Noninvasive Neuromonitoring of Hypothermic Circulatory Arrest in Aortic Surgery.

BACKGROUND AND AIMS: Circulatory arrest carries a high risk of neurological damage, but modern monitoring methods lack reliability, and is susceptible to the generalized effects of both anesthesia and hypothermia. The objective of this prospective, explorative study was to research promising, reliable, and noninvasive methods of neuromonitoring, capable of predicting neurological outcome after hypothermic circulatory arrest. MATERIALS AND METHODS: Thirty patients undergoing hypothermic circulatory arrest during surgery of the thoracic aorta were recruited in a single center and over the course of 4 years. Neuromonitoring was performed with a four-channel electroencephalogram montage and a near-infrared spectroscopy monitor. All data were tested off-line against primary neurological outcome, which was poor if the patient suffered a significant neurological complication (stroke, operative death). RESULTS: A poor primary neurological outcome seen in 10 (33%) patients. A majority (63%) of the cases were emergency surgery, and thus, no neurological baseline evaluation was possible. The frontal hemispheric asymmetry of electroencephalogram, as measured by the brain symmetry index, predicted primary neurological outcome with a sensitivity of 79 (interquartile range; 62%-88%) and specificity of 71 (interquartile range; 61%-84%) during the first 6 h after end of circulatory arrest. CONCLUSION: The hemispheric asymmetry of frontal electroencephalogram is inherently resistant to generalized dampening effects and is predictive of primary neurological outcome. The brain symmetry index provides an easy-to-use, noninvasive neuromonitoring method for surgery of the thoracic aorta and postoperative intensive care.

Long-Term Survival and Quality of Life After Hypothermic Circulatory Arrest in Aortic Surgery.

BACKGROUND AND AIMS:: Hypothermic circulatory arrest carries a high risk of mortality and neurological complications. An important part of assessing surgical treatment is the evaluation of long-term survival and postoperative health-related quality of life. MATERIAL AND METHODS:: In this prospective study, 30 patients undergoing hypothermic circulatory arrest during surgery of the thoracic aorta, and 31 comparison patients undergoing elective coronary artery surgery without hypothermic circulatory arrest were evaluated for long-term survival and health-related quality of life, using the RAND 36-Item Health Survey questionnaire. The results were compared to national age- and sex-matched reference populations of the chronically ill and healthy adults. RESULTS:: After 4.6-8.0 years, available study (88%) and comparison (59%) patients were interviewed. The life expectancy was similar with 4- and 8-year survival of 90%, and 87% for the study group, and 94%, and 94% for the comparison group, respectively (log rank test, p = 0.62). The RAND-36 scores for study and comparison groups were congruent in all dimensions, describing physical, mental, and social domains. The study patients' health-related quality of life results were similar to the national reference population with chronic illnesses. CONCLUSION:: After hypothermic circulatory arrest, patients undergoing surgery of the thoracic aorta achieve a similar long-term life expectancy and health-related quality of life as do patients undergoing coronary surgery without hypothermic circulatory arrest, and a health-related quality of life similar to the national reference population with chronic illnesses. These results justify operative treatment in this high-risk patient population.

Impact of early angiographic evaluation on the frequency of emergency reoperations after coronary bypass surgery.

BACKGROUND AND AIMS: early graft failure following coronary bypass surgery results in elevated morbidity and mortality. This study focused on the impact of angiographic graft evaluation. MATERIAL AND METHODS: of 5251 coronary artery bypass grafting (CABG) patients, 36 with postoperative persistent ischaemia underwent early angiography (23) or emergency resternotomy (13) 2000-2007 (Angiography era). Of the 23 patients, who underwent angiography, five were subsequently reoperated. Of 8807 CABG patients, 76 underwent postoperative emergency resternotomy 1988-1999 (Pre-angiography era) and served as controls. RESULTS: the angiography era patients were older (64.0 years vs. 58.2 years, P = 0.002) and the proportion of female patients (22% vs. 43%, P = 0.029) was smaller. The rate of emergency reoperations decreased (0.86% vs 0.34%, P < 0.001) during the Angiography era and graft repairs (P = 0.013) or additional grafts (P = 0.006) were less frequent, although occluded anastomoses were observed more often (P = 0.043). In 5 Angiography era patients graft complications were corrected with percutaneous coronary intervention. ICU stay (5.72 + 0.98 days vs. 5.53 + 0.68 days) and hospital stay (12.2 + 1.54 days vs. 13.1 + 1.63 days) did not differ between the groups, but the rate of myocardial infarction (63.8% vs. 92.1%, P < 0.001) and in-hospital death (22.2% vs. 46.1%, P = 0.015) decreased. CONCLUSION: after the introduction of early postoperative angiographic evaluation of CABG patients the rate of emergency reoperations and related morbidity and mortality decreased.

Tenascin is expressed in post-transplant obliterative bronchiolitis.

Tenascin is expressed in inflammatory and fibroproliferative processes, both contributing to posttransplant obliterative bronchiolitis (OB) in association with epithelial cell injury and airway obliteration. We studied bronchial allografts to elucidate the role of tenascin during this alloimmune response. Bronchial segments were subcutaneously implanted into eight pigs. Allografts and autograft controls were serially obtained until total obliteration in allografts and processed for histology and immunocytochemistry for CD4, CD8, and tenascin. Findings were graded on a scale from 0 to 3. In autografts the operative epithelial damage recovered and bronchi stayed patent with mild-graded fibrosis and inflammation. Partial recovery was observed in allografts on day 4, thereafter the epithelial loss gradually increased. Total recovery was achieved on day 11 (P < .001). Fibroblast proliferation resulted in total luminal obliteration on day 21 (P < .001). The number of inflammatory cells increased rapidly (P < .05) with numerous CD4+ and CD8+ cells on day 14 (P < .0001). Prior to total epithelial loss in allografts, tenascin expression was observed on day 7 in 69% of epithelial cells, whereas in only 5% of epithelial cells in recovered autografts. Paralleling the most intense fibroproliferation, tenascin-positive cells were observed in the bronchial wall on day 7 and day 11 (P < .001). Tenascin expression was demonstrated during the inflammatory response and fibroblast proliferation during the early stage of obliterative bronchiolitis showing that tenascin contributes to posttransplant obliterative bronchiolitis development.

Collagens I and III in a porcine bronchial model of obliterative bronchiolitis.

The main extracellular matrix components of the lung, type I and III collagens, were studied in chronic allograft rejection developing in a porcine heterotopic bronchial transplantation model. Specific porcine complementary DNA probes were constructed for detection of the expression of type I and III procollagen messenger RNAs in the bronchial wall structures and in the obliterative plug by in situ hybridization. In autografts, and in allografts immunosuppressed with 40-O-(2-hydroxyethyl)-rapamycin, cyclosporine A, and methylprednisolone, no histological changes of obliterative bronchiolitis (OB) developed, and the number of fibroblast-like cells expressing type I and III procollagen mRNA remained low. In nontreated allografts obliterating within 21 d, a preponderance of fibroblast-like cells showing positivity for type III procollagen mRNA existed in the obliterative plug and bronchial wall. This study shows for the first time the temporal and spatial activation of type I and III procollagen genes during the course of obliterative bronchiolitis. The number of cells expressing procollagen III mRNA increased parallel to developing obliteration and fibrosis in nontreated allografts, whereas autografts and immunosuppressed allografts exhibited no such trend. This finding suggests a positive association between type III collagen mRNA expression in fibroblast-like cells and development of obliterative bronchiolitis.

Immune cells and immunosuppression in a porcine bronchial model of obliterative bronchiolitis.

BACKGROUND: To study obliterative bronchiolitis (OB), we have developed a porcine heterotopic bronchial model. Allografts obliterate within 3 weeks, the immunosuppression cyclosporine (CsA)-azathioprine (AZA)-methylprednisolone (MP) delays OB, but OB is prevented when AZA is switched to 40-0-(2-hydroxyethyl)-rapamycin (RAD). To characterize our model, we studied immune cells under various immunosuppressive conditions. METHODS: The groups studied were autografts (U), allografts (A), and allografts given either CsA-RAD-MP (R), or CsA-AZA-MP (C). The implants were harvested at 3, 7, 10, 14, 21, 30, 60, and 90 days after transplantation. Epithelial damage and obliteration were graded histologically, and the number of CD4, CD8, MHC class II expressing cells, macrophages, and B lymphocytes were counted (mean+SEM)/high-power visual field. RESULTS: In group U, normal epithelium was regained with no obliteration and only few immune cells. In group A, consistent with initially acute ejection, an influx of CD4 (105+23), CD8 (166+23), and class II (92+20) cells was seen up to day 21, when total obliteration preceded by epithelial destruction had already developed. Some macrophages were seen and B cells were scarce. In group R, epithelial damage and obliteration were insignificant, but moderate numbers of CD4, CD8, and class II cells were seen. In group C, epithelial damage and obliteration were only delayed, but the immune cell response was clearly blunted. CONCLUSIONS: In our model, rejection with significant immune cell influx was still active when obliteration was total in nontreated allografts. In immunosuppressed allografts, decrease in the number of immune cells alone did prevent OB. These results support OB being T-cell mediated. RAD may have additional important effects on growth factors and proliferation in prevention of OB.

Biodegradation of the copolymeric polylactide stent. Long-term follow-up in a rabbit aorta model.

The behavior of biodegradable polylactide as a stent material has not yet been fully established in small vessels such as arteries with a diameter <3 mm. The aim of this study was to investigate the long-term effect of a copolymeric polylactide (PLA96) stent. Appropriately sized spiral PLA96 stents were implanted into the infrarenal aortas of 20 rabbits. Intraoperative systemic heparinization (150 IU/kg), perioperative subcutaneous enoxaheparin sodium (10 mg), ticlopidine (250 mg/day) for 1 month, and acetosalicylic acid (12.5 mg/day) were continuously administered. Animals were euthanized according to a fixed timetable for up to 34 months for histologic and scanning-electron-microscopic assessment. Endothelialization was complete within 1 month. In 2 of the 3 aortas sampled 3 months after implantation, a mild inflammatory reaction was visible, with no sign of granulomatous or foreign-body reaction in the vessel wall. Instead, in 1 sample examined at the same time point, neointimal chondroid metaplasia was detected. After 6 months, inflammatory reaction declined in the vessel wall. Hydrolyzation of the stent was histologically evident at 12 months, with mild foreign-body reaction detectable in 2 of 5 aortas sampled at this time point. The stent disintegrated without fragmentation by 24 months, as it was gradually replaced by fibrosis. The vessel lumen remained patent at all time points. We conclude that the PLA96 stent degraded with minimal tissue response within 24 months. PLA96 may thus be a promising stent core material for small vessels in the future, although further investigation is needed to establish its final biocompatibility.

Reperfusion injury associated with one-fourth of deaths after coronary artery bypass grafting.

BACKGROUND: This study of reperfusion injury after coronary artery bypass grafting focuses on its contribution to fatal outcome, on its connection with myocardial infarction (MI) and on risk factors. METHODS: A consecutive series of 190 patients (mean age 61.7+/-8.9 years) dying within 30 days following coronary artery bypass grafting was autopsied with concomitant postmortem angiography during 1980 to 1993. RESULTS: Reperfusion injury was revealed in 49 (25.8%) patients, with concomitant MI in almost all (46 of 49) (p < 0.01). Reperfusion injury occurred in association with preoperative New York Heart Association (NYHA) III classification (p < 0.05), coronary endarterectomy (p < 0.01), long aortic clamping time (p < 0.01), and short postoperative survival (p < 0.05). CONCLUSIONS: Reperfusion injury was observed in one fourth of the deaths in association with MI. It occurred more often in patients with preoperative NYHA III symptoms and in those in whom endarterectomy was carried out and the anoxic time of the myocardium was longer. The shorter postoperative survival time indicates the lethal nature of this complication.

Obliterative lesions in a heterotopic bronchial xenograft model--a preliminary study.

BACKGROUND: We further developed our heterotopic pig model of obliterative bronchiolitis to study airway obliteration in xenografts. METHODS: Four domestic piglets each received 40 bronchial xenografts s.c. from a donor lamb. Piglet X was not immunosuppressed. The other animals received daily oral cyclosporine, 15 mg/kg (XC), or SDZ RAD, 1.5 mg/kg (XR), or both (XCR). Five implants at a time were serially removed from each animal during 17 days for histological assessment. RESULTS: In contrast to the grafts of the others, the xenografts of XCR recovered after initial ischemic damage. No epithelial damage (P<0.01) or mural necrosis occurred on day 7. Airway obliteration developed in all, but was significantly delayed in XCR. CONCLUSIONS: Invariably developing airway obliteration in nontreated xenografts was delayed by immunosuppression, making the model useful, especially in testing the efficacy of immunosuppressive drugs in a xenogeneic system.

Obliterative airway disease in a porcine heterotopic bronchial allograft model.

Representative animal models are needed for the study of posttransplant obliterative bronchiolitis (OB). Because human OB originates in terminal bronchi, the validity of tracheal models can be questioned. Using our hetrotopic model, we implanted pieces of a lobar bronchus subcutaneously into domestic pigs. Five groups were included: autograft implants, allograft implants, allograft implants with 2 regimens of cyclosporine (CsA)azathioprine (AZA)-methylprednisolone (MP), and allograft implants with CsA-SDZ RAD-MP. Samples were harvested at 2 weeks and at 1, 2, and 3 months. The histological findings were graded from 0 to 3. Following initial ischemic epithelial damage, autograft implants recovered, but untreated allografts and those treated with CsA-AZA-MP were totally and permanently damaged within one month. In the group treated with CsA-SDZ RAD-MP, a maximal grade 1.5 +/- 0.5 epithelial injury was seen at one month. Epithelial damage preceded and correlated with luminal obliteration. The obliterative lesions histologically resembled human OB. Differences from our previous findings with terminal bronchioles were minor. This study supports the use of larger-size airways in the study of OB.

Prevention of small airway obliteration in a swine heterotopic lung allograft model.

BACKGROUND: In our swine model of obliterative bronchiolitis preventing obliteration by the standard immunosuppression with cyclosporine, methylprednisolone, and azathioprine was not successful. The purpose of this study was to test the ability of a new immunosuppressive regimen to prevent alloimmune reaction and obliteration of the allografts. This regimen includes the novel macrolide SDZ RAD, i.e., 40-O-(2hydroxyethyl)-rapamycin. METHODS: Donor lung allografts of 1 cm3 were implanted sub-cutaneously into 11 random-bred non-related domestic pigs receiving daily oral cyclosporine (10 mg/kg) and methylprednisolone (20 mg). In addition, the animals received either oral azathioprine (2 mg/kg) (Group 1) or oral SDZ RAD (1.5 mg/kg) (Group 2). Histologic alterations were graded from 0 to 3 based on repeatedly removed implants during a follow-up period of 3 months. RESULTS: Total epithelial destruction and permanent luminal obliteration occurred within 37 days in Group 1. After an initial grade of 2.3+/-0.3 destruction, epithelial recovery was evident in Group 2 (P < 0.01), and the bronchi stayed patent. Cartilaginous destruction was milder in Group 2 (P < 0.05) than in Group 1, but chondrocytic proliferation was more intense (P < 0.05). Alveolar tissue and native structures of the bronchial wall were destroyed in Group 1, but preserved in Group 2 with total recovery after a mild-grade initial necrosis. CONCLUSIONS: Unlike the standard triple therapy, SDZ RAD combined with cyclosporine and methylprednisolone preserves the pulmonary allografts and prevents epithelial destruction and subsequent luminal obliteration. This suggests that this regimen might efficiently suppress obliterative bronchiolitis and improve long-term results in lung transplant recipients.

Alloimmune injury preceding airway obliteration in porcine heterotopic lung implants: a histologic and immunohistologic study.

BACKGROUND: Obliterative bronchiolitis (OB), the major long-term complication of lung transplantation, has thus far lacked a good large-animal model. Our goal was to develop such a model on the basis of previous rodent models with tracheal implants. METHODS: Fragments of pulmonary tissue with structures of terminal bronchi were subcutaneously transplanted to four random-bred domestic piglets. Each animal received 10 autograft and 10 allograft implants. The histologic findings were graded from 0 to 3 for implants harvested repeatedly over 2 months. RESULTS: In autografts, partial destruction of the respiratory epithelium and gradual luminal obliteration as well as mild damage to the cartilage and the bronchial wall underwent rapid reversal after initial ischemic injury. In the allografts, epithelial destruction and gradual obliteration were total within 14 days, the difference being statistically significant (P<0.05) in both. The histologic features of the obliterative plug were similar to those of human OB. In the allografts, cartilaginous destruction and pericartilaginous inflammation increased gradually to severe levels, significantly worse than in the autografts (P<0.05). Necrosis and inflammation of the bronchial wall were also more severe in the allografts (P<0.05). CONCLUSIONS: At the end of follow-up, all autografts were vital, whereas the allografts were almost totally rejected and were without native structures. All bronchi in the allografts exhibited accelerated obliteration with histologic features characteristic of human OB, thus providing a model for research into OB and its prevention.

Ceftriaxone versus vancomycin prophylaxis in cardiovascular surgery.

The efficacy of antibiotic prophylaxis in cardiac surgery was compared between 97 patients receiving a single 2 g dosage of ceftriaxone and 103 receiving 500 mg of vancomycin i.v. every 6 h for 48 h. The overall infection rate was 13.4% in the ceftriaxone and 10.7% in the vancomycin group. Four (4%) wound infections, including one mediastinitis, occurred in the ceftriaxone group and five (5%) in the vancomycin group, with no statistically significant difference. The findings of this study support the adequacy of a simple single dose of ceftriaxone prophylaxis in cardiac surgery, at least in hospitals with low incidence of vancomycin-resistant staphylococcal infections.

Post-mortem cast angiography in the diagnostics of graft complications in patients with fatal outcome following coronary artery bypass grafting (CABG).

The advantages and limitations of a novel post-mortem angiographic method using solidifying silicone rubber and lead oxide as a contrast medium in detecting coronary artery graft complications on a routine basis were evaluated in a series of 223 consecutive patients with fatal outcome within 30 days following coronary artery bypass grafting (CABG). Of these patients, 166 (74.4%) were male and 57 (25.6%) female (mean age 61.9 +/- 9). Coronary grafts totalled 660 (3.0 per patient) with 517 aortic and 838 coronary anastomoses. At autopsy, the rubber cast model of the grafts and coronary arterial tree was exposed by a bend scalpel and sites of possible complications were examined. Post-mortem angiographs were re-evaluated and compared with preoperative angiographs and dissection findings. By combining the findings of angiography and heart dissection, 122 (54.7%) of the 223 patients were found to have some type of complication of the graft or the anastomosis. The diagnostic sensitivity and specificity of post-mortem angiography was 100% in assessing narrowing or twisting of the graft as well as narrowing of the aortal anastomosis, whereas these findings were revealed with difficulty by autopsy dissection only. In cases with correct x-ray projection, narrowing and occlusion of the proximal aortal and distal coronary anastomosis were also reliably revealed by angiography. In contrast, graft thrombosis was clearly overdiagnosed by angiography, leading to a lower specificity (84%) but high sensitivity (100%) in detecting this complication. Post-mortem angiography also failed to detect dissection of the wall of the graft or anastomosis. Technical problems with this angiographic method were due to too low perfusion pressure, too rapid polymerizing of the silicone rubber, leakage of contrast medium into the ventricles, or faulty x-ray projections. These results suggest that our post-mortem angiographic technique, yielding a permanent rubber-cast model of the graft and anastomosis site, improves the accuracy of diagnostics of postoperative CABG complications and eases postoperative autopsy dissection, which can now be directed to confirm suspected complications.

Small airway obliteration in a new swine heterotopic lung and bronchial allograft model.

BACKGROUND: We studied a heterotopic large-animal model with obliterative airway lesions caused by allograft rejection. METHODS: Lung fragments (1 cm3) with airways (LB), and 1 to 2 mm diameter bronchi alone (B) were implanted subcutaneously in 11 domestic piglets weighing 20 kg. Six animals each received 40 implants from nonrelated donors without immunosuppression (group A). Another 5 animals had autograft implants (group U). The implants were harvested consecutively for histologic analysis over 3 months in group A and 6 months in group U. RESULTS: In group U, the initial ischemia caused mild to moderate epithelial damage with moderate metaplasia but with a return to normal ciliary epithelium within 1 month. Transient mild luminal obliteration with granulation tissue and mononuclear cells was observed during the first weeks, but after 4 weeks the lumen was patent and filled with mucus. In the bronchial wall, moderate fibrosis developed in LB implants, whereas mild fibrosis was seen in B implants. In group A, the epithelium was totally absent by 2 weeks, and mild inflammation, fibrosis, and destruction of the cartilage with pericartilaginous mononuclear accumulation were observed in the bronchial wall. Small airways were gradually obliterated between days 7 and 21, initially by granulation tissue and mononuclear cells and later by progressive fibrosis. CONCLUSIONS: In this model, autografted airway implants stayed patent for at least 6 months, whereas total luminal obliteration histologically resembling obliterative bronchiolitis developed in allografts within 21 days. Because small airways, including bronchioli, can be transplanted with the use of this model, it may be useful for research into the causes of airway obliteration, which may be relevant to the pathogenesis of obliterative bronchiolitis in lung recipients.

Obliterative lesions in small airways in an immunosuppressed porcine heterotopic bronchial allograft model.

We have recently developed a heterotopic large-animal model for research into obliterative lesions in small airways caused by allograft rejection. In this model, the small airways of subcutaneously implanted allografts gradually obliterate, whereas autografts remain patient. Twenty lung fragments and 20 segments of bronchi were implanted in domestic pigs weighing 20 kg from non-related donors. The histology of five animals receiving daily cyclosporine A (CsA) (10 mg/kg), azathioprine (2 mg/kg) and methylprednisolone (20 mg), Group C, was compared with that of six animals without immunosuppression, Group A. Four animals received monotherapy with CsA (10 mg/kg) or methylprednisolone (3 mg/kg). The histological findings were graded from 0 to 3 on the basis of implants harvested repeatedly over 3 months. Epithelial destruction and bronchial obliteration was rapid and permanent in all the allografts. Inflammation and fibrosis of the bronchial wall was less prominent in Group C than in Group A and the onset of fibrosis was delayed. Cartilage degeneration and pericartilagineous inflammation were significantly less severe in Group C (P < 0.05). Monotherapy was less potent than triple therapy. This large-animal model is useful for studying the effects of immunosuppressive drugs on obliterative airway disease.