Randomized supplementation of 4000 IU vitamin D3 daily vs placebo on the prevalence of anemia in advanced heart failure: the EVITA trial.

BACKGROUND: Low 25-hydroxyvitamin D (25OHD) levels (< 75 nmol/l) are inversely associated with anemia prevalence. Since anemia and low 25OHD levels are common in patients with heart failure (HF), we aimed to investigate whether vitamin D supplementation can reduce anemia prevalence in advanced HF. METHODS: EVITA (Effect of Vitamin D on Mortality in Heart Failure) is a randomized, placebo-controlled clinical trial in patients with initial 25OHD levels < 75 nmol/l. Participants received either 4000 IU vitamin D3 daily or a matching placebo for 36 months. A total of 172 patients (vitamin D group: n = 85; placebo group: n = 87) were investigated in this pre-specified secondary data analysis. Hemoglobin (Hb) and other hematological parameters were measured at baseline and study termination. Assessment of between-group differences in anemia prevalence and Hb concentrations was performed at study termination, while adjusting for baseline differences. RESULTS: In the vitamin D and placebo group, baseline proportions of patients with anemia (Hb < 12.0 g/dL in females and < 13.0 g/dL in males) were 17.2% and 10.6%, respectively (P = 0.19). At study termination, the proportion of patients with anemia in the vitamin D and placebo groups was 32.2% and 31.8%, respectively (P > 0.99). There was no between-group difference in change in the Hb concentrations (- 0.04 g/dL [95%CI:-0.53 to 0.45 g/dL]; P = 0.87). Results regarding anemia risk and Hb concentrations were similar in the subgroup of patients with chronic kidney disease (vitamin D group: n = 26; placebo group: n = 23). Moreover, results did not differ substantially when data analysis was restricted to patients with deficient baseline 25OHD levels. CONCLUSIONS: A daily vitamin D supplement of 4000 IU did not reduce anemia prevalence in patients with advanced HF. Data challenge the clinical relevance of vitamin D supplementation to increase Hb levels. TRIAL REGISTRATION: The study was registered at EudraCT (No. 2010-020793-42) and clinicaltrials.gov ( NCT01326650 ).

Association between circulating 25-hydroxyvitamin D levels and medication use in patients scheduled for cardiac surgery.

BACKGROUND AND AIM: Low vitamin D status, i.e. circulating 25-hydroxyvitamin D (25OHD) levels <50 nmol/l, is independently associated with increased CVD risk. Medication use may influence 25OHD levels. We therefore investigated the association of circulating 25OHD with medication use in patients scheduled for cardiac surgery. METHODS AND RESULTS: A total of 11,256 patients were included in this cross-sectional study. We compared 25OHD levels of medication users (18 groups of continuously used and 5 groups of intermittently used medications) with levels of non-users. Moreover, we assessed variables (medications, demographic and clinical parameters) that were independently associated with 25OHD levels <50 nmol/l. The prevalence of 25OHD levels <50 nmol/l was 65.7%. The use of statins and immunosuppressive agents was significantly associated with higher 25OHD levels and lower odds ratios of 25OHD levels <50 nmol/l. The use of ACE-inhibitors, catecholamines and antibiotics was associated with lower 25OHD levels and higher odds ratios of 25OHD levels <50 nmol/l. However, only use of antibiotics, immunosuppressive agents and catecholamines showed clinically relevant differences in 25OHD levels, i.e. differences of more than +4 nmol/l or -4 nmol/l, compared with respective non-users. These medications were prescribed either intermittently (antibiotics, catecholamines) and/or infrequently (<2%; immunosuppressive agents, catecholamines) and/or its causal relationship with circulating 25OHD is questionable (antibiotics). Female sex and blood drawing during wintertime were associated with the highest odds ratios of 25OHD levels <50 nmol/l. CONCLUSION: Data indicate that in patients with high cardiovascular risk profile medication use does not substantially contribute to 25OHD levels <50 nmol/l.

[Heart and combined heart-lung transplantation. Indications, chances and risks]. / Herz- und Herz-Lungen-Transplantation. Indikationen, Chancen, Risiken.

Orthotopic heart transplantation (HTX) is nowadays the worldwide accepted gold standard for the treatment of terminal heart failure. The main indications for HTX are non-ischemic dilatative (54%) and ischemic (37%) heart failure. In the acute phase after HTX the survival rate is approximately 90%. Good short and long-term results with survival rates ranging from 81% after 1 year to more than 50% after 11 years demonstrate that there is currently no real treatment alternative to HTX for treatment of end-stage heart failure. In the case of irreversible pulmonary hypertension in combination with end-stage heart failure or complex congenital heart syndromes, a combined heart and lung transplantation (HLTX) is necessary. Compared with HTX the short-term survival of HLTX is reduced, mostly for technical reasons. Improved long-term results after HTX and HLTX are a result of highly specialized transplantation units and effective immunosuppression. However, a major problem is the shortage of organ donors in Germany and the resulting long waiting times for patients with frequently occurring blood groups of up to 10 months for transplantation. The consequence of the latter is the ever increasing number of implanted cardiac assist devices in patients not only as a bridge to transplant but also as destination therapy.

Body mass index, cardiac surgery and clinical outcome. A single-center experience with 9125 patients.

BACKGROUND AND AIM: There is evidence for a J-shaped association between Body Mass Index (BMI) and all-cause mortality in general populations. In cardiac surgical patients, the effect of BMI on mortality and major adverse cardiac and cerebrovascular events (MACCE) is not completely clear. METHODS AND RESULTS: We investigated the effect of BMI on MACCE (primary endpoint), as well as intensive care unit (ICU)-related outcomes and mid-term mortality in 9125 consecutive patients who were operated on at our institution between July 2009 and July 2012. Of the study cohort, 3.0% were underweight (BMI < 20 kg/m(2)), 28.0% had a normal BMI (20-24.99 kg/m(2)), 43.1% were overweight (BMI 25-29.99 kg/m(2)), 19.3% were obese (BMI 30-34.99 kg/m(2)), and 6.6% were severely obese (BMI ≥ 35 kg/m(2)). Compared with overweight patients (lowest incidence of MACCE), the multivariable-adjusted odds ratio of MACCE in severely obese patients was 1.39 (95% CI: 1.03-1.87). Underweight and severely obese patients had the longest risk-adjusted duration of mechanical ventilator support and ICU stay (P-values 0.004-0.001). The red blood cell concentrates requirement was highest in underweight patients (P < 0.001). Compared with normal and overweight patients, the multivariable-adjusted hazard ratio of 2-year mortality was higher in underweight patients (1.72 [95% CI: 1.26-2.36] and =2.07 [95% CI: 1.51-2.83], respectively), but did not differ significantly in severely obese patients. CONCLUSION: Data demonstrate that both severe obesity and underweight are independent risk factors for operative complications in cardiac surgical patients. With respect to mid-term survival, special attention should be paid to underweight patients scheduled for cardiac surgery.

Intraoperative sRAGE kinetics. A new age-related outcome predictor of cardiac surgery.

BACKGROUND: Glycated proteins (advanced glycation endproducts, AGE) in tissue are associated with degenerative diseases. This study evaluated the role of sRAGE (soluble receptor for advanced glycation endproducts), a decoy receptor of AGEs in blood, for the outcome of patients after coronary artery bypass grafting (CABG). METHODS: A total of 90 patients undergoing CABG were analysed in two centres. Perioperative blood samples were collected before surgery up to 1 week postoperatively. sRAGE was measured by ELISA. Patients were subdivided regarding age (< 64 versus > 70 years, 14 % versus 35 % female), euroSCORE (< 3 versus > 4, 14 % versus 29 % female) and sRAGE changes between sternotomy and end of the operation (< 30 % versus > 45 %, 33 % versus 33 % female) and subsequently analysed with respect of postoperative outcome parameters. RESULTS: Preoperative sRAGE values did not correlate with the outcome of the patients. sRAGE levels increase within 10 min from 1,539 ± 96 to 5,311 ± 187 pg/ml after sternotomy, then returning to baseline levels within 2 days after surgery. Comparing the analysed possible risk factors age, euroSCORE and sRAGE changes, no difference was observed regarding 30-day mortality. Age and the euroSCORE are superior with respect of tachyarrythmia, whereas sRAGE kinetics seems to be superior with respect of prolonged postoperative respiration time/stay in the intensive care unit or catecholamine support. CONCLUSION: A prolonged, increased intraoperative sRAGE level is a new outcome predictor for patients undergoing CABG surgery, mutually complementary to the euroSCORE.

[Hybrid operation theatre from the point of view of cardiac surgery. The future for the heart team]. / Hybridoperationssaal aus Sicht der Herzchirurgie. Zukunft für das Herzteam.

Nowadays, increasing numbers of procedures jointly conducted by cardiac surgeons and cardiologists are performed as minimally invasive surgical procedures or interventions. Transcatheter aortic valve implantation, endovascular aortic aneurysm repair and a large variety of hybrid procedures for congenital heart disease have become current standards. Some of these hybrid procedures were shown to improve the therapeutic safety and efficacy, effects particularly true for high-risk patients and complex interventions. Hybrid procedures require indirect imaging, commonly provided by an angiography system in the hybrid operation theatre. This article describes the technical prerequisites required for a hybrid operation theatre as well as indications and rationales for hybrid procedures conducted in this environment. It is likely that the indications for cardiovascular hybrid procedures will continue to be expanded and that the hybrid operation theatre may become a laboratory for developing innovative approaches in the cardiovascular field. Therefore, the hybrid operation theatre will not only be the working environment for hybrid surgeons and interventionalists but also help to evolve their future.

Moderate dosage of tranexamic acid during cardiac surgery with cardiopulmonary bypass and convulsive seizures: incidence and clinical outcome.

BACKGROUND: Convulsive seizures (CS) occur in ∼1% of the patients after cardiac surgery with cardiopulmonary bypass. Recent investigations indicate an up to seven-fold increase in CS in cardiac surgical patients receiving high doses (≥60 mg kg(-1) body weight) of tranexamic acid (TA). METHODS: In a retrospective data analysis of 4883 cardiac surgical patients, we investigated the incidence of CS in patients receiving a moderate dose of TA (24 mg kg(-1) body weight) compared with a reference group not receiving TA as a primary endpoint. Secondary endpoints were intensive care unit stay and in-hospital mortality. We performed propensity score (PS)-adjusted logistic regression analysis to test the association between TA use/non-use and clinical outcomes. RESULTS: Compared with the reference group, the PS-adjusted odds ratio (OR) for CS in the TA group was 1.703 [95% confidence interval (CI): 1.01-2.87; P=0.045; incidence 2.5% vs 1.2%]. Log-ICU-stay was significantly longer (P=0.004) and PS-adjusted relative in-hospital mortality risk was significantly higher for the TA group compared with the reference group (OR=1.89; 95% CI: 1.21-2.96; P=0.005). Both the TA-associated CS incidence and the in-hospital mortality risk were only significant in patients undergoing open-heart surgery (OR=2.034, 95% CI: 1.07-3.87; P=0.034 and OR=2.20, 95% CI: 1.32-3.69; P=0.003, respectively) but not in patients undergoing coronary artery bypass grafting (OR=1.21, 95% CI: 0.49-3.03; P=0.678 and OR=1.13, 95% CI: 0.42-3.02; P=0.809, respectively). CONCLUSIONS: In open-heart surgery, even moderate TA doses are associated with a doubled rate of CS and in-hospital mortality. Prospective trials are needed to further evaluate the safety profile of TA in cardiac surgery.

Future directions in vitamin D and cardiovascular research.

AIMS: Evidence is accumulating that vitamin D status may influence the risk of cardiovascular disease (CVD). Final confirmation for a causal relationship between vitamin D and CVD is however still lacking. The present viewpoint article outlines several future research directions to close this gap. DATA SYNTHESIS: Future directions include the need of performing large randomised controlled supplementation trials with vitamin D in specific risk groups. In addition, large register sets of data on vitamin D supplementation can be used, provided that adequate statistical methods such as propensity score modelled analysis are applied. To better understand vitamin D-mediated effects on CVD risk, the routine measurement of circulating levels of the hormonal vitamin D form, 1,25-dihydroxyvitamin D, is also necessary, in addition to the determination of its precursor 25-hydroxyvitamin D. Further, genetic association studies may help in clarifying the contribution of vitamin D to the development of CVD. Finally, the interrelationship of vitamin D with physical activity should be considered when studying CVD risk. CONCLUSIONS: Overall, it can be expected that the next 10-15 years will provide an increased clarity concerning the role of vitamin D in CVD.

Everolimus plus dosage reduction of cyclosporine in cardiac transplant recipients with chronic kidney disease: a two-year follow-up study.

The calcineurin inhibitor cyclosporine (CSA) displays nephrotoxic side effects. We switched 95 maintenance heart transplant recipients with chronic kidney disease (CKD) stages 3-4 from CSA to everolimus (EVL). The CSA dosage was reduced by 50%. Kidney function, lipid metabolism, and cardiac function investigated during a 2-year follow-up were compared with heart transplant recipients with CKD stages 2-3 who continued to receive CSA (CSA group; n = 84). Whereas 64/95 patients received reduced CSA plus EVL during the entire follow-up period (EVL continued subgroup, ECN), 31 discontinued EVL (EVL discontinued subgroup, EDS) after 4.3 months (median) because of various clinically relevant adverse events. Glomerular filtration rates (estimated using the modification of diet in renal disease formula) increased by 4.0 mL/min/1.73 m(2) in the ECN subgroup but decreased by 2.4 mL/min/1.73 m(2) and 9.0 mL/min/1.73 m(2) in the EDS subgroup and the CSA group, respectively (P < .001). Triglyceride and total cholesterol concentrations increased significantly among the ECN group, but remained constant in the EDS subgroup and the CSA group. Statin use was increased by 15% in the ECN group (P < .01). Mortality and cardiac rejection rates did not differ significantly among the 3 groups. In summary, EVL combined with low-dose CSA had modest beneficial effects on kidney function in heart transplant recipients with CKD stages 3-4. A significant percentage of patients had to stop EVL because of various adverse events.

Treatments effects from randomized trials and propensity score analyses were similar in similar populations in an example from cardiac surgery.

OBJECTIVE: Analyses comparing randomized to nonrandomized clinical trials suffer from the fact that the study populations are usually different. We aimed for a comparison of randomized clinical trials (RCTs) and propensity score (PS) analyses in similar populations. STUDY DESIGN AND SETTING: In a systematic review, we "meta-matched" RCTs and PS analyses that compared the off- and the on-pump technique in coronary artery bypass grafting. "Meta-confounders" were summarized in a "meta-propensity score" and were used for "meta-matching." We compared treatment effects between RCTs and PS analyses for 10 previously defined binary clinical outcomes in this "meta-matched" population as differences in "meta-odds ratios." RESULTS: For all clinical outcomes, the estimated differences in "meta-odds ratios" were below an absolute value of 0.15, all confidence intervals included the null. CONCLUSIONS: In our example, treatment effects of off-pump versus on-pump surgery from RCTs and PS analyses were very similar in a "meta-matched" population of studies, indicating that only a small remaining bias is present in PS analyses.

Diffusion-weighted magnetic resonance imaging for the detection of ischemic brain lesions in coronary artery bypass graft surgery: relation to extracorporeal circulation and heparinization.

AIM: Cognitive decline is a well recognized complication after on-pump coronary artery bypass graft (CABG) surgery. We investigated whether the design of extracorporeal circulation (ECC) and the extent of perioperative heparinization have an impact on neurological dysfunction. METHODS: Sixty-three CABG surgery patients were randomly perfused with an uncoated ECC-set (group A) or with two different heparin-coated ECC-sets (groups B and C). In groups A and B, systemic heparin was given in doses of 400 IU/kg body weight, whereas group C received 150 IU/kg body weight. ECC sets in group C included a diagonal pump and low priming as opposed to roller pumps in groups A and B. Furthermore, in group C blood contact to surfaces other than endothelium and heparin coated material was eliminated. Brain lesions were detected by diffusion-weighted magnetic resonance imaging (DWI). Neurological complications were assessed clinically until discharge (manifest motoric, sensitive or cognitive disturbance). Biochemical coagulation and inflammation parameters were measured pre-, peri-, and postoperatively. RESULTS: No major neurological events were observed in either group until discharge. DWIs showed 61 new lesions in 19 of 45 patients who terminated all MRI study procedures. Number and volume of the lesions did not differ between groups (P>0.05). Biochemical and inflammatory parameters showed the expected time courses and variations between groups. CONCLUSION: Ischemic brain lesions are frequently observed in CABG surgery patients but are neither associated with clinically relevant neurological complications nor with ECC set-up and intraoperative heparin dosage. DWI may help in the development of new surgical strategies to reduce postoperative brain damage.

Inflammatory response in on- versus off-pump myocardial revascularization: is ECC really the culprit?

A review of inflammatory mediators in on- versus off-pump surgery reveals that parameters of systemic inflammation differ quantitatively, not qualitatively between these approaches. Mediator system and cellular activation is observed after surgical trauma and following ischemia/reperfusion. Such activation is also modulated by genetic factors. The available literature does not permit definitive conclusions to be made on the advantages of off-pump surgery with respect to the systemic inflammatory response. The relationship between mediator systems and clinical course needs to be assessed in large patient populations to demonstrate to what extent off-pump surgery is more than just theoretically superior to on-pump surgery.

Advanced glycation end products, diabetes and ageing.

Advanced glycation end products (AGEs) are formed in vivo by a non-enzymatic reaction of proteins with carbohydrates and accumulate in many tissues during ageing. They are discussed as being responsible for many age- and diabetes-related diseases. On the other hand, AGEs are formed by the heating of food and are taken up by the nutrition. The contribution of endogenously formed versus exogenous intake of AGEs to age-related diseases is still under discussion.

Regulation of cytokine synthesis in cardiac surgery: Role of extracorporeal circuit and humoral mediators in vivo and in vitro.

OBJECTIVE AND DESIGN: Cardiopulmonary bypass (CPB) impairs monocyte and neutrophil proliferation, cytokine synthesis, and antigen presentation. This study compares in vivo data with results from an extracorporeal circulation (ECC) model, distinguishing direct effects on cytokine synthesis from regulatory mechanisms. PATIENTS AND METHODS: Whole blood from 18 patients prior to, during and after CPB was stimulated with lipopolysaccharide (LPS). Tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, and IL-8 levels were measured. Additionally, blood from 4 volunteers was circulated in an ECC model. Cytokine levels were measured before and during mock ECC. RESULTS: LPS-induced cytokine synthesis was reduced after CPB (TNF-alpha: 11 %; IL-6: 29 %; IL-8: 48 % of preoperative values, all p < 0.001). In mock ECC, cytokine production (except IL-8) was suppressed: TNF-alpha production was lowest 60 min after starting ECC, IL-6 synthesis was lowest at 90 min (33 % and 15 % vs. pre-ECC levels; both p < 0.001). Patient sera contained cytokine-inhibitory activity after CPB, an activity not found in mock ECC. CONCLUSIONS: (1) In patients, CPB induces early transient LPS hyporesponsiveness; (2) blood contact with foreign surfaces induces LPS hyporesponsiveness; (3) serum cytokine-inhibitory activities are released after CPB, but not in mock ECC. Impaired leukocyte function may explain increased susceptibility to infections after CPB.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) restores decreased monocyte HLA-DR expression after cardiopulmonary bypass.

OBJECTIVES: Cardiopulmonary bypass (CPB) is associated with a disturbed immune response, e.g., impaired HLA-DR expression on monocytes and the release of pro- and anti-inflammatory cytokines. Cytokine release plays a role in the pathogenesis of postoperative systemic inflammatory response syndrome (SIRS) and immune system deterioration, e.g., impaired monocyte and polymorphonuclear neutrophil (PMN) function, factors that ultimately lead to an increased susceptibility to infections. To gain a further understanding, we investigated HLA-DR expression on monocytes and on B- and T-lymphocytes. In addition, we investigated the IN VITRO effect of the immunostimulating hematopoietic growth factor granulocyte-macrophage colony-stimulating factor (GM-CSF) on HLA-DR expression of these cell types. Neither HLA-DR expression on B- and T-lymphocytes nor the effects of GM-CSF in cardiac surgical patients have been studied before. METHODS: In 16 patients undergoing elective cardiac surgery with CPB, counts of circulating leukocyte subsets as well as HLA-DR expression on monocytes, B- and T-lymphocytes were measured by flow cytometry before, immediately after CPB, and on the 2nd and 10th postoperative days. Treatment with GM-CSF was performed IN VITRO in whole blood cultures with 100 ng/ml recombinant human GM-CSF for 20 h. RESULTS: Monocyte HLA-DR expression was attenuated immediately after CPB (125 +/- 4 mean channel fluorescence [MCF] vs. 143 +/- 2 MCF preoperatively, mean +/- SEM, P < 0.001). HLA-DR expression further decreased on the 2nd day after CPB and did not normalize until the 10th day after the operation. In contrast, HLA-DR expression on T-cells was unchanged, whereas HLA-DR expression on B-cells did not decrease before the 2nd day after CPB (152 +/- 3 MCF vs. 170 +/- 2 MCF preoperatively, P < 0.001). IN VITRO GM-CSF treatment increased HLA-DR expression on monocytes prepared after CPB to a degree comparable to preoperative values. HLA-DR expression on B-lymphocytes could not be restored by GM-CSF. CONCLUSIONS: Immune system suppression after cardiac surgery is reflected in prolonged diminished HLA-DR expression on monocytes and B-lymphocytes. Suppression is not irreversible but can - at least IN VITRO - be overridden by the immunostimulating compound GM-CSF.

["Descending necrotizing mediastinitis" due to deep neck infections. Incidence and management]. / "Descending necrotizing mediastinitis" infolge tiefer Halsinfektionen. Inzidenz und Management.

BACKGROUND: "Descending necrotizing mediastinitis" (DNM) is a rare but potentially life-threatening complication of deep neck infections caused by the rapid downward spread of a oropharyngeal infection along the facial planes into the mediastinum. MATERIAL AND METHODS: Between June 1997 and December 2004, 6 patients with DNM were treated in our department. The primary etiology was a peritonsillar abscess in 2 cases, a parapharyngeal abscess in 3 cases and in 1 case an odontogenic abscess. Most patients presented with risk factors such as diabetes mellitus or alcoholism, the mean age was 44.3 years and the mean duration of signs before diagnosis was 6.3 days. Thoracotomy was associated with the cervical approach in 4 cases and tracheostomy was also performed in 4 cases. RESULTS: Four patients were successfully treated, the mean duration of hospitalisation was 48.2 days and 2 patients died from sepsis and multiorgan failure despite intensive treatment. CONCLUSIONS: Descending necrotizing mediastinitis must be detected as soon as possible. The mean symptoms are persistent complaints after treatment of oropharyngeal infections, which may be masked by analgetic treatment. Only an immediate computer tomographic scanning, aggressive surgical drainage and debridement of the neck and the mediastinum can reduce the high mortality rate.

Tumor necrosis factor-alpha production in whole blood after cardiopulmonary bypass: downregulation caused by circulating cytokine-inhibitory activities.

OBJECTIVES: Cardiopulmonary bypass is associated with the release of proinflammatory cytokines (tumor necrosis factor alpha, interleukin 1beta, interleukin 6, and interleukin 8) and anti-inflammatory cytokines (interleukin 10 and transforming growth factor beta(1)). On the one hand this cytokine release is related to the postoperative systemic inflammatory response syndrome, and on the other hand it is related to deterioration of the immune system, for example in monocyte or polymorphonuclear neutrophil function, leading to an increased susceptibility to infections. To gain further insight into the alterations of immune cell reactivity and possible regulatory mechanisms, we studied lipopolysaccharide-induced tumor necrosis factor alpha synthesis in whole blood from cardiac surgical patients. METHODS: Fifteen patients undergoing elective heart surgery with cardiopulmonary bypass were included in the study. Ex vivo lipopolysaccharide-induced tumor necrosis factor alpha synthesis was measured in a whole blood assay before, during, and after bypass. Corresponding tumor necrosis factor alpha messenger RNA levels were determined by semiquantitative reverse transcriptase-polymerase chain reaction. In addition, the influence of patient serum on whole blood responsiveness and its relationship to anti-inflammatory cytokines were evaluated in vitro. RESULTS: Tumor necrosis factor alpha synthesis was significantly reduced after 30 minutes of cardiopulmonary bypass and showed the lowest values at the end of bypass (mean +/- SD 0.109 +/- 0.105 ng/10(6) white blood cells after 30 minutes of bypass and 0.050 +/- 0.065 ng/10(6) white blood cells at the end of bypass, vs 0.450 +/- 0.159 ng/10(6) white blood cells preoperatively, P <.001). As a further indication of reduced cytokine biosynthesis, diminished messenger RNA levels for tumor necrosis factor alpha were detected. Serum withdrawn from patients at the end of cardiopulmonary bypass reduced tumor necrosis factor alpha synthesis in heterologous blood from healthy volunteers highly significantly to 39.93% +/- 23.18% relative to control serum (P =.005) and preoperatively drawn serum (P =.024). This effect was dose dependent and was not specific for lipopolysaccharide-induced tumor necrosis factor alpha synthesis. Anesthesia and heparin administration did not influence tumor necrosis factor alpha production significantly. Ex vivo tumor necrosis factor alpha synthesis was negatively related to interleukin 10 serum levels, positively but weakly related to interleukin 4, and was not related to transforming growth factor beta(1) (Spearman correlation coefficients -0.565, P <.001, 0.362, P <.001, and -0.062, P =.460, respectively). However, interleukin 10 levels in patient serum after cardiopulmonary bypass were 300-fold below the quantities needed for half-maximal inhibition of tumor necrosis factor alpha synthesis in vitro. Moreover, the inhibitory activity could not be removed by immune absorption of interleukin 10. CONCLUSIONS: These results suggest that during cardiac operations cytokine-inhibitory serum activities are released or newly formed. These activities could not be explained by the actions of interleukins 4 and 10 or transforming growth factor beta(1). Although their exact nature remains undetermined, these substances may contribute to the diminished immune cell functions after cardiopulmonary bypass and thus need further characterization.

Lipopolysaccharide-binding protein (LBP) and markers of acute-phase response in patients with multiple organ dysfunction syndrome (MODS) following open heart surgery.

Cardiopulmonary bypass (CPB) is associated with an immunological injury that may cause pathophysiological alterations in the form of a systemic inflammatory response syndrome (SIRS) or a multiple organ dysfunction syndrome (MODS). Previous studies on this issue have reported different changes of immunological parameters during and after CPB, but there are no reports about the lipopolysaccharide-binding protein (LBP) in relationship to other markers of inflammation in patients with MODS following cardiovascular surgery. In the present study, we investigated the acute-phase response of patients with MODS of infectious and non-infectious origin following open-heart-surgery. Plasma levels of procalcitonin (PCT), c-reactive protein (CRP), interleukin-6 (IL-6), and LBP were measured in the first four postoperative days in 12 adult male patients with the signs of SIRS and two or more organ dysfunctions after myocardial revascularization (MODS-group), and 12 patients without organ insufficiencies (SIRS-group). There were no significant differences regarding age, weight, height, preoperative NYHA-classification, preoperative LVEDP, or the number of anastomosis. Patients with MODS had a significantly longer operation time, duration of ischemia, and duration of extracorporeal circulation. None of the patients in the SIRS group died, whereas in the MODS group, 4 patients died due to septic multiorgan failure. Plasma PCT and IL-6 concentrations were significantly elevated in all MODS patients. CRP and LBP showed no differences between the MODS and the SIRS group. Comparing the MODS patients with and without positive microbial findings, we found significantly elevated levels of PCT and LBP in those patients with documented infections. Our results indicate that LBP may be a new marker for the differentiation between a severe non-infectious SIRS and an ongoing bacterial sepsis in the early postoperative course following CPB, while a microbiological result is still missing.

Ischemic pre-conditioning of 5 minutes but not of 10 minutes improves lung function after warm ischemia in a canine model.

BACKGROUND: Protection from reperfusion injury by ischemic pre-conditioning (IPC) before prolonged ischemia has been proven for the heart and the liver. We now assess the efficacy of IPC to protect lungs from reperfusion injury. METHODS: Eighteen foxhounds (25 to 30 kg) were anesthetized, intubated, and ventilated with a fraction of inspired oxygen of 0.3 at a volume-controlled mode to maintain arterial pCO2 of 30 to 40 mm Hg. After left thoracotomy, we performed warm ischemia for 3 hours by clamping the left hilus, and followed with 8 hours of reperfusion (control, n = 6). In the treated groups, IPC was performed either for 5 minutes followed by 15-minute reperfusion (n = 6, IPC-5), or by 2 successive cycles of 10-minute ischemia, followed by 10-minute reperfusion (n = 6, IPC-10) before prior to the 3-hours warm-ischemia period. Pulmonary compliance and gas exchange were determined separately for each lung, and we recorded pulmonary and systemic hemodynamics. We performed bronchoalveolar lavage (BAL) at the end of the experiment and determined total protein concentration as well as tumor necrosis factor alpha (TNF-alpha) mRNA expression in cell-free supernatant and in BAL cells, respectively. We also assessed the wet/dry ratio of the lung. RESULTS: In the controls, on reperfusion, we encountered a progressive deterioration of gas exchange, especially of the reperfused left lung, which we could largely avoid using the IPC-5 protocol. Similarly, pulmonary compliance steadily declined but was much better in the ICP-5 group. Parallel to the improvement of gas exchange and lung mechanics, we found less total alveolar protein content and TNF-alpha mRNA expression in BAL cells in the IPC-5 than in the controls. However, we did not find IPC-10 to be paralleled by a significant improvement of lung function. Neither IPC-5 nor IPC-10 influenced the pulmonary vascular resistance index or the fluid accumulation in the lung. CONCLUSION: The major finding of the present study was that 5 minutes of IPC improved lung function after 3 hours of warm ischemia of the lung.