Arndt-Holger Kiessling

The influence of selective pulmonary perfusion on the inflammatory response and clinical outcome of patients with chronic obstructive pulmonary disease undergoing cardiopulmonary bypass

OBJECTIVES Patients undergoing cardiac surgery presenting with chronic obstructive pulmonary disease (COPD) have a higher 30-day mortality risk. In these patients, pulmonary dysfunction linked to an inflammatory response is frequent after cardiac operations using cardiopulmonary bypass (CPB), which causes pulmonary hypoperfusion. We hypothesize that selective pulmonary perfusion (sPP) of the lungs leads to a reduction of pulmonary inflammation and a better clinical outcome. METHODS Fifty-nine COPD patients (forced expiratory volume in 1 s/vital capacity <70%) undergoing cardiac surgery procedures (coronary artery bypass grafting 64%, valve 14%) were block-randomized to sPP (venous blood, temperature 2°C, 4 l) or standard CPB (28/28). The primary end-point of the study was to evaluate the effect of pulmonary perfusion on gas exchange by measuring alveolar-arterial oxygen gradient. The surrogate end-points were inflammatory response, intensive care unit (ICU) stay, time on respirator (TOR) and major adverse cardiac and cerebrovascular events. A cytokine assay for interleukin-1β, IL-6, IL-10, tumour necrosis factor-α (TNF-α) and polymorphonuclear elastase was performed with peripheral blood at different time-points [(t1) pre-CPB, (t2) end of CPB, (t3) 3 h, (t4) 24 h, (t5) 48 h postoperatively]. Repeated-measure analysis of variance and non-parametric statistics were used to assess the between-group and during time differences. RESULTS The two groups proved comparable for perioperative variables. Serum cytokines were not different in the two groups throughout the study (P > 0.05 at single time-points), but as a function of time, the markers of the inflammatory response increased after CBP (P < 0.05 pre-CPB to 24 h). Clinical end-points were statistically comparable in both groups, but with a trend towards a shorter TOR (72 ± 159 h/106 ± 193 h) and ICU stay (3.9 ± 7.2 days/5.5 ± 9.2 days) in the sPP group despite a slightly longer time on extracorporeal circulation (120 vs 158 min). CONCLUSIONS These results indicate a non-significant trend that repeated hypothermic lung perfusion with venous blood during CPB may have a protective effect on the lungs. A multicentre study design and larger cohort seem necessary to demonstrate the benefits of sPP more clearly.

Pre-filling of the extracorporeal circuit with autologous blood is safe, but not effective in optimizing biocompatibility in high-risk patients

Objectives: Haemodilution resulting from crystalloid priming of the cardiopulmonary bypass circuit represents a major risk factor for blood transfusions in high-risk cardiac surgery patients. We designed this study to evaluate the effects of antegrade autologous priming (AAP) on reducing perioperative blood transfusion and markers of the inflammatory response in older patients (>75 years). Methods: Seventy-two patients undergoing first-time coronary bypass and/or aortic valve replacement were prospectively randomised to a cardiopulmonary bypass (CPB) with or without AAP. AAP was performed by adding the patient’s own blood to the prime solution (mean 280ml). Perfusion and anaesthetic techniques were as usual. The haematocrit was maintained at a minimum of 21% during CPB. Patients were well matched for all preoperative variables, including established transfusion risk factors. The primary endpoint was the requirement of red cell transfusion. The surrogate endpoints were renal function, inflammatory response and ischaemic parameters. Blood samples were drawn pre- and intraoperatively and at intervals of 6 hours till POD 6. Results: Current analysis shows no differences in patients receiving homologous packed red cell transfusions. Also, markers of the inflammatory response (IL6, IL8), renal function (cystatin C, creatinine) and myocardial ischaemia (troponin T, CK-MB) were comparable in both groups (p>0.05). Clinical outcomes were similar with respect to pulmonary, renal and hepatic function, length of ICU stay and hospital stay. Conclusion: These data suggest that antegrade autologous priming is a safe procedure, but an ineffective way for improving biocompatibility and reducing the need for blood transfusion in older patients.

Influence of gender on postoperative outcome after intra-aortic balloon counter-pulsation and cardiac surgery.

INTRODUCTION Female gender is an established risk factor for worse outcomes after cardiac surgery, and women are more likely to experience postoperative complications. Our aim was to analyze the influence of gender on outcome and postoperative complications after the use of intra-aortic balloon counter-pulsation (IABP) in cardiac surgery patients. METHODS Fifty-seven consecutive female patients (mean age: 73 ± 9 years) requiring an IABP at our department from January 2007 to January 2010 were retrospectively analyzed and compared with 182 male patients receiving IABP support within the same period. The collected data included patient demographics, preoperative state, operative details, postoperative pharmacological treatment, IABP-associated complications, and inhospital mortality. Preoperative mortality risk was calculated by logistic EuroSCORE. RESULTS There were no differences regarding the type of operation, preoperative renal or hepatic failure, though the prevalence of peripheral artery occlusive disease was higher in men. Furthermore, female patients receiving an IABP were significantly older (73 ± 9 vs. 67 ± 10 years), had a higher ejection fraction (EF) (45% ± 24% vs. 36% ± 14%), and had a higher EuroSCORE (25% ± 20% vs. 19% ± 17%; p < 0.05). Postoperative catecholamine support was significantly higher in the female patients. Women had a prolonged length of stay (LOS) at the ICU (10.64 ± 9.7 vs. 7.6 ± 7.6 days), higher incidence of renal replacement therapy, and a higher mortality (19 [19.4%] vs. 35 [33.9%]; p < 0.05) after the use of IABP. CONCLUSION Women have a worse outcome after the use of IABP, including LOS at the ICU, postoperative renal failure, and inhospital mortality, despite higher EF, when compared with men.

Red blood cells treated with the amustaline (S-303) pathogen reduction system: a transfusion study in cardiac surgery: AMUSTALINE RBCs IN CARDIAC SURGERY

Nucleic acid–targeted pathogen inactivation technology using amustaline (S‐303) and glutathione (GSH) was developed to reduce the risk of transfusion‐transmitted infectious disease and transfusion‐associated graft‐versus‐host disease with red blood cell (RBC) transfusion.

ATG-Fresenius Inhibits Blood Circulating Cell Proliferation in a Dose-Dependent Manner: An Experimental Study

INTRODUCTION Antithymocyte globulin (ATG)-Fresenius (Neovii-Biotech, Graefelfing, Germany), a highly purified rabbit polyclonal antihuman T-lymphocyte immunoglobulin resulting from immunization of rabbits with the Jurkat T-lymphoblast cell line, is currently used for the prevention of acute rejection in patients receiving solid organ transplants. Our aim was to investigate the in vitro activity of ATG-Fresenius regarding the proliferation of peripheral blood mononuclear cells (PBMCs), an important mechanism of rejection after solid organ transplantation. METHODS PBMCs were isolated from 6 healthy donors. Proliferation was assayed using [(3)H] thymidine incorporation. For analysis of mitogen-stimulated proliferation, the PBMCs were incubated at 37°C with various concentrations of ATG-Fresenius in the absence/presence of 40 μg/mL phytohemagglutinin. For analysis of the mixed lymphocyte reaction, PBMCs were incubated at 37°C with various concentrations of ATG-Fresenius for 3 days. On day 3, PBMCs (stimulator cells) from allogeneic donors were incubated with 25 μg/mL mitomycin C. The responder cells (preincubated with ATG-Fresenius) were then cultured at 37°C with the stimulator cells for 6 days. Groups were compared using ANOVA and the Tukey-Kramer multiple comparison test. RESULTS Preincubation of PBMCs with ATG results in concentration-dependent inhibition of phytohemagglutinin-stimulated proliferation. The effect was more pronounced after 2 and 3 days of treatment with ATG compared with 1 day. There was a concentration-dependent decrease in the mixed lymphocyte reaction-induced proliferation (up to 80%) at ATG-Fresenius concentrations as low as 0.05 to 0.5 μg/mL. No further effect on proliferation at ATG-Fresenius concentrations of 0.5 to 50 μg/mL was seen, and higher concentrations (>100 μg/mL) totally inhibited proliferation. CONCLUSIONS Our in vitro results provide more evidence of the beneficial effect of ATGs in the early phase of solid organ transplantation, by reducing effector cell proliferation.

Pharmacokinetics of Intraluminally Administered Serum Papaverine for Spasm Prophylaxis of the Internal Mammary Artery

BACKGROUND Papaverine (Paveron N™ Linden Arzneimittel Vertrieb GmbH, Germany) is a widely used agent for preventing spasm in mammary artery preparations. The question addressed in this study is whether the intraluminal administration of papaverine can result in detectable absorption of the drug into the systemic arterial circulation. METHODS In 15 patients (age 65 ± 6 years; body mass index 28.9 ± 3.7), an internal mammary artery (IMA) was prepared during coronary artery bypass grafting (CABG). A maximum of 3 mL of a 1 mg/1 mL diluted papaverine solution was injected intravascularly (intraluminally) for spasm prophylaxis. The IMA was closed proximally and distally with bulldog clamps. Blood samples were taken immediately after administration (T1), after 20 minutes (T2), and at the end of the operation (T3). Samples were measured in a liquid chromatography-tandem mass spectrometry (LC-MS/MS) system consisting of a binary pump from Agilent (Waldbronn, Germany) coupled to a high-throughput screening (HTS) PAL injection system (CTC, Zwingen, Switzerland) and a tandem mass spectrometer (API 4000, AB Sciex, Darmstadt, Germany). Papaverine was analyzed in positive mode using an electrospray ion source. Quantitation was performed using Analyst 1.5 software (AB Sciex, Darmstadt, Germany). RESULTS The newly developed LC-MS/MS method was successfully established for the detection of papaverine in plasma samples. The highest plasma papaverine levels were determined at time point T1 (mean 54.7 ± 39 ng/mL, range 16.6-179 ng/mL). The concentration was already halved 20 minutes after administration (T2) (mean 23.3 ± 2 ng/mL, range 4.6-118 ng/mL). Because of the short half-life and the hemodilution in the extracorporeal circulation, at the end of the operation papaverine (T3) had already fallen to just above the limit of detection (mean 4.1 ± 3.9 ng/mL, range 1.3-16.9 ng/mL). At time point T1, a significant negative correlation was determined between plasma levels and systemic diastolic, but not systolic, blood pressure. CONCLUSION Papaverine was successfully determined systemically in plasma by LC-MS/MS after intraluminal administration in the IMA. Systemic circulatory effects are dependent on the detected quantity. Group size and the absence of a control group are considerable limitations.

Retrospective analysis of pre- and intraoperative risk factors for readmission to the intensive care unit after fast track cardiac surgery

Objectives: The introduction of fast-track treatment procedures following cardiac surgery has significantly shortened hospitalisation times in intensive care units (ICU). Readmission to intensive care units is generally considered a negative quality criterion. The aim of this retrospective study is to statistically analyse risk factors and predictors for re-admission after a fast-track patient management program. Methods: 229 operated patients (67 ± 11 ys, 75% male, BMI 27 ± 3, 6/2010 – 5/2011) with use of extracorporeal circulation (70 ± 31 min aortic crossclamping, CABG 62%) were selected for a preoperative fast-track procedure (transfer on the day of surgery to an intermediate care (IMC) unit, stable circulatory conditions, extubated). 58 items were recorded and analysed. Results: Over the 11-month study period, 36% of all preoperatively declared fast-track patients could not be transferred to an IMC unit on the day of surgery or had to be readmitted to the ICU after the first postoperative day usually because of bleeding- (22%), pulmonary- (14%) or renal (11%) problems. Readmission signifies a dramatic worsening of the patient outcome (mortality 0/10%, hospital stay 10.3 ± 2.5/16.5 ± 16.3, transfusion rate 1.4 ± 1.7/5.3 ± 9.1). Predicators for failure of the fast-track procedure are a preoperative ASA> 3, NYHA>III and an operation time > 267 min ± 74. The significant risk factors for a major postoperative event are a poor EF (OR 2.7 CI 95% 0.98 – 7.6) and the described ICU readmission (OR 0.14 CI95% 0.05 – 0.36). Conclusions: The failure of a fast-track patient management concept is associated with a high loss of patient outcome. Major pre-operative selection factors of suitable fast-track patients are the ASA- and NYHA classes as well as intraoperatively recorded operation time.

Associated Risk of Recombinant Activated Factor VIIa Application

BACKGROUND The recombinant human coagulation FVIIa was approved for the treatment of bleeding in hemophilia patients. The reports of a good hemostatic effect were followed by studies and applications without a regulatory extension of the therapeutic indication (off-label use). The aim of this retrospective study is the evaluation of thromboembolic adverse events and side effects in a large cohort of patients with FVIIa therapy. METHODS In the period from January 2009 to March 2011, a total of 143/2453 (5.8%) cardiac surgical patients (69% male; age 67 ± 11 years; 39% thoracic aorta) were treated with different doses (mean, 6.1 mg; range, 1 to 27.2 mg) of factor VIIa. The administration of FVIIa was seen as a last therapeutic option and administered at the end of the treatment algorithm for severe bleeding. RESULTS Due to an acute bleeding situation in 143 patients, 7.9 ± 5.8 units of packed red blood cells, 9.5 ± 6.1 units of fresh frozen plasma, 1740 ± 1860 IU PPSB (Prothrombin-Proconvertin-Stuart Factor-Antihemophilic Factor B), 5.6 ± 4 g fibrinogen, and 7.9 ± 7.6 units of platelets were administered. A re-thoracotomy was necessary, despite maximal procoagulant therapy, in 55% of patients. The in-hospital mortality was 36% (51/2453 = 2%). Thrombotic complications occurred with a frequency of 16% (mesenteric infarction, n = 9; stroke/transient ischemic attack, n = 3; myocardial infarction, n = 3; other, n = 8). CONCLUSION The proof of direct causality of the events in relation to the administration of FVIIa is difficult because the temporal and therapeutic relationships with concomitant vasoconstrictive and procoagulant therapies were not obvious. However, there remains a suspicion that a higher rate of mesenteric infarctions may be provoked by the administration of FVIIa.