Red blood cells treated with the amustaline (S-303) pathogen reduction system: a transfusion study in cardiac surgery.

BACKGROUND: 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. STUDY DESIGN AND METHODS: A randomized, double-blind, controlled study was performed to assess the in vitro characteristics of amustaline-treated RBCs (test) compared with conventional (control) RBCs and to evaluate safety and efficacy of transfusion during and after cardiac surgery. The primary device efficacy endpoint was the postproduction hemoglobin (Hb) content of RBCs. Exploratory clinical outcomes included renal and hepatic failure, the 6-minute walk test (a surrogate for cardiopulmonary function), adverse events (AEs), and the immune response to amustaline-treated RBCs. RESULTS: A total of 774 RBC unis were produced. Mean treatment difference in Hb content was -2.27 g/unit (95% confidence interval, -2.61 to -1.92 g/unit), within the prespecified equivalence margins (±5 g/unit) to declare noninferiority. Amustaline-treated RBCs met European guidelines for Hb content, hematocrit, and hemolysis. Fifty-one (25 test and 26 control) patients received study RBCs. There were no significant differences in RBC usage or other clinical outcomes. Observed AEs were within the spectrum expected for patients of similar age undergoing cardiovascular surgery requiring RBCs transfusion. No patients exhibited an immune response specific to amustaline-treated RBCs. CONCLUSION: Amustaline-treated RBCs demonstrated equivalence to control RBCs for Hb content, have appropriate characteristics for transfusion, and were well tolerated when transfused in support of acute anemia. Renal impairment was characterized as a potential efficacy endpoint for pivotal studies of RBC transfusion in cardiac surgery.

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-1ß, 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.

Early postoperative serum cystatin C predicts severe acute kidney injury following cardiac surgery: a post-hoc analysis of a randomized controlled trial.

OBJECTIVE: Acute kidney injury (AKI) after cardiac surgery procedures is associated with poor patient outcomes. Cystatin C as a marker for renal failure has been shown to be of prognostic value; however, a wide range of its predictive accuracy has been reported. The aim of the study was to evaluate whether the measurement of pre- and postoperative serum cystatin C improves the prediction of AKI. METHODS: In a single-centre, prospective study of 70 patients (74 ± 9 ys; range 47-85 ys; 77% male), cystatin C was measured six times: (T1=preoperative, T2=start cardiopulmonary bypass (CPB), T3=20 min after CPB, T4=end of operation; T5=24 h postoperatively; T6=7d postoperatively). Predictive property, in terms of the need for renal replacement therapy (RRT), was analysed by receiver operating characteristics (ROC) statistics and described by the area under the curve (AUC). RESULTS: With respect to RRT (n=8), serum cystatin C was significantly higher at the end of the operation (T4), 24 h postoperatively at T5 and at T6. The AUCs for preoperative T1 and intraoperative T2/3 cystatin C were <0.7 (95% CI, 0.47-0.85). The earliest significant predictive AUCs were found at the end of the operation (T4: p=0.03 95% CI 0.58-0.88 AUC 0.73) and 24 h postoperatively (T5: p=0.003 95% CI 0.74-0.96 AUC 0.85). CONCLUSIONS: Early postoperative serum cystatin C increase appears to be a moderate biomarker in the prediction of AKI, whereas a preoperative and intraoperative cystatin C increase has only a limited diagnostic and predictive value.

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.

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.

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.

Case report: fatal hepatic failure after aortic valve replacement and sevoflurane exposure.

PURPOSE: To report a case of lethal hepatotoxicity possibly caused by sevoflurane. CLINICAL FEATURES: A 76-yr-old woman with a history of four previous minor surgical procedures developed acute liver failure after general anesthesia with sevoflurane, sufentanil and propofol for aortic valve replacement. After an uneventful procedure the patient was extubated 4.5 hr after surgery. On the second postoperative day, serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) increased. On the third postoperative day liver failure occurred, ALT peaked at 10504 UxL(-1) and AST at 15516 UxL(-1), and coagulopathy with an international normalized ratio of 4.6 developed. Liver transplantation was considered but rejected as a therapeutic option. The patient died three days after the operation in multiple organ failure triggered by hepatic failure. Other possible causes for liver failure were excluded. CONCLUSIONS: Sevoflurane hepatitis as a cause for liver failure may be implicated in this patient undergoing valve surgery. Unlike other halogenated anesthetic drugs, sevoflurane is not metabolized to hepatotoxic trifluoroacetyl proteins. However, compound A may react with proteins and may be transformed into antigenic material. We suggest that all halogenated anesthetics may be implicated with acute liver injury.

Relationship between factor XIII activity, fibrinogen, haemostasis screening tests and postoperative bleeding in cardiopulmonary bypass surgery.

We investigated the relationship between factor XIII, fibrinogen, blood coagulation screening tests and postoperative bleeding in 98 patients undergoing cardiopulmonary bypass (CPB) surgery. All patients received aprotinin. Blood samples were collected preoperatively (T1),after termination of CPB (T2),12 h (T3) and 24 h (T4) after surgery to determine FXIII activity, fibrinogen, platelet count, prothrombin time (PT), activated partial thromboplastin time (APTT) and D-dimers (DD). Laboratory results were correlated with the chest tube drainage 24 h after surgery and compared between patients with 24-hour chest tube drain volumes in the lower (Group 1) with those in the upper tertile (Group 3). Median FXIII and fibrinogen levels dropped by 33.9% and 34.2%, respectively, during CPB. No association between FXIII activity and the extent of postoperative bleeding was found. However, chest tube bleeding was significantly correlated with preoperative and postoperative fibrinogen. This was confirmed by comparing Groups 1 and 3. Group 3 patients had significantly lower fibrinogen levels than Group 1 at T1 - T4, although most fibrinogen values were within or above the reference range (medians, g/l: 3.5 vs. 4.0, p = 0.043 at T1; 2.3 vs. 2.7, p = 0.015 at T2; 2.9 vs. 3.3, p = 0.008 at T3; 4.2 vs. 5.2, p = 0.002 at T4). There was also a significant relationship of platelet count, PT and APTT, as measured after CPB (T2), with postoperative chest tube drainage. In conclusion, plasma FXIII activity does not influence postoperative bleeding in patients undergoing CPB surgery. There is however an inverse association between preoperative or postoperative plasma fibrinogen levels and postoperative bleeding. These findings indicate a modulation of postoperative bleeding by fibrinogen levels.

Levosimendan in patients with cardiogenic shock undergoing surgical revascularization: a case series.

BACKGROUND: Levosimendan is a new calcium sensitizer, which enhances myocardial contractility while simultaneously having vasodilatory and cardioprotective effects. These properties could be advantageous in patients with myocardial ischemia requiring inotropic support. MATERIAL/METHODS: 10 patients with acute myocardial ischemia, cardiogenic shock, and/or cardiopulmonary resuscitation undergoing emergency surgical revascularization were treated with levosimendan (bolus 6 microg.kg(-1), continuous infusion 0.2 microg.kg(-1).min(-1)) in addition to catecholamines. RESULTS: All patients treated with levosimendan and catecholamines were weaned successfully from CPB on the 1st attempt. All patients needed additional norepinephrine because of vasodilation. In 4 patients, levosimendan was stopped in the early postoperative period. 2 patients died, 8 patients survived without any multiorgan failure. Only 2 patients needed an additional intra-aortic balloon pump. In the surviving patients, postoperative ventilation lasted for 8-72 hours. CONCLUSIONS: Levosimendan may have exerted positive inotropic and cardioprotective effects in these high risk patients with acute myocardial ischemia. However, these preliminary results supporting the use of levosimendan as an inoprotective drug need to be confirmed by a large randomized prospective trial.

Robotic surgery using Zeus MicroWrist technology: the next generation.

BACKGROUND: The use of computer-animated surgical instruments for various cardiac operations has been shown to be feasible, but to date, the available information regarding the operative and technical details of these procedures is still inadequate. METHODS: We used the Zeus (Computer Motion Inc., Goleta, Calif, USA) telemanipulation system to perform the internal mammary artery (IMA) takedown in 56 patients, in 12 of whom we used the newest model with MicroWristTM (Computer Motion Inc., Goleta, Calif, USA) technology. Port orientation was based on thoracic anatomy, the decisive landmarks being the mammillary line and the axillary line. The distance between ports was at least 9 cm, and the patient's arm was positioned with the left shoulder raised and angulated by not more than 90 degrees. RESULTS: Mean setup time was 44 +/- 18 minutes for the first five patients and 16 +/- 7 minutes for the last five patients, with an overall average of 24 +/- 12 minutes. IMA harvest time at the beginning reached a mean of 95 +/- 23 minutes and decreased to 44 +/- 18 minutes in the last five cases. Average IMA takedown time was 58 +/- 17 minutes. The IMA was patent with a good flow in all 56 patients. CONCLUSIONS: The introduction of robotic technology into clinical routine has resulted in safe procedures with a short learning curve. However, basic training in the modality is a must in order to achieve technical excellence.

Diltiazem may preserve renal tubular integrity after cardiac surgery.

PURPOSE: To evaluate the influence of dopamine and diltiazem on renal function and markers for acute renal failure, including urinary alpha-glutathion s-transferase (alpha-GST), alpha-1-microglobulin (alpha(1)-MG) and N-acetyl-ss-glucosaminidase (ss-NAG) after extracorporeal circulation. METHODS: In a randomized, placebo-controlled, double-blind trial we evaluated the efficacy of dopamine (2.5 micro g x kg(-1) x min(-1)), diltiazem (2 micro g x kg(-1) x min(-1)) or placebo administered over 48 hr postoperatively to maintain renal tubular integrity in 60 elective cardiac surgery patients. alpha-GST, alpha(1)-MG, ss-NAG, and creatinine clearance were measured from urine collected during surgery (T0), the first four hours (T1), 24 hr (T2) and 48 hr (T3) postoperatively. RESULTS: Cumulative urine output in the diltiazem group (9.0 +/- 2.8 L) increased significantly compared with placebo (7.0 +/- 1.6 L), but not compared with dopamine (7.8 +/- 1.8 L). Creatinine clearance showed no significant intergroup differences. In all groups alpha(1)-MG increased from T0 to T3, but we found no significant intergroup differences. alpha-GST increased significantly from T0 to T3 in the placebo (2.1 +/- 1.8 to 11.4 +/- 8.6 micro g x L(-1)) and in the dopamine groups (2.7 +/- 1.8 to 13.6 +/- 14.9 micro g x L(-1)), but not in the diltiazem group (1.8 +/- 1.4 to 3.2 +/- 3.2 micro g x L(-1)). Forty-eight hours postoperatively alpha-GST was significantly lower in the diltiazem group than in both other groups. CONCLUSIONS: Diltiazem stimulates urine output, reduces excretion of alpha-GST and ss-NAG and may be useful to maintain tubular integrity after cardiac surgery.