Effect of 4% Albumin Solution vs Ringer Acetate on Major Adverse Events in Patients Undergoing Cardiac Surgery With Cardiopulmonary Bypass: A Randomized Clinical Trial.

Importance: In cardiac surgery, albumin solution may maintain hemodynamics better than crystalloids and reduce the decrease in platelet count and excessive fluid balance, but randomized trials are needed to compare the effectiveness of these approaches in reducing surgical complications. Objective: To assess whether 4% albumin solution compared with Ringer acetate as cardiopulmonary bypass prime and perioperative intravenous volume replacement solution reduces the incidence of major perioperative and postoperative complications in patients undergoing cardiac surgery. Design, Setting, and Participants: A randomized, double-blind, single-center clinical trial in a tertiary university hospital during 2017-2020 with 90-day follow-up postoperatively involving patients undergoing on-pump coronary artery bypass grafting; aortic, mitral, or tricuspid valve surgery; ascending aorta surgery without hypothermic circulatory arrest; and/or the maze procedure were randomly assigned to 2 study groups (last follow-up was April 13, 2020). Interventions: The patients received in a 1:1 ratio either 4% albumin solution (n = 693) or Ringer acetate solution (n = 693) as cardiopulmonary bypass priming and intravenous volume replacement intraoperatively and up to 24 hours postoperatively. Main Outcomes and Measures: The primary outcome was the number of patients with at least 1 major adverse event: death, myocardial injury, acute heart failure, resternotomy, stroke, arrhythmia, bleeding, infection, or acute kidney injury. Results: Among 1407 patients randomized, 1386 (99%; mean age, 65.4 [SD, 9.9] years; 1091 men [79%]; 295 women [21%]) completed the trial. Patients received a median of 2150 mL (IQR, 1598-2700 mL) of study fluid in the albumin group and 3298 mL (IQR, 2669-3500 mL) in the Ringer group. The number of patients with at least 1 major adverse event was 257 of 693 patients (37.1%) in the albumin group and 234 of 693 patients (33.8%) in the Ringer group (relative risk albumin/Ringer, 1.10; 95% CI, 0.95-1.27; P = .20), an absolute difference of 3.3 percentage points (95% CI, -1.7 to 8.4). The most common serious adverse events were pulmonary embolus (11 [1.6%] in the albumin group vs 8 [1.2%] in the Ringer group), postpericardiotomy syndrome (9 [1.3%] in both groups), and pleural effusion with intensive care unit or hospital readmission (7 [1.0%] in the albumin group vs 9 [1.3%] in the Ringer group). Conclusions and Relevance: Among patients undergoing cardiac surgery with cardiopulmonary bypass, treatment with 4% albumin solution for priming and perioperative intravenous volume replacement solution compared with Ringer acetate did not significantly reduce the risk of major adverse events over the following 90 days. These findings do not support the use of 4% albumin solution in this setting. Trial Registration: ClinicalTrials.gov Identifier: NCT02560519.

Endothelial glycocalyx during early reperfusion in patients undergoing cardiac surgery.

BACKGROUND: Experimental cardiac ischemia-reperfusion injury causes degradation of the glycocalyx and coronary washout of its components syndecan-1 and heparan sulfate. Systemic elevation of syndecan-1 and heparan sulfate is well described in cardiac surgery. Still, the events during immediate reperfusion after aortic declamping are unknown both in the systemic and in the coronary circulation. METHODS: In thirty patients undergoing aortic valve replacement, arterial concentrations of syndecan-1 and heparan sulfate were measured immediately before and at one, five and ten minutes after aortic declamping (reperfusion). Parallel blood samples were drawn from the coronary sinus to calculate trans-coronary gradients (coronary sinus-artery). RESULTS: Compared with immediately before aortic declamping, arterial syndecan-1 increased by 18% [253.8 (151.6-372.0) ng/ml vs. 299.1 (172.0-713.7) ng/ml, p < 0.001] but arterial heparan sulfate decreased by 14% [148.1 (135.7-161.7) ng/ml vs. 128.0 (119.0-138.2) ng/ml, p < 0.001] at one minute after aortic declamping. There was no coronary washout of syndecan-1 or heparan sulfate during reperfusion. On the contrary, trans-coronary sequestration of syndecan-1 occurred at five [-12.96 ng/ml (-36.38-5.15), p = 0.007] and at ten minutes [-12.37 ng/ml (-31.80-6.62), p = 0.049] after reperfusion. CONCLUSIONS: Aortic declamping resulted in extracardiac syndecan-1 release and extracardiac heparan sulfate sequestration. Syndecan-1 was sequestered in the coronary circulation during early reperfusion. Glycocalyx has been shown to degrade during cardiac surgery. Besides degradation, glycocalyx has propensity for regeneration. The present results of syndecan-1 and heparan sulfate sequestration may reflect endogenous restoration of the damaged glycocalyx in open heart surgery.

Dramatic increase in serum trypsinogens, SPINK1 and hCGß in aortic surgery patients after hypothermic circulatory arrest.

The concentrations of several diagnostic markers have been found to increase dramatically in critically ill patients with a severe disturbance of normal physiological homeostasis, without indication of the diseases they are normally associated with. To prevent false diagnoses and inappropriate treatments of critically ill patients, it is important that the markers aiding the selection of second-line treatments are evaluated in such patients and not only in the healthy population and patients with diseases the markers are associated with. The levels of trypsinogen isoenzymes, the trypsin inhibitor serine peptidase inhibitor Kazal type 1 (SPINK1), hCG and hCGß, which are used as pancreatitis and cancer markers, were analyzed by immunoassays from serum samples of 17 adult patients who have undergone surgery of the ascending aorta during hypothermic circulatory arrest (HCA) with optional selective cerebral perfusion. Highly elevated levels of trypsinogen-1, -2 and -3, SPINK1 and hCGß were observed in patients after HCA. This was accompanied by increased concentrations of S100ß and NSE. In conclusion, this study highlights the importance of critically evaluating the markers used for aiding selection of second line of treatments in critically ill patients.

Effect and safety of 4% albumin in the treatment of cardiac surgery patients: study protocol for the randomized, double-blind, clinical ALBICS (ALBumin In Cardiac Surgery) trial.

BACKGROUND: In cardiac surgery with cardiopulmonary bypass (CPB), large amounts of fluids are administered. CPB priming with crystalloid solution causes marked hemodilution and fluid extravasation. Colloid solutions may reduce fluid overload because they have a better volume expansion effect than crystalloids. The European Medicines Agency does not recommend the use of hydroxyethyl starch solutions (HES) due to harmful renal effects. Albumin solution does not impair blood coagulation but the findings on kidney function are conflicting. On the other hand, albumin may reduce endothelial glycocalyx destruction and decrease platelet count during CPB. No large randomized, double-blind, clinical trials have compared albumin solution to crystalloid solution in cardiac surgery. METHODS/DESIGN: In this single-center, double-blind, randomized controlled trial comprising 1386 adult cardiac surgery patients, 4% albumin solution will be compared to Ringer's acetate solution in CPB priming and volume replacement up to 3200 mL during surgery and the first 24 h of intensive care unit stay. The primary efficacy outcome is the number of patients with at least one major adverse event (MAE) during 90 postoperative days (all-cause death, acute myocardial injury, acute heart failure or low output syndrome, resternotomy, stroke, major arrhythmia, major bleeding, infection compromising post-procedural rehabilitation, acute kidney injury). Secondary outcomes are total number of MAEs, incidence of major adverse cardiac events (MACE; cardiac death, acute myocardial injury, acute heart failure, arrhythmia), amount of each type of blood product transfused (red blood cells, fresh frozen plasma, platelets), total fluid balance at the end of the intervention period, total measured blood loss, development of acute kidney injury, days alive without mechanical ventilation in 90 days, days alive outside intensive care unit at 90 days, days alive at home at 90 days, and 90-day mortality. DISCUSSION: The findings of this study will provide new evidence regarding efficacy and safety of albumin solution in adult patients undergoing cardiac surgery with CPB. TRIAL REGISTRATION: EudraCT (clinicaltrialsregister.eu) 2015-002556-27 Registered 11 Nov 2016 and ClinicalTrials.gov NCT02560519. Registered 25 Sept 2015.

The origin of plasma neutrophil gelatinase-associated lipocalin in cardiac surgery.

BACKGROUND: Acute kidney injury (AKI) is common after heart surgery. Neutrophil gelatinase-associated lipocalin (NGAL) is produced in injured kidney. NGAL has been used as an early plasma biomarker for AKI in patients undergoing heart surgery. Neutrophils contain all isoforms (25-kDa, 45-kDa and 145-kDa) but the kidney produces almost exclusively the 25-kDa isoform of NGAL. We investigated first, whether there is association between NGAL and neutrophil activation, and second whether activated neutrophils are a significant source of circulating NGAL in plasma in patients undergoing cardiac surgery. METHODS: Two separate patient cohorts were studied: 1) the "kinetic cohort" (n = 29) and 2) the "FINNAKI cohort" (n = 306). As NGAL is strictly co-localized with lactoferrin in neutrophils, NGAL and lactoferrin were measured with enzyme-linked immunosorbent assay in all patients. In sixty-one patients of the "FINNAKI cohort" Western blot was used to separate NGAL isoforms according to their molecular size. Mann-Whitney U, Kruskal-Wallis H, Pearson's and Spearman's tests were used as appropriate. RESULTS: There was strong intraoperative association between NGAL and lactoferrin at all four time-points in the "kinetic cohort". In the "FINNAKI cohort", NGAL and lactoferrin concentrations correlated preoperatively (R = 0.59, p < 0.001) and at admission to the intensive care unit (R = 0.69, p < 0.001). At admission to intensive care unit, concentrations of NGAL and lactoferrin were higher in AKI than in non-AKI patients (NGAL: p < 0.001; lactoferrin: p < 0.029). In Western blot analyses, neutrophil specific 45-kDa isoform (median 41% [IQR 33.3-53.1]) and mostly neutrophil derived 145-kDa isoform (median 53.5% [IQR 44.0-64.9%]) together represented over 90% of total NGAL in plasma. Potentially kidney derived NGAL isoform (25-kDa) accounted for only 0.9% (IQR 0.3 - 3.0%) of total NGAL in plasma. There were no statistically significant differences in the distribution of NGAL isomers between AKI and non-AKI patients. CONCLUSIONS: Plasma NGAL during cardiac surgery is associated with neutrophil activation. Based on molecular size, the majority of circulating NGAL is derived from neutrophils. Neutrophil activation is a confounding factor when interpreting increased plasma NGAL in cardiac surgery.

Impact of pre-operative antimicrobial treatment on microbiological findings from endocardial specimens in infective endocarditis.

Treatment of infective endocarditis (IE) should be initiated promptly. This might hamper the chances to identify the causative organism in blood cultures. Microbiological sampling of infected valve in patients undergoing surgery might identify the causative organism. The impact of pre-operative antimicrobial treatment on the yield of valve samples is not known. This study evaluated the impact of the duration of the pre-operative antibiotic treatment on valve culture and 16S rRNA PCR findings from resected endocardial samples. Patients meeting the modified Duke criteria of definite or possible IE and undergoing valve surgery due to IE during 2011-2016 were included from Southern Finland. Eighty-seven patients were included. In patients with shorter than 2 weeks of pre-operative antimicrobial treatment, PCR was positive in 91% (n = 42/46) and valve culture in 41% (n = 19/46) of cases. However, in patients who had 2 weeks or longer therapy before operation, PCR was positive in 53% (n = 18/34) and all valve cultures were negative. In 14% of patients, PCR had a diagnostic impact. In blood-culture negative cases (n = 13), PCR could detect the causative organism in ten patients (77%). These included five cases of Bartonella quintana, one Tropheryma whipplei, and one Coxiella burnetii. Long pre-operative antimicrobial treatment was shown to have a negative impact on microbiological tests done on resected endocardial material. After 2 weeks of therapy, all valve cultures were negative, but PCR was positive in half of the cases. PCR aided in diagnostic work-up, especially in blood culture negative cases.

Heparin Binding Protein in Adult Heart Surgery.

BACKGROUND: Heparin binding protein (HBP) is released from neutrophilic secretory vesicles upon neutrophil adhesion on the endothelium. HBP mediates capillary hyperpermeability experimentally. In sepsis, HBP predicts organ dysfunction. Cardiopulmonary bypass induces neutrophil activation and hyperpermeability. We hypothesized that in cardiopulmonary bypass, HBP is released in the reperfused coronary circulation concomitantly with neutrophil adhesion. METHODS: In 30 patients undergoing aortic valve replacement, concomitant blood samples were drawn from the coronary sinus and arterial line before aortic cross-clamping and 5 minutes after reperfusion to calculate transcoronary differences. Plasma HBP concentrations, neutrophil markers lactoferrin and myeloperoxidase, myocardial injury marker heart-type fatty acid binding protein, and leukocyte differential counts were measured. RESULTS: Arterial HBP was 4.1 ng/mL (interquartile range [IQR], 3.6 to 5.3 ng/mL) preoperatively and 150.0 ng/mL (IQR, 108.2 to 188.6 ng/mL) after aortic declamping. HBP increased 39-fold, lactoferrin 16-fold, and myeloperoxidase fourfold during cardiopulmonary bypass. Before cardiopulmonary bypass, there were marginal transcoronary differences in HBP (1.4 ng/mL; IQR, -0.4 to 3.6 ng/mL; p = 0.001) and heart-type fatty acid binding protein (0.4 ng/mL; IQR, -0.04 to 3.5 ng/mL; p = 0.001) but not in the other indicators. During reperfusion, transcoronary HBP release (6.4 ng/mL; IQR, 1.8 to 13.7; ng/mL; p < 0.001) was observed concomitantly with transcoronary neutrophil sequestration (-0.14 × 109/L; IQR, -0.28 to 0.01 × 109/L; p = 0.001) and transcoronary heart-type fatty acid binding protein release (6.9 ng/mL; IQR, 3.0 to 25.8 ng/mL; p < 0.001). There were no transcoronary differences in lactoferrin or myeloperoxidase during reperfusion. CONCLUSIONS: Cardiopulmonary bypass results in substantial increase in circulating HBP. HBP is also released from the reperfused coronary circulation concomitantly with coronary neutrophil adhesion and myocardial injury. HBP may be one candidate for a humoral factor mediating capillary leak in cardiopulmonary bypass.

Novel Zero-Heat-Flux Deep Body Temperature Measurement in Lower Extremity Vascular and Cardiac Surgery.

OBJECTIVE: The aim of this study was to compare deep body temperature obtained using a novel noninvasive continuous zero-heat-flux temperature measurement system with core temperatures obtained using conventional methods. DESIGN: A prospective, observational study. SETTING: Operating room of a university hospital. PARTICIPANTS: The study comprised 15 patients undergoing vascular surgery of the lower extremities and 15 patients undergoing cardiac surgery with cardiopulmonary bypass. INTERVENTIONS: Zero-heat-flux thermometry on the forehead and standard core temperature measurements. MEASUREMENTS AND MAIN RESULTS: Body temperature was measured using a new thermometry system (SpotOn; 3M, St. Paul, MN) on the forehead and with conventional methods in the esophagus during vascular surgery (n = 15), and in the nasopharynx and pulmonary artery during cardiac surgery (n = 15). The agreement between SpotOn and the conventional methods was assessed using the Bland-Altman random-effects approach for repeated measures. The mean difference between SpotOn and the esophageal temperature during vascular surgery was+0.08°C (95% limit of agreement -0.25 to+0.40°C). During cardiac surgery, during off CPB, the mean difference between SpotOn and the pulmonary arterial temperature was -0.05°C (95% limits of agreement -0.56 to+0.47°C). Throughout cardiac surgery (on and off CPB), the mean difference between SpotOn and the nasopharyngeal temperature was -0.12°C (95% limits of agreement -0.94 to+0.71°C). Poor agreement between the SpotOn and nasopharyngeal temperatures was detected in hypothermia below approximately 32°C. CONCLUSIONS: According to this preliminary study, the deep body temperature measured using the zero-heat-flux system was in good agreement with standard core temperatures during lower extremity vascular and cardiac surgery. However, agreement was questionable during hypothermia below 32°C.

Frontal electroencephalogram variables are associated with the outcome and stage of hepatic encephalopathy in acute liver failure.

Acute liver failure (ALF) and hepatic encephalopathy (HE) can lead to an elevated intracranial pressure (ICP) and death within days. The impaired liver function increases the risks of invasive ICP monitoring, whereas noninvasive methods remain inadequate. The purpose of our study was to explore reliable noninvasive methods of neuromonitoring for patients with ALF in the intensive care unit (ICU) setting; more specifically, we wanted to track changes in HE and predict the outcomes of ALF patients treated with albumin dialysis. The study included 20 patients with severe ALF at admission who had been referred to the ICU of the liver transplantation (LT) center for albumin dialysis treatment and evaluation for transplantation. Data were collected from all study patients in the form of continuous frontal electroencephalography (EEG) recordings and transcranial Doppler (TCD) measurements of cerebral blood flow. Among the studied EEG variables, the 50% spectral edge frequency decreased and the delta power increased as the HE stage increased. Both variables were predictive of the stage of HE [prediction probability (PK) of 50% spectral edge frequency = 0.23, standard error (SE) = 0.03; PK of delta power = 0.76, SE = 0.03]. The total wavelet subband entropy, a novel variable that we used for tracking abnormal EEG activity, predicted the outcome of ALF patients treated with albumin dialysis (PK = 0.88, SE = 0.09). With a threshold value of 1.6, the TCD pulsatility index had an odds ratio of 1.1 (95% confidence interval = 0.1-9.3) for a poor outcome (LT or death). In conclusion, EEG variables are useful for the monitoring of HE and can be used to predict outcomes of ALF. TCD measurements do not predict patient outcomes.

Ingraft chimerism in lung transplantation--a study in a porcine model of obliterative bronchiolitis.

BACKGROUND: Bronchial epithelium is a target of the alloimmune response in lung transplantation, and intact epithelium may protect allografts from rejection and obliterative bronchiolitis (OB). Herein we study the influence of chimerism on bronchial epithelium and OB development in pigs. METHODS: A total of 54 immunosuppressed and unimmunosuppressed bronchial allografts were serially obtained 2-90 days after transplantation. Histology (H&E) was assessed and the fluorescence in situ hybridization (FISH) method for Y chromosomes using pig-specific DNA-label was used to detect recipient derived cells in graft epithelium and bronchial wall, and donor cell migration to recipient organs. Ingraft chimerism was studied by using male recipients with female donors, whereas donor cell migration to recipient organs was studied using female recipients with male donors. RESULTS: Early appearance of recipient-derived cells in the airway epithelium appeared predictive of epithelial destruction (R=0.610-0.671 and p<0.05) and of obliteration of the bronchial lumen (R=0.698 and p<0.01). All allografts with preserved epithelium showed epithelial chimerism throughout the follow-up. Antirejection medication did not prevent, but delayed the appearance of Y chromosome positive cells in the epithelium (p<0.05), or bronchial wall (p<0.05). CONCLUSIONS: In this study we demonstrate that early appearance of Y chromosomes in the airway epithelium predicts features characteristic of OB. Chimerism occurred in all allografts, including those without features of OB. Therefore we suggest that ingraft chimerism may be a mechanism involved in the repair of alloimmune-mediated tissue injury after transplantation.

Medico-legal autopsy in postoperative hemodynamic collapse following coronary artery bypass surgery.

Sudden unexpected postoperative hemodynamic collapse with a high mortality develops in 1-3% of patients undergoing coronary artery bypass surgery (CABG). The contribution of surgical graft complications to this serious condition is poorly known and their demonstration at autopsy is a challenging task. Isolated CABG was performed in 8,807 patients during 1988-1999. Of the patients, 76 (0.9%) developed sudden postoperative hemodynamic collapse resulting in subsequent emergency reopening of the median sternotomy and open cardiac massage. Further emergency reoperation could be performed in 62 (82%) whereas 14 patients died prior to reoperation and a further 21 did not survive the reoperation or died a few days later. All 35 (46%) patients who did not survive were subjected to medico-legal autopsy combined with postmortem cast angiography. By combining clinical data with autopsy and angiography data, various types of graft complications were observed in 27 (36%, 1.3 per patient) of the 76 patients with hemodynamic collapse. There were no significant differences in the frequency (33 vs. 40%) or number of complicated grafts per patient (1.2 vs. 1.4) between those who survived reoperation and who did not. Autopsy detected 25 major and minor findings not diagnosed clinically. Postmortem cast angiography visualized 2 graft twists not possible to detect by autopsy dissection only. Surgical graft complications were the most frequent single cause for sudden postoperative hemodynamic collapse in CABG patients leading to a fatal outcome in almost half of the cases. Postmortem angiography improved the accuracy of autopsy diagnostics of graft complications.

Long-term survival and quality of life after cardiac resuscitation following coronary artery bypass grafting.

OBJECTIVE: Follow-up studies of patients surviving emergency resternotomy, open cardiac massage, and additional emergency cardiac surgery following coronary artery bypass grafting (CABG) remain sparse and studies focusing on health-related quality of life are lacking. Our aim was to elucidate the long-term course of patients experiencing this hazardous complication. METHODS: Between 1988 and 1999, 76 patients suffered sudden hemodynamic collapse following isolated CABG. All patients underwent emergency resternotomy and open cardiac massage. An emergency cardiac reoperation was performed in the 62 (82%) primary survivors. Additional 76 patients were pair-matched to the study patients on the basis of their preoperative characteristics and served as controls. Of the study patients, 41 (54%), and of the controls, 76, (100%) were discharged. In December 2009, all patients were traced with respect to mortality data and the health-related quality of life of living patients was studied using the RAND-36 Item Health Survey questionnaire. RESULTS: Altogether 19 (73%) of the 26 study patients, and 38 (84%) of the 45 controls were available. After exclusion of the early deaths, the life expectancy was similar between the groups: neither overall (p = 0.60) nor cardiac (p = 0.64) survival differed significantly after a mean follow-up time of 15.1 ± 3.5 years. In addition, cardiac re-interventions were equally frequently required in both the groups. The RAND-36 scores were congruent (p = ns) between the groups and the age- and sex-matched national reference population in the health-related quality-of-life dimensions describing physical, mental, and social domains. CONCLUSIONS: Patients who have survived severe hemodynamic collapse, open cardiac massage, and emergency cardiac reoperation following CABG achieve similar long-term prognosis in terms of survival and cardiac interventions as the pair-matched control patients. In addition, 15 years postoperatively, they have a good health-related quality of life, similar to that of an age- and sex-matched national reference population.

Local C-reactive protein expression in obliterative lesions and the bronchial wall in posttransplant obliterative bronchiolitis.

The local immunoreactivity of C-reactive protein (CRP) was studied in a heterotopic porcine model of posttranplant obliterative bronchiolitis (OB). Bronchial allografts and control autografts were examined serially 2-28 days after subcutaneous transplantation. The autografts stayed patent. In the allografts, proliferation of inflammatory cells (P < .0001) and fibroblasts (P = .02) resulted in occlusion of the bronchial lumens (P < .01). Influx of CD4+ (P < .001) and CD8+ (P < .0001) cells demonstrated allograft immune response. CRP positivity simultaneously increased in the bronchial walls (P < .01), in macrophages, myofibroblasts, and endothelial cells. Local CRP was predictive of features characteristic of OB (R = 0.456-0.879, P < .05-P < .0001). Early obliterative lesions also showed CRP positivity, but not mature, collagen-rich obliterative plugs (P < .05). During OB development, CRP is localized in inflammatory cells, myofibroblasts and endothelial cells probably as a part of the local inflammatory response.

Outcome of aortic valve replacement with bioprostheses in the elderly.

BACKGROUND AND AIM OF THE STUDY: Today, the elderly population continues to increase worldwide, and rates of aortic stenosis (AS) climb with age. Since aortic valve replacement (AVR) is the current treatment for elderly patients with symptomatic AS, the number of patients undergoing AVR is expected to grow. METHODS: Among patients operated on at Helsinki University Hospital between 1992 and 1997, a cohort (n = 145) was followed after AVR with a bioprosthesis. The patients were allocated to three groups, based on their age at the time of surgery: > or = 80 years (n = 30), < 80 to > or = 70 years (n = 94), and < or = 70 years (n = 21). All data relating to preoperative risk factors were collected. A control examination, which included echocardiography, was performed at least five years after surgery, and the follow up was continued until July 2006. The number of deaths and causes of death, as well as valve-related complications, were noted. RESULTS: The 30-day mortality rates were 3.3% in the oldest (> or = 80-year) group, 6.4% in the middle (< 80 to > or = 70-year) group, and zero in the youngest (< or = 70-year) group. The mean age at death was 88 and 81 years in the oldest and middle groups, respectively. In the oldest and youngest groups, there were no reoperations, but five valve-related reoperations were performed during follow up in the middle group. At the control visit, the left ventricular ejection fraction was > 60% in all groups. In the oldest and middle groups the aortic valve gradient was lower than the preoperative level, while the left ventricular diameters and wall dimensions were smaller (p < 0.05). Valve calcification was observed in one patient in the youngest group. CONCLUSION: Elderly patients who had undergone AVR with a bioprosthesis had a good outcome after more than 10 years of follow up, with an improved cardiac function being preserved for at least seven years after surgery. Despite a severely impaired preoperative aortic valve function, octogenarians especially had a good life expectancy, possibly due to their low comorbidity rates. Hence, AVR with a bioprosthesis proved to be an excellent treatment in this patient group.

Epithelial tenascin predicts obliterative airway disease.

BACKGROUND: Epithelial cell injury, inflammation, fibrosis and airway obliteration result in remodeling of terminal bronchi in post-transplant obliterative bronchiolitis. Tenascin as an extracellular matrix glycoprotein is expressed in several remodeling processes. METHODS: Heterotopic bronchial allografts of pigs were studied to assess tenascin expression during development of post-transplant obliterative bronchiolitis. A total of 157 allografts or autograft controls were serially obtained 2 to 28 days after transplantation and processed for histology and immunocytochemistry for tenascin, CD4, CD8 and macrophages. Epithelial tenascin index was calculated by multiplying the percentage of positive cells by the grade of tenascin intensity (1 to 3). RESULTS: Epithelial tenascin expression occurred during the initial ischemic damage to the respiratory epithelium. After partial recovery and before total epithelial loss and subsequent airway obliteration, tenascin expression peaked in allografts (p < 0.001). Epithelial tenascin index on Day 7 was predictive of subsequent epithelial damage, bronchial wall inflammation and the number of (CD4(+) and CD8(+)) cells, fibroproliferation, and obliteration of the bronchial lumen (R > or = 0.47, p < or = 0.01). Tenascin expression in the bronchial wall was more intense in allografts (p < 0.001), paralleling proliferation of fibroblasts and influx of inflammatory cells, and was predictive of inflammatory alterations also in the early obliterative lesions (R > or = 0.45, p < 0.05). Expression decreased during maturation of fibrosis (p < 0.05). CONCLUSIONS: Epithelial tenascin was predictive of features observed in post-transplant obliterative bronchiolitis, demonstrating a role for tenascin in the development of obliterative bronchiolitis. Tenascin may have relevant properties in serving as a clinical marker for early obliterative bronchiolitis.

Platelet-derived growth factor, transforming growth factor-beta, and connective tissue growth factor in a porcine bronchial model of obliterative bronchiolitis.

The expression of platelet-derived growth factor (PDGF), transforming growth factor (TGF)-beta, and connective tissue growth factor (CTGF) and the effect of imatinib, an agent inhibiting PDGF receptors, were assessed in a porcine bronchial transplantation model of obliterative bronchiolitis (OB). Up-regulation of PDGF-A, PDGF receptors alpha and beta, and TGF-beta expression occurred in allografts, whereas PDGF-B and CTGF expression was similar in allo- and autografts. Imatinib modified the inflammatory responses and expression patterns of PDGF-A and PDGF receptors. This study further confirms PDGF and TGF-beta as mediators of OB and supports the concept of the importance of the pathways signaled through PDGF receptors in post-transplant OB.

Risk evaluation of cardiac surgery in octogenarians.

OBJECTIVE: To assess the predictive value of risk factors in the European System for Cardiac Operative Risk Evaluation (EuroSCORE) for cardiac surgery on octogenarians. DESIGN: An observational study of octogenarians undergoing cardiac surgery and average-aged controls matched according to the cardiac surgical procedure. SETTING: A university hospital. PARTICIPANTS: One hundred sixty-two consecutive patients 80 years or older who underwent cardiac surgery between January 1, 2001, and June 30, 2003, and 162 average-aged controls. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Risk factors according to the EuroSCORE (The European System for Cardiac Risk Evaluation) model and EuroScore algorithm without an age component (EuroSCOREex) were evaluated. The EuroSCORE model and EuroSCOREex predicted mortality (odds ratio 1.4) and morbidity (odds ratio 1.2 and 1.3, respectively) equally well in both age groups. Adding age group information into the EuroSCOREex model in combined data, the odds ratio estimate was 3.5 for age group. The 30-day mortality of octogenarians was 8.6% versus 1.9% in controls (p < 0.01). Incidences of organ-related complications were comparable. Octogenarians spent more days in the hospital's intensive care unit and surgical ward than did controls (3.4 +/- 3.3 days v 2.7 +/- 3.1 days, p < 0.01; 9.9 +/- 5.8 days v 8.6 +/- 3.8 days, p = 0.02). Only 31 (19.1%) octogenarians were discharged home, whereas the corresponding number was 66 (40.7%) in controls (p < 0.01). CONCLUSIONS: Risk factors other than age were not higher in octogenarians, and the EuroSCORE model predicted mortality and morbidity. Age was an important single risk factor predicting mortality.

Predictive factors of hemodynamic collapse after coronary artery bypass grafting: a case-control study.

OBJECTIVE: Sudden hemodynamic collapse after coronary artery bypass graft (CABG) surgery is a complication with high morbidity and mortality. The aim of this study was to explore factors possibly predictive of this major complication. DESIGN: Retrospective case-control study. SETTING: University hospital, department of cardiothoracic surgery. PARTICIPANTS: Between 1988 and 1999, of 8,807 CABG patients, a total of 76 (0.9%) suffered hemodynamic collapse after CABG surgery unrelated to pericardial tamponade or bleeding. Preoperatively matched patients (by age, sex, New York Heart Association classification, number of diseased vessels, left ventricular ejection fraction, and diabetes) served as a control group (n = 76). INTERVENTIONS: Patients with sudden cardiovascular collapse underwent emergency reopening of the sternotomy and open cardiac massage (OCM group). Several pre-, intra-, and postoperative variables were compared, and significant parameters in match-pair analysis were further tested with regression techniques. MEASUREMENTS AND MAIN RESULTS: Of the 76 OCMs, 57 (75%) occurred during the first 5 postoperative hours. In-hospital mortality was 46% (35 of 76) versus 0% in controls; 5-year survival was 49% versus 95%. In the OCM group, cardiopulmonary bypass (CPB) time was significantly prolonged (p = 0.0024), and cardiac index (p = 0.05) and the first acid-base values after CPB were lower (pH, p = 0.0057; BE, p = 0.0014). Postoperative myocardial ischemia appeared in 33% of patients in the OCM group and in 8% of controls (p < 0.0001). OCM-group patients more frequently required postoperative inotropic (epinephrine, p = 0.0002) and mechanical support (intra-aortic balloon pump, p = 0.005). Regression analysis revealed a correlation between cardiopulmonary resuscitation risk and low cardiac index, postoperative ischemia, and low pH level. CONCLUSION: Inadequate tissue perfusion, postoperative myocardial ischemia, and increased need for inotropic and mechanical support preceded hemodynamic collapse. Interventions to improve tissue perfusion and to prevent and treat myocardial ischemia may result in a more favorable outcome.

Immune cells in a heterotopic lamb-to-pig bronchial xenograft model.

We developed our porcine model to elucidate the cellular rejection mechanisms of xenografts. Bronchial segments from a donor lamb were implanted into domestic pigs. The immunosuppressive regimens consisted of no immusuppression, or of daily oral cyclosporine A (CsA) 15 mg/kg, or of everolimus, 1.5 mg/kg, or of both. Implants were serially harvested during 17 days. Epithelial damage and obliteration were graded histologically, followed by a count of CD4+, CD8+, MHC class II-expressing cells, and macrophages. Furthermore, we studied the pharmocokinetics of everolismus. Epithelial damage preceded luminal obliteration, which was eventually total, except when both drugs had been given. In xenografts, an influx of cells with CD8+ cells dominating peaked on day 9, thereafter declining, except in the combination drug group. There, the immunological reaction was delayed and blunted, with CD4+ cells dominating. More macrophages appeared in xenografts than in allografts except with the combination CsA and everolimus. A dose of 1.5 mg/kg everolimus yields adequate blood concentrations for porcine studies. In this xenograft model, chronic rejection appears to be caused by an immune response to the graft, but it is more short-lived than the response in allografts. The combination of CsA and everolimus was able to blunt the response and delay the subsequent obliteration.

Matrix metalloproteinase induction in post-transplant obliterative bronchiolitis.

BACKGROUND: Epithelial cell injury, inflammation, fibrosis, and airway obliteration are associated in post-transplant obliterative bronchiolitis. Fibrosis is a consequence of fibroblastic activity and of collagen deposition after disturbances in the balance of protein formation and degradation. Proteolytic enzymes such as the matrix metalloproteinases mediate degradation. To assess matrix metalloproteinases during obliterative bronchiolitis development, we studied porcine, heterotopic bronchial allografts. METHODS: A total of 119 allografts or autografts were harvested serially at 3 to 60 days after transplantation and processed for histology and in situ hybridization for matrix metalloproteinases 2 and 9. Immunocytochemistry for vimentin and alpha-smooth-muscle-cell actin was performed with specific antibodies. RESULTS: Implants had initial ischemic injury to airway epithelium and to the bronchial wall. Recovery was rapid in autografts and in immunosuppressed allografts. In matrix metalloproteinase-2 mRNA activity in fibroblasts, correlation with endothelial expression and expression in macrophages occurred during intense fibroproliferation. We observed intense matrix metalloproteinase-9 positivity during onset of inflammation and fibroproliferation in endothelial cells (p < 0.01), fibroblasts (p < 0.05), macrophages (p < 0.05), and lymphocytes (p < 0.05). Matrix metalloproteinase-9 mRNA activity in fibroblasts correlated with that in endothelial and inflammatory cells and also proved predictive of early obliteration. CONCLUSIONS: Matrix metalloproteinase-2, and especially matrix metalloproteinase-9, gene activity was associated with onset of inflammation and fibroblastic proliferation in allografts, predicting early obliteration. Although this may be the case in the model described, its role in human-allograft post-transplant obliterative bronchiolitis requires further supportive data.