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.

Purely ropivacaine-based TEA vs single TAP block in pain management after elective laparoscopic colon surgery within an upgraded institutional ERAS program.

BACKGROUND: The aim of this study was to compare thoracic epidural analgesia (TEA) with transversus abdominis plane (TAP) block in post-operative pain management after laparoscopic colon surgery. METHODS: One hundred thirty-six patients undergoing laparoscopic colon resection randomly received either TEA or TAP with ropivacaine only. The primary endpoint was opioid requirement up to 48 h postoperatively. Intensity of pain, time to onset of bowel function, time to mobilization, postoperative complications, length of hospital stay, and patients' satisfaction with pain management were also assessed. RESULTS: We observed a significant decrease in opioid consumption on the day of surgery with TEA compared with TAP block (30 mg vs 14 mg, p < 0.001). On the first two postoperative days (POD), the balance shifted to opioid consumption being smaller in the TAP group: on POD 1 (15.2 mg vs 10.6 mg; p = 0.086) and on POD 2 (9.2 mg vs 4.6 mg; p = 0.021). There were no differences in postoperative nausea/vomiting or time to first postoperative bowel movement between the groups. No direct blockade-related complications were observed and the length of stay was similar between TEA and TAP groups. CONCLUSION: TEA is more efficient for acute postoperative pain than TAP block on day of surgery, but not on the first two PODs. No differences in pain management-related complications were detected.

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.

Relationship of Edoxaban Plasma Concentration and Blood Coagulation in Healthy Volunteers Using Standard Laboratory Tests and Viscoelastic Analysis.

The capability of viscoelastic measurement parameters to screen anticoagulation activity of edoxaban in relation to its plasma concentrations was evaluated in 15 healthy male volunteers. Blood samples were drawn before the oral administration of edoxaban 60 mg and 2, 4, 6, 8, and 24 hours after administration. At each time, standard coagulation tests were performed, blood viscoelastic properties were measured with a thromboelastometry device ROTEM delta analyzer (Instrumentation Laboratory, Werfen, Barcelona, Spain), and edoxaban plasma concentrations were measured. Our primary interest was the possible correlation between edoxaban plasma concentrations and values for ROTEM ExTEM, and FibTEM. We also studied the correlation of edoxaban plasma concentrations with the results of standard coagulation tests. We saw the effect of a single dose of edoxaban most clearly in clotting time (CT) of ROTEM ExTEM and FibTEM. Changes in these parameters correlated significantly with edoxaban plasma concentrations up to 6 hours from the ingestion of the drug. Activated partial thromboplastin time, prothrombin time, and anti-factor Xa were also affected. Peak changes were observed 2 and 4 hours after administration of edoxaban. The changes were mostly reversed after 8 hours. In conclusion, ROTEM CT correlates significantly with edoxaban plasma concentrations and can be used to estimate the effect of edoxaban. ROTEM should be considered as part of the assessment of coagulation, with the big advantage of being readily available on site.

Heparin Dose and Point-of-Care Measurements of Hemostasis in Cardiac Surgery-Results of a Randomized Controlled Trial.

OBJECTIVE: High heparin doses during cardiopulmonary bypass (CPB) have been suggested to reduce thrombin activation and consumption coagulopathy and consequently bleeding complications. The authors investigated the effect of a high heparin dose during CPB on point-of-care measurements of coagulation. The authors hypothesized that during CPB a high heparin dose compared with a lower heparin dose would reduce thrombin generation and platelet activation and tested whether this would be reflected in the results of rotational thromboelastometry (TEM) and platelet aggregation, measured with multiple electrode aggregometry (MEA). DESIGN: Prospective, randomized, controlled, open single-center study. SETTING: University teaching hospital. PARTICIPANTS: Sixty-three consecutive patients undergoing elective coronary artery bypass grafting with CPB were enrolled. INTERVENTIONS: Patients were randomly assigned to receive either a high (600 IU/kg, n = 32) or a low (300 IU/kg, n = 31) initial dose of heparin. Target levels of activated clotting time during CPB were >600 seconds in the high heparin dose group and >400 seconds in the low heparin dose group. MEASUREMENTS AND MAIN RESULTS: Blood samples were collected (1) preoperatively after induction of anesthesia, (2) 10 minutes after aortic declamping, (3) 30 minutes after protamine administration, and (4) 3 hours after protamine administration. TEM and MEA were then measured. There was no difference in blood loss up to 18 hours postoperatively (median 735 mL for high dose v 610 mL for low dose; p < 0.056) or transfusions between the groups. Total median heparin dose (54,300 IU v 27,000 IU; p = 0.001) and median antifactor Xa levels during CPB (9.38 U/mL v 5.04 U/mL; p = 0.001) were greater in the high than in the low heparin dose group. However, neither TEM nor MEA results differed significantly between the groups. CONCLUSIONS: Compared with a lower dose of heparin during CPB, a high dose of heparin had little effect on the point-of-care measurements of hemostasis, TEM, and MEA. Based on the similarity of platelet and coagulation activity assessments, the higher heparin dose does not appear to offer benefit during CPB.

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.

Graft glycocalyx degradation in human liver transplantation.

OBJECTIVE: Ischaemia/reperfusion-injury degrades endothelial glycocalyx. Graft glycocalyx degradation was studied in human liver transplantation. METHODS: To assess changes within the graft, blood was drawn from portal and hepatic veins in addition to systemic samples in 10 patients. Plasma syndecan-1, heparan sulfate and chondroitin sulfate, were measured with enzyme-linked immunosorbent assay. RESULTS: During reperfusion, syndecan-1 levels were higher in graft caval effluent [3118 (934-6141) ng/ml, P = 0.005] than in portal venous blood [101 (75-121) ng/ml], indicating syndecan-1 release from the graft. Concomitantly, heparan sulfate levels were lower in graft caval effluent [96 (32-129) ng/ml, P = 0.037] than in portal venous blood [112 (98-128) ng/ml], indicating heparan sulfate uptake within the graft. Chondroitin sulfate levels were equal in portal and hepatic venous blood. After reperfusion arterial syndecan-1 levels increased 17-fold (P < 0.001) and heparan sulfate decreased to a third (P < 0.001) towards the end of surgery. CONCLUSION: Syndecan-1 washout from the liver indicates extensive glycocalyx degradation within the graft during reperfusion. Surprisingly, heparan sulfate was taken up by the graft during reperfusion. Corroborating previous experimental reports, this suggests that endogenous heparan sulfate might be utilized within the graft in the repair of damaged glycocalyx.

Minimal volume ventilation during robotically assisted mitral valve surgery.

INTRODUCTION: A minimal volume ventilation method for robotically assisted mitral valve surgery is described in this study. In an attempt to reduce postoperative pulmonary dysfunction, 40 of 174 patients undergoing robotically assisted mitral valve surgery were ventilated with a small tidal volume during cardiopulmonary bypass. METHODS: After propensity score matching, 31 patients with minimal volume ventilation were compared with 54 patients with no ventilation. Total ventilation time, PaO2/FiO2 ratio, arterial lactate concentration, and the rate of unilateral pulmonary edema in the matched minimal ventilation and standard treatment groups were evaluated. RESULTS: Patients in the minimal ventilation group had shorter ventilation times, 12.0 (interquartile range: 9.9-15.0) versus 14.0 (interquartile range: 12.0-16.3) hours (p = 0.036), and lower postoperative arterial lactate levels, 0.99 (interquartile range: 0.81-1.39) versus 1.28 (interquartile range: 0.99-1.86) mmol/L (p = 0.01), in comparison to patients in the standard treatment group. There was no difference in postoperative PaO2/FiO2 ratio levels or in the rate of unilateral pulmonary edema between the groups. CONCLUSION: Minimal ventilation appeared beneficial in terms of total ventilation time and blood lactatemia, while there was no improvement in arterial blood gas measurements or in the rate of unilateral pulmonary edema. The lower postoperative arterial lactate levels may suggest improved lung perfusion among patients in the minimal volume ventilation group. The differences in the ventilation times were in fact small, and further studies are required to confirm the possible advantages of the minimal volume ventilation method in robotically assisted cardiac surgery.

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.

Point-of-care laboratory analyses of intraosseous, arterial and central venous samples during experimental cardiopulmonary resuscitation.

INTRODUCTION: Screening and correcting reversible causes of cardiac arrest (CA) are an essential part of cardiopulmonary resuscitation (CPR). Point-of-care (POC) laboratory analyses are used for screening pre-arrest pathologies, such as electrolyte disorders and acid-base balance disturbances. The aims of this study were to compare the intraosseous (IO), arterial and central venous POC values during CA and CPR and to see how the CPR values reflect the pre-arrest state. METHODS: We performed an experimental study on 23 anaesthetised pigs. After induction of ventricular fibrillation (VF), we obtained POC samples from the IO space, artery and central vein simultaneously at three consecutive time points. We observed the development of the values during CA and CPR and compared the CPR values to the pre-arrest values. RESULTS: The IO, arterial and venous values changed differently from one another during the course of CA and CPR. Base excess and pH decreased in the venous and IO samples during untreated VF, but in the arterial samples, this only occurred after the onset of CPR. The IO, arterial and venous potassium values were higher during CPR compared to the pre-arrest arterial values (mean elevations 4.4 mmol/l (SD 0.72), 3.3 mmol/l (0.78) and 2.8 mmol/l (0.94), respectively). CONCLUSIONS: A dynamic change occurs in the common laboratory values during CA and CPR. POC analyses of lactate, pH, sodium and calcium within IO samples are not different from analyses of arterial or venous blood. Potassium values in IO, arterial and venous samples during CPR are higher than the pre-arrest arterial values.

Glycocalyx Degradation and Inflammation in Cardiac Surgery.

OBJECTIVE: Experimental inflammation induces degradation of glycocalyx. The authors hypothesized that inflammation is an important determinant of glycocalyx degradation in patients undergoing cardiac surgery with cardiopulmonary bypass (CPB). DESIGN: A prospective observational study. SETTING: Operation theater and intensive care unit of a university hospital. PARTICIPANTS: Two separate prospective patient cohorts. INTERVENTIONS: Blood samples were collected at 5 perioperative time points in the trial cohort (30 patients) and only preoperatively in the preoperative cohort (35 patients). Plasma syndecan-1 (biomarker of glycocalyx degradation), interleukin-6 (IL-6), IL-8, and IL-10 were measured. MEASUREMENTS AND MAIN RESULTS: In the trial cohort, preoperative ranges were as follows: 0.8-198 ng/mL for syndecan-1; 0-902 pg/mL for IL-6; 0-314.9 pg/mL for IL-8, and 0-2,909 pg/mL for IL-10. Seven out of 30 patients were outliers in terms of plasma concentrations of syndecan-1 and all cytokines preoperatively. The increase of syndecan-1 was 2.7-fold, and those of IL-6 and IL-8 were both 2.5-fold. The increase of IL-10 was modest. Plasma syndecan-1 correlated with all cytokines preoperatively (IL-6: R = 0.66, p < 0.001; IL-8: R = 0.67, p = 0.001; IL-10: R = 0.73, p < 0.001) as well as at 6 hours postoperatively (IL-6: R = 0.49, p = 0.006; IL-8: R = 0.43, p = 0.02; IL-10: R = 0.41, p = 0.03) and on the postoperative morning (IL-6: R = 0.57, p = 0.001; IL-8: R = 0.37, p = 0.06; IL-10: R = 0.51, p = 0.005) but not intraoperatively. The preoperative findings of the trial cohort could be confirmed in the preoperative cohort. CONCLUSIONS: In patients undergoing cardiac surgery with CPB, inflammation in terms of proinflammatory cytokines IL-6 and IL-8 and anti-inflammatory cytokine IL-10 is associated with glycocalyx degradation measured as plasma syndecan-1 concentrations.

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.

Randomized evaluation of fibrinogen versus placebo in complex cardiovascular surgery: post hoc analysis and interpretation of phase III results.

OBJECTIVES: In a multicentre, randomized-controlled, phase III trial in complex cardiovascular surgery (Randomized Evaluation of Fibrinogen vs Placebo in Complex Cardiovascular Surgery: REPLACE), single-dose human fibrinogen concentrate (FCH) was associated with the transfusion of increased allogeneic blood products (ABPs) versus placebo. Post hoc analyses were performed to identify possible reasons for this result. METHODS: We stratified REPLACE results by adherence to the transfusion algorithm, pretreatment fibrinogen level (≤2 g/l vs >2 g/l) and whether patients were among the first 3 treated at their centre. RESULTS: Patients whose treatment was adherent with the transfusion algorithm [FCH, n = 47 (60.3%); placebo, n = 57 (77.0%); P = 0.036] received smaller quantities of ABPs than those with non-adherent treatment (P < 0.001). Among treatment-adherent patients with pretreatment plasma fibrinogen ≤2 g/l, greater reduction in 5-min bleeding mass was seen with FCH versus placebo (median -22.5 g vs -15.5 g; P = 0.071). Considering patients with the above conditions and not among the first 3 treated at their centre (FCH, n = 15; placebo, n = 22), FCH was associated with trends towards reduced transfusion of ABPs (median 2.0 vs 4.0 units; P = 0.573) and greater reduction in 5-min bleeding mass (median -21.0 g vs -9.5 g; P = 0.173). Differences from a preceding single-centre phase II study with positive outcomes included more patients with pretreatment fibrinogen >2 g/l and fewer patients undergoing thoracoabdominal aortic aneurysm repair. CONCLUSIONS: None of the patient stratifications provided a clear explanation for the lack of efficacy seen for FCH in the REPLACE trial versus the positive phase II outcomes. However, together, the 3 factors demonstrated trends favouring FCH. Less familiarity with the protocol and procedures and unavoidable differences in the study populations may explain the differences seen between the phase II study and REPLACE. CLINICAL TRIAL REGISTRATION: NCT01475669 https://clinicaltrials.gov/ct2/show/NCT01475669; EudraCT trial no: 2011-002685-20.

Transfusion Threshold of Hemoglobin 80 g/L Is Comparable to 100 g/L in Terms of Bleeding in Cardiac Surgery: A Prospective Randomized Study.

OBJECTIVE: Anemia is common after cardiac surgery and, according to some suggestive evidence, may be associated with increased bleeding, other morbidity, and mortality. However, transfusion of red blood cells (RBC) may cause adverse effects and increase cost. The authors hypothesized that the restrictive hemoglobin threshold (Hb of 80 g/L) may aggravate bleeding more than the higher Hb threshold (Hb 100 g/L). DESIGN: Prospective randomized trial. TYPE OF HOSPITAL: University Hospital of Helsinki, Finland. PARTICIPANTS: Eighty patients with written informed consent, scheduled for elective open-heart surgery were randomized in 2 groups. INTERVENTIONS: Two study groups had RBC transfusion threshold of either Hb 80 g/L or 100 g/L. These triggers were followed for a 24-hour period postoperatively. A medical follow-up was carried out for 7 days after surgery. MEASUREMENTS AND MAIN RESULTS: Rotational thromboelastometry (ROTEM) and conventional laboratory tests were performed to evaluate coagulation. There was no significant difference in bleeding or ROTEM parameters between the groups. Complication rate and Hb concentration after 7-day follow-up were not different between the groups, but Group 100 g/L had received twice the amount of RBC transfusions. CONCLUSION: Hb threshold of 80 g/L for RBC transfusion in cardiac surgery is comparable to 100 g/L in terms of bleeding and possibly short-term complications.

Is Brain-Dead Donor Fluid Therapy With Colloids Associated With Better Kidney Grafts?

OBJECTIVES: Fluid therapy is required to maintain perfusion to donor organs. Recent reviews on the choices of fluids have emphasized the safety of using crystalloids, as opposed to fluid therapy with colloids, which has been reported to be either unequivocally or potentially harmful in a number of studies on various patient populations. We aimed to analyze whether the type of fluid administered to donors is connected with kidney transplant outcomes. MATERIALS AND METHODS: A total of 100 consecutive brain-dead multiorgan donors and their respective 181 kidney recipients were studied retrospectively. Data concerning donor fluid therapy, the characteristics of the donors and the recipients, and outcomes after kidney transplant were extracted from organ retrieval and patient records. Cases with early graft function were compared with cases with delayed graft function. RESULTS: Donors had received both crystalloids and colloids in most cases (84%). Fluid therapy with crystalloids alone was more common among the 40 recipients with delayed (30%) than in the 103 recipients with early graft function (11%) (P = .005). Donor age, time on renal replacement therapy before transplant, and donor fluid therapy with crystalloids alone were independent risk factors for delayed graft function in multivariate analysis. CONCLUSIONS: Our results suggest that donor fluid therapy including colloids could be beneficial instead of harmful compared with treatment with crystalloids alone. This finding needs to be evaluated in prospective studies.

Effect of Albumin in Combination With Mannitol on Whole-blood Coagulation In Vitro Assessed by Thromboelastometry.

BACKGROUND: Albumin and mannitol may interfere with hemostasis, but their coinfluence is unclear. We aimed to determine the effects of albumin alone and in combination with mannitol or Ringer acetate (RAC) on hemostasis in crossover in vitro study. MATERIALS AND METHODS: From citrated fresh whole blood withdrawn from 10 volunteers, we prepared 2.5, 5, 10, 15, and 20 vol% dilutions of 4% albumin (Alb group). Each sample was thereafter diluted by 15% mannitol (Alb/Man group) or RAC (Alb/RAC group) at a ratio of 9:1. Using thromboelastometry, FibTEM (fibrinogen ROTEM) and ExTEM (extrinsic ROTEM) tests were performed. RESULTS: A 20 vol%, but not 2.5 to 15 vol% dilution of albumin caused a prolonged clot formation time, α-angle decrease, and maximum clot firmness (MCF) weakening compared with undiluted sample (P<0.05). Clot formation time prolonged more in Alb5/Man than in Alb5 and Alb5/RAC dilution (P<0.05). In Alb2.5/Man, Alb10/Man, and Alb15/Man, dilution α-angle was lower than in corresponding Alb/RAC and Alb-group dilutions (P<0.05). In ExTEM, MCF decreased similarly in every dilution of Alb/Man and Alb/RAC compared with Alb group (P<0.05). In FibTEM, MCF decreased more in Alb10/Man than in Alb10/RAC dilution (P<0.05). CONCLUSIONS: In up to 15 vol% dilutions, albumin alone did not impair hemostasis in vitro, but in combination with mannitol or RAC coagulation was disturbed similarly at most concentrations. There was some significant additional effect with mannitol at certain concentrations. Our results indicate that coadministration of mannitol and albumin needs further study in vivo.

The effect of 50% compared to 100% inspired oxygen fraction on brain oxygenation and post cardiac arrest mitochondrial function in experimental cardiac arrest.

BACKGROUND AND AIM: We hypothesised that the use of 50% compared to 100% oxygen maintains cerebral oxygenation and ameliorates the disturbance of cardiac mitochondrial respiration during cardiopulmonary resuscitation (CPR). METHODS: Ventricular fibrillation (VF) was induced electrically in anaesthetised healthy adult pigs and left untreated for seven minutes followed by randomisation to manual ventilation with 50% or 100% oxygen and mechanical chest compressions (LUCAS®). Defibrillation was performed at thirteen minutes and repeated if necessary every two minutes with 1mg intravenous adrenaline. Cerebral oxygenation was measured with near-infrared spectroscopy (rSO2, INVOS™5100C Cerebral Oximeter) and with a probe (NEUROVENT-PTO, RAUMEDIC) in the frontal brain cortex (PbO2). Heart biopsies were obtained 20min after the return of spontaneous circulation (ROSC) with an analysis of mitochondrial respiration (OROBOROS Instruments Corp., Innsbruck, Austria), and compared to four control animals without VF and CPR. Brain rSO2 and PbO2 were log transformed and analysed with a mixed linear model and mitochondrial respiration with an analysis of variance. RESULTS: Of the twenty pigs, one had a breach of protocol and was excluded, leaving nine pigs in the 50% group and ten in the 100% group. Return of spontaneous circulation (ROSC) was achieved in six pigs in the 50% group and eight in the 100% group. The rSO2 (p=0.007) was lower with FiO2 50%, but the PbO2 was not (p=0.93). After ROSC there were significant interactions between time and FiO2 regarding both rSO2 (p=0.001) and PbO2 (p=0.004). Compared to the controls, mitochondrial respiration was decreased, with adenosine diphosphate (ADP) levels of 57 (17)pmols-1mg-1 compared to 92 (23)pmols-1mg-1 (p=0.008), but there was no difference between different oxygen fractions (p=0.79). CONCLUSIONS: The use of 50% oxygen during CPR results in lower cerebral oximetry values compared to 100% oxygen but there is no difference in brain tissue oxygen. Cardiac arrest disturbs cardiac mitochondrial respiration, but it is not alleviated with the use of 50% compared to 100% oxygen (Ethical and hospital approvals ESAVI/1077/04.10.07/2016 and HUS/215/2016, §7 30.3.2016, Funding Helsinki University and others).

Prone Versus Sitting Position in Neurosurgery-Differences in Patients' Hemodynamic Management.

OBJECTIVE: Neurosurgery in general anesthesia exposes patients to hemodynamic alterations in both the prone and the sitting position. We aimed to evaluate the hemodynamic profile during stroke volume-directed fluid administration in patients undergoing neurosurgery either in the sitting or the prone position. METHODS: In 2 separate prospective trials, 30 patients in prone and 28 patients in sitting position were randomly assigned to receive either Ringer acetate (RAC) or hydroxyethyl starch (HES; 130 kDa/0.4) for optimization of stroke volume. After combining data from these 2 trials, 2-way analysis of variance was performed to compare patients' hemodynamic profile between the 2 positions and to evaluate differences between RAC and HES consumption. RESULTS: To achieve comparable hemodynamics during surgery, a higher mean cumulative dose of RAC than HES was needed (679 mL ± 390 vs. 455 mL ± 253; P < 0.05). When fluid consumption was adjusted with weight, statistical difference was lost. Fluid administration did not differ between the prone and sitting position. Mean arterial pressure was lower and cardiac index and stroke volume index were higher over time in patients in the sitting position. CONCLUSIONS: The sitting position does not require excess fluid treatment compared with the prone position. HES is slightly more effective than RAC in achieving comparable hemodynamics, but the difference might be explained by patient weight. With goal-directed fluid administration and moderate use of vasoactive drugs, it is possible to achieve stable hemodynamics in both positions.

Effects of Perioperative Fluid Replacement Therapy in Lung Transplant Patients.

OBJECTIVES: Approximately 10 to 25 lung transplant procedures are performed annually in Finland, and 1-year survival has been 95% over the last 10 years. Our aim was to find associations between perioperative fluid replacement therapies and postoperative patient outcomes, with special emphasis on the use of colloids and blood products. MATERIALS AND METHODS: We retrospectively evaluated data from 100 patients who underwent lung transplant with cardiopulmonary bypass support in Finland from 2007 to 2013. Outcomes of interest were length of intensive care unit and hospital stays, time in ventilator, use of extracorporeal membrane oxygenation postoperatively, postoperative renal replacement therapy, postoperative graft failure, and 1-year mortality. RESULTS: Of 100 patients, 12 were on extracorporeal membrane oxygenation preoperatively. The 1-year mortality was 5/100 (5%), and the 3-year mortality was 7/100 (7%). Intraoperative fluid balance was positive (4762 a 3018 mL) but fell significantly postoperatively (below +1000 mL on postoperative day 1). During postoperative days 2 to 7, net fluid balance continued decreasing and stayed negative. Intraoperative use of hydroxyethyl starch and fresh frozen plasma were significantly higher in patients who died during follow-up versus those who survived (P < .05). Intraoperative use of fresh frozen plasma, but not red blood cells or platelets, correlated with graft failure (P = .012). Postoperative use of colloids or blood products did not correlate with mortality or graft failure. Patients who were on extracorporeal membrane oxygenation preoperatively stayed longer on ventilators and had longer intensive care unit and hospital stays (P < .001). Eight patients needed postoperative renal replacement therapy. CONCLUSIONS: Intraoperative use of fresh frozen plasma and hydroxyethyl starch is associated with increased mortality and graft failure. Postoperative use of colloids and red blood cells did not correlate with patient outcome. Use of extracorporeal membrane oxygenation preoperatively resulted in prolonged length of hospital stay.

Decreased maximum clot firmness in rotational thromboelastometry (ROTEM®) is associated with bleeding during extracorporeal mechanical circulatory support.

BACKGROUND:: We aimed to characterize the coagulation disturbances which may increase the risk of bleeding, thrombosis or death shortly after implantation of an extracorporeal membrane oxygenation (ECMO) or ventricular assist (VAD) device. METHODS:: Antithrombotic treatment was started in 23 VAD and 24 ECMO patients according to the hospital protocol. Additionally, conventional laboratory testing, rotational thromboelastometry (ROTEM®) and platelet function analysis (Multiplate®) were performed at predetermined intervals. RESULTS:: Four out of twenty-four (16.7%) of ECMO patients and 6/23 (26.1%) of VAD patients had severe bleeding after the procedure. When all the patients were analyzed together, low maximum clot firmness (MCF) in ExTEM and FibTEM analyses was associated with severe bleeding (p<0.05) and low MCF in FibTEM with 30-day mortality. Low platelet count and hematocrit levels were also associated with severe bleeding. When VAD and ECMO patients were separated into different groups, the association between ROTEM® parameters, bleeding and survival was found only in limited time points. Four patients with VAD had cerebral ischemia indicative of thromboembolism. However, this had no significant correlation with ROTEM® or Multiplate® parameters. CONCLUSION:: Hypocoagulation shown by ROTEM® was associated with bleeding complications in patients with mechanical circulatory support. In contrast, hypercoagulation did not correlate with clinical thrombosis.