Early and late airway complications after lung transplantation: incidence and management

BACKGROUND: Airway anastomosis complications continue to be a source of morbidity for lung transplant recipients. METHODS: This study analyzes incidence, treatment, and follow-up of airway anastomotic complications occurring in 127 consecutive lung transplant airway anastomoses (77 single lung and 25 bilateral sequential lung). Complications were categorized as stenosis (11), granulation tissue (8), infection (7), bronchomalacia (5), or dehiscence (3). Follow-up after treatment ranged from 6 months to 4 years. RESULTS: Nineteen airway anastomosis complications (15.0%) occurred in 18 patients. Telescoping the airway anastomosis reduced the complication rate to 12 of 97 (12.4%), compared with 7 of 30 (23.3%) for omental wrapping, (p = 0.15). Complications developed in 13 of 77 single-lung airway anastomoses (16.9%) versus 6 of 50 bilateral sequential lung recipients (12.0%). Treatment consisted of stenting (9 airway anastomoses), bronchodilation (8), laser debridement (4), rigid bronchoscopic debridement (2), operative revision (2), and growth factor application (2). There was no difference in actuarial survival between patients with or without airway anastomosis complications (p = 1.0). CONCLUSIONS: Airway anastomosis complications can be successfully managed in the immediate or late postoperative period with good outcome up to 4 years after intervention.     

Protein catabolism after lung transplantation and heart transplantation

Any surgical intervention is associated with an activation of protein catabolism, the extent of which is dependent on the severity of surgical trauma. There is a paucity of reports on protein catabolism after transplantation of chest organs (lung transplantation (LTX) and heart transplantation (HTX)). The aim of the present study was to quantify and compare the extent of postoperative protein catabolism and associated metabolic perturbations in patients after LTX and HTX. Eighteen consecutive patients after LTX and 15 consecutive patients after HTX who required postoperative intensive care for more than 4 days, constituted the study population. The nitrogen balance (assessed on the basis of the urea nitrogen production rate and nitrogen intake) was assessed retrospectively and correlated with insulin requirements, immunosuppression and the clinical course. Within the first 5 days the nitrogen balance became progressively negative in both groups, reaching a maximum on the 5th day. Thereafter the nitrogen balance of patients following LTX remained negative, whereas the nitrogen balance of patients following HTX tended to improve. The evolution of nitrogen balance significantly differed between both groups (p < 0.01). The mean nitrogen loss was -0.29 +/- 0.17g/kg BW/day after LTX versus -0.22 +/- 0.12g/kg BW/day after HTX. Smaller amounts of glucocorticoids were used for immunosuppression in patients after HTX than in patients after LTX; nevertheless, heart transplant recipients required higher doses of insulin to maintain normoglycemia. A regression analysis revealed that the duration of stay at the intensive care unit (p < 0.001) and the amount of glucocorticoids (p < 0.01) negatively affected the nitrogen balance, whereas an increased protein intake (p < 0.001) exerted a positive effect. Compared to other major surgical procedures, protein catabolism is excessively elevated in patients after thoracic transplantation. Immunosuppressive therapy with glucocorticoids contributes to protein degradation; the nitrogen balance after LTX is more negative than that after HTX because of higher glucocorticoid requirements following LTX. More aggressive nutritional intervention and especially an increased nitrogen intake might help to reduce protein losses in these patients.     

Obliterative bronchiolitis after lung and heart-lung transplantation

Obliterative bronchiolitis (OB) has emerged as the main cause of morbidity and mortality in the long-term follow-up after lung and heart-lung transplantation. The pathogenesis of OB is multifactorial, with acute rejection and cytomegalovirus infection being the main risk factors for the development of OB. The final common pathway of all inciting events seems to be an alloimmune injury, with subsequent release of immunologic mediators and production of growth factors leading to luminal obliteration and fibrous scarring of the small airways. Analyzing the 14 years of experience in 163 patients at Stanford University, we found a current incidence of bronchiolitis obliterans syndrome or histologically proven OB within the first 3 years after lung and heart-lung transplantation of 36.3%, with an overall prevalence of 58.1% after heart-lung and 51.4% after lung transplantation. Both pulmonary function indices (forced expiratory flow between 25% and 75% of forced vital capacity and forced expiratory volume in 1 second) and transbronchial biopsies have proven helpful in diagnosing bronchiolitis obliterans syndrome or OB at an early stage. Early diagnosis of OB and improved management have achieved survival rates in patients with OB after 1, 3, 5, and 10 years of 83%, 66%, 46%, and 22%, compared with 86%, 83%, 67%, and 67% in patients without OB. Recently, different experimental models have been developed to investigate the cellular and molecular events leading to OB and to evaluate new treatment strategies for this complication, which currently limits the long-term success of heart-lung and lung transplantation.     

Lymphangioleiomyomatosis: recurrence after single lung transplantation

Lymphangioleiomyomatosis (LAM) is a rare disease which afflicts young women of childbearing age. Recently, it has been listed as an indication for lung transplantation. We describe a case of recurrent LAM in a 31-year-old woman occurring in the allograft of a male donor after single lung transplantation. Nonisotopic in situ hybridization shows that the smooth muscle cell proliferation is of donor origin.     

Diaphragmatic dysfunction after heart or lung transplantation

The research presented here investigated platelet activation in cyanotic and acyanotic congenital heart diseases (CHD). Children with cyanotic CHD are prone to both thrombosis and hemorrhage. However, patients with acyanotic CHD may also have a mild bleeding disorder. The platelet activation in CHD was investigated in support of a hypothesis that platelet activation may play a role in the hemostatic abnormalities reported in these patients. Platelet activation was determined by using flow cytometry with anti-CD62 monoclonal antibody (mAb), which has been shown to be a specific marker of platelet activation. Thirteen children with cyanotic CHD, 33 children with acyanotic CHD and 17 healthy children serving as controls were studied. Platelet activation was significantly higher in the cyanotic group and also in the acyanotic group compared with the healthy children (P = 0.0000 and P = 0.019, respectively). In the cyanotic group, platelet activation showed a direct correlation with arterial O2 saturation (SaO2) (P = 0.014). There was no correlation between platelet activation and erythrocyte related parameters in either group. Platelet activation occurs in CHD, particularly in patients with cyanotic CHD (even in patients with no evidence of clinical thrombosis) and it may play a role in the pathogenesis of thrombotic disorders seen in these patients.     

Controlled reperfusion after lung ischemia: implications for improved function after lung transplantation

OBJECTIVES: Despite improvements in organ preservation, reperfusion injury remains a major source of morbidity and mortality after lung transplantation. This pilot study was designed to investigate the effects of controlled reperfusion after lung ischemia. METHODS: Twenty adult pigs underwent 2 hours of warm lung ischemia by crossclamping the left bronchus and pulmonary artery. In five (group 1), the clamp was simply removed at the end of ischemia (uncontrolled reperfusion). The 15 other pigs underwent modified reperfusion using blood from the femoral artery to perfuse the lung through the pulmonary artery (pressure 40 to 50 mm Hg) for 10 minutes before removing the pulmonary artery clamp. In five (group 2), the blood was mixed with crystalloid, resulting in a substrate-enriched, hypocalcemic, hyperosmolar, alkaline solution. In five (group 3), the blood was circulated through a leukocyte-depleting filter, and the last five (group 4) underwent reperfusion with both a modified solution and white blood cell filter. Lung function was assessed 60 minutes after reperfusion, and biopsy specimens were taken. RESULTS: Controlled reperfusion with both a white blood cell filter and modified solution (group 4) completely eliminated the reperfusion injury that occurred with uncontrolled reperfusion (group 1), resulting in complete preservation of compliance (98% +/- 1% vs 77% +/- 1%; p < 0.001, and arterial/alveolar ratio (97% +/- 2% vs 27% +/- 2%; p < 0.001); no increase in pulmonary vascular resistance (106% +/- 1% vs 198% +/- 1%; p < 0.001); lowered tissue edema (82.1% +/- 0.4% vs 84.3% +/- 0.2%; p < 0.001), and myeloperoxidase activity (0.18 +/- 0.02 vs 0.35 +/- 0.02 deltaOD/min/mg protein; p < 0.001). In contrast, using either a white blood cell filter or modified solution separately improved but did not avoid the reperfusion injury, resulting in pulmonary function and tissue edema levels that were intermediate between group 1 (uncontrolled reperfusion) and group 4 (white blood cell filter and modified solution). CONCLUSION: After 2 hours of warm pulmonary ischemia, (1) a severe lung injury occurs after uncontrolled reperfusion, (2) controlled reperfusion with either a modified reperfusion solution or white blood cell filter limits, but does not avoid, a lung reperfusion injury, (3) reperfusion using both a modified reperfusate and white blood cell filter results in complete preservation of pulmonary function. We therefore believe surgeons should control the reperfusate after lung transplantation to improve postoperative pulmonary function.     

Prospective study of the value of transbronchial lung biopsy after lung transplantation

Transbronchial lung biopsy (TBB) has become the gold standard for the diagnosis of acute rejection and cytomegalovirus (CMV) pneumonia in lung transplant recipients. The aim of this study was to assess the value of regular surveillance TBB in stable asymptomatic patients and to establish the role of TBB as a follow-up procedure 1 month after a previous pathological biopsy result. We prospectively evaluated 76 TBBs performed in 17 lung transplant recipients. A definite pathological results was found in 14 of 15 TBBs performed for clinical indications: CMV pneumonia (5), acute rejection grade > or = A2 according to the criteria of the International Society for Heart and Lung Transplantation (ISHLT) (4), bronchiolitis obliterans (3), and desquamative interstitial pneumonitis (2). Fifteen of 45 surveillance TBBs performed in asymptomatic patients revealed significant abnormalities. Ten episodes of acute rejection ISHLT grade > or = A2 and three episodes of CMV pneumonia detected by TBB had direct therapeutic consequences. Nine of 16 follow-up TBBs performed 1 month after a pathological biopsy result again showed relevant pathological findings. With the exception of one severe haemorrhage, no life-threatening complications occurred. Our results suggest that transbronchial lung biopsies performed on a regular basis after lung transplantation are important for the detection of asymptomatic and/or persistent acute rejection or injection. In the long-term, this strategy might be the most effective tool in reducing the incidence of bronchiolitis obliterans, which is still the main obstacle for further improvement of long-term survival after lung transplantation.     

Radiologic interventions in anastomosis complications after lung transplantation

Over a period of one year the iodine content of the milk of 28 bavarian dairies was determined monthly by a gaschromatographical method. The annual mean value was 115 micrograms/l. In March, April and November, December, respectively a distinct increase of the concentration was observed. In the southern part of Bavaria the iodine contents were below 100 micrograms/l in contrast to the region Oberpfalz and Franken where contents up to 150 micrograms/l could be determined. Compared with concentrations in different tables the iodine content in bavarian milk could increase the iodine uptake up to 6%.     

Lymphoproliferative disorders after lung transplantation: imaging features

The intensity of the fluorescence emission of the fluorescent 1,4-dihydropyridine (DHP) derivative felodipine increased upon binding to both isolated cardiac sarcolemma (SLM) and skeletal muscle sarcoplasmic reticulum (SR) preparations, the latter containing SR-transversal tubule junctional diads and triads. The fluorescence enhancement was due to the binding of felodipine to high-affinity (Kd's of 0.35 and 1.25 nM in cardiac SLM and skeletal SR, respectively) 1,4-dihydropyridine sites of the dihydropyridine receptor (DHPR), as evidenced in competition experiments with the DHP analog isradipine. In both cardiac SLM and SR, the felodipine fluorescence was sensitive to conformational changes of the DHPR, as diltiazem that binds to DHPR at a separate site altered the values of both the Kd and the Hill coefficient characteristic for felodipine binding. In skeletal muscle membranes containing intact TT-SR junctions, ryanodine, a specific ligand of the ryanodine receptor calcium release channel (RyRC), also induced changes in felodipine fluorescence, which was eliminated by detergent and high-salt treatment to solubilize the RyRC. These results suggest that i) felodipine fluorescence is useful to probe conformational changes of the DHPR and ii) coupled conformational changes between the DHPR and the RyRC in skeletal muscle indeed occur and could be monitored by measuring felodipine fluorescence.     

Effects of proinflammatory cytokines and bacterial toxins on neutrophil rheologic properties

OBJECTIVE: To examine the changes in neutrophil deformability, aggregation, and adherence in response to stimulation with proinflammatory cytokines and bacterial toxins. DESIGN: Prospective, randomized trial. SETTING: Research laboratory. SUBJECTS: Neutrophils isolated from healthy volunteers. INTERVENTIONS: Neutrophils were exposed to tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-8, their combination, endotoxin (LPS), lipoteichoic acid (LTA), and staphyloccocal enterotoxin B (SEB). Neutrophil deformability was measured as percent neutrophils filtered through 5-microm diameter filters. Aggregation was measured using a platelet aggregometer. Adherence was determined by examining the binding of neutrophils to albumin-coated latex beads. MEASUREMENTS AND MAIN RESULTS: Exposure to TNF-alpha and IL-1beta led to significant decreases in neutrophil filterability, which was attenuated by cytochalasin D pretreatment. LPS and LTA also decreased deformability, suggesting that these toxins directly stimulated neutrophils independent of cytokines. IL-8 and SEB did not significantly affect neutrophil deformability. TNF-alpha and LPS were associated with significant neutrophil aggregation, which was inhibited by pretreatment with anti-CD18 antibodies. Neutrophil aggregation was not affected by IL-1beta, LTA, or SEB. TNF-alpha, IL-8, and LPS increased neutrophil adherence, which also was attenuated by pretreatment with anti-CD18 antibodies. IL-1beta, LTA, and SEB did not significantly affect neutrophil adherence. CONCLUSIONS: Cytokines and bacterial toxins differ in their effects on neutrophil deformability, aggregation, and adherence. Of the cytokines examined, TNF-alpha appears to have the greatest direct effects on neutrophil rheology. Similarly, endotoxin appears to have greater direct effects on neutrophil rheology than the Gram-positive bacterial toxins, LTA, and staphylococcal enterotoxins.     

Induced hypothermia in critical respiratory failure after lung transplantation

A practical approach to detect and identify ceftazidime-hydrolyzing extended-spectrum mutants of OXA-10 beta-lactamase is presented. Large numbers of bacteria were screened by colony hybridization, a 720-bp part of blaOXA was amplified by PCR from the hybridization-positive isolates, and the products were digested by PvuII and HaeIII.     

Does airway pressure release ventilation alter lung function after acute lung injury?

BACKGROUND: During airway pressure release ventilation (APRV), tidal ventilation occurs between the increased lung volume established by the application of continuous positive airway pressure (CPAP) and the relaxation volume of the respiratory system. Concern has been expressed that release of CPAP may cause unstable alveoli to collapse and not reinflate when airway pressure is restored. OBJECTIVE: To compare pulmonary mechanics and oxygenation in animals with acute lung injury during CPAP with and without APRV. DESIGN: Experimental, subject-controlled, randomized crossover investigation. SETTING: Anesthesiology research laboratory, University of South Florida College of Medicine Health Sciences Center. SUBJECTS: Ten pigs of either sex. INTERVENTIONS: Acute lung injury was induced with an intravenous infusion of oleic acid (72 micrograms/kg) followed by randomly alternated 60-min trials of CPAP with and without APRV. Continuous positive airway pressure was titrated to produce an arterial oxyhemoglobin saturation of at least 95% (FIO2 = 0.21). Airway pressure release ventilation was arbitrarily cycled to atmospheric pressure 10 times per minute with a release time titrated to coincide with attainment of respiratory system relaxation volume. MEASUREMENTS: Cardiac output, arterial and mixed venous pH, blood gas tensions, hemoglobin concentration and oxyhemoglobin saturation, central venous pressure, pulmonary and systemic artery pressures, pulmonary artery occlusion pressure, airway gas flow, airway pressure, and pleural pressure were measured. Tidal volume (VT), dynamic lung compliance, intrapulmonary venous admixture, pulmonary vascular resistance, systemic vascular resistance, oxygen delivery, oxygen consumption, and oxygen extraction ratio were calculated. MAIN RESULTS: Central venous infusion of oleic acid reduced PaO2 from 94 +/- 4 mm Hg to 52 +/- 9 mm Hg (mean +/- 1 SD) (p < 0.001) and dynamic lung compliance from 40 +/- 6 mL/cm H2O to 20 +/- 6 mL/cm H2O (p = 0.002) and increased venous admixture from 13 +/- 3% to 32 +/- 7% (p < 0.001) in ten swine weighing 33.3 +/- 4.1 kg while they were spontaneously breathing room air. After induction of lung injury, the swine received CPAP (14.7 +/- 3.3 cm H2O) with or without APRV at 10 breaths per minute with a release time of 1.1 +/- 0.2 s. Although mean transpulmonary pressure was significantly greater during CPAP (11.7 +/- 3.3 cm H2O) vs APRV (9.4 +/- 3.8 cm H2O) (p < 0.001), there were no differences in hemodynamic variables. PaCO2 was decreased and pHa was increased during APRV vs CPAP (p = 0.003 and p = 0.005). PaO2 declined from 83 +/- 4 mm Hg to 79 +/- 4 mm Hg (p = 0.004) during APRV, but arterial oxyhemoglobin saturation (96.6 +/- 1.4% vs 96.9 +/- 1.3%) did not. Intrapulmonary venous admixture (9 +/- 3% vs 11 +/- 5%) and oxygen delivery (469 +/- 67 mL/min vs 479 +/- 66 mL/min) were not altered. After treatment periods and removal of CPAP for 60 min, PaO2 and intrapulmonary venous admixture returned to baseline values. DISCUSSION: Intrapulmonary venous admixture, arterial oxyhemoglobin saturation, and oxygen delivery were maintained by APRV at levels induced by CPAP despite the presence of unstable alveoli. Decrease in PaO2 was caused by increase in pHa and decrease in PaCO2, not by deterioration of pulmonary function. We conclude that periodic decrease of airway pressure created by APRV does not cause significant deterioration in oxygenation or lung mechanics.     

Preliminary experience with mycophenolate mofetil used after lung transplantation

This study reports our preliminary experience with mycophenolate mofetil (MMF)-based immune suppression after lung transplantation. Thirteen patients (group 1) received MMF as primary therapy immediately after transplantation. Use of MMF was associated with a linearized rate of 0.85 episodes of acute rejection per 100 patient days during the first 3 months after transplantation, as compared with rates of 1.49 and 1.38, observed in two groups of historical control subjects (p = .094 and p = .053, respectively). Rejection rates after the first 3 months were not lower than in historical control subjects. Nine additional patients were switched from azathioprine to MMF because of recurrent episodes of high-grade acute rejection (group 2). In this group, the linearized rate of acute rejection episodes declined significantly (p = .004) after initiation of MMF therapy. These data suggest a potential role for MMF in reducing the rate of acute rejection episodes after lung transplantation.     

Aspergillus airway colonization and invasive disease after lung transplantation

To assess the effect of hemolysis on serum retinol concentrations determined by direct fluorometry, we assayed 196 blood samples from children 6-72-mo of age with various grades of hemolysis for serum retinol by both fluorescence and HPLC. Mean serum retinol concentrations determined by HPLC did not differ significantly according to hemolysis grade; however, fluorometric values did. Additionally, serum retinol concentrations obtained from HPLC and those obtained from direct fluorometry were significantly different in samples with severe hemolysis. Multivariate-regression analysis showed that hemolysis grade was a significant predictor of the difference in mean serum retinol values determined by the two methods. Although severe hemolysis interfered with determinations of serum retinol by direct fluorometry, this method is still a viable choice for field studies of vitamin A status.     

Abdominal operations after lung transplantation. Indications and outcome

OBJECTIVE: To assess the outcomes of abdominal operations in patients with lung transplants and identify adverse risk factors. DESIGN: Matched cohort study. SETTING: University referral center. PARTICIPANTS: Twelve lung transplant recipients who required abdominal operations (hereafter referred to as case patients) and 12 age-, sex-, and pulmonary diagnosis-matched lung transplant recipients who had not undergone an abdominal procedure (hereafter referred to as control patients). INTERVENTIONS: Elective abdominal operations including laparoscopic cholecystectomies (n = 5), laparoscopic repair of a colovaginal fistula (n = 1), and open colectomy for a benign colovesical fistula (n = 1) and urgent operations including bowel resections (n = 3), subtotal pancreatectomy (n = 1), and hepatorrhaphy for an iatrogenic liver injury (n = 1). MAIN OUTCOME MEASURES: Morbidity and mortality. RESULTS: Abdominal operations were performed in 12 (11%) of the patients undergoing lung transplantation at the university referral center since 1987, with an associated mortality rate of 25%. Morbidity and mortality rates of electively performed procedures were 28% and 14%, respectively. An urgent indication for abdominal procedure was associated with 100% morbidity and 40% mortality. Compared with a matched group of 12 control patients, the long-term survival of the case patients was reduced (18% vs 64% at 4 years). Case patients undergoing an abdominal procedure in the posttransplantation period tended to have a higher prevalence of previous rejection (67% vs 25%), a higher perioperative steroid dosage (53 mg/d vs 36 mg/d), and a significantly lower posttransplantational forced expiratory volume in 1 second (FEV1, 1.23 L vs 1.91 L; P < .05). CONCLUSIONS: Elective abdominal operations are relatively safe in properly prepared lung transplant recipients. However, laparotomy for urgent surgical conditions is associated with increased morbidity and mortality rates caused in part by the magnitude of the abdominal operation and influenced by the status of the lung transplant as manifested by previous rejection episodes, perioperative steroid dosages, and FEV1 values.