma, amyloidosis).

All organs are taken from donor corpses with brain death, which should be less than 60 years and which should have normal functions of the heart and lungs and not have a history of coronary heart disease and other heart diseases. The donor and recipient should have the same blood groups and heart size. About 25% of the needy recipients die before selecting a suitable donor organ. Devices of artificial ventilation and artificial heart provide temporary hemodynamics for patients waiting for a transplant. However, if this equipment remains for a long time, there is a risk of developing sepsis, hardware insufficiency and thromboembolism.

Global statistics show that after a rapid growth in the mid-1980s, the annual number of heart transplants reached an average of about 3,000 and then did not change significantly due to the limited availability of donor organs. An increase in the number of heart transplants was accompanied by a natural accumulation of experience in conducting operations and an increase in the survival of recipients. Before the administration of cyclosporine, the annual survival was approximately 40%. The introduction of cyclosporine into a wide clinical practice, together with intensive immunological control with endomyocardial biopsy and active treatment of rejection by lymphospecific monoclonal antibodies, increased the survival rate of recipients to 80% at an annual and more than 70% with a 5-year follow-up. Some centers reported that the 4-year survival rate is 90%. Other conditional results are considered very encouraging, for example, assessing the quality of life of patients.

Anesthesia in orthotopic heart transplantation has certain features related to the initial severity of the patient's condition, the need to stop the recipient's heart, connect it to the AIC, the specific effect of drugs on the denervated heart, and so on.

[1], [2], [3], [4], [5]

Pathophysiological changes in terminal heart failure

The majority of patients who are included in the waiting list of heart transplantation are in the terminal stage of HF, which practically does not lend itself to therapeutic therapies against exhausted compensatory possibilities. The terminal stage of the disease can be the result of congenital or acquired heart disease or vascular system. The leading causes are ischemic and valvular heart disease, as well as primary cardiomyopathy. Depending on the cause, the beginning of decompensation is preceded by various periods of physiological adaptation, which usually ends with the manifestation of congestive heart failure. Since the manifestation of this syndrome, the prognosis for 5-year survival is less than 50%, and in patients with a rapid progression of the symptomatology this figure is even lower.

Prognostically extremely unfavorable occurrence of rhythm disturbances and data indicative of a pumping function deficiency (for example, a low ejection fraction). In LV lesions, the main compensatory mechanism is an increase in the LV diastolic volume, which increases the resting time of myocardial fibers and stimulates their more effective reduction. Such changes restore the shock volume at the cost of increasing pressure in the LP and an increase in the overload of the venous bed of the lungs. Other compensatory mechanisms include increasing the level of catecholamines and increasing the production of renin, leading to the retention of salt and water in the body.

Progression of these pathophysiological mechanisms ultimately reduces the strength and effectiveness of CB and leads to severe congestive heart failure, refractory to conventional pharmacotherapy. At this point, some patients may still be treated outpatiently, with small functional reserves, others are not subject to ambulatory treatment due to the presence of severe dyspnea or dependence on intravenous injection of inotropic drugs, mechanical support of blood circulation and / or ventilation.

Long periods of low CB threaten other vital functions of the organs, causing the development of passive liver overload and prerenal azotemia. Gradual progression of inadequate perfusion of the heart concludes with an irreversible decrease in cardiac activity. Heart transplantation can be shown at any of these stages and even after it becomes necessary to use mechanical support of the circulation. It is noted that survival rates remain relatively high even in those patients who require mechanical support of blood circulation as a temporary measure prior to transplantation, as well as those who have received a temporary artificial heart.

Typical diagnoses for transplantation are ischemic cardiomyopathy with LVEF less than 20%, idiopathic and viral cardiomyopathy, and some congenital malformations. Indication for heart transplantation is a patient's condition corresponding to the IV class of the New York Cardiology Association (extremely severe), and an unfavorable prognosis persistently persisting despite intensive medical therapy.

The expressed pulmonary hypertension with parameters of an average DLA above 50 mm Hg. Art. Are considered a contraindication for heart transplantation, and a 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 the normal donor heart is unable to quickly cope with the sharply increased, steady-state resistance of pulmonary vessels and is rapidly decompensated.

In such patients, a chance for survival is heart transplantation with the lungs or a heart-lung complex.

Heart or heart-lung transplantation is the method of choice for patients with end-stage lung disease complicated by right ventricular failure, or in the terminal stage of AMS with secondary involvement of 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.

When selecting potential donors, certain difficulties may arise that are associated with possible infection, damage, neurotoxic pulmonary edema, and aspiration of gastric contents. For optimal lung safety, hyperoxia should be avoided - FiO2 should not be above 0.4-0.5, oxygen saturation should be 90-100%. The danger is the excessive infusion of crystalloids, as it is important to avoid the accumulation of fluid in the lungs.

Preoperative preparation

Despite the fact that in the preoperative period candidates for cardiac transplantation receive intensive medical treatment, most of them have signs of impairment of the functions of various body systems. Low SV can lead to chronic passive liver overload, hepatomegaly and the presence of ascites in the abdominal cavity. From the lungs, pulmonary venous congestion and interstitial edema are observed. Signs of venous stasis are aggravated by the development of oliguria and prerenal azotemia, an increase in the level of renin and plasma catecholamines. Periodic disturbances of consciousness are frequent as a consequence of low CB.

Candidates for such a procedure as heart transplantation usually get inside or in / in inotropic drugs (eg, digoxin, amrinone), vasodilators of L C (captopril) and diuretics and, if necessary, antiarrhythmics. Patients with large dilated heart and low CB are prone to the formation of an intracardiac thrombus, and therefore they are shown 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 superior to the graft rejection syndrome in terms of risk.

Premedication

Diazepam v / m 10-20 mg, once for 25-30 minutes before the patient's delivery to the operating room or Midazolam IM 7.5-10 mg, once for 25-30 minutes before the patient is sent to the operating room

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Diphenhydramine 50-100 mg, once for 25-30 minutes before the patients in the operating room or Chloropyramine IM 20 mg, once for 25-30 minutes before the patient was sent to the operating room

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Cimetidine in / m 200 mg, once for 25-30 minutes before the patient's delivery to the operating room

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Betamethasone IV IM 4 mg, once for 25-30 minutes before the patient's delivery 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 or flunitrazepam iv 0.02-0.025 mg / kg, single dose

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Fentanyl IV 4-5 μg / kg, single dose

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Atracuria besylate IV 25-50 mg (0.4-0.7 mg / kg), once or Pipecuronium bromide IV 4-6 mg, once or Cisatracurium bezylate iv 10-15 mg (0.15 mg / kg) 0,3 mg / kg), once

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Ketamine IV 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, in the appointment of premedication, the preoperative sedative effect should be used cautiously, especially since the inefficient operation of the heart of patients in the terminal stage of heart failure largely depends on the elevated level of endogenous catecholamines. These patients are extremely sensitive to drugs that depress the CNS, due to a relative decrease in the volume of distribution, poor peripheral circulation and high concentration of drugs in well-perfused organs and tissues.

Regardless of whether the patient has been hospitalized for a long time or has just acted urgently, it turns out that most of these patients have recently taken food, and the situation of the donor heart requires a quick start of the operation. Gastric emptying through the probe is necessary, however, the timing of the possible administration of cyclosporine inwards, prescribed before the operation, should be considered.

When induction is used, reduced bolus doses of drugs. In a number of works, the expediency of slow infusion of induction drugs and methods for their titration is indicated. The main means for induction are IV anesthetics (ketamine, etomidate), analgesics (fentanyl), nondepolarizing muscle relaxants (pipecuronium bromide, cisatracurium bezylate, etc.). For the induction of anesthesia, various variants of ataralge-zia (diazepam 0.15-0.2 mg / kg, midazolam 0.2-0.25 mg / kg, flunitrazepam 0.02-0.025 mg / kg), combination with an analgesic fentanyl (4-5 μg / kg) and / or ketamine (1.7-1.9 mg / kg). Maintenance of anesthesia: (general balanced anesthesia based on isoflurane)

Isoflurane inhalation 0.6-2 MAK (in the minimal-flow mode)

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

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Fentanyl IV bolusno 0,1-0,2 mg, the periodicity of the introduction is determined by the clinical feasibility

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Midazolam IV bolus 0.5-1 mg, the frequency of administration is determined by clinical feasibility or

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

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Diazepam iv in 0,08-0,13 mg / kg / h, the periodicity of administration is determined by the clinical feasibility

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

Muscle relaxation:

Atracuria besylate iv 1 - 1.5 mg / kg / h or Pipecuronium bromide iv 0.03-0.04 mg / kg / h or Cisatracurium bezylate iv 0.5-0.75 mg / kg / h. During orthotopic transplantation at the stage before AIC connection, all manipulations with the heart should be minimal to avoid displacement of intracardiac thrombi. The main task of the anesthesiologist is to maintain the stability of hemodynamics and to exclude the use of large doses of inotropic drugs, intra-aortic balloon counterpulsation, artificial LV, and an emergency onset of infarction. Avoiding oppression of blood circulation when achieving deep anesthesia is possible if one avoids the use of anesthetics with cardiodepressive and pronounced vasodilating properties, preferring fentanyl or small doses of ketamine. Estimated doses of drugs injected with a perfusor are 1.1-1.2 mg / kg / h of ketamine, 0.08-0.13 mg / kg / h of diazepam, 4-7 μg / 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 in response to vasodilation the heart of these patients is not capable of increasing productivity.

After successive cannulation of the vena cava and the aorta, extrapulmonary infrared begins, and patients are cooled, as in conventional cardiological operations, to 26-28 ° C. The volume perfusion rate is 2.4-2.6 l / min. In recipients with severe metabolic acidosis and high oxygen debt, it may be necessary to perform perfusion at a higher rate before normalizing these parameters. During the period of hypothermia, the diseased heart is removed. Surgical anastomoses of the atrial walls of the donor heart and the atrial stump of the recipient are then performed. Particular caution must be exercised in order to keep the anterior wall of the donor heart cold even during anastomosing the posterior wall; premature warming can subsequently lead to insufficient function of the prostate. The heart is filled with cold saline solution to displace most of the air, an aortic anastomosis is performed, and after repeated air removal the clamps are removed (the end of the ischemia time). Quite often electromechanical activity is restored spontaneously, and the final part of the operation is the implementation of an anastomosis of the pulmonary artery.

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

Intraoperatively, they may need to maintain adequate diuresis, so in some cases it becomes necessary to connect hemofiltration or plasmapheresis. 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 the values of potassium in the plasma at least 4.5 mmol / l for effective prevention and reduction in the frequency of heart rhythm disturbances.

In many centers, 500 mg of methylprednisolone is injected immediately before the removal of the arterial clamp to prevent the "hyperosstra" of the immune reaction in /

Methylprednisolone IV / 500 mg, once.

Immediately after removal of the arterial clamp, a slow atrioventricular rhythm or AV blockade is usually observed. At this point, infusion of isoproterenol or another catecholamine with a positive chronotropic effect often begins to temporarily maintain the heart rate. Most arrhythmias disappear, but in some cases they persist persist even in the absence of rejection reaction. Eventually, approximately 5% of recipients require the implantation of a permanent pacemaker. If the heart rate is less than 60-70 / min, epicardial electrodes are applied and stimulation begins.

Immediately after transplantation, heart function is often not effective enough, and therefore, in many transplant centers, a long-term infusion of inotropic drugs is usually used. Reactions to catecholamine infusion are generally similar to those observed in other cardiosurgical patients.

Significantly increased LSS is a contraindication to orthotopic transplantation. But short-term pulmonary vasospasm can occur at the time of disconnection from the IC even in patients with initially normal DLA, causing a life-threatening right heart failure. Infusion of alprostadil - synthetic PG E1 at a rate of 0.025-0.2 mg / kg / min may be effective for discharge of the right heart. However, in order to maintain systemic vascular resistance, simultaneous infusion of alprostadil and norepinephrine is sometimes required:

Alprostadz in / in 0.025-0.2 mg / kg / min

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Norepinephrine i / in 10-20 ng / kg / min.

Elevated LSS during surgery is often reduced, which allows the cessation of alprostadil infusion. In critical cases, it is possible to use methods of mechanical support that are successfully applied in different periods of the operation.

Monitoring and induction of anesthesia with procedures such as heart transplantation or heart-lung complexes are generally the same as in heart transplantation, but it is important to remember that complete cessation of ventilation at the stage of surgery and pulmonary hypertension are additional factors that can lead to hemodynamic instability. At any time, you must be ready to start the auxiliary IR. Difficulties in gas exchange during induction can lead to hypercarbia or hypoxia and increase LSS. Patients with AMS may have bidirectional intracardiac shunts, mainly from right to left, leading to severe hypoxemia. These shunts can also cause a paradoxical air embolism, so you should carefully avoid the presence of vesicles in the infusion systems. In chronically cyanotic patients, pronounced polycythemia is often observed (hematocrit> 60%) and clotting disorders appear. For all recipients, large-size intubation tubes are preferred to facilitate therapeutic bronchoscopies. Special attention in intubation should be given to measures to prevent damage to the mucosa of the trachea, the introduction of the endotracheal tube to a minimum depth and the location of the inflated cuff above tracheal anastomosis.

In the period before IR, surgical manipulation can be complicated by multiple pleural spikes and possible bleeding. During the IR, a heart-lung unit is implanted, which is relatively simple and is performed by successive tracheal, right atrial and aortic anastomoses. Execution of tracheal anastomosis involves a specific technique that prevents divergence of the joints, for example wrapping the seam line with a vascularized gland. In order to reduce the risk of damage to the anastomosis sutures, the pressure in the tracheobronchial tree decreases by decreasing the respiratory volume with increasing respiratory rate. In addition, the oxygen fraction in the gas-narcotic mixture is reduced, reducing the partial pressure of oxygen in the lungs.

During surgery, due to pulmonary bleeding or inadequate protection, pulmonary compliance and gas exchange may deteriorate, so PEEPs are often required. When inflating the transplanted lungs, bronchoscopy is used to relieve the obstruction from mechanical obstruction. For the treatment of bronchospasm arising after surgery, intensive therapy with bronchodilators, including beta-adrenomimetics, euphyllin, halothane, may be required.

Of the features of surgery, it should be noted that the diaphragmatic, wandering and recurrent guttural nerves can be damaged by both crossing and local cooling. Due to the extensive dissection of the mediastinum and pleura, the early period after infarction may be complicated by bleeding leading to coagulopathy.

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

Auxiliary therapy

Correspond to those for other organ transplant operations and for heart operations.

[6], [7], [8], [9], [10], [11]

Heart transplantation in children

In the mid-1990s, the number of heart transplants with AMS exceeded the number of transplants in dilated cardiomyopathy, which was a clear indicator of the priority use of this operation in children, most of the recipients were under 5 years old. However, the overall mortality of young children remains higher than in adolescents and adults (the annual survival is 76% vs. 81%). The cause of most early deaths are cardiac complications - they arise in the presence of complex vascular anatomy, with an increase in the LSS and the presence of previous operations on the heart. The factor of pulmonary hypertension is a well-recognized contraindication to heart transplantation for adults, but it is often difficult to quantify accurately the magnitude of hypertension in children. If the values of LSS are at a high level, the normal transplant can not quickly adapt to postnagruzka and develops an uncontrollable right heart failure. Long-term survival may be limited to the accelerated form of coronary atherosclerosis, as well as in adults.

In contrast to the usual practice for other transplant organs, newborns have common indications for a procedure such as heart transplantation, determined with arterial atresia and hypoplastic left heart syndrome. If aortic arch reconstruction is required, deep hypothermia and circulatory arrest are usually needed. Positional inconsistency or disproportion of large vessels and abnormal location of systemic and / or pulmonary veins can complicate this operation, and these factors do not allow one-year survival of the operated newborns above 66%.

Procedure of heart transplantation

The donor heart is stored in hypothermia. It should be transplanted within 4-6 hours. The recipient is on the apparatus of artificial circulation; the heart of the recipient is removed, keeping in situ the posterior wall of the right atrium. Then, the heart of the donor is transplanted orthotopically with the formation of aortic anastomoses, anastomoses of the pulmonary arteries and veins; a simple anastomosis connects the remaining posterior wall of the atrium to the donor organ.

Immunosuppressive regimens are diverse, but similar to those used for kidney and liver transplantation (for example, monoclonal antibodies to IL-2 receptors, calcineurin inhibitors, glucocorticoids). At 50-80% of patients, at least one episode of rejection is observed (on average 2 or 3); in most patients it is asymptomatic, but 5% develop pulmonary ventilation dysfunction or atrial arrhythmias. The maximum number of cases of acute rejection falls on the first month, their number decreases in the next 5 months and stabilizes by the year. Factors that increase the risk of rejection include young age, female sex of recipients and donors, a negroid donor race and a mismatch in HLA antigens. Infection with cytomegalovirus also increases the risk of rejection.

Since damage to the transplant can be irreversible and catastrophic, an endomyocardial biopsy is performed once a year; the samples determine the extent and prevalence of mononuclear cell infiltrates and the presence of damaged myocytes. In differential diagnosis, ischemia is excluded around the operating area, cytomegalovirus infection, idiopathic B-cell infiltration (changes in Quilty). A weak degree of rejection (stage 1) without significant clinical manifestations does not require any treatment; the average and severe degree of rejection (stage 2 to 4) or a weak degree with clinical manifestations is treated with glucocorticoids and antitumocyte globulin or, if necessary, OKTZ.

The main complication is the defeat of the blood vessels of the cardiac allograft, the form of atherosclerosis, in which there is a diffuse narrowing or obliteration of the lumen of the vessels (in 25% of patients). This 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 the purpose of early diagnosis during endomyocardial biopsy, a stress test or coronary angiography with or without intravascular ultrasound is often performed. Treatment consists in aggressive lowering of lipids level, appointment of diltiazem; As a preventive measure, you can use everolimus 1.5 mg orally 2 times a day.

What prognosis does heart transplant have?

The survival rate after 1 year is 85%, and the annual mortality in the future is about 4%. Pre-transplantation prognostic factors of mortality in the first year are the need for pre-operative ventilation or ventilation, cachexia, female sex of the recipient or donor, other diseases in addition to heart failure or IHD. Post-transplantation prognostic factors include elevated levels of SRV and troponin. The cause of death during the first year is most often acute rejection and infection; causes of death after the first year - vasculopathy of the cardiac allograft or lymphoproliferative diseases. The prognosis for recipients who have lived more than one year is fine; the possibility of physical exercise is lower than normal, but sufficient for daily activity and may increase over time in connection with sympathetic reinnervation. More than 95% of patients reach the I functional class according to the classification of the New York Heart Association (NYHA), and more than 70% return to full-time work.

Assessment of the patient's condition after heart transplantation

The early postoperative period is the most difficult and responsible when adapting the donor heart to new conditions of functioning. In many respects the outcome of the operation is determined by the occurrence of right ventricular failure, the frequency of which at this stage reaches 70%. Despite the apparent effectiveness and power of the transplanted organ, the anesthetist should avoid the temptation of promptly stopping the isoproterenol infusion in the postperfusion or early postoperative period. When disabling inotropic support, bradyarrhythmias or atrio-ventricular blockade can occur and there is a need for temporary pacing. Practically all patients in the postoperative period have abnormalities of rhythm (81,2% - supraventricular, 87,5% - ventricular). In addition to arrhythmia in the donor heart, arrhythmias of the remaining part of the atria of the recipient, syndrome of weakness of the sinus node, are often recorded in patients. In some patients, there is a need for implantation of permanent pacemakers. The presence of a constant low CB can be the result of rejection or reperfusion injury. The only accurate method of establishing a diagnosis in this case is endomyocardial biopsy.

The causes of RV dysfunction, which is a characteristic complication of the early post-transplant period, can be isolated right-to-right dysfunction with elevated and normal LSS and right ventricular failure in combination with LV failure. Isolated right ventricular failure can be successfully treated with sympathomimetics in combination with vasodilators.

The most unfavorable combination is the failure of the right and left ventricles, which may be a result of a mismatch between the donor's and recipient's heart sizes, as well as myocardial injury and hypoxic and metabolic heart damage at the donor stage of transplantation. Intensive therapy in such patients requires the use of large doses of inotropic drugs and is accompanied by high mortality.

The function of the heart usually returns to normal after 3 to 4 days. Therapy with inotropic drugs is terminated after stable stabilization of CB. Gradually, I / O is replaced by oral. In the first days after transplantation, the required heart rate is 90-120 / min to maintain optimal CB. The difference of the transplanted heart is the symptom complex of denervation. It can include the absence of pain in the heart, even in the presence of coronary insufficiency, mild tachycardia at rest, lack of response to atropine or Valsalva, the presence of two teeth P, the absence of reflex changes in heart rate during breathing, pressing on the carotid sinus and sudden changes in body position. The reasons for these changes are the absence of regulation of the heart of the central nervous system, in particular the parasympathetic system.

In patients previously subjected to heart surgery and treated with conventional methods, severe mediastinal bleeding and coagulopathy can occur. With constant maintenance of hemodynamic stability, moderate preoperative organ disorders gradually disappear. However, if there is a poor function of the transplanted heart, the activity of organs with preoperative disorders can quickly decompensate. Since the danger of infectious complications is great, active prophylaxis and the determination of possible sources of fever are necessary.

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

In the postoperative period, with such procedures as heart transplantation or heart-lung complex, episodes of rejection often occur, accompanied by infiltrates, fever and deterioration of gas exchange. A pulmonary transplant can be rejected without significant disturbances in endomiocardial biopsy specimens, so low CB is not a mandatory sign of rejection. Recipients are also highly susceptible to bacterial pneumonia, which has a clinical picture of rejection; therefore, it may be necessary to perform bronchoalveolar lavage or transbronchial biopsy to establish an accurate diagnosis. A formidable problem soon after the transplantation of the heart-lung complex is the failure of the suture line of the trachea, which can lead to fatal mediastinitis. Later, a significant number of survivors develop obliterating bronchiolitis. The etiology of it is not yet known, but it is clear that this condition is associated with a progressive decrease in physical tolerance.

[12], [13], [14]