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Thoracic organ transplantation: an overview for perfusionists Andreas Hoschtitzky Overview OCTx HCTx HLTx DLTx SLTx History OCTx 1905 Alexis Carrel transplanted a puppy's heart into the neck of a dog; because of the lack of immunosuppression, the experiment was unsuccessful. Early investigators included Frank C. Mann of the Mayo Clinic, V.P. Demikov of the Soviet Union, and Marcus Wong. These early efforts in transplantation were thwarted by the infancy of cardiopulmonary bypass and a lack of understanding of the immune system. As knowledge in these areas advanced, so did the field of cardiac transplantation. Shumway developed modern day transplantation protocols. 1967 Christian Barnard: first successful heart transplant in a human. 1983 The clinical use of cyclosporine as an immunosuppressant revolutionized the field of transplantation. Recipient survival rates improved, thus producing an explosive increase in the number of transplant centers offering cardiac transplantation. The remaining limiting factor: number of available organ donors. OCTx transplantation Indications: patients with end-stage congestive heart failure with a prognosis of less than a year to live without the transplant and who are not candidates for conventional medical therapy or have not been helped by conventional medical therapy. In the US approximately 4000 individuals are waiting for hearts. In 1999, about 2000 heart transplants were performed in the US. UK around 300-400 per year. Availability of organs is a major issue. OCTx transplantation Frequency: The annual frequency of the procedure is about 1% of the general population with heart failure Etiology: adults: – Idiopathic cardiomyopathy 54% – Ischemic cardiomyopathy 45% – Congenital heart disease and other diseases 1% children: congenital heart disease and cardiomyopathy most common: HLHS commonest Pathophysiology OCTx Transplanted heart is unique: – denervation of the organ makes it dependent on its intrinsic rate. – as a result of the lack of neuronal input, some left ventricular hypertrophy results. – right ventricular function is directly dependent upon ischaemic time and adequacy of preservation. – right ventricle is easily damaged and may initially function as a passive conduit until recovery occurs. Allograft rejection 2 forms: cellular and humoral. – Cellular rejection is the classic form of rejection: perivascular infiltration of lymphocytes with subsequent myocyte damage and necrosis if left untreated. – Humoral rejection is much more difficult to characterize and diagnose. Generalized antibody response initiated by several unknown factors. The antibody deposition into the myocardium results in global cardiac dysfunction. Diagnosis is generally made on the basis of clinical suspicion and exclusion because endomyocardial biopsy is of little value. Coronary artery disease: late process, common to all cardiac allografts. Diffuse myointimal hyperplasia of the small- and medium-sized vessels, occuring from 3 months to several years after implantation. Etiology: still unclear, though cytomegalovirus (CMV) infection and chronic rejection have been implicated. The mechanism of the process is thought to be dependent upon growth-factor production in the allograft initiated by circulating lymphocytes. Treatment: re-transplantation. Indications OCTx Deteriorating cardiac function and having a prognosis of less than 1 year to live: NYHA class III or IV symptoms EF < 25% Intractable angina or malignant cardiac arrhythmias for which conventional therapy has been exhausted PVR < 6-8 Wood units Age < 65 years Normal renal, hepatic, pulmonary and CNS function Absence of malignancy, infection, recent pulmonary infarct, severe peripheral vascular or cerebrovascular disease Ability to comply with medical follow-up care OCTx Donor criteria Brain death Consent next of kin ABO compatible with recipient > 1year old Within 20% size as recipient No cardiac disease in medical history Normal ventricular wall motion on ECHO Normal heart as assessed by donor team 20% recipients die on waiting list though…. Management of the Potential Cardiac Recipient TAILORED MEDICAL THERAPY FOR END-STAGE CARDIAC FAILURE Conventional outpatient management of congestive heart failure includes ACE inhibitors, AR blockers, beta blockers, and diuretics (especially spironolactone). PHARMACOLOGIC BRIDGE TO TRANSPLANTATION Critically compromised patients require admission to the intensive care unit for intravenous inotropic therapy. Milrinone, dobutamine, and dopamine are the agents of choice. Placement of an intra-aortic balloon pump (IABP) also may be necessary in heart failure refractory to initial pharmacologic measures. Patients with continued pulmonary congestion or global hypoperfusion despite maximal pharmacologic and IABP therapies have been shown to improve with placement of mechanical devices as bridges to transplantation. MECHANICAL BRIDGE TO TRANSPLANTATION The increased success of cardiac transplantation in conjunction with the static number of available organs has created a need for mechanical assist devices as a bridge to transplantation. Ventricular assist devices (VAD) or total artificial hearts (TAH) may be indicated in potential cardiac recipients who remain unstable after 24 to 48 hours of maximal pharmacologic support. Since these devices are rarely weaned, however, it is imperative that the patient's candidacy for transplantation be scrutinized prior to placement of a VAD or TAH. Patient selection for a mechanical device is a complex, evolving field. Recent data shows that approximately 70% of patients are successfully bridged to transplantation and the actuarial survival is 80% at one year. Most large series suggest an improvement in survival because the devices allow patients to be rehabilitated while on the device. Initial results from the Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure (REMATCH) study indicate that patients with devices have improved survival and quality of life at 1 year compared to medical therapy and may prove to be an acceptable long term option in those patients who are not candidates for cardiac transplantation. LIFE-THREATENING VENTRICULAR ARRHYTHMIAS Symptomatic VT or VF and a history of sudden cardiac death (SCD) are indications for placement of an automatic implantable cardioverter-defibrillator (AICD), long-term amiodarone therapy, or occasionally radiofrequency catheter ablation. SCD is the most common cause of death in patients awaiting heart transplantation and is most common within the first 3 months after referral for transplantation. Several studies have shown that implantation of a defibrillator improved survival in patients with either a history of or inducible ventricular tachycardia or fibrillation. Management of the Cardiac Donor Complex physiological phenomenon of brain death and the need to coordinate procurement with other organ donor teams. Optimal care requires that the donor be treated as any other intensive care unit patient with invasive hemodynamic monitoring, ventilatory support, and meticulous attention to intravascular volume status and electrolytes. Continuous monitoring of arterial pressure, central venous pressure, and urinary output is mandatory. As the number of marginal donors increases with the acceptance of more lenient eligibility criteria, some transplant centers have established mobile intensive care teams that are dispatched to ensure appropriate management of these highly labile patients. Haemodynamic instability in the donor may result from vasomotor dysfunction, hypovolemia, hypothermia, and dysrhythmias. Increased intracranial pressure may lead to massive sympathetic discharge with elevated levels of circulating endogenous catecholamines. The resultant episodes of systemic hypertension and coronary vasospasm place the allograft at significant risk of ischemic injury. Rapid afterload reduction may be achieved with sodium nitroprusside, whereas volatile anesthetics assist in reducing the intensity of sympathetic bursts. To minimize cerebral edema prior to the declaration of brain death, potential donors have been intravascularly volume depleted via strict fluid restriction and osmotic diuresis. Aggressive volume resuscitation is sometimes necessary and may require use of a Swan-Ganz catheter. Fluid overload, however, should be avoided to prevent postoperative allograft dysfunction caused by chamber distention and myocardial edema. Blood transfusions are indicated to optimize oxygen delivery if the hemoglobin falls below 10 g/dL. Mean arterial pressure should be maintained between 80 and 90 mm Hg. If fluid resuscitation is inadequate to restore blood pressure in the hypotensive donor, a dopamine infusion is initiated for inotropic support. Vasopressors are occasionally indicated for hypotension caused by loss of systemic vasomotor tone. Prolonged administration of high-dose catecholamine therapy (dopamine >10–15 µg/ kg/min) has been associated with poor cardiac function in the posttransplant period because of depletion of myocardial norepinephrine stores. Traditionally, these patients were rejected for use as cardiac donors, but high-dose inotropic support is no longer an absolute contraindication for donation. Maintenance of normal temperatures, electrolyte levels, osmolarity, acid-base balance, and oxygenation is critical for optimal donor management. Common electrolyte disturbances include hypernatremia, hypokalemia, hypomagnesemia, and hypophosphatemia.97 Central diabetes insipidus develops in more than 50% of donors because of pituitary dysfunction, and massive diuresis complicates fluid and electrolyte management. A low-dose aqueous vasopressin (Pitressin) infusion is initiated at 0.8 to 1.0 U/h and titrated to keep urinary output at approximately 100 to 200 mL/h. Alternatively, vasopressin may be administered periodically subcutaneously or intramuscularly (10 U every 4 hours). Standard ventilator management with endotracheal suctioning is essential in these vulnerable patients. Broad-spectrum antibiotic therapy with a cephalosporin is initiated following collection of blood, urine, and tracheal aspirate for culture. Brain death is associated with the depletion of a variety of hormones, including free triiodothyronine (T3), cortisol, and insulin. Donor pretreatment with hormone replacement therapy has proven to be beneficial. Donor Heart Procurement The heart is inspected and palpated for evidence of cardiac disease or injury. The SVC, IVC and azygous vein are encircled with ties. The aorta is dissected from the pulmonary artery and isolated with tape. To facilitate access to the epigastrium by the liver procurement team, the cardiac team often then temporarily retires from the operating room table or assists with retraction. Once preparation for liver, pancreas, lung, and kidney explantation is completed, the patient is administered 30,000 IU of heparin intravenously. OCTx donor operation The azygous vein and SVC are ligated and divided distal to the azygous vein leaving a long segment of superior vena cava. The inferior vena cava is clamped at the level of the diaphragm (if the abdominal IVC is vented) and divided proximal to the clamp to permit efflux of the cardioplegia. Additional venting is achieved with transection of the right superior pulmonary vein. The cross-clamp is applied at the takeoff of the innominate artery and the heart is arrested with a single flush (500 mL) of cardioplegic solution infused through a 14-gauge needle inserted proximal to the cross-clamp. Rapid cooling of the heart is achieved with copious amounts of cold saline and cold saline slush. The apex of the heart is elevated cephalad and the pulmonary veins are divided. This maneuver is appropriately modified to retain adequate left atrial cuffs for both lungs and the heart if the lungs also are being procured. While applying caudal traction to the heart with the nondominant hand, the ascending aorta is transected proximal to the innominate artery and the pulmonary arteries are divided distal to bifurcation (modification is necessary if the lungs are being procured). More generous segments of the great vessels and superior vena cava may be required for recipients with congenital heart disease. Donor heart for OCTx Donor heart is removed from the transport cooler and placed in a basin of cold saline. Preparation of the donor heart is accomplished. Electrocautery and sharp dissection are used to separate the aorta and pulmonary artery. The left atrium is incised by connecting the pulmonary vein orifices and excess atrial tissue is trimmed forming a circular cuff tailored to the size of the recipient left atrial remnant. Organ preservation OCTx Safe ischaemic period is around 4 to 6 hours, beyond this “marginal donors”. Postoperative myocardial dysfunction is secondary to suboptimal donor management, hypothermia, ischemia-reperfusion injury, and depletion of energy stores. A single flush of a cardioplegic or preservative solution followed by static hypothermic storage. No single preservation regimen has demonstrated consistent, clinically significant superior myocardial protection when used within the current safe limits of ischemia. Controversy surrounds optimal storage temperature, composition of cardioplegic and storage solutions, techniques of solution delivery, additives, and reperfusion modification. Hypothermia remains the cornerstone of organ preservation. The ideal storage temperature is unknown, but most institutions aim for temperatures between 4°C and 10°C. Crystalloid solutions of widely different compositions are available and the debate over them speaks for the fact that no ideal solution currently exists. Depending on their ionic composition, solutions are classified as intracellular or extracellular. Intracellular solutions, characterized by moderate to high concentrations of potassium and low concentrations of sodium, purportedly reduce hypothermia-induced cellular edema by mimicking the intracellular milieu. Commonly used examples of these solutions include University of Wisconsin, Euro-Collins, and in Europe, Bretschneider (HTK) solutions. Extracellular solutions, characterized by low to moderate potassium and high sodium concentrations, avoid the theoretical potential for cellular damage and increased vascular resistance associated with hyperkalemic solutions. Stanford, Hopkins, and St. Thomas Hospital solutions are representative extracellular cardioplegic solutions. Organ preservation OCTx Additives for cardioplegic storage solutions: The greatest potential for future routine use may lie with impermeants, substrates, and antioxidants. Impermeants (mannitol, lactobionate, raffinose, and histidine) counteract intracellular osmotic pressure to reduce hypothermia-induced cellular edema in the allograft. The preservation of myocardial high-energy phosphates during ischemia (to prevent contracture bands) and their rapid regeneration at reperfusion (to fuel the newly contracting heart) are the primary objectives for the use of substrate-enhanced media. Adenosine, L-pyruvate, and L-glutamate have been studied most intensely. Recognizing that oxygen-derived free radicals and neutrophils likely are critical mediators of myocardial reperfusion injury, considerable investigative effort has been undertaken to modify the untoward effects of ischaemia-reperfusion with antioxidant additives including allopurinol, glutathione, superoxide dismutase, catalase, mannitol, and histidine. A variety of pharmacologic and mechanical strategies for leukocyte inhibition and depletion are also being explored. Benefits of continuous perfusion preservation techniques are currently overshadowed by exacerbation of extracellular cardiac edema and logistical problems inherent to a complex perfusion apparatus. Experimental low-pressure (microperfusion) and intermittent flush techniques theoretically provide sufficient oxygen and substrates for basal metabolic demands without causing significant edema. 20% of peri-operative deaths are still caused by cardiac dysfunction…. OCTx vs HCTx Orthotopic cardiac transplantation: replacement of part (or occasionally all) of the recipient's heart with a healthy donor allograft. Heterotopic cardiac transplantation, the piggybacking of an allograft onto the patient's heart, is rarely performed today. Indicated if orthotopic transplantation is not possible because of elevated pulmonary vascular resistance or when a donor heart is too small to sustain the recipient. Results are not equivalent to orthotopic transplant. OCTx: ANAESTHETIC MANAGEMENT Once donor team has given go-ahead, recipient induction commences. High-dose narcotics (e.g. fentanyl) usually are employed for induction and maintenance anaesthesia. In light of the poor ventricular function of the recipient, all anesthetic agents should be titrated carefully with inotropic and vasoactive agents readily accessible for the rapid management of induction-induced hypotension. Inhaled agents may be added if necessary, but their potential myocardial depressant effects limit widespread use in this patient population. Prior to skin incision, some centers initiate aprotinin or aminocaproic acid therapy to minimize perioperative blood loss. OCTx: OPERATIVE RECIPIENT PREPARATION Median sternotomy and vertical pericardiotomy, the patient is heparinized and prepared for cardiopulmonary bypass. Bicaval venous cannulation and distal ascending aortic cannulation just proximal to the origin of the innominate artery is optimal. Umbilical tape snares are passed around the superior and inferior vena cava. Bypass is initiated, the patient is cooled to 28°C, caval snares are tightened, and the ascending aorta is cross-clamped. The great vessels are transected above the semilunar commissures, whereas the atria are incised along the atrioventricular grooves leaving cuffs for allograft implantation. Removal of the atrial appendages reduces the risk of postoperative thrombus formation. Following cardiectomy, the proximal 1 to 2 cm of aorta and pulmonary artery are separated from one another with electrocautery, taking care to avoid injuring the right pulmonary artery. Continuous aspiration of pulmonary venous return from bronchial collaterals is achieved by insertion of a vent into the left atrial remnant, either directly or via the right superior pulmonary vein. Timing of donor and recipient cardiectomies is critical to minimize allograft ischaemic time and recipient bypass time. Frequent communication between the procurement and transplant teams permits optimal coordination of the procedures. Ideally, the recipient cardiectomy is completed just prior to the arrival of the cardiac allograft. OCTx implantation A double-ended 3-0 Prolene is taken through the recipient left atrial cuff at the level of the left superior pulmonary vein and then through the donor left atrial cuff near the base of the atrial appendage. The allograft is lowered into the recipient mediastinum atop a cold sponge to insulate it from direct thermal transfer from adjacent thoracic structures. The suture is continued in a running fashion caudally and then medially to the inferior aspect of the interatrial septum. Upon completion of the posterior left atrial suture line, continuous topical cold saline irrigation of the pericardial well is initiated, and the patient is oriented in a left side down–head up position to allow drainage of the saline away from the operative field and maximal cold saline exposure of the left and right ventricles. OCTx implantation OCTx implantation The second arm of the suture is run along the roof of the left atrium and down the interatrial septum. It is important to continually assess size discrepancy between donor and recipient atria so that appropriate plication of excess tissue may be performed. The left atrium is filled with saline and the two arms of suture are tied together on the outside of the heart. Some centers introduce a line into the left atrial appendage for continuous endocardial cooling of the allograft (50–75 mL/min) and evacuation of intracardiac air Left atrial anastomosis is complete, a curvilinear incision is made from the IVC toward the RA appendage of the allograft. This reduces the risk of injury to the sinoatrial node and accounts for the preservation of sinus rhythm observed in most recipients. The tricuspid apparatus and interatrial septum are inspected. Recipients are predisposed to increased right-sided heart pressures in the early postoperative period owing to preexisting pulmonary hypertension and volume overload. Both conditions are poorly tolerated by the recovering right ventricle. To avoid refractory arterial desaturation associated with right-to-left shunting, patent foramen ovale is oversewn. OCTx implantation RA anastomosis is performed in a running fashion similar to the left with the initial anchor suture placed either at the most superior or inferior aspect of the interatrial septum so that the ends of the suture meet in the middle of the anterolateral wall. The end-to-end pulmonary artery anastomosis is next performed using a 4-0 Prolene suture beginning with the posterior wall from inside of the vessel and then completing the anterior wall from the outside. It is crucial that the pulmonary artery ends be trimmed to eliminate any redundancy in the vessel that might cause kinking. OCTx implantation Rewarming is initiated at this time. Finally, the aortic anastomosis is performed using a technique similar to the pulmonary artery except that some redundancy is desirable in the aorta as it facilitates visualization of the posterior suture line. Rewarming is usually begun prior to the aortic anastomosis, which is performed in a standard end-toend fashion. Routine de-airing techniques are then employed. Cold saline lavage is discontinued, lidocaine (100–200 mg IV) is administered, and the aortic cross-clamp is removed. Half of patients require electrical defibrillation. A needle vent is inserted in the ascending aorta for final de-airing with the patient in steep Trendelenburg. Inotrope infusion is initiated and titrated to achieve a heart rate between 90 and 110 bpm. Temporary epicardial pacing wires are placed in the donor right atrium and ventricle. The patient is weaned from cardiopulmonary bypass and the cannulae are removed. Anatomy Recent trend: bicaval anastomoses rather than right atrial anastomoses in an attempt to decrease the incidence of postoperative tricuspid insufficiency. In the transplantation process, the sinoatrial nodes of the donor and recipient remain intact, and both are present within the recipient. For approximately 3 weeks after surgery, the electrocardiogram demonstrates 2 P waves; however, the heart rate and electrical activity of the new heart are purely dependent on the intrinsic electrical system of the heart and not on the neurological input from the recipient. ALTERNATIVE TECHNIQUES FOR ORTHOTOPIC HEART TRANSPLANTATION Two alternative techniques for orthotopic heart transplantation have been gaining popularity over the past several years: – total heart transplantation involves complete excision of the recipient heart with bicaval end-to-end anastomoses – bilateral pulmonary venous anastomoses. The Wythenshawe bicaval technique is performed in a similar fashion except that the recipient left atrium is prepared as a single cuff with all four pulmonary vein orifices. Although these procedures are more technically difficult than standard orthotopic transplantation, series using these techniques have reported shorter hospital stays and reduced postoperative dependence on diuretics, in addition to lower incidences of atrial dysrhythmias, conduction disturbances, mitral and tricuspid valve incompetence, and right ventricular failure. Furthermore, a recently completed randomized study comparing biatrial versus bicaval transplant showed an improved twelve month survival in the bicaval group. Long term outcomes and additional randomized studies evaluating these alternative techniques are still needed RECIPIENTS WITH CONGENITAL ANOMALIES Unlike children and infants, transplantation in adults with previous palliative procedures for congenital anomalies is uncommon. Generous donor cardiectomy be performed so that sufficient tissue is available for optimal reconstruction. There are a variety of anomaly-specific implantation techniques. Heterotopic Heart Transplantation Pulmonary hypertension and right heart failure has remained one of the leading causes of death in cardiac transplantation. This has led to an interest in heterotopic heart tranplantation. Currently, heterotopic heart transplants are indicated in patients with irreversible pulmonary hypertension or significant donor-recipient size mismatch. DONOR ALLOGRAFT PREPARATION Like the cardiectomy for patients with congenital disease, the maximal length of aorta, superior vena cava, and pulmonary arteries is procured. The inferior vena cava and the right pulmonary veins are oversewn, and a common left pulmonary vein orifice is created. A linear incision is made along the long axis of the posterior right atrium extending 3 to 4 cm into the superior vena cava. Domino Donor Procedure The Domino donor procedure was used to avoid wasting relatively healthy hearts from selected heartlung transplant recipients. These organs were transplanted into a different recipient using standard orthotopic or heterotopic techniques. Heterotopic CTx The sequence of anastomoses is as following: donor left pulmonary vein orifice to recipient left atrium, donor superior vena cava-right atrial orifice to recipient right atrium, end-to-side aortic-aortic anastomosis, and finally an end-to-side anastomosis joining the pulmonary arteries of donor and recipient. By employing this technique, the strengths of both the native and transplanted heart are utilized. The conserved recipient's right ventricle provides the necessary assistance to the transplanted heart to overcome significant pulmonary hypertension. The incidence of tricuspid regurgitation is reported to be as high as 47-98% following heart transplantation (Chan, 2001). Some centers have now begun to prophylactically perform tricuspid annuloplasty on donor grafts before performing the transplantation (McGee, 2004). POSTOPERATIVE MANAGEMENT Because of denervation the SA node of the transplanted heart fires at its increased intrinsic resting rate of 90 to 110 bpm. The allograft relies on distant noncardiac sites as its source for catecholamines; thus, its response to stress (e.g. hypovolemia, hypoxia, anemia) is somewhat delayed until circulating catecholamines can exert their positive chronotropic effect on the heart. Careful examination of the electrocardiogram occasionally may reveal a distinct P wave originating from the innervated atrial remnant of the recipient, and an increase in its rate may be used as an early indicator of stress. The absence of a normal reflex tachycardia in response to venous pooling accounts for the frequency of orthostatic hypotension in transplant patients. Denervation alters the heart's response to therapeutic interventions that act directly through the cardiac autonomic nervous system. Carotid sinus massage, Valsalva maneuver, and atropine have no effect on sinoatrial node firing or atrioventricular conduction. Because of depletion of myocardial catecholamine stores associated with prolonged inotropic support of the donor, the allograft often requires high doses of catecholamines. ROUTINE HEMODYNAMIC MANAGEMENT Donor myocardial performance is transiently depressed in the immediate postoperative period. Allograft injury associated with donor hemodynamic instability and the hypothermic, ischemic insult of preservation contribute to the reduced ventricular compliance and contractility characteristics of the newly transplanted heart. Abnormal atrial dynamics owing to the midatrial anastomosis exacerbate the reduction in ventricular diastolic loading. An infusion of epinephrine or dobutamine is initiated routinely in the operating room to provide temporary inotropic support. Restoration of normal myocardial function usually permits the cautious weaning of inotropic support within 2 to 4 days. EARLY ALLOGRAFT FAILURE Early cardiac failure accounts for up to 25% of perioperative deaths of transplant recipients. The cause may be multifactorial, but the most important etiologies are pulmonary hypertension, ischemic injury during preservation, and acute rejection. Mechanical support with an intra-aortic balloon pump or ventricular assist device is indicated in cases refractory to pharmacologic interventions. Re-transplantation in this setting is associated with very high mortality. Chronic left ventricular failure frequently is associated with elevated pulmonary vascular resistance, and the unprepared donor right ventricle may be unable to overcome this increased afterload. Although recipients are screened to ensure that those with irreversible pulmonary hypertension are not considered for transplantation, right heart failure remains a leading cause of early mortality. Initial management involves employing pulmonary vasodilators such as inhaled nitric oxide, nitroglycerin, or sodium nitroprusside. Pulmonary hypertension refractory to these vasodilators will often respond to prostaglandin E1 (PGE1). Inhalation nitric oxide is considered the standard at several institutions. Intra-aortic or pulmonary artery balloon counterpulsation and right ventricular assist devices have been utilized in patients unresponsive to medical therapy. DYSRHYTHMIAS Sinus or junctional bradycardia occurs in more than half of transplant recipients. The primary risk factor for sinus node dysfunction is prolonged organ ischemia. Adequate heart rate is achieved with inotropic drug infusions and/or temporary epicardial pacing. Most bradyarrhythmias resolve over 1 to 2 weeks, although recovery may be further delayed in patients who received preoperative amiodarone therapy. Theophylline has been effective in patients with bradyarrhythmias and has decreased the need for permanent pacemakers in this patient population. Ventricular arrhythmias, primarily premature ventricular beats (PVCs) and nonsustained ventricular tachycardia, have been reported in up to 60% of recipients when monitored continuously. AF/flutter is treated with digoxin, but at a higher dose than used in the setting of an innervated heart. Arrhythmias occasionally are markers for acute rejection. SYSTEMIC HYPERTENSION Mean arterial pressures greater than 80 mm Hg should be treated to prevent unnecessary afterload stress on the allograft. In the early postoperative period, intravenous sodium nitroprusside or nitroglycerin is administered. Nitroglycerin is associated with less pulmonary shunting because of a relative preservation of the pulmonary hypoxic vasoconstrictor reflex. If hypertension persists, an oral antihypertensive can be added to permit weaning of the parenteral agents. Respiratory Management The respiratory management is the same as following routine cardiac surgery. Renal Function Preoperative renal insufficiency owing to chronic heart failure and the nephrotoxic effects of cyclosporine places the recipient at increased risk of renal insufficiency. Acute cyclosporine-induced renal insufficiency usually will resolve with the reduction in cyclosporine dose. Patients at risk for renal failure initially may receive cyclosporine as a continuous intravenous infusion to eliminate the wide fluctuations in levels associated with oral dosing. Furthermore, concurrent administration of mannitol with cyclosporine may reduce its nephrotoxicity. Alternatively, some centers administer a cytolytic agent in the immediate postoperative period and delay the initiation of cyclosporine therapy. Intermediate Care Unit and Convalescent Ward The increasing risk of nosocomial infections with resistant organisms has led to shorter hospital stays for cardiac transplant recipients. Most patients are discharged 7 to 14 days following transplantation. Patient education is performed by the cardiac nursing staff. Topics include medications (regimens and potential side effects), diet, exercise (routines and restrictions), and infection recognition. Outpatient Follow-up Close follow-up by an experienced transplant team is the cornerstone for successful long-term survival after cardiac transplantation. This comprehensive team facilitates the early detection of rejection, opportunistic infections, patient noncompliance, and adverse sequelae of immunosuppression. Clinic visits routinely are scheduled concurrently with endomyocardial biopsies and include physical examination, a variety of laboratory studies, CXR and ECG. IMMUNOSUPPRESSIVE THERAPY An organism's ability to distinguish self from non-self is critical for its survival in a hostile environment. In transplantation, the recipient's host defense mechanisms recognize the human leukocyte antigens (HLA) on allograft cells as being non-self and, if permitted, will respond to eradicate the foreign cells. The ultimate goal of immunosuppressive therapy is the selective modulation of the recipient's immune response to prevent rejection, whilst sparing immune defenses against infections or neoplasia and minimizing the toxicity associated with immunosuppressive agents Pharmacologic Immunosuppressive Strategies Early induction phase followed by a long-term maintenance phase. This basic strategy essentially is universal, although the choice of immunosuppressive agents, dosages, and combination protocols vary among transplantation centers. Tendency for allograft rejection is greatest in the early postoperative period: the most intense immunosuppression is administered during this induction phase. Most programs employ a triple immunosuppressive regimen while some centers also provide additional induction prophylaxis with potent polyclonal antibodies, and OKT3 or IL-2 blockers. After several months, immunosuppression and rejection surveillance are gradually reduced to chronic maintenance phase levels and frequencies. Most centers use triple drug therapy: cyclosporine, steroids, and mycophenolate mofentil or azathioprine. The use of a multidrug regimen permits adequate immunosuppression with reduced doses of individual agents to minimize their toxicity. The use of cyclosporine has allowed for steroid-free maintenance immunosuppression, thus avoiding the multiple untoward sequelae associated with chronic corticosteroid therapy immunosuppression.The timing of steroid withdrawal varies as some clinicians discontinue prednisone within several weeks of transplantation, whereas others delay the taper until 6 to 12 months posttransplantation. Recently, it has been suggested that the majority of patients can be completely tapered off steroids without an increased incidence of rejection. Attempts at corticosteroid withdrawal in patients with history of rejection, however, have usually been unsuccessful. Hyperacute Rejection Results from pre-formed, donor-specific antibodies in the recipient. ABO blood group and panel reactive antibody screening have made this condition a rare complication. The onset of hyperacute rejection occurs within minutes to several hours after transplantation and the results are catastrophic. Gross inspection reveals a mottled or dark red, flaccid allograft, and histologic examination confirms the characteristic global interstitial hemorrhage and edema without lymphocytic infiltrate. Immunofluorescence techniques reveal deposits of immunoglobulins and complement on the vascular endothelium. No treatment is effective except retransplantation, and even this aggressive strategy frequently is unsuccessful. Complications Bleeding from the suture lines is a rare occurrence but may require reexploration. Hyperacute rejection can occur immediately after blood flow is restored to the Infection is the primary concern. Preventive measures should be instituted. Early on Psychiatric disturbances from steroid therapy can occur in the immediate allograft and up to 1 week after surgery despite therapeutic immunosuppression. bacterial and fungal infections. Fungal infections can appear if the patient is diabetic or overimmunosuppressed. Prophylaxis for Pneumocystis carinii is universally administered, as is therapy for CMV infection. Maintain vigilance for other uncommon infectious processes including Listeria, Legionella, Chlamydia, and Nocardia infections. posttransplant period. These disturbances may be predicted from the pre-transplantation psychiatric evaluation and thus averted. Cardiac rejection is to be expected and should be detected by endomyocardial biopsy. Depending upon the severity of the incident, the process can be treated with steroid therapy alone, polyclonal antibody therapy, or monoclonal antibody therapy. Allograft vascular disease is the main cause of late graft failure and death. The coronary arteries develop a progressive concentric myointimal hyperplasia. This hyperplasia can develop as early as 3 months after transplantation. The cause of the process is unclear. However, CMV infection and recurrent rejection episodes are thought to be associated with the cause. Current research indicates that the initial ischemia/reperfusion injury of the allograft coupled with repeated rejection episodes might contribute to the process. The only available therapy is re-transplantation. The process can sometimes be treated by stenting of the diseased vessels. CHRONIC COMPLICATIONS Allograft Coronary Artery Disease Long-term survival of cardiac transplant recipients is primarily limited by the development of allograft coronary artery disease (ACAD), the leading cause of death after the first posttransplantation year.343–345 Angiographically detectable ACAD is reported in approximately 50% of patients by 5 years after transplantation. The etiology of this allograft vasculopathy is multifactorial and involves both immunologic and nonimmunologic components. Recently, it has been shown that immune-related risk factors appear to be more significant in the development of ACAD.346–348 Likewise, many nonimmune-associated related risks have been implicated in ACAD including increased donor age, hyperlipidemia, and CMV infection.349–352 These immune and nonimmune risk factors lead to unique coronary pathology characterized by diffuse, concentric intimal proliferation with infiltration by smooth muscle cells and macrophages leading to narrowing along the entire length of the vessel.353–354 Furthermore, collateral vessels are notably absent. ACAD may begin within several weeks posttransplantation and insidiously progress at an accelerated rate to complete obliteration of the coronary lumen with allograft failure secondary to ischemia.355 The clinical diagnosis of ACAD is difficult and complicated by allograft denervation resulting in silent myocardial ischemia. Ventricular arrhythmias, congestive heart failure, and sudden death are commonly the initial presentation of significant ACAD. Noninvasive screening tests (e.g., thallium scintigraphy) are unreliable in transplant recipients.356 Annual coronary angiogram is the current gold standard for ACAD surveillance. However, due to the previously mentioned pathological changes, it underestimates the extent of disease and is insensitive to early atherosclerotic lesions.357 This has led to growing interest in intravascular ultrasound (IVUS) devices. IVUS is better equipped to provide important quantitative information regarding vessel wall morphology and the degree of intimal thickening.358–359 Some centers have begun to use IVUS for the early detection of ACAD; however, concerns have been raised concerning its ability to assess more long-term lesions.360 Currently, the only definitive treatment for advanced ACAD is retransplantation due to the diffuse and distal nature of ACAD. Based on this lack of effective treatment options, an emphasis has been placed on prevention of ACAD. Currently, prophylactic management focuses on empiric risk factor modification (dietary and pharmacologic reduction of serum cholesterol, cessation of smoking, hypertension control, etc.). Several studies have demonstrated a decrease in ACAD in patients treated with a calcium channel blocker or HMG-CoA reductase inhibitors.348,361 Renal Dysfunction Irreversible interstitial fibrosis caused by cyclosporine nephrotoxicity is chiefly responsible for the chronic renal dysfunction observed in cardiac transplant recipients.362–363 Its pathogenesis is unclear but is believed to be secondary to afferent arteriolar vasoconstriction with secondary ischemia.364–365 Direct tubular toxicity also may play a contributory role.366 Most renal injury occurs during the first 6 months following transplantation concurrent with the highest levels of cyclosporine. Little additional decline in renal function occurs after 1 year.367 Frequent monitoring of cyclosporine levels and avoidance of intravascular volume depletion are important preventive measures.368 Approximately 3% to10% of patients develop end-stage renal failure requiring dialysis or renal transplantation.369 Hypertension Moderate to severe systemic hypertension afflicts 50% to 90% of cardiac transplant recipients and is a difficult problem to manage. Peripheral vasoconstriction in combination with fluid retention seem to play the greatest role. Although the exact mechanisms are unclear, it likely involves a combination of cyclosporine-induced tubular nephrotoxicity and vasoconstriction of renal and systemic arterioles mediated by sympathetic neural activation. No single class of antihypertensive agents has proven uniformly effective, and treatment of this refractory hypertension remains empiric and difficult. Malignancy Chronic immunosuppression is associated with an increased incidence of malignancy. The estimated risk of carcinoma is almost 100-fold greater than in the general population Lymphoproliferative disorders and carcinoma of the skin are most common. The risk of these malignancies is increased further following monoclonal and polyclonal antibody therapy There is a predilection for unusual extranodal locations (e.g., lung, bowel, and brain). Treatment options in transplantation include: a reduction in immunosuppression and high-dose acyclovir (to attenuate EBV replication) in addition to conventional therapies for carcinoma (chemotherapy, radiation therapy, and surgical resection). Other Hyperlipidemia eventually develops in the majority of recipients and is managed with dietary restrictions, exercise, and lipid-lowering agents. Osteoporosis Avascular necrosis of weight-bearing joints Obesity Cholelithiasis RESULTS OF OCTx Operative mortality: 5% to 10%. Primary graft failure is the most frequent cause of early death. Overall 1-year survival is approx. 80% with a 4% mortality per year for subsequent years. Infection and rejection account for the majority of deaths in the first 6 months; thereafter, accelerated coronary artery disease eventually claims the lives of most recipients. Risk factors associated with increased mortality include ventilator dependence, previous cardiac transplantation, preoperative VAD or IABP, recipient age greater than 65 years, female gender (donor or recipient), and donor age greater than 50 years. Health-related quality of life (HRQOL) in patients following cardiac transplantation demonstrates that most experience a HRQOL that approaches that of the normal population. Although cardiac reserve is reduced, exercise tolerance is improved dramatically compared to preoperative level, and recipients usually can enjoy an active lifestyle. Nevertheless, because of concerns about future disability, recipients often encounter significant problems with postoperative employment and health insurance coverage particularly if over 50 years of age. CARDIAC RE-TRANSPLANTATION Re-transplantation accounts for fewer than 3% of the cardiac transplants. Primary indications: allograft coronary artery disease and refractory acute rejection. Actuarial survival remains markedly reduced following retransplantation if performed within 6 months of the initial procedure or in the setting of acute rejection. Recent data suggest that the survival rate for cardiac re-transplantation at 1 year is 55%. Recent data from the International Society for Heart and Lung Transplantation (ISHLT) also shows though that if retransplantation occurs 2 years after the initial transplant procedure, the 1-year survival rate markedly improves but remains approximately 4% to 6% below that of primary cardiac transplantation. FUTURE Clinical outcome of heart transplantation has dramatically improved. Although cardiac replacement remains the best therapeutic option for patients with end-stage heart failure, a number of challenges await future investigators to further improve survival and reduce transplant-related morbidity. A major factor limiting long-term survival of recipients is allograft rejection and the untoward effects of immunosuppression. Development of reliable, noninvasive diagnostic studies will permit more frequent evaluations for the early detection of rejection and for monitoring the effectiveness of therapy. Ultimately, this will allow more precise control of immunosuppression, and in turn a reduction in cumulative allograft injury and infectious complications. Immunosuppressive strategists will continue their efforts to establish specific unresponsiveness to antigens of transplanted organs in hopes of preserving much of the recipient's immune responses. Novel immunosuppressive agents and techniques are under continuous investigation for this purpose. Alternatively, donor organs may be made less susceptible to immunologic attack through genetic engineering techniques by altering the expression of cell membrane-bound molecules. This approach is being currently utilized in the pursuit of clinically applicable xenotransplant sources. Xenografts eventually may be an additional source of donor organs, although extended xenograft survival remains an elusive goal. Complicating this alternative are unresolved ethical issues concerning transgenic experimentation and the potential for transmission of veterinary pathogens to an immunosuppressed recipient. Future improvements in organ preservation permitting extension of the storage interval will have several benefits. In addition to a modest increase in the donor pool, extension of storage times would permit better allocation of organs with respect to donor-recipient immunologic matching. There is growing evidence that human lymphocyte antigen (HLA) matching may be important for long-term graft function through attenuation of chronic rejection. Reducing the ischemic injury may also result in an attenuation of transplant coronary artery disease. Mechanical assist devices are being used more frequently in patients with end-stage heart failure and may prove to be the best solution for the current organ shortage. Assist devices are being currently used both as a bridge to transplantation and a destination therapy. The Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure (REMATCH) study demonstrated a survival benefit in heart failure patients in which assist devices were utilized versus all other forms of treatment for heart failure.61 It appears that as the technology of assist devices continues to improve, it is only a matter of time before they become a long-term solution for patients with severe congestive heart failure. History heart-lung and lung transplantation First lung transplantation: James Hardy 1963. But it took another 20 years before routine. First Heart-Lung transplantation Demikhov in dogs 1962, Reitz 1981 human Initial graft failure secondary to: inadequate preservation long ischaemic times lack of good immuno-suppressive drugs technical difficulties with bronchial anastomoses En-bloc double lung replacement: introduced by Patterson in 1988. This technique was later replaced by sequential bilateral lung transplantation, by Pasque in 1990. More recent operative innovations include living lobar transplantation, an alternative to cadaveric bilateral lung transplantation. Combined heart-lung and isolated lung transplantation have emerged as lifesaving procedures for patients with end-stage cardiopulmonary or pulmonary disease. To date, 2861 combined heart-lung transplants, 7204 single lung transplants, and 5420 bilateral lung transplants have been performed worldwide. While the number of heart-lung transplants performed annually has declined in recent years, the number of single and bilateral lung transplantation procedures remains stable. Indications HLTx Indications for single and bilateral lung transplantation Contra-indications to HLTx and LTx Age > 50 (heart-lung), > 55 (bilateral lung), > 60 (single lung) Significant systemic or multisystem disease (e.g., peripheral or cerebrovascular disease, portal hypertension, poorly controlled diabetes mellitus) Significant irreversible hepatic or renal dysfunction (e.g., bilirubin > 3.0 mg/dL, creatinine clearance < 50 mg/mL/min) Active malignancy Corticosteroid therapy (> 10 mg/day) Panresistant respiratory flora Cachexia or obesity (< 70% or > 130% ideal body weight) Current cigarette smoking Psychiatric illness or history of medical noncompliance Drug or alcohol abuse Previous cardiothoracic surgery (considered on a case-by-case basis) Severe osteoporosis Prolonged mechanical ventilation HIV or HBsAg positivity Hepatitis C infection with biopsy-proven liver disease Recipient selection HLTx and LTx Progressively disabling cardiopulmonary or pulmonary disease who still possess the capacity for full rehabilitation after transplantation.. Life expectancy of less than 18 to 24 months despite the use of appropriate medical or alternative surgical strategies. On average, waiting times can be from 6 to 36 months. Unfortunately, mortality while on the waiting list remains nearly 20% for both lung and heartlung transplant candidates. Disabling symptoms prompting consideration for transplantation typically include dyspnea, cyanosis, syncope, and haemoptysis. NYHA classes III or IV. Evaluation includes a complete history, physical examination, laboratory tests, specialized studies, and a psychosocial evaluation. Tests and studies recipient evaluation HLTx and LTx Laboratory tests and studies routine haematology including clotting, blood type and antibody screen, Immunology panel (FANA, RF), U&E, LFTs Electrolytes, including Mg2 + CK with isoenzymes Serum protein electrophoresis Urinalysis Viral serologies Compromised host panel (cytomegalovirus, adenovirus, varicella-zoster, herpes simplex, Epstein-Barr virus) Hepatitis A, B, and C antibodies, hepatitis B surface antigen (HBsAg) Cytomegalovirus (quantitative antibodies and IgM) Human immunodeficiency virus Electrocardiogram Chest x-rayStudies obtained as indicated Echocardiogram with bubble study MUGA for right and left ventricular ejection fraction Cardiac catheterization with coronary angiogram Thoracic CT scan Quantitative ventilation-perfusion scans Carotid duplex Mammogram Sputum for Gram stain, AFB smear, KOH, and routine bacterial, mycobacterial, and fungal cultures Required for listing (phase II)HLA and DR typing Transplant antibody Quantitative immunoglobulins Histoplasma, Coccidiodes, and Toxoplasma titers PPD Pulmonary function tests with arterial blood gases 12-hour urine collection for creatinine clearance and total protein Urine viral culture It is extremely important that a candidate's medical condition be optimized prior to heart-lung and lung transplantation. Standard medical measures should be aggressively employed by the patient's local physician, and the patient should have routine follow-up at the transplant center. Supplemental oxygen is recommended for any patient exhibiting arterial hypoxemia, defined as either an arterial oxygen saturation less than 90% or an arterial Po2 less than 60 mm Hg at rest, during exertion, or while asleep. For patients with heart failure, standard therapeutic measures are applied, including dietary restrictions, diuretics, and vasodilators. Dietary water and salt restriction as well as diuretic therapy facilitate intravascular fluid management. However, particular care must be exercised when using loop diuretics in patients with underlying pulmonary disease; this class of potent diuretics results in a metabolic alkalosis that depresses the effectiveness of carbon dioxide as a stimulus for breathing. Vasodilators result in afterload reduction, and have been proven to effectively improve functional capacity and prolong survival in patients suffering from severe cardiac failure.Commonly used vasodilators include nitrates, hydralazine, and angiotensin-converting enzyme inhibitors. Despite the clinical heterogeneity among patients with primary pulmonary hypertension, conventional medical therapy targets the sequelae of the pulmonary vascular derangements associated with this disease process. Supplemental oxygen therapy is recommended to eliminate the stimulus for hypoxic pulmonary vasoconstriction and secondary erythropoiesis, thus lessening the burden placed on the right side of the heart and diminishing the likelihood of cardiac arrhythmias. Pulmonary vasodilator therapy is important in the treatment of primary pulmonary hypertension, and includes the use of calcium channel blockers and continuous prostacyclin infusions. Because most standard vasodilators have potent systemic effects, careful dosing and follow-up is essential. Approximately 20% of patients with primary pulmonary hypertension will respond to calcium channel blockers, and this favorable response can usually be predicted by the response to short-acting vasodilators during cardiac catheterization, but response to the acute vasodilator challenge does not always predict the response to long-term prostacyclin infusion. Interstitial lung disease in patients awaiting transplantation results from a wide variety of diffuse inflammatory processes, such as sarcoidosis, asbestosis, and collagen-vascular diseases. Increases in pulmonary vascular resistance leading to right-sided heart failure are thought to result from interstitial inflammatory infiltrates that entrap and eventually destroy septal arterioles, reducing the distensibility of the remaining pulmonary vessels.This process, coupled with closure of peripheral bronchioles, results in arterial hypoxemia, which further aggravates pulmonary hypertension. Corticosteroids are the mainstay of treatment in this class of diseases. The adverse effects of steroids on airway healing are well established, and mandate significant dose reductions in anticipation of heart-lung and isolated lung transplantation. The multisystem manifestations of cystic fibrosis, particularly chronic bronchopulmonary infection, malabsorption, malnutrition, and diabetes mellitus, pose difficult management problems and require aggressive chest physiotherapy, antibiotics, enteral or parenteral nutritional supplementation, and tight serum glucose control. Certain underlying diagnoses are associated with increased rates of pulmonary and systemic thrombosis and embolization. These include dilated cardiomyopathy, congestive heart failure, and primary pulmonary hypertension, and most centers recommend routine prophylactic anticoagulation with heparin, warfarin, or antiplatelet agents. HLTx and LTx donor selection criteria < 40 (heart-lung), < 50 (lung) Smoking history less than 20 pack-years Arterial Po2 of 140 mm Hg on an Fio2 of 40% or 300 mm Hg on an Fio2 of 100% Normal chest x-ray Sputum free of bacteria, fungus, or significant numbers of white blood cells on Gram and fungal staining Bronchoscopy showing absence of purulent secretions or signs of aspiration Absence of thoracic trauma HIV negative Donor Management Maintenance of haemodynamic stability and pulmonary function. Patients suffering from acute brain injury are often haemodynamically unstable due to neurogenic shock, excessive fluid losses, and bradycardia. Donor lungs are prone to neurogenic pulmonary oedema, aspiration, nosocomial infection, and contusion. Continuous arterial and central venous pressure monitoring, judicious fluid resuscitation, vasopressors, and inotropes are usually required. Meticulous fluid management prevents intra-operative blood pressure instability and minimizes the need for inotropes and vasopressors that stress the myocardium. Intravascular volume replacement should be given to maintain the central venous pressure between 5 and 8 mm Hg, though fluids should not be administered at rates far in excess of hourly urine output. In general, crystalloid fluid boluses are to be avoided. Diabetes insipidus is common in organ donors and requires the use of intravenous vasopressin (0.8 to 1.0 IU/hr) to reduce excessive urine losses. Maintain adequate perfusion pressures: dopamine is the standard inotropic agent used, although alpha agonists (e.g. phenylephrine) are often appropriate. Blood transfusions should be used sparingly to maintain the haemoglobin concentration around 10 g/dL to ensure adequate myocardial oxygen delivery. CMV-negative and leukocyte-filtered blood should be used whenever possible. Hypothermia should be avoided because it predisposes to ventricular arrhythmias and metabolic acidosis. Mechanical ventilation: Fio2 values in excess of 40%, especially 100% oxygen "challenges," should be avoided, since these oxygen levels may be toxic to the denervated lung. Ventilator settings should include positive end-expiratory pressures (PEEP) between 3 and 5 cm H2O to prevent atelectasis. Donor Operation HLTx/LTx Median sternotomy Both pleural spaces are opened immediately with inspection of the lungs and pleural spaces, particularly in cases of trauma. The lungs are briefly deflated, and the pulmonary ligaments are divided inferiorly using electrocautery. The thymic remnant is completely excised. Pericardium is opened vertically and laterally on the diaphragm and cradled during dissection of the great vessels and trachea. Umbilical tapes are placed around the ascending aorta and venae cavae. The pericardium overlying the trachea is incised vertically, and the trachea is encircled with an umbilical tape between the aorta and superior vena cava at the highest point possible and at least four rings above the carina. The entire anterior pericardium is excised back to each hilum. Donor operation HLTx Cardioplegia and pulmonoplegia are infused simultaneously into the aorta and main pulmonary artery after aortic cross-clamping. Application of topical cold Physiosol follows immediately. The venae cavae and aorta are divided, and the heart-lung bloc is dissected free from the esophagus and posterior hilar attachments. After the trachea is stapled and divided at the highest point possible, the entire heart-lung bloc is removed from the chest. Organ Preservation and Transport Maximum of 6 to 8 hours of ischaemia in lung and heart-lung allografts. human studies: retrospective studies from the University of Pittsburgh and the University of Virginia that showed comparable long-term survival and rates of acute rejection and bronchiolitis obliterans among recipients of grafts with over 6 hours of ischaemia compared with those with less than 4 or with 4 to 6 hours of ischaemia. animal studies: successful transplantation of lung allografts with cold ischaemia times up to 18 hours have been reported. However, it is believed that beyond a certain threshold, organ ischaemia will likely lead to primary graft failure and/or impaired long-term function. The principle of preservation: minimise I/R injury, mediated by reactive oxygen species, which disrupt the homeostatic mechanisms in myocyte and endothelial cells. As receptors for leukocyte adhesion molecules are upregulated and leukocyte chemotactic factors are released, an inflammatory response ensues, leading to cellular injury. Approaches to minimise I-R injury: donor pre-treatment, specialized preservation solutions, and recipient treatments. Hypothermia reduces the tissue's metabolic demand by up to 99%. Small number of centers, hypothermic preservation includes donor core cooling on CPB. Universally, hypothermia is employed during explantation, storage, and implantation. During explantation, organs are flushed with cold plegic solutions (between 0°C to 10 °C, depending on the institution and solution employed). They are stored at 0°C to 10°C, and during implantation, they are covered with gauze soaked in saline slush or recipients are cooled through CPB. The optimal temperature for flush and storage of organs remains unknown, but common practice is to rely on ice bath temperature for convenience. Organ preservation and transport Heart-lung and lung blocs are typically preserved with a cold pulmonary artery flush in conjunction with standard crystalloid cardioplegic arrest. A variety of crystalloid flush solutions are used worldwide, and they can be divided into two categories based on their electrolyte compositions: intracellular and extracellular. Euro-Collins is the most frequently used. Prostaglandins are commonly used for donor pretreatment and as an additive in pulmonary flush solutions. PGE1, a vasodilator, is given to counteract reflex pulmonary vasoconstriction resulting from the cold flush and to permit uniform distribution of the perfusate throughout the lung. Experimental studies also suggest that PGE1 treatment may minimize reperfusion injury through its anti-inflammatory properties. Another commonly used donor pretreatment strategy is steroid treatment. Experimental evidence suggests that donor lymphocytes may play a role in ischaemic lung graft injury, so methylprednisolone is given intravenously to the donor to inactivate them. Lung graft function is improved when the explanted organ is inflated, when 100% oxygen is used for inflation, and when the lung is transported at 10°C. Research in the field of lung preservation has recently focused on the role of various flush and storage solution additives, such as antioxidants, which may act as free radical scavengers. Other additives that have been shown to decrease reperfusion injury in research models include nitric oxide donors and phosphodiesterase inhibitors. Additional areas of research interest include the development of leukocyte depletion strategies, examining the role of gene therapy in modifying donor organ susceptibility to ischemia-reperfusion injury, and the development of colloid-based perfusates. HLTx RECIPIENT OPERATION The recipient operation in heart-lung and lung transplantation proceeds in two phases. The first is excision of the native organ(s) and the second is implantation of the allograft. Cardiopulmonary bypass is mandatory in heart-lung transplantation and occasional in single and bilateral lung transplantation. At all times, it should be available as stand-by. Anaesthetic monitoring includes arterial pressure monitoring, pulse oximetry, continuous electrocardiography, pulmonary artery catheter monitoring, temperature monitoring, and urine output monitoring. The use of double-lumen endotracheal tubes is particularly helpful, allowing for single lung ventilation during certain portions of the dissection. Large bore intravenous lines are placed for volume infusion. TOE is often performed during the procedure. HLTx recipient operation The recipient is positioned supine on the operating table. The chest is entered through a median sternotomy, a sternal retractor is placed, and both pleural spaces are opened anteriorly from the level of the diaphragm to the level of the great vessels. Any pleural adhesions are divided using electrocautery. In patients in whom dense pleural adhesions are anticipated, such as those with previous thoracotomies or cystic fibrosis, a bilateral "clamshell" thoracotomy is performed. Combined with the use of perioperative antifibrinolytic therapy (e.g., aprotinin) and an argon beam coagulator, this approach improves exposure and facilitates both lysis of adhesions and hemostasis. The anterior pericardium is excised, while lateral segments are preserved to support the heart and protect the phrenic nerves. A 3-cm border of the pericardium should be left both anteriorly and posteriorly to each phrenic nerve extending from the level of the diaphragm to the level of the great vessels. After fully heparinizing the recipient, the ascending aorta is cannulated near the base of the innominate artery, and the venae cavae are individually cannulated laterally and snared. Cardiopulmonary bypass with systemic cooling to 28°C to 30°C is instituted, and the heart is excised at the midatrial level. The aorta is divided just above the aortic valve, and the pulmonary artery is divided at its bifurcation. The left atrial remnant is then divided vertically at a point halfway between the right and left pulmonary veins. The posterior edge of the left atrial and pulmonary venous remnant is developed in a manner that allows the left inferior and superior pulmonary veins to be displaced over into the left chest. Following division of the pulmonary ligament, the left lung is moved into the field, allowing full dissection of the posterior aspect of the left hilum, being careful to avoid the vagus nerve posteriorly. Once this is completed, the left main pulmonary artery is divided, and the left main bronchus is stapled with a TA30 stapler and divided. The same technique of hilar dissection and division is repeated on the right side, and both lungs are removed from the chest. The native main pulmonary artery remnant is removed, leaving a portion of the pulmonary artery intact adjacent to the underside of the aorta near the ligamentum arteriosum to preserve the left recurrent laryngeal nerve. Attention is then turned to preparing the distal trachea for anastomosis. The stapled ends of the right and left bronchi are grasped and dissection is carried up to the level of the distal trachea. Bronchial vessels are individually identified and carefully ligated. Patients with congenital heart disease and pulmonary atresia or severe cyanosis secondary to Eisenmenger's syndrome may have large mediastinal bronchial collaterals that must be meticulously ligated. Perfect hemostasis is necessary in this area of the dissection, because it is obscured once graft implantation is completed. Once absolute hemostasis is achieved, the trachea is divided at the carina with a no. 15 blade. The chest is now prepared to receive the heart-lung graft. The donor heart-lung bloc is removed from its transport container and prepared by irrigating, aspirating, and culturing the tracheobronchial tree and by trimming the trachea to leave one cartilaginous ring above the carina. The heart-lung graft is then lowered into the chest, passing the right lung beneath the right phrenic nerve pedicle. The left lung is then gently manipulated under the left phrenic nerve pedicle. The tracheal anastomosis is performed using continuous 3-0 polypropylene suture. The posterior membranous portion of the anastomosis is performed first, followed by completion of the anastomosis anteriorly. The lungs are then ventilated with room air at half-normal tidal volumes to inflate the lungs and reduce atelectasis. Topical cooling with a continuous infusion of cold Physiosol into both thoraces is begun. To augment endomyocardial cooling and to exclude air from the graft, a third cold "bubble-free" line is placed directly into the left atrial appendage. Next, the bicaval venous anastomosis is performed. The recipient inferior vena cava is anastomosed to the donor inferior vena cava-right atrial junction with a continuous 4-0 polypropylene suture. At this point the patient is rewarmed toward 37°C, and the superior vena caval and aortic anastomoses are performed end-to-end with continuous 4-0 polypropylene sutures. After the ascending aorta and pulmonary artery are cleared of air, the aortic cross-clamp and caval tapes are removed. The left atrial catheter is removed, and the atrium is allowed to drain. The amputated left atrial stump is oversewn, and the pulmonoplegia infusion site on the pulmonary artery is closed. The heart is defibrillated, and the patient is gradually weaned from cardiopulmonary bypass in the standard fashion. Methyprednisolone (500 mg) is administered to the recipient following heparin reversal with protamine sulfate. PEEP at 3 to 5 cm H2O and an Fio2 of 40% are maintained. As in cardiac transplantation, isoproterenol (0.005 to 0.01 µg/kg/min) is usually initiated on graft reperfusion to increase the heart rate to about 100 to 110 bpm and to lower pulmonary vascular resistance. Temporary right atrial and ventricular pacing wires are placed. Right and left pleural chest tubes (right angle) are placed along each diaphragm, as well as one mediastinal tube. The chest is closed in the standard fashion. Finally, the double-lumen endotracheal tube is exchanged for a single-lumen tube and the tracheal anastomosis is checked endoscopically before transporting the patient to the intensive care unit. Lick et al at the University of Texas and the University of Arizona have recently described an interesting alternative to the standard technique in which the pulmonary hila are placed anterior to the phrenic nerves and direct caval anastomoses are used whenever feasible. This modification obviates extensive dissection of the phrenic nerves and posterior mediastinum, decreasing the likelihood of phrenic and vagus nerve injury. Furthermore, the posterior mediastinum can be inspected more easily for bleeding after implantation by rotating the heart-lung bloc anteriorly and medially while still on bypass. Bilateral Lung Transplantation recipient operation Sequential single lung transplants through a bilateral anterior thoracosternotomy (clamshell) incision is made at the level of the fourth intercostal space. The lung with the least amount of function (as determined by a preoperative ventilationperfusion scan) is removed first and replaced with an allograft as described for single lung transplantation above. Once ventilation and perfusion are established in the first allograft, the second native lung is explanted and the second allograft is implanted. Bilateral chest tubes are placed and the chest is closed. Bronchoscopy is performed to evaluate the bronchial anastomoses. Many centers use CPB routinely during bilateral lung transplantation. It allows for improved exposure, shorter graft ischemic times, controlled reperfusion, and the use of leukocyte-depleting filters. Because the risk of bleeding may be increased with CPB, strategies have been developed to minimize the chance of haemorrhage. These include the routine use of aprotinin and heparin-coated CPB circuits, as well as the availability of an argon beam coagulator. Single LTx recipient operation If possible, the lung with the least function determined by preoperative ventilation-perfusion scan is selected for replacement. The patient is placed in a standard thoracotomy position, with access to the groin should CPB be needed. A posterior lateral thoracotomy is made at the level of the fourth or fifth intercostal space. Adhesions are lysed and the hilar dissection is performed. The pulmonary artery, the superior and inferior pulmonary veins, and the mainstem bronchus are isolated. A trial occlusion of the pulmonary artery is used to determine whether the procedure will be tolerated without CPB. If it is tolerated, the pulmonary artery is ligated and divided distal to the upper lobe branch. The pulmonary veins are also ligated and divided. The mainstem bronchus is stapled and divided, and the native lung is explanted. The donor lung is removed from its transport container and prepared for implantation. The donor bronchus is opened and secretions are aspirated and cultured. The bronchus is trimmed, leaving two cartilaginous rings proximal to the orifice of the upper lobe. Any remaining pericardial and lymphatic tissue is removed, and the left atrial cuff is trimmed as needed. The donor lung is then placed in the recipient's chest and covered with saline slush and iced laparotomy pads. The sequence of anastomoses is a matter of preference, though most perform the deepest anastomosis (the bronchial anastomosis) first and then proceed to the more superficial ones. The bronchial anastomosis is fashioned with 4-0 polypropylene suture. We favour a continuous suture technique; alternatively, the membranous portion can be sewn with interrupted suture. Alternatively, the entire anastomosis can be sewn with a running suture. Variations on the end-to-end bronchial anastomosis include the use of a telescoping technique, in which the donor bronchus is intussuscepted into the recipient bronchus, and the placement of an omental pedicle flap around the anastomosis. These techniques were developed to prevent bronchial anastomotic dehiscence but are now rarely performed. Once the bronchial anastomosis is complete, attention is then turned to making the pulmonary venous anastomosis. A side-biting clamp is applied to the left atrium to include the pulmonary veins. The recipient pulmonary vein stumps are opened and the intervening atrial tissue is cut. This creates a cuff that is anastomosed to the donor atrial remnant using continuous 4-0 polypropylene suture; this suture is not tied down until reperfusion. Donor and recipient pulmonary arteries are anastomosed with 5-0 polypropylene suture. Upon graft inflation, kinking can occur if the arteries are left too long, so they must be carefully trimmed to an appropriate length before fashioning the anastomosis. The pulmonary artery anastomosis is de-aired. The lung is inflated, and the pulmonary artery clamp is temporarily released to allow flushing of air through the atrial suture line, and the left atrial clamp is removed to allow retrograde de-airing of the atrial anastomosis. The pulmonary venous anastomosis is then secured. After haemostasis is ensured, apical and basal chest tubes are inserted. The ribs are reapproximated and the chest is closed in a standard fashion. The double-lumen endotracheal tube is exchanged for a single-lumen tube and bronchoscopy is performed to evaluate the bronchial anastomosis. Arguments pro- and con CPB in LTx Pro: improved exposure of the hilar strutures, which is particularly helpful in patients with dense adhesions and bronchial collaterals allows for early pneumonectomies without hemodynamic or respiratory instability ischemic time of the second lung is substantially reduced when compared to off-CPB bilateral lung transplants Its use also prevents overperfusion of the first lung graft with the entire cardiac output In patients with suppurative lung disease, the use of CPB facilitates careful washout of the distal trachea and proximal bronchi to prevent contamination of the first implanted lung. Con: increased blood loss, transfusion needs, and reperfusion injury. POSTOPERATIVE MANAGEMENT Heart-Lung and Lung Graft Physiology Denervation of the lungs results in diminished cough reflex as well as impaired mucociliary clearance mechanisms. This predisposes recipients to pulmonary infections and necessitates aggressive postoperative pulmonary toilet. Moreover, ischaemia and reperfusion injury in the transplanted lung, along with disrupted pulmonary lymphatics, can result in increased vascular permeability and varying degrees of interstitial oedema. For the heart-lung recipients, denervation of the cardiac allograft leads to additional physiologic characteristics. The denervated heart has lost its sympathetic and parasympathetic autonomic regulation; therefore recipients of heartlung grafts do not have normal autonomic regulation of heart rate, contractility, or coronary artery caliber. The resting heart rate is generally higher due to the absence of vagal tone. Respiratory sinus arrhythmia and carotid reflex bradycardia are absent. Interestingly, the denervated heart develops an increased sensitivity to catecholamines; this is due to an increase in beta-adrenergic receptor density and a loss of norepinephrine uptake in postganglionic sympathetic neurons. This augmented sensitivity plays an important role in maintaining an adequate cardiac response to exercise and stress. During exercise, the recipient experiences a steady but delayed increase in heart rate, primarily due to a rise in circulating catecholamines. This initial rise in heart rate is subsequently accompanied by an immediate increase in filling pressures resulting from augmented venous return. These changes lead to an augmentation of stroke volume and cardiac output sufficient to sustain an increase in activity. The ability of the coronary circulation to dilate and increase blood flow in response to increased myocardial oxygen demand is normal in cardiac transplant recipients and would likewise be expected to be so in recipients of heart-lung grafts. Conversely, graft coronary vasodilator reserve is abnormal in the presence of rejection, hypertrophy, or regional wall abnormalities. Clinical Management in the Early Postoperative Period The primary objective in heart-lung and isolated lung graft recipients in the immediate postoperative period is to maintain adequate perfusion and gas exchange in the recipient while minimizing intravenous fluid administration, cardiac work, and barotrauma. Cardiac rhythm and arterial and central venous pressures are monitored. Strict isolation precautions, previously enforced to reduce the incidence of infection in these immunosuppressed patients, are no longer required; simple handwashing is now considered sufficient. Approximately 10% to 20% of heart-lung graft recipients experience some degree of transient sinus node dysfunction in the immediate perioperative period, often manifested as sinus bradycardia, which usually resolves within a week. The use of bicaval venous anastomoses has been reported to lower the incidence of sinus node dysfunction and improve tricuspid valve function. Because cardiac output is primarily rate dependent after heart-lung transplantation, the heart rate should be maintained between 90 and 110 bpm during the first few postoperative days using temporary pacing or isoprenalinel (0.005–0.01 µg/kg/min) as needed. Although rarely seen, persistent sinus node dysfunction and bradycardia may require a permanent transvenous pacemaker. The systolic blood pressure should be maintained between 90 and 110 mm Hg using afterload reduction in the form of nitroglycerin or nitroprusside if necessary. Renal-dose dopamine (3–5 µg/kg/min) is used frequently to augment renal blood flow and urine output. The adequacy of cardiac output is indicated by warm extremities and a urine output great than 0.5 mL/kg/hr without diuretics. Cardiac function generally returns to normal within 3 to 4 days, at which time parenteral inotropes and vasodilators can be weaned. Depressed global myocardial performance in the acute postoperative setting. The myocardium is potentially subject to prolonged ischemia, inadequate preservation, or catecholamine depletion prior to implantation. Hypovolemia, cardiac tamponade, sepsis, and bradycardia may also be contributory and should be treated expeditiously if they are present. A Swan-Ganz pulmonary artery catheter should be used in cases of persistently abnormal haemodynamics. Ventilatory management is a key element in the postoperative management of both heart-lung and isolated lung graft recipients. Barotrauma and high airway pressures that might compromise bronchial mucosal flow should be avoided. Lower tidal volumes and flow rates may be necessary to limit peak airway pressures to less than 40 cm H2O. Upon arrival to the ICU, an anteroposterior chest x-ray is obtained, and the ventilator is typically set to an Fio2 of 50%, tidal volume of 10 to 15 mL/kg, an assist-control rate of 10 to 14 breaths per minute, and PEEP of 3 to 5 cm H2O. These settings are adjusted every 30 minutes to achieve an arterial Po2 greater than 75 mm Hg on an Fio2 of 40%, an arterial carbon dioxide pressure (Paco2 between 30 and 40 mm Hg, and a pH between 7.35 and 7.45. Pulmonary toilet with endotracheal suctioning is an effective means of reducing mucous plugging and atelectasis. Ventilatory weaning is initiated after the patient is deemed stable, awake, and alert. Usually, weaning is accomplished through successive decrements in intermittent mandatory ventilation rate followed by a trial of continuous positive airway pressure. Once ventilatory mechanics and arterial blood gases are deemed acceptable, the patient is extubated. This usually occurs within the first 24 hours after transplantation. Subsequent pulmonary care consists of vigorous diuresis, supplemental oxygen for several days, continued aggressive pulmonary toilet and incentive spirometry, and serial chest x-rays. A diffuse interstitial infiltrate is often found on early postoperative chest x-rays. Previously referred to as a reimplantation response, this finding is better defined as graft edema due to inadequate preservation, reperfusion injury, or early rejection. It appears that the degree of pulmonary edema is inversely related to the quality of preservation. Judicious administration of fluid and loop diuretics is required to maintain fluid balance and minimize this pulmonary edema. Early lung graft dysfunction manifested by persistent marginal gas exchange without evidence of infection or rejection occurs in less than 15% of transplants.This primary graft failure is often the result of ischemia-reperfusion injury and is manifested histologically by diffuse alveolar damage. Of course, technical causes of graft failure, such as pulmonary venous anastomotic stenosis or thrombosis, must always be considered. In cases of persistent severe pulmonary graft dysfunction refractory to mechanical ventilatory maneuvers, extracorporeal membrane oxygenation (ECMO) and inhaled nitric oxide have been used successfully to stabilize gas exchange in several patients. In others, urgent retransplantation has been performed. Expedient removal of vascular lines has been shown to reduce the incidence of line sepsis. Pleural and mediastinal chest tubes are removed when drainage has fallen to less than 25 mL/h. For heart-lung graft recipients, pacing wires are removed between 7 and 10 days after transplantation, provided that pacing is not required. After several days, barring significant complications, the patient is transferred from the ICU to a standard cardiothoracic surgical ward for the remainder of the hospital stay. Immunosuppressive Management: Early and Late Postoperative Regimens For heart-lung and lung graft recipients, immunosuppression begins intraoperatively and is continued for the patient's lifetime. The conventional triple-drug combination consists of cyclosporine, azathioprine, and prednisone. Initially, high doses of these drugs are given, and they are later tapered for chronic administration. Cyclosporine is initiated in the early postoperative period, initially intravenously (0.05–0.1 mg/kg/h) and subsequently orally when oral intake is well established (5–10 mg/kg/d in two divided doses). Dosing is titrated to maintain a trough serum concentration between 150 and 250 ng/mL in the first few weeks after transplantation and from 100 to 150 ng/mL thereafter. Azathioprine is administered intravenously at 4 mg/kg preoperatively and subsequently maintained at approximately 2 to 3 mg/kg/d. Azathioprine dosages are adjusted to maintain the white blood cell count greater than 4000 cells/mm3. Methylprednisolone is administered intraoperatively at graft reperfusion (500 mg intravenously) and then continued for the first 24 hours at 125 mg intravenously every 8 hours. Steroids are then suspended for 2 weeks, based on experimental and clinical evidence that they impede bronchial anastomotic healing. After 2 weeks, prednisone is started at a daily oral dose of 0.6 mg/kg and gradually tapered over the next 3 to 4 weeks to 0.1 to 0.2 mg/kg/d. The conventional triple-drug combination of cyclosporine, azathioprine, and prednisone is modified at some centers. Tacrolimus (FK506) and mycophenolate mofetil are two drugs that have been used widely in kidney and liver transplantation; experience with use of these drugs in heartlung and lung transplant recipients is limited. Many centers have added prophylactic induction therapy to the standard triple-drug regimen. This includes the use of OKT3, antithymocyte globulin (RATG and ATGAM), and daclizumab. OKT3 is a murine monoclonal antibody preparation that recognizes the CD3 antigen of human T cells. Side effects: Cyclosporine is commonly associated with nephrotoxicity, hypertension, hepatotoxicity, hirsutism, and an increased incidence of lymphoma. The primary toxicity of azathioprine is generalized bone marrow depression, which manifests as leukopenia, anemia, and thrombocytopenia. Steroids are associated with a myriad of side effects, including the development of cushingoid features, hypertension, diabetes, osteoporosis, and peptic ulcer disease. Initial doses of OKT3 and antithymocyte globulin can be associated with a "cytokine release syndrome"; significant hypotension, bronchospasm, and fever can result. Therefore, patients receiving these induction agents are premedicated with acetominophen, antihistamines, and corticosteroids, and are monitored closely. Interestingly, daclizumab is not associated with the cytokine release syndrome. Infection Prophylaxis Antiviral and antifungal prophylaxis are important components of postoperative management in heart-lung and lung transplant recipients. Cytomegalovirus prophylaxis (CMV) with ganciclovir is employed by many centers in any CMV-positive recipient and in any CMV-negative recipient receiving an allograft from a CMV-positive donor. Ganciclovir is typically given for a several week course, and can be associated with leukopenia. Some patients may require G-CSF if their white blood cell count falls below 4000. Fungal prophylaxis against mucosal Candida infection includes use of daily nystatin swish and swallow. Pneumocystis carinii prophylaxis consists of trimethoprim- sulfamethoxazole or aerosolized pentamidine. In the immediate postoperative period, Aspergillus colonization is inhibited by the use of aerosolized amphotericin B. For Toxoplasma-negative recipients of grafts from Toxoplasma-positive patients, pyrimethamine prophylaxis is maintained for the first 6 months after transplantation. Graft Surveillance: Patient Follow-Up Schedule Routine clinical follow-up for heart-lung and lung allograft recipients is required to monitor graft function and modify immunosuppressive regimens. Regular surveillance protocols have been developed to monitor graft function, and these typically consist of serial pulmonary function tests, arterial blood gases, and bronchoscopic evaluation at 2 weeks, 4 to 6 weeks, 12 weeks, and 6 months after transplantation, and yearly thereafter. Transbronchial biopsies are obtained from each transplanted lung, and lavage specimens are submitted for staining (i.e., Gram, fungal, acid-fast bacillus, and silver), culture, and cytology. Surveillance endomyocardial biopsies are performed at 3 months and then annually in heart-lung graft recipients. In addition to routine surveillance, follow-up is often needed to address changes in clinical status. Complications related to transplantation are many, and these must be addressed carefully and expediently to prevent long-term graft failure. POSTOPERATIVE COMPLICATIONS Haemorrhage Early Graft Dysfunction and Primary Graft Failure Hyperacute Rejection Acute Rejection Chronic Rejection Airway Complications Infection Neoplasm Causes of death HLTx and LTx Long-term survival HLTx and LTx