**7. Diagnosis and management of early surgical complication**

The major surgical complications are bleeding, anastomotic complications and mal-rotation of the graft (24). The latter two are rare with current understanding and experience. Bleeding is less common and is due to refinement in surgical techniques, judicious use of pharmacological agents and blood products. The patients at high risk are the ones with extensive pleural adhesions, large and extensive mediastinal collateral vessels and patients with connective tissue disorders with secondary pulmonary hypertension. Patients with right heart failure and congested liver or patients on chronic anticoagulation or anti-platelet therapy are particularly susceptible and correction of coagulation defect is mandatory in these patients. If a patient persists with significant blood loss (>100 cc/hr), for 4-6 hours, the

Lung Transplantation 303

be given sublingually at a dose of 0.03 mg/kg twice daily. Target tacrolimus trough levels range between 10-20 ng/ml in the first six months after transplantation, followed by levels around 10ng/ml thereafter. Cyclosporine is administered at a rate of 3 mg/kg over 24 hours with target trough levels between 350-450 ng/ ml in the first month, between 300-350 ng/ml during the first year and between 200-300 ng/ml thereafter. Both of these medications are available in oral formulation and should be given orally after extubation. Although current data have not shown a superiority of one of the calcineurin inhibitors, there has been an increasing use of tacrolimus in the lung transplant population due to reports of improved pulmonary function and possibly a reduction in the incidence of bronchiolitis obliterans

Antimetabolites (either azathioprine or mycophenolate mofetil) are the second immunosuppressive medication that are used in the treatment of lung transplant recipients. The first dose may be initially administered prior to implantation of the lung allograft. Azathioprine is dosed at 2mg/kg daily and can be administered either intravenously or orally. Mycophenolate mofetil is dosed orally at 2-3 gram in daily divided doses. In general, antimetabolites may be associated with myelosuppression and gastrointestinal distress and doses may be adjusted based on these side effects. Two randomized multicenter studies that have not shown any difference in acute rejection, or survival between these two agents

Corticosteroids have been the mainstay of immunosuppression since the advent of successful lung transplantation in the 1980s. First dose of methylprednisolone (between 500 to 1000 mg intravenously) is usually given prior to reperfusion of the graft in the operating room. Subsequent doses of corticosteroids range between 0.5-1 mg/kg during the first few weeks after transplantation. In general, corticosteroids are tapered to the equivalent of 5-10

The role of induction therapy in lung transplantation has yet to be defined. There are several different types of induction therapy that are currently being used in lung transplantation including the interleukin- 2 receptor antagonists (daclizumab, basiliximab), the polyclonal agents(ATGAM, thymoglobulin) and the monoclonal antibody (OKT3). Several reports have suggested that induction therapies may reduce the incidence of acute rejection during the first six months after lung transplantation. However, longer term outcomes including prevention of chronic rejection or improving survival have not been associated with the use

Infections remain a major source of morbidity and mortality after lung transplantation. Prophylaxis against bacterial, viral and fungal organisms usually starts immediately postoperatively in the recipients. Initial antibiotic prophylaxis should be directed towards adequate anaerobic coverage and tailored towards any positive donor or recipient culture detected prior to transplantation. These antibiotics are usually continued between three to fourteen days post transplant depending upon the individual transplant center's protocol. Lung transplant recipients with septic lung disease (cystic fibrosis, bronchiectasis) who may be colonized with resistant organisms often receive two synergistic antibiotics based on

mg of prednisone daily by three to six months after transplantation.

of induction therapy after lung transplantation (30-32).

**10. Infection prophylaxis** 

prior sensitivities during this time period.

syndrome (26,27).

(28,29).

patient needs to return to the operating room unless there is evidence of significant coagulation abnormalities.

The dreaded complication of complete bronchial anastomotic dehiscence is rarely seen now but stenosis at the anastomotic site is not that uncommon, being reported between 5-25% of the anastomoses. This complication is usually delayed for several weeks following transplantation (25). In the presence of anatamotic site infection or significant donor bronchial ischemia minor bronchial dehiscence may present as early as 1-2 weeks.

Vascular anastomotic complications are infrequently reported, and their real incidence may be higher than that reported in the literature. The venous complication if severe enough can present few hours following transplantation as acute graft dysfunction. This presents as rapidly progressing pulmonary edema, with diffuse, dense infiltrate of the affected lung or lobe. This is a potentially lethal condition and diagnosis require high index of suspicion. TEE is helpful to confirm diagnosis. Surgical correction is required if this is due to anatomotic narrowing due to surgical technique. Thrombus formation at the anastomotic site can also cause venous obstruction and this is insidious in origin and progressive. Thrombolytic agents had been successfully used in these circumstances. Arterial anastomotic stenosis presents as hypoxemia, usually associated with exercise. This should be suspected if there is no other reason for hypoxemia. Pulmonary angiogram is diagnostic and catheter based intervention including stent placement has been successfully employed. Mal-rotation of Lobar or lung on its axis is a rare complication and if not corrected

immediately will result in necrosis of the lobe or lung. Complete opacification of the lobe or lung is noted in chest radiograph. Bronchoscopic examination is confirmatory of the bronchial torsion.

#### **8. Pain management**

Patients undergoing thoracic surgery require effective pain relief to allow deep breathing, coughing and facilitate early ambulation. In lung transplant patients this becomes crucial as they are chronically debilitated and have difficulty clearing secretions. While providing effective pain relief it is necessary to prevent sedation to promote early ambulation and therefore avoidance of narcotics is preferred. Thoracic epidural analgesia is effective in providing pain relief without causing sedation. We advocate placement of the thoracic epidural pre-operatively or place it soon after patient is extubated. NSAID are avoided because of the potential interactions with other nephrotoxic agents particularly the calcineurin inhibitors. Transitioning to oral pain medication is monitored carefully prior to discharge from the hospital.

#### **9. Immunosuppression**

Immunosuppression after lung transplantation includes three major categories of immunosuppressive agents; calcineurin inhibitors (tacrolimus, cyclosporine A), antimetabolites (azathioprine, mycophenolate mofetil) and corticosteroids. In addition, approximately 45% of lung transplant patients receive induction therapy after lung transplantation. The calcineurin inhibitors are administered within hours after transplantation and may be given either intravenously or sublingually. In general, tacrolimus is dosed at 0.05-0.1 mg/ kg over 24 hours by continuous infusion and may also

patient needs to return to the operating room unless there is evidence of significant

The dreaded complication of complete bronchial anastomotic dehiscence is rarely seen now but stenosis at the anastomotic site is not that uncommon, being reported between 5-25% of the anastomoses. This complication is usually delayed for several weeks following transplantation (25). In the presence of anatamotic site infection or significant donor

Vascular anastomotic complications are infrequently reported, and their real incidence may be higher than that reported in the literature. The venous complication if severe enough can present few hours following transplantation as acute graft dysfunction. This presents as rapidly progressing pulmonary edema, with diffuse, dense infiltrate of the affected lung or lobe. This is a potentially lethal condition and diagnosis require high index of suspicion. TEE is helpful to confirm diagnosis. Surgical correction is required if this is due to anatomotic narrowing due to surgical technique. Thrombus formation at the anastomotic site can also cause venous obstruction and this is insidious in origin and progressive. Thrombolytic agents had been successfully used in these circumstances. Arterial anastomotic stenosis presents as hypoxemia, usually associated with exercise. This should be suspected if there is no other reason for hypoxemia. Pulmonary angiogram is diagnostic and catheter based intervention including stent placement has been successfully employed. Mal-rotation of Lobar or lung on its axis is a rare complication and if not corrected immediately will result in necrosis of the lobe or lung. Complete opacification of the lobe or lung is noted in chest radiograph. Bronchoscopic examination is confirmatory of the

Patients undergoing thoracic surgery require effective pain relief to allow deep breathing, coughing and facilitate early ambulation. In lung transplant patients this becomes crucial as they are chronically debilitated and have difficulty clearing secretions. While providing effective pain relief it is necessary to prevent sedation to promote early ambulation and therefore avoidance of narcotics is preferred. Thoracic epidural analgesia is effective in providing pain relief without causing sedation. We advocate placement of the thoracic epidural pre-operatively or place it soon after patient is extubated. NSAID are avoided because of the potential interactions with other nephrotoxic agents particularly the calcineurin inhibitors. Transitioning to oral pain medication is monitored carefully prior to

Immunosuppression after lung transplantation includes three major categories of immunosuppressive agents; calcineurin inhibitors (tacrolimus, cyclosporine A), antimetabolites (azathioprine, mycophenolate mofetil) and corticosteroids. In addition, approximately 45% of lung transplant patients receive induction therapy after lung transplantation. The calcineurin inhibitors are administered within hours after transplantation and may be given either intravenously or sublingually. In general, tacrolimus is dosed at 0.05-0.1 mg/ kg over 24 hours by continuous infusion and may also

bronchial ischemia minor bronchial dehiscence may present as early as 1-2 weeks.

coagulation abnormalities.

bronchial torsion.

**8. Pain management** 

discharge from the hospital.

**9. Immunosuppression** 

be given sublingually at a dose of 0.03 mg/kg twice daily. Target tacrolimus trough levels range between 10-20 ng/ml in the first six months after transplantation, followed by levels around 10ng/ml thereafter. Cyclosporine is administered at a rate of 3 mg/kg over 24 hours with target trough levels between 350-450 ng/ ml in the first month, between 300-350 ng/ml during the first year and between 200-300 ng/ml thereafter. Both of these medications are available in oral formulation and should be given orally after extubation. Although current data have not shown a superiority of one of the calcineurin inhibitors, there has been an increasing use of tacrolimus in the lung transplant population due to reports of improved pulmonary function and possibly a reduction in the incidence of bronchiolitis obliterans syndrome (26,27).

Antimetabolites (either azathioprine or mycophenolate mofetil) are the second immunosuppressive medication that are used in the treatment of lung transplant recipients. The first dose may be initially administered prior to implantation of the lung allograft. Azathioprine is dosed at 2mg/kg daily and can be administered either intravenously or orally. Mycophenolate mofetil is dosed orally at 2-3 gram in daily divided doses. In general, antimetabolites may be associated with myelosuppression and gastrointestinal distress and doses may be adjusted based on these side effects. Two randomized multicenter studies that have not shown any difference in acute rejection, or survival between these two agents (28,29).

Corticosteroids have been the mainstay of immunosuppression since the advent of successful lung transplantation in the 1980s. First dose of methylprednisolone (between 500 to 1000 mg intravenously) is usually given prior to reperfusion of the graft in the operating room. Subsequent doses of corticosteroids range between 0.5-1 mg/kg during the first few weeks after transplantation. In general, corticosteroids are tapered to the equivalent of 5-10 mg of prednisone daily by three to six months after transplantation.

The role of induction therapy in lung transplantation has yet to be defined. There are several different types of induction therapy that are currently being used in lung transplantation including the interleukin- 2 receptor antagonists (daclizumab, basiliximab), the polyclonal agents(ATGAM, thymoglobulin) and the monoclonal antibody (OKT3). Several reports have suggested that induction therapies may reduce the incidence of acute rejection during the first six months after lung transplantation. However, longer term outcomes including prevention of chronic rejection or improving survival have not been associated with the use of induction therapy after lung transplantation (30-32).
