Triclosan-coated sutures and sternal wound infections: a prospective randomized clinical trial.

Surgical site infection is a common complication following cardiac surgery. Triclosan-coated sutures have been shown to reduce the rate of infections in various surgical wounds, including wounds after vein harvesting in coronary artery bypass grafting patients. Our purpose was to compare the rate of infections in sternotomy wounds closed with triclosan-coated or conventional sutures. A total of 357 patients that underwent coronary artery bypass grafting were included in a prospective randomized double-blind single-center study. The patients were randomized to closure of the sternal wound with either triclosan-coated sutures (Vicryl Plus and Monocryl Plus, Ethicon, Inc., Somerville, NJ, USA) (n = 179) or identical sutures without triclosan (n = 178). Patients were followed up after 30 days (clinical visit) and 60 days (telephone interview). The primary endpoint was the prevalence of sternal wound infection according to the Centers for Disease Control and Prevention (CDC) criteria. The demographics in both groups were comparable, including age, gender, body mass index, and rate of diabetes and smoking. Sternal wound infection was diagnosed in 43 patients; 23 (12.8%) sutured with triclosan-coated sutures compared to 20 (11.2%) sutured without triclosan (p = 0.640). Most infections were superficial (n = 36, 10.1%), while 7 (2.0%) were deep sternal wound infections. There were 16 positive cultures in the triclosan group and 17 in the non-coated suture group (p = 0.842). The most commonly identified main pathogens were Staphylococcus aureus (45.4%) and coagulase-negative staphylococci (36.4%). Skin closure with triclosan-coated sutures did not reduce the rate of sternal wound infection after coronary artery bypass grafting. (clinicaltrials.gov: NCT01212315).

Expanding the donor pool: lung transplantation with donors 55 years and older.

The scarcity of donor organs is one of the major limitations to lung transplantation. This has led to a progressive expansion of criteria for donor selection in lung transplantation. This study evaluated the outcome of recipients of lungs from donors >/=55 years. We performed a retrospective analysis of 212 consecutive lung transplantations. Recipients were divided into two groups, those receiving lungs from donors >/=55 years (older donor group) and those receiving lungs from donors <55 years (younger donor group). Recipient baseline characteristics, time in the intensive care unit (ICU), early mortality, and long-term survival (Kaplan-Meier) were compared between the groups. Forty-one donors (19%) were >/=55 years. Mean recipient age in the older donor group was higher than in the younger donor group (52 +/- 8 vs. 47 +/- 12 years; P = .015). Indication for transplantation did not differ between the groups. ICU stay was comparable between the two groups (6 +/- 12 vs. 7 +/- 11 days; P = .64). Actual 30-day mortality (10.8% vs. 6.4%; P = .32), 1-year mortality (17.1 vs. 19.6%; P = .50), and cumulative long-term survival (65% and 62% at 5 years, P = 1.00) did not differ between the older and younger donor group. This study indicated that transplantation of lungs from selected donors aged >/=55 years did not impair short-or long-term results. The use of lungs from elderly donors may help to increase the number of donor organs for lung transplantation.

Persistent high BAL fluid granulocyte activation marker levels as early indicators of bronchiolitis obliterans after lung transplant.

The major cause of mortality in the long-term in lung transplant recipients is chronic rejection. This is a fibroproliferative process in the small airways leading to obliterative bronchiolitis and progressive loss of lung function, both constituting the clinical entity bronchiolitis obliterans syndrome (BOS). Granulocyte activation has been implicated as one factor behind BOS. Granulocyte markers in bronchoalveolar lavage (BAL) fluid were prospectively and longitudinally studied in order to identify possible association with BOS. BAL fluid from 266 bronchoscopy procedures performed in twelve single lung, eight bilateral lung and five heart/lung transplant recipients were analysed. The majority (19 of 25) were studied for a period of 2 yrs after surgery. Myeloperoxidase (MPO), eosinophil cationic protein (ECP) and interleukin-8 (IL-8) levels were used as indirect markers of activation and attraction of granulocytes. Five patients developed BOS. Ninety-eight episodes of acute rejection, nine of bacterial infection, 19 of cytomegalovirus pneumonitis, nine of Pneumocystis carinii infection, two of aspergillus infection and two of respiratory syncytial virus infection were diagnosed. BOS patients had significantly higher mean levels of MPO, ECP and IL-8 compared to patients without BOS, irrespective of acute rejection status. Over time, the five patients with BOS had significantly elevated BAL fluid levels of MPO and ECP as well as neutrophil percentages, and in four patients this increase preceded the clinical diagnosis of BOS by several months. Elevated bronchoalveolar lavage fluid neutrophil percentage as well as levels of the granulocyte activation markers myeloperoxidase and eosinophil cationic protein appear to be early signs of development of BOS in lung transplant recipients.

Compromised antioxidant status and persistent oxidative stress in lung transplant recipients.

Oxidative stress may be a key feature, and hence important determinant, of tissue injury and allograft rejection in lung transplant recipients. To investigate this, we determined the antioxidant status (urate, ascorbate, thiols and alpha-tocopherol) and lipid peroxidation status (malondialdehyde) in bronchoalveolar lavage (BAL) fluid and blood serum of 19 consecutive lung transplant recipients 2 weeks and 1, 2, 3, 6, and 12 months post-surgery. BAL fluid and blood samples from 23 control subjects and blood from 8 patients two days before transplantation were obtained for comparison. Before surgery, the antioxidant status of patients was poor as serum ascorbate and total thiol concentrations were significantly (p < 0.05) lower than control subjects. Two weeks post-surgery, ascorbate and total thiol concentrations were still low and urate concentrations had fallen compared to control subjects (p < 0.01). At this time, BAL fluid urate concentration was higher (p < 0.01), ascorbate concentration was lower (p < 0.01) and reduced glutathione concentrations were similar to control subjects. MDA, a product of lipid peroxidation, was higher (p < 0.01) in both BAL fluid and serum obtained from transplant patients compared to control subjects. During the first 12 months post-surgery, little improvement in antioxidant status or extent of lipid peroxidation was seen in transplant recipients. Regression analysis indicated no difference in serum or BAL fluid antioxidant status in patients with acute rejection compared to those without. In conclusion, lung transplant recipients have a compromised antioxidant status before surgery and it remains poor for at least the first year following the operation. In addition, these patients have elevated MDA concentrations in both their lung lining fluid and blood over most of this time. Oxidative stress is not, however, a sufficiently sensitive endpoint to predict tissue rejection in this group.

Bronchiolitis obliterans syndrome in lung transplant recipients is associated with increased neutrophil activity and decreased antioxidant status in the lung.

Long-term survival of lung transplant recipients is limited by the advent of obliterative bronchiolitis and irreversible airways obstruction, e.g. bronchiolitis obliterans syndrome (BOS). This study investigated whether inflammatory cells and their activation markers were increased in bronchoalveolar lavage (BAL) and transbronchial biopsies (TBB) from patients with BOS. Levels of antioxidants in BAL fluid were also assessed. BAL fluid and TBB from six single-lung, two bilateral-lung, and five heart-lung transplanted patients with diagnosis of BOS were compared with 13 transplant recipients without BOS. BAL fluid levels of myeloperoxidase (MPO), eosinophil cationic protein (ECP) and interleukin (IL)-8 were used as markers for the activation and attraction of neutrophils and eosinophils, respectively. Immunohistochemical staining of TBB with monoclonal antibodies to MPO and ECP (EG2) was performed. Significantly increased BAL percentages of neutrophils and levels of MPO were found in patients with BOS. The findings correlated well with the degree of monoclonal staining for MPO in TBB. BAL levels of ECP and IL-8 were significantly increased in BOS patients. BAL concentrations of the water-soluble antioxidants ascorbate, urate and glutathione were generally lower in BOS patients. The results indicate that neutrophil infiltration and activation, as well as oxidative stress, may play a role in the development and/or progression of bronchiolitis obliterans syndrome. Markers for neutrophil activation could have a potential role in monitoring disease activity in patients with this syndrome.

Butylated hydroxytoluene and N-acetylcysteine attenuates tumor necrosis factor-alpha (TNF-alpha) secretion and TNF-alpha mRNA expression in alveolar macrophages from human lung transplant recipients in vitro.

BACKGROUND: Tumor necrosis factor-alpha (TNF-alpha) is a polypeptide cytokine principally produced by macrophages/monocytes and commonly associated with inflammatory conditions. The present study was designed to investigate whether the antioxidants butylated hydroxytoluene (BHT) and N-acetylcysteine (NAC) modified TNF-alpha production in stimulated and unstimulated alveolar macrophages from lung transplant recipients in vitro. METHODS: The effects of BHT and NAC on TNF-alpha production were studied both with and without lipopolysaccharide (LPS) activation of alveolar macrophages from bronchoalveolar lavage fluid. TNF-alpha was quantitated in cell culture medium using an enzyme-linked immunosorbent assay. TNF-alpha mRNA expression was analyzed by quantitative reverse transcription-polymerase chain reaction on total RNA extracted from the incubated alveolar macrophages. RESULTS: In unstimulated alveolar macrophages, TNF-alpha levels were significantly reduced by incubation with BHT or NAC. When alveolar macrophages from patients with cytomegalovirus infection were incubated with BHT, TNF-alpha secretion was significantly lowered. A significant reduction of TNF-alpha levels in LPS-stimulated alveolar macrophages was obtained in the presence of BHT or NAC. Our data from quantitative reverse transcription-polymerase chain reaction showed that the observed decrease in protein levels of TNF-alpha was associated with a decrease in TNF-alpha mRNA expression. CONCLUSIONS: Our results indicate that antioxidant treatment may be an effective step to lower the inflammatory process caused by cytomegalovirus infection or in endotoxin (LPS)-activated macrophages. The therapeutic use of antioxidant compounds could, therefore, be of interest in conditions such as lung transplantation, in which oxidative stress and inflammation can contribute significantly to the loss of allograft function.

Treatment with an antioxidant inhibits vascular changes caused by circulating lymphocytes during acute lung rejection in dogs.

BACKGROUND: Experiments were designed to evaluate the effect of treatment with an inhibitor of lipid peroxidation, H 290/51, on the interaction of lymphocytes and pulmonary arteries during acute lung rejection. It was hypothesized that inhibition of lipid peroxidation would reduce contractions of the pulmonary arteries to autogenous rejection-activated lymphocytes. METHODS: Single-lung transplantation was performed in three groups of dogs: group 1 was maintained on immunosuppression for 8 days postoperatively; in group 2, immunosuppression was discontinued on postoperative day 5, so that rejection occurred on postoperative day 8; in group 3, immunosuppression was discontinued after 5 days, and the lipid peroxidation inhibitor H 290/51 was given orally for 3 days. The pulmonary arteries were removed, cut into rings, and suspended in organ chambers for measurement of isometric force. RESULTS: Macrophage-depleted mononuclear cells (MNCs; lymphocytes) isolated from blood caused cell number-dependent contractions in rings of the pulmonary arteries from all dogs. In the rejecting dogs treated with H 290/51 (group 3), contractions to MNCs were significantly greater in rings without endothelium compared to rings with endothelium. Contractions to MNCs with or without endothelium were reduced by adding deteroxamine to the medium but not by adding superoxide dismutase and catalase. CONCLUSIONS: The results of this study show that treatment with a lipid peroxidation inhibitor, H 290/51, does not prevent acute rejection of transplanted lungs. The treatment with the peroxidation inhibitor modifies contractions of the pulmonary arteries in response to rejection-activated lymphocytes, indicating that reactive oxidative metabolites may be involved in the vasoactive response resulting from this interaction.

Inflammatory cells and activation markers in BAL during acute rejection and infection in lung transplant recipients: a prospective, longitudinal study.

Acute rejection of the transplanted lung is a clinical problem, since it decreases graft survival and predisposes the patient to chronic rejection and obliterative bronchiolitis (OB). In an earlier study, we had indications that eosinophil cationic protein (ECP) from activated eosinophils and hyaluronan (HYA) from fibroblasts were associated with acute pulmonary rejection. This prospective longitudinal study was designed to investigate whether molecules from activated inflammatory cells in bronchoalveolar lavage (BAL) fluid could serve as clinically useful diagnostic markers for acute rejection. BAL fluid from 138 bronchoscopies performed in 10 single lung, four bilateral lung and five heart-lung transplant recipients were analysed. Nine patients were studied for a period of more than 1 yr (mean 13.4 months) after surgery. Differential cell counts were made from the BAL fluid. ECP, myeloperoxidase (MPO), HYA and interleukin-8 (IL-8) were used as indirect markers for activation and attraction of eosinophils, neutrophils and fibroblasts, respectively. Fifty four episodes of acute rejection were diagnosed. Two patients developed OB. Nine episodes of bacterial infection, 13 episodes of cytomegalovirus (CMV) pneumonitis, three of Pneumocystis carinii infection and one of respiratory syncytial virus (RSV) infection were diagnosed. The mean levels of ECP, MPO, HYA and IL-8 were all higher during rejection episodes, but differences were not statistically significant compared to no rejection, when the confounding factors of time, concomitant infection, and repeated measures in the same individual had been accounted for. We could not confirm that measurements of eosinophil cationic protein, myeloperoxidase, hyaluronan and interleukin-8 in bronchoalveolar lavage fluid can be used as diagnostic markers for acute rejection in the postoperative follow-up of lung transplant recipients.

Activation of eosinophils and fibroblasts assessed by eosinophil cationic protein and hyaluronan in BAL. Association with acute rejection in lung transplant recipients.

Lung transplantation has become an accepted therapy for end-stage lung disease. Acute rejection of the transplanted hung still remains a major clinical problem since it decreases graft survival. Eosinophil cationic protein (ECP) from activated eosinophils, hyaluronan (HYA) from fibroblasts, and circulating intercellular adhesion molecule 1 (1CAM-1) have been associated with acute rejection in kidney and liver grafts. We investigated whether these, as well as other molecules, were increased in acute rejection of lung allografts. Serum and BAL fluid from 38 bronchoscopies performed in 9 single lung, 2 bilateral lung, and 4 heart-lung transplant patients were studied. Differential cell counts were made from the BAL fluid. Levels of ECP, myeloperoxidase (MPO), and HYA were used as indirect markers for activation of eosinophils, neutrophils, and fibroblasts, respectively. In addition, levels of circulating ICAM-1, cVCAM-1, and cE-selectin were analyzed. Twenty-two episodes with acute rejection were diagnosed. Of these, 7 were minimal, 13 were mild, and 2 were of moderate character. We found increased levels of ECP and HYA in BAL fluid during mild acute rejection of the allograft. Numbers of eosinophils were also increased. Activation of neutrophils or neutrophil numbers were not significantly increased. Levels of circulating ICAM-1, cVCAM-1, and cE-selectin did not differ between the groups. This retrospective study shows that measurements of ECP and HYA can give information about the inflammatory process present during acute rejection in patients who have undergone lung transplants. Analysis of cCAMS, however, appears to be of limited value as markers for acute rejection.

Impaired endothelium-mediated vasodilatation in the peripheral vasculature of patients with acute pulmonary allograft rejection.

BACKGROUND: Experimental studies have provided evidence that, during acute pulmonary allograft rejection, endothelial dysfunction occurs not only in the transplanted lung but also in arteries of organs native to the transplant recipient. We therefore tested the hypothesis that allograft rejection leads to the release of factors into the circulation that could affect the endothelial function in lung transplant recipients. METHODS: Acetylcholine (10, 30, and 60 micrograms/min) and sodium nitroprusside (1, 3, and 6 micrograms/min) were infused into the brachial artery in nine transplant recipients (five single lung, one double lung, three heart-lung) 2 to 37 weeks after transplantation, during both acute rejection and rejection-free episodes. Changes in forearm blood flow were assessed with venous occlusion plethysmography. Plasma levels of interleukin-2, -6, and -8, endothelin-1, L-arginine, and asymmetric dimethylarginine were measured and correlated to rejection episodes. RESULTS: The vasodilatory response to acetylcholine was significantly reduced during acute rejection compared with rejection-free episodes (percentage increase from basal flow: 156% +/- 21%, 395% +/- 65%, and 585% +/- 87% during rejection versus 272% +/- 75%, 633% +/- 113%, and 933% +/- 158% during absence of rejection, p < 0.05). No statistically significant difference was found between vasodilatory responses to nitroprusside during acute rejection and rejection-free episodes. Plasma levels of L-arginine, asymmetric dimethylarginine, interleukin-6, and endothelin-1 were not significantly altered during lung rejection. CONCLUSIONS: These data indicate that a reversible peripheral decrease in endothelium-dependent vasodilatation occurs during acute rejection in lung transplant recipients. This result may be due to interactions among circulating cytokines and leukocytes activated by the rejection process and the endothelium.

Systemic vascular effects during acute rejection of lung allografts.

Circulating leukocytes activated during rejection of organ allografts could potentially have generalized effects on systemic blood vessels of the transplant recipient. Experiments were designed, therefore, to determine the function of the endothelium and smooth muscle of arteries from nontransplanted organs in dogs who received single lung transplants. Dogs underwent single lung allotransplantation and were immunosuppressed for 5 days. Immunosuppression was then withheld for 3 days, allowing rejection to occur. Dogs were studied at this time (rejecting) or following treatment for rejection for an additional 6-8 days (treated). Arteries from unoperated, untreated dogs also were studied to provide baseline responses of healthy tissue. Rings cut from left circumflex coronary, nonoperated native pulmonary, and renal arteries were suspended in organ chambers for measurement of isometric force. Endothelium-dependent relaxations to the calcium ionophore A23187 were not affected by rejection in any of the arteries. Contractions to angiotensin I were reduced significantly only in native pulmonary arteries. Contractions to KCI and endothelin-1 increased in renal arteries with endothelium during rejection. These contractions in renal arteries were reduced following treatment of rejection. None of the responses of the coronary arteries were affected significantly by rejection of the lung allograft. These results demonstrate that contractions of arteries in the transplant recipient's native organs are altered during rejection of lung allografts. The effects are organ specific, may include production of endothelium-derived contractile factors in renal arteries, and can be partially reversed by treatment of rejection.

Effects of acute rejection and antirejection therapy on arteries and veins from canine single lung allografts.

Experiments were designed to compare the function of the endothelium and smooth muscle in intralobar pulmonary arteries and veins of transplanted lungs during acute rejection and after treatment of rejection. Single lung allografts were performed in dogs. Dogs were monitored for 5 days to allow good recovery from the operation and resolution of early chest radiographic changes. In group I, immunosuppression (cyclosporine A, azathioprine, and methylprednisone) was withdrawn to allow rejection, which typically occurred after 3 days. In group II, immunosuppression was reinstituted at this time during acute rejection until the chest roentgenograms again cleared (approximately after 6 days). The blood vessels were studied at this time. Rings were cut from intralobar pulmonary arteries and veins of the allotransplanted lungs and suspended for the measurement of isometric force in organ chambers. Contractions of arteries and veins to phenylephrine but not endothelin-1 were significantly reduced during acute rejection. In arteries and veins, endothelium-dependent relaxations to bradykinin but not the calcium ionophore A23187 were reduced with rejection. Relaxations of the smooth muscle to histamine increased with rejection in both blood vessels. Relaxations to nitric oxide were reduced with rejection in veins but not arteries. Treatment of rejection reversed all responses toward those observed in arteries and veins in lungs from dogs not undergoing transplantation. These results suggest that responses of the endothelium and smooth muscle of pulmonary arteries and veins of transplanted lungs are altered similarly during rejection. Further, treatment of rejection restores function of the pulmonary blood vessels of lung allografts toward that observed in unoperated lungs.

Increased levels of endothelin-1 in bronchoalveolar lavage fluid of patients with lung allografts.

The aim of the present study was to determine levels of endothelin-1 in bronchoalveolar lavage fluid and in plasma in patients with lung and heart-lung allografts. The aim was based on the hypothesis that levels of endothelin-1 are elevated in the bronchoalveolar lavage fluid of patients with lung allografts. Patients (n = 23) undergoing heart-lung (n = 8), single-lung (n = 10), or bilateral lung (n = 5) transplantation were included in the study. In patients with single-lung allografts, endothelin-1 levels were analyzed in bronchoalveolar lavage fluid from both the transplanted and the nontransplanted, native lung. The level of endothelin-1 was also analyzed in bronchoalveolar lavage fluid from 12 patients who did not undergo transplantation. Transbronchial biopsies and bronchoalveolar lavage were done routinely or when clinically indicated on 64 different occasions, between 2 and 104 weeks after transplantation. The level of endothelin-1 was measured in bronchoalveolar lavage fluid and plasma by radioimmunoassay. Immunoreactive endothelin-1 was detectable in bronchoalveolar lavage fluid from all patients. The concentration of endothelin-1 in bronchoalveolar lavage fluid from transplanted lungs (2.94 +/- 0.30 pg/ml, n = 64) was significantly higher compared with that in bronchoalveolar lavage fluid from patients without allografts (0.86 +/- 0.20 pg/ml, n = 12, p < 0.01). In patients who received single-lung transplantation because of emphysema, the level of endothelin-1 in bronchoalveolar lavage fluid from the transplanted lung was significantly greater than that from the native lung (5.61 +/- 1.9 versus 0.39 +/- 0.05 pg/ml, p < 0.05). Concentrations of endothelin-1 in bronchoalveolar lavage fluid did not correlate with grade of rejection, infection, or time after transplant. Plasma levels of endothelin-1 were unchanged with pulmonary rejection. These results indicate that endothelin-1 is released into bronchi of transplanted human lungs. The release is not associated with rejection or infection. Because of its potent mitogenic properties, endothelin-1 may have a potential impact in the development of posttransplant complications such as bronchiolitis obliterans.