Whole Blood Point-of-Care Testing for Incomplete Reversal With Idarucizumab in Supratherapeutic Dabigatran.

BACKGROUND: Incomplete reversal with a recommended 5-g dose of idarucizumab has been reported in patients with excessively high dabigatran concentrations. A timely detection of reversal failure after idarucizumab using whole blood (WB) coagulation testing is clinically useful. The aims of this study were to determine residual dabigatran activity after idarucizumab on thrombin generation (TG) using in vitro supratherapeutic dabigatran models and to compare 4 WB point-of-care tests (activated partial thromboplastin time [aPTT], prothrombin time [PT], and 2 thromboelastometry tests) with the TG results. METHODS: Blood samples from 12 healthy volunteers were spiked in vitro with 0-5000 ng/mL of dabigatran. Dabigatran reversal was evaluated by adding 1000 µg/mL of idarucizumab (Praxbind) to dabigatran-spiked samples, which reflect the administration of 5-g idarucizumab to a 70-kg patient. Residual dabigatran activity was assessed using the calibrated automated TG (Thrombinoscope) in platelet-poor plasma samples. The TG results were compared with WB aPTT (DRIHEMATO APTT-S) and PT (DRIHEMATO PT-S) using CG02N analyzer, thromboelastometry (ROTEM) triggered by ellagic acid (INTEM) and tissue factor (EXTEM). RESULTS: At a therapeutic concentration of dabigatran (200 ng/mL), the lag time was prolonged, and peak TG was decreased. The effects of dabigatran on TG were increased up to 1000 ng/mL, and TG was obliterated at higher supratherapeutic dabigatran levels (P < .001 versus control, respectively). TG was fully restored with idarucizumab when dabigatran was ≤2000 ng/mL, but residual anticoagulant activity was observed at higher dabigatran levels. Dabigatran prolonged WB aPTT and PT concentration dependently, and residual prolongations were observed when idarucizumab was added to 3000 or 5000 ng/mL of dabigatran (P < .001 versus control, respectively). In contrast, both INTEM and EXTEM clotting times were reversed toward reference ranges at all dabigatran concentrations when idarucizumab was added. CONCLUSIONS: Our data indicate that the recommended dose of idarucizumab may not restore TG completely with excessively elevated concentrations of dabigatran. All WB measurements with aPTT, PT, and thromboelastometry predicted supratherapeutic dabigatran concentrations, whereas those tests varied in sensitivity to residual anticoagulant activity after reversal. WB aPTT corresponded well with plasma TG changes among those measurements, but the use of thromboelastometry may overestimate the effect of idarucizumab. Caution should be exercised before extrapolating in vitro point-of-care data to the clinical monitoring of dabigatran reversal.

Prohemostatic Activity of Factor X in Combination With Activated Factor VII in Dilutional Coagulopathy.

BACKGROUND: Recombinant activated factor VII (rFVIIa) concentrate reduces allogeneic blood transfusions, but it may increase thromboembolic complications in complex cardiac surgery. The mixture of activated factor VII (FVIIa) and factor X (FX) (FVIIa/FX) (FVIIa:FX = 1:10) is a novel bypassing agent for hemophilia patients. We hypothesized that the combination of FX and FVIIa could improve thrombin generation (TG) in acquired multifactorial coagulation defects such as seen in cardiac surgery and conducted in vitro evaluation of FVIIa/FX in parallel with other coagulation factor concentrates using in vitro and in vivo diluted plasma samples. METHODS: Plasma samples were collected from 9 healthy volunteers and 12 cardiac surgical patients. We measured TG (Thrombinoscope) using in vitro 50% dilution plasma and in vivo dilution plasma after cardiopulmonary bypass, in parallel with thromboelastometry (ROTEM) and standard coagulation assays. In vitro additions of FVIIa/FX (0.35, 0.7, and 1.4 µg/mL, based on the FVIIa level), rFVIIa (1.4, 2.8, and 6.4 µg/mL), prothrombin complex concentrate (0.3 international unit), and 20% plasma replacement were evaluated. RESULTS: In diluted plasma, the addition of either FVIIa/FX or rFVIIa shortened the lag time and increased the peak TG, but the effect in lag time of FVIIa/FX at 0.35 µg/mL was more extensive than rFVIIa at 6.4 µg/mL. Prothrombin complex concentrate increased peak TG by increasing the prothrombin level but failed to shorten the lag time. No improvement in any of the TG variables was observed after 20% volume replacement with plasma. The addition of factor concentrates normalized prothrombin time/international normalized ratio but not with plasma replacement. In cardiac patients, similar patterns were observed on TG in post-cardiopulmonary bypass samples. FVIIa/FX shortened clotting time (CT) in a concentration-dependent manner on CT on thromboelastometry. Plasma replacement did not improve CT, but a combination of plasma and FVIIa/FX (0.35 µg/mL) more effectively shortened CT than FVIIa/FX alone. CONCLUSIONS: The combination of FVIIa and FX improved TG more efficiently than rFVIIa alone or plasma in dilutional coagulopathy models. The required FVIIa dose in FVIIa/FX was considerably lower than those reported during bypassing therapy in hemophilia patients (1.4-2.8 µg/mL). The combination of plasma could restore coagulation more efficiently compared to FVIIa/FX alone. Lesser FVIIa requirement to exert procoagulant activity may be favorable in terms of reducing systemic thromboembolic complications.

Changes in MicroRNA Expression Level of Circulating Platelets Contribute to Platelet Defect After Cardiopulmonary Bypass.

OBJECTIVES: Platelet defect mechanisms after cardiopulmonary bypass remain unclear. Our hypothesis microRNA expressions in circulating platelets significantly change between pre and post cardiopulmonary bypass, and consequent messenger RNA and protein expression level alterations cause postcardiopulmonary bypass platelet defect. DESIGN: Single-center prospective observational study. SETTING: Operating room of Kyoto Prefectural University of Medicine. PATIENTS: Twenty-five adult patients scheduled for elective cardiac surgeries under cardiopulmonary bypass. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: In the initial phase, changes in microRNA expression between pre and post cardiopulmonary bypass underwent next generation sequencing analysis (10 patients). Based on the results, we focused on changes in mir-10b and mir-96, which regulate glycoprotein 1b and vesicle-associated membrane protein 8, respectively, and followed them until messenger RNA and protein syntheses (15 patients) using quantitative polymerase chain reaction and Western blotting. Seven microRNAs including mir-10b and mir-96 exhibited significant differences in the initial phase. In the subsequent phase, mir-10b-5p and mir-96-5p overexpressions were confirmed, and glycoprotein 1b and vesicle-associated membrane protein 8 messenger RNA levels were significantly decreased after cardiopulmonary bypass: fold differences (95% CI): mir-10b-5p: 1.35 (1.05-2.85), p value equals to 0.01; mir-96-5p: 1.59 (1.06-2.13), p value equals to 0.03; glycoprotein 1b messenger RNA: 0.46 (0.32-0.60), p value of less than 0.001; and vesicle-associated membrane protein messenger RNA: 0.70 (0.56-0.84), p value of less than 0.001. Glycoprotein 1b and vesicle-associated membrane protein 8 were also significantly decreased after cardiopulmonary bypass: glycoprotein 1b: 82.6% (71.3-93.8%), p value equals to 0.005; vesicle-associated membrane protein 8: 79.0% (70.7-82.3%), p value of less than 0.001. CONCLUSIONS: Expressions of several microRNAs in circulating platelets significantly changed between pre and post cardiopulmonary bypass. Overexpressions of mir-10b and mir-96 decreased glycoprotein 1b and vesicle-associated membrane protein 8 messenger RNA as well as protein, possibly causing platelet defect after cardiopulmonary bypass.

A Comparative Study of Point-of-Care Prothrombin Time in Cardiopulmonary Bypass Surgery.

OBJECTIVE: Point-of-care (POC) devices allow for prothrombin time/international normalized ratio (PT/INR) testing in whole blood (WB) and timely administration of plasma or prothrombin complex concentrate during cardiopulmonary bypass surgery. This study evaluated the sensitivities of a new POC PT test, a dry-hematology method with heparin neutralization technology (DRIHEMATO PT-S [DRI PT-S]; A&T Corporation, Kanagawa, Japan), and compared it with other POC tests currently available. DESIGN: Prospective, observational study. SETTING: University hospital, single center. PARTICIPANTS: Healthy volunteers and warfarin-treated and cardiac surgical patients. MEASUREMENT AND MAIN RESULTS: In WB samples obtained from 6 healthy volunteers, PT-INR results of DRI PT-S were not affected by an in vitro addition of heparin <6.0 U/mL. In warfarin-treated samples (n = 88, PT/INR 0.98-3.87), PT-INR with DRI PT-S showed acceptable correlation with the laboratory method (r2 = 0.85, p < 0.001). In blood samples obtained from cardiac surgical patients (n = 72), heparin prolonged the PT/INR with the laboratory assay, dry-hematology method with non heparin neutralization technology (DRI PT), Coaguchek XS (Roche Diagnostics, Basel, Switzerland), and Hemochron Jr. (Accriva Diagnostics, Edison, NJ), but DRI PT-S was not affected by heparin anticoagulation. In nonheparinized samples, different methods between DRI PT-S and the laboratory method yielded acceptable correlations (r2 = 0.76, p < 0.0001). There was a moderate correlation between factor levels and the PT-INR with DRI PT-S (factor [F]II: r2 = 0.63, FVII: r2 = 0.47, FX: r2 = 0.67; p < 0.0001). CONCLUSIONS: This study demonstrated that PT/INR can be accurately assessed using the dry-hematology method in WB under therapeutic heparin levels. Currently available other POC PT/INR tests are affected by heparin, and thus they are not recommended for coagulation monitoring during cardiopulmonary bypass.

Potential contribution of erythrocyte microRNA to secondary erythrocytosis and thrombocytopenia in congenital heart disease.

BackgroundChildren with cyanotic heart disease develop secondary erythrocytosis and thrombocytopenia via unknown mechanisms. Mature erythrocyte microRNAs may reflect clinical pathologies and cell differentiation processes pre-enucleation. This study evaluated erythrocyte microRNAs in children with cyanotic heart disease.MethodsErythrocyte microRNAs from children with cyanotic and acyanotic heart disease and without cardiac disease were quantified with Ion PGM System (n=10 per group). Differential expression was confirmed by quantitative PCR (qPCR; n=20 per group).ResultsMir-486-3p, mir-486-5p, and mir-155-5p increased in patients with cyanotic heart disease compared with those without heart disease: fold differences (95% confidence interval): mir-486-3p: 1.92 (1.14-3.23), P=0.011; mir-486-5p: 2.27 (1.41-3.65), P<0.001; and mir-155-5p: 1.44 (1.03-2.03), P=0.028. Mir-486-5p was increased, and let-7e-5p and mir-1260a were decreased in patients with acyanotic heart disease compared with those without heart disease: mir-486-5p: 1.66 (1.03-2.66), P=0.035; let-7e-5p: 0.66 (0.44-0.99), P=0.049; and mir-1260a: 0.53 (0.29-0.99), P=0.045.ConclusionSeveral microRNA levels changed in children with cyanotic and acyanotic heart disease. Mir-486-3p and -5p are associated with hematopoietic differentiation. Mir-486-3p regulates the erythroid vs. megakaryocyte lineage fate decision. Mir-155 is a hypoxia-inducible microRNA, whose overexpression inhibits megakaryocyte differentiation. Erythrocyte microRNA expression changes may contribute to erythrocytosis and thrombocytopenia in children with cyanotic heart disease.

Flow-dynamics assessment of mitral-valve surgery by intraoperative vector flow mapping.

OBJECTIVES: We assessed vortex patterns and energy loss in left ventricular flow in patients who underwent mitral valve repair or replacement with bioprosthetic valves. METHODS: Vector flow mapping was performed before and after the procedure in 15 and 17 patients who underwent repair and replacement, respectively. The preprocedure mitral-septal angle was measured in all patients. Relationships between vortex patterns or energy loss change (ELC) and annuloplasty ring or bioprosthetic valve sizes or the effect of mitral leaflet resection in the repair group were statistically analysed. RESULTS: Normal vortex patterns were observed in 13 and 1 patients who underwent repair and replacement, respectively. Abnormal vortex patterns were observed in 2 and 16 patients who underwent repair and replacement, respectively. ELC was significantly higher in the replacement group (196.6 ± 180.8) than in the repair group (71.9 ± 43.9). In the repair group, preoperative mitral-septal angles in patients with normal vortex patterns (79.2° ± 3.4°) were significantly larger than those in patients with abnormal vortex patterns (67.5° ± 3.5°). No significant differences were observed in the effects of annuloplasty ring and bioprosthetic valve sizes on vortex patterns and ELC, and in the effect of mitral valve resection (80.4 ± 56.3) and respect (without leaflet resection) (53.8 ± 28.4) on ELC in the repair group. CONCLUSIONS: Mitral valve replacement alters the intraventricular vortex pattern and increases flow energy loss. A small mitral-septal angle is a risk factor for abnormal vortex patterns after mitral valve repair surgery.

A Practical Training Program for Peripheral Radial Artery Catheterization in Adult Patients: A Prospective, Randomized Controlled Trial.

BACKGROUND: The main cause of unsuccessful peripheral radial artery catheterization using traditional palpation is imprecisely locating the arterial center. The authors evaluated factors causing disparities between the arterial centers determined by palpation versus ultrasound. The authors applied them to create and test a novel catheterization training program. METHODS: The arterial central axis was determined by ultrasound and palpation in 350 adults. Potential independent predictors of disparity included sex, body mass index, pulse pressure, transverse arterial diameter, subcutaneous arterial depth, chronic hypertension, and experience as an anesthesiologist (less than 3 vs. greater than or equal to 3 yr). Using the results, the authors developed a radial artery catheterization training program. It was tested by enrolling 20 first-year interns, randomized to a training or control group. The time to successful insertion was the primary outcome measure. The success rate and time required for catheterization by palpation were evaluated in 100 adult patients per group. RESULTS: Independent predictors of central axis disparity were pulse pressure, subcutaneous radial artery depth, years of experience, and chronic hypertension. Training improved the catheterization time (training group 56 ± 2 s vs. control group 109 ± 2 s; difference -53 ± 3 s; 95% CI, -70 to -36 s; P < 0.0001) and total success rate (training group 83 of 100 attempts, 83%; 95% CI, 75 to 90 vs. control group 57 of 100, 57%; 95% CI, 47 to 66; odds ratio, 3.7; 95% CI, 2.7 to 5.1). CONCLUSIONS: Misjudging the central axis position of the radial artery is common with a weak pulse and/or deep artery. The authors' program, which focused on both these issues, shortened the time for palpation-guided catheterization and improved success.

Optimal site for ultrasound-guided venous catheterisation in paediatric patients: an observational study to investigate predictors for catheterisation success and a randomised controlled study to determine the most successful site.

INTRODUCTION: Venous catheterisation in paediatric patients can be technically challenging. We examined factors affecting catheterisation of invisible and impalpable peripheral veins in children and evaluated the best site for ultrasound-guided catheterisation. METHODS: Systolic pressure, age, sex, and American Society of Anaesthesiologists (ASA) physical status were determined in 96 children weighing less than 20 kg. Vein diameter and subcutaneous depth were measured with ultrasound. Logistic regression was used to evaluate the contribution of these factors to cannulation success with (n = 65) or without (n = 31) ultrasound guidance. Thereafter, we randomly assigned 196 patients for venous catheter insertion in the dorsal veins of the hand, the cephalic vein in the forearm, or the great saphenous vein. Success rates and vein diameters were evaluated by using Dunn tests; insertion time was evaluated by using Kaplan-Meier cumulative incidence analysis. RESULTS: Independent predictors of catheterisation were ultrasound guidance (odds ratio (OR) = 7.3, 95% confidence interval (CI) 2.0 to 26.0, P = 0.002), vein diameter (OR = 1.5 per 0.1 mm increase in diameter, 95% CI 1.1 to 2.0, P = 0.007), and ASA physical status (OR = 0.4 per status 1 increase, 95% CI 0.2 to 0.9, P = 0.03). Cephalic veins were significantly larger (cephalic diameter 1.8 mm, P = 0.001 versus saphenous 1.5 mm, P <0.001 versus dorsal 1.5 mm). Catheterisation success rates were significantly better at the cephalic vein than either the dorsal hand or saphenous vein (cephalic 95%, 95% CI 89% to 100%, P <0.001 versus dorsal 69%, 95% CI 56% to 82%, P = 0.03 versus saphenous 75%, 95% CI 64% to 86%). CONCLUSIONS: The cephalic vein in the proximal forearm appears to be the most appropriate initial site for ultrasound-guided catheterisation in invisible and impalpable veins of paediatric patients. TRIAL REGISTRY NUMBER: UMIN Clinical Trials Registry as UMIN000010961. Registered on 14 June 2013.

Fibrinogen measurements in plasma and whole blood: a performance evaluation study of the dry-hematology system.

BACKGROUND: An accurate and rapid determination of fibrinogen level is important during hemorrhage to establish a timely hemostatic intervention. The accuracy of fibrinogen measurements may be affected by the specific methodology for its determination, fluid therapies, and anticoagulant agents. The dry-hematology method (DRIHEMATO®) is a novel approach to determine fibrinogen levels in plasma and whole blood based on thrombin-activated coagulation time. We hypothesized that plasma or whole blood fibrinogen level using the dry-hematology method would be similar to those measured with conventional plasma fibrinogen assays. METHODS: Acquired hypofibrinogenemia was modeled by serial dilutions of blood samples obtained from 12 healthy volunteers. Citrated whole blood samples were diluted with either normal saline, 5% human albumin, or 6% hydroxyethyl starch to achieve 25%, 50%, and 75% volume replacement. The dry-hematology method, the Clauss method, the prothrombin time (PT)-derived method, determination of antigen levels, and thromboelastometric fibrin formation were compared in plasma or whole blood samples. The effect of heparin on each assay was examined (0 to 6 IU/mL). Comparisons of dry-hematology and other methods were also conducted using ex vivo samples obtained from cardiac surgical patients (n = 60). RESULTS: In plasma samples, there were no significant differences between dry-hematology and the Clauss method, while dry-hematology showed lower fibrinogen levels compared with PT-derived and antigen level methods. The dry-hematology method yielded acceptable concordance correlation coefficients (Pc) with the Clauss method, the PT-derived method, and fibrinogen antigen levels (Pc = 0.91-0.99). The type of diluents and heparin affected the results of the PT-derived method and thromboelastometric assay, but not the dry-hematology method. In cardiac surgical patients, the overall correlation in fibrinogen levels between dry-hematology and the other methods was comparable to the results from in vitro dilution experiments. The dry-hematology reported higher fibrinogen values in whole blood compared with those measured in plasma samples, but hematocrit adjustment decreased the bias between whole blood and plasma samples from 73 mg/dL (95% prediction interval: 40, 106) to -13 mg/dL (95% prediction interval: -35, 8.5). CONCLUSIONS: This study demonstrated that fibrinogen levels can be accurately assessed by the dry-hematology method in plasma and the results are not affected by heparin or colloids. For whole blood fibrinogen measurements by dry-hematology, hematocrit adjustment is necessary to compensate for dynamic changes in hematocrit in perioperative bleeding settings.

A novel method for ultrasound-guided radial arterial catheterization in pediatric patients.

BACKGROUND: Radial arterial catheterization in pediatric patients is occasionally difficult despite ultrasound guidance. We therefore assessed the factors affecting catheterization and tested an intervention designed to improve its success. METHODS: For initial assessment, we performed multiple logistic regression analyses using 102 pediatric patients. Dependent variables included first-attempt and overall success or failure; independent variables were systolic blood pressure, weight, ASA physical status, trisomy 21, arterial diameter, and subcutaneous depth of the radial artery (<2, 2-4, ≥4 mm). The effect of subcutaneous arterial depth on cannulation success was assessed using Kaplan-Meier curves with log-rank and Dunn tests. We then assessed catheterization success in 60 patients who were randomized to no treatment or subcutaneous saline injection, as necessary, to increase the subcutaneous arterial depth from <2 to 2 to 4 mm. RESULTS: Subcutaneous arterial depth of 2 to 4 mm was derived as a significant independent predictor of initial and overall success from the multiple logistic regression analyses. The 2 to 4 mm group had a significantly shorter catheterization time compared with the other 2 groups in the log-rank test (2-4 vs <2 mm group; P = 0.01, 2-4 vs ≥4 mm group; P < 0.001), and higher success rate in the first attempt (<2 [43.8%] vs 2-4 mm [76.9%], P = 0.02; 2-4 [76.9%] vs ≥4.0 mm [19.4%], P < 0.001), and the overall attempt (<2 [62.5%] vs 2-4 mm [89.7%], P = 0.04; 2-4 [89.7%] vs ≥4.0 mm [51.6%], P = 0.002). Injecting subcutaneous saline to bring arterial depth from <2 mm to 2 to 4 mm significantly shortened catheterization time (P = 0.002), and improved the success rate in the first-attempt (saline injection [85.0%] vs <2 mm [30.0%], P < 0.001), and the overall attempt (saline injection [90.0%] vs <2 mm [55.0%], P = 0.02). CONCLUSIONS: Ultrasound-guided radial artery catheterization in pediatric patients was fastest and most reliable when the artery was 2 to 4 mm below the skin surface. For arteries located <2 mm below the skin surface, increasing the depth to 2 to 4 mm by subcutaneous saline injection reduced catheterization time and improved the success rate.

[Perioperative management after non-cardiac surgery in patients with chronic kidney disease].

The number of patients with chronic kidney disease (CKD) continues to increase all over the world for the past ten years. It follows that we have more CKD patients with various complications who need perioperative management in Japan. Previous studies revealed that impaired renal function in preoperative period was the independent predictor of postoperative renal dysfunction. Safe comprehensive anesthetic management is required in order not to aggravate the preoperative CKD. In this review, we will take up some recent topics and novel concept in association with noncardiac surgery for the perioperative management of CKD patients.

The RACHS-1 risk category can be a predictor of perioperative recovery in Asian pediatric cardiac surgery patients.

PURPOSE: The Risk Adjustment for Congenital Heart Surgery (RACHS-1) classification was originally designed to facilitate the prediction of in-hospital mortality for pediatric cardiac surgery patients. However, there have been few reports on clinical outcomes predicted by the RACHS-1 category, especially in an Asian population. The aim of this study was to determine whether RACHS-1 classification can predict patient outcomes. METHODS: A total of 580 pediatric cardiac surgery procedures performed from January 2005 to December 2009 were retrospectively classified into the six RACHS-1 categories. The association between RACHS-1 category and clinical outcomes, including length of catecholamine requirement, mechanical ventilation time, intensive care unit stay, and in-hospital mortality, were examined. RESULTS: The frequencies of RACHS-1 categories in the study population were: category 1, 10.7 %; category 2, 36.7 %; category 3, 42.8 %; category 4, 6.6 %; category 5, 0.0 %; category 6, 3.3 %. There was a significant linear correlation between RACHS-1 category and in-hospital mortality (r = 0.96, p < 0.001). Kaplan-Meier analysis demonstrated that length of catecholamine infusion, mechanical ventilation time, and ICU stay were significantly different (p < 0.05) in the different RACHS-1 categories, except for those between category 4 and 6 (p = 0.09). CONCLUSIONS: Based on the results of our analysis, we conclude that the RACHS-1 stratification system can predict in-hospital mortality and patient outcomes in patients undergoing pediatric cardiac surgery.

[How much dosage of heparin do you administer? The relationship between heparin dosage and activated coagulation time (ACT) value during cardiovascular surgery: a multi center investigations].

BACKGROUND: In cardiac surgery, unfractionated heparin is widely used for anticoagulation. There are differences of heparin dosages among institutions for cardiac surgery with and without cardiopulmonary bypass (CPB). The aim of this clinical investigation is to find out the optimal dosage of heparin for initiation of CPB. METHODS: In cardiac cases with CPB, patients' weight, initial dosage of heparin, ACT values after heparin administration, product name of heparin and ACT measurement devices were recorded. RESULTS: There were significant differences in initial dosages of heparin, basal ACT values and increment of ACT values per units of heparin among institutions. CONCLUSIONS: A significant difference was revealed among institutions regarding the initial heparin dosage for CPB, in spite of the same target of ACT. There was no evidence to determine the optimal dosage of heparin for initiation of CPB.

Phosphodiesterase 3 inhibition reduces platelet activation and monocyte tissue factor expression in knee arthroplasty patients.

BACKGROUND: Tissue damage during surgery activates platelets and provokes a prothrombic state. The current study attempted to determine the impact of phosphodiesterase 3 inhibitors on platelet activation, platelet-leukocyte aggregate formation, and monocyte tissue factor expression during and after total knee arthroplasty. METHODS: Thirty-four patients undergoing scheduled total knee arthroplasty were randomly assigned to receive either the phosphodiesterase 3 inhibitor milrinone or the same amount of saline perioperatively. The effects of milrinone on platelet and leukocyte function in vitro were then assessed in healthy volunteers. RESULTS: Perioperative infusion of milrinone significantly attenuated platelet activation; phosphorylation of intraplatelet p38 mitogen-activated protein kinase, extracellular signal-regulated kinase 1/2, and Akt; and platelet-leukocyte aggregation. Furthermore, perioperative tissue factor expression on monocytes and fibrin monomer complex production were reduced by milrinone infusion in patients undergoing total knee arthroplasty. In vitro studies using adenosine diphosphate- and collagen-stimulated blood samples from healthy volunteers confirmed the antiplatelet effects and reduced monocyte tissue factor expression by milrinone. These studies further showed that platelet aggregation and integrin alpha(IIb)beta(3) activation were modified by intraplatelet phosphatidylinositol 3-kinase/Akt and mitogen-activated protein kinase/extracellular signal-regulated kinase pathways, and that P-selectin expression on platelets and platelet-leukocyte aggregation were modulated by intraplatelet p38 mitogen-activated protein kinase pathway. CONCLUSION: Continuous milrinone infusion has the potential to reduce platelet activation and monocyte tissue factor expression during the perioperative period in total knee arthroplasty. These events may be mediated in part by the ability of milrinone to reduce activation of intraplatelet mitogen-activated protein kinases and phosphatidylinositol 3-kinase. The clinical impact of phosphodiesterase 3 inhibition on perioperative hemostasis remains to be elucidated.

[Current aspects of research on adrenergic receptor].

Adrenergic receptor is one of the superfamilies of G-protein-coupled receptor. Its members are homologous in structure and diverse in function and are among the most pursued targets for drug development. Molecular pharmacological studies have established classification, structure, and function of adrenergic receptors approximately 100 years after Dr Langley had first referred to the philosophical concept of receptive substance. Molecular technology can identify mediating receptor subtype for each function. In this review, I focus on the current and evolving understanding of adrenergic receptor, especially relevant to the clinical settings such as heart failure and inverse agonism, and research topics such as desensitization and polymorphism, for all anesthesiologists.

[Dietary-induced thermogenesis and perioperative thermoregulation].

After the ingestion or infusion of nutrients, there is an increase in energy expenditure which has been referred to as dietary or nutrient-induced thermogenesis. This thermogenesis induced by protein or amino acids is well known to be largest and most prolonged. According to these physiological backgrounds, preoperative amino acid infusion was reported to prevent postoperative hypothermia during general anesthesia and spinal anesthesia. Also, perioperative amino acid infusion is reported to improve the outcome of the patients undergoing off-pump CABG. Amino acid infusion was observed to shift upward the threshold core temperature for thermoregulatory vasoconstriction as well as to increase energy expenditure. Fructose also prevents perioperative hypothermia during surgery by the same mechanisms.

Perioperative amino acid infusion improves recovery and shortens the duration of hospitalization after off-pump coronary artery bypass grafting.

Perioperative amino acid infusion helps maintain core temperature and improves patient outcomes after gynecologic and orthopedic surgery. In the present study we prospectively determined the effect of amino acid infusion on esophageal core temperature and postoperative outcomes during off-pump coronary artery bypass grafting (CABG). One-hundred-eighty consecutive patients undergoing primary elective or urgent off-pump CABG were randomly divided into two groups: the i.v. amino acid infusion group (4 kJ kg(-1) h(-1) starting 2 h before surgery) and the saline infusion group (similar period and volume of saline infusion). The esophageal core temperature at the end of surgery was 35.6 (35.3-35.8) degrees C [mean (95% confidence interval)] in the saline infusion group and 36.1 degrees C (35.9-36.3) degrees C in the amino acid infusion group (P = 0.01). Kaplan-Meier analysis demonstrated that patients given amino acids required a significantly shorter duration of postoperative mechanical ventilation than patients given saline [median (95% confidence interval), 3.0 (2.5-3.9) vs 4.5 (3.8-5.8) h; P = 0.01]. Furthermore, intensive care unit stay [20 (19.5-38.4) vs 44 (21-45) h; P = 0.001] and days until fit for discharge from hospital [10 (9-11) vs 12 (11-13) days; P = 0.004] were significantly shorter in patients given amino acid. Perioperative amino acid infusion in patients undergoing off-pump CABG effectively minimizes intraoperative hypothermia and improves postoperative recovery.

Fructose administration increases intraoperative core temperature by augmenting both metabolic rate and the vasoconstriction threshold.

BACKGROUND: The authors tested the hypothesis that intravenous fructose ameliorates intraoperative hypothermia both by increasing metabolic rate and the vasoconstriction threshold (triggering core temperature). METHODS: Forty patients scheduled to undergo open abdominal surgery were divided into two equal groups and randomly assigned to intravenous fructose infusion (0.5 g . kg(-1) . h(-1) for 4 h, starting 3 h before induction of anesthesia and continuing for 4 h) or an equal volume of saline. Each treatment group was subdivided: Esophageal core temperature, thermoregulatory vasoconstriction, and plasma concentrations were determined in half, and oxygen consumption was determined in the remainder. Patients were monitored for 3 h after induction of anesthesia. RESULTS: Patient characteristics, anesthetic management, and circulatory data were similar in the four groups. Mean final core temperature (3 h after induction of anesthesia) was 35.7 degrees +/- 0.4 degrees C (mean +/- SD) in the fructose group and 35.1 degrees +/- 0.4 degrees C in the saline group (P = 0.001). The vasoconstriction threshold was greater in the fructose group (36.2 degrees +/- 0.3 degrees C) than in the saline group (35.6 degrees +/- 0.3 degrees C; P < 0.001). Oxygen consumption immediately before anesthesia induction in the fructose group (214 +/- 18 ml/min) was significantly greater than in the saline group (181 +/- 8 ml/min; P < 0.001). Oxygen consumption was 4.0 l greater in the fructose patients during 3 h of anesthesia; the predicted difference in mean body temperature based only on the difference in metabolic rates was thus only 0.4 degrees C. Epinephrine, norepinephrine, and angiotensin II concentrations and plasma renin activity were similar in each treatment group. CONCLUSIONS: Preoperative fructose infusion helped to maintain normothermia by augmenting both metabolic heat production and increasing the vasoconstriction threshold.

Atlantoaxial subluxation in different intraoperative head positions in patients with rheumatoid arthritis.

BACKGROUND: Disorders of the cervical spine are often observed in patients with rheumatoid arthritis (RA). However, the best head position for RA patients with atlantoaxial subluxation in the perioperative period is unknown. This study investigated head position during general anesthesia for the patients with RA and proven atlantoaxial subluxation. METHODS: During anesthesia of patients with RA and proven atlantoaxial subluxation, the authors used fluoroscopy to obtain a lateral view of the upper cervical spine in four different positions: the mask position, the intubation position, the flat pillow position, and the protrusion position. Copies of the still fluoroscopic images were used to determine the anterior atlantodental interval, the posterior atlantodental interval, and the angle of atlas and axis (C1-C2 angle). RESULTS: The anterior atlantodental interval was significantly smaller in the protrusion position (2.3 mm) than in the flat pillow position (5.1 mm) (P < 0.05). The posterior atlantodental interval was significantly greater in the protrusion position (18.9 mm) than in the flat pillow position (16.2 mm) (P < 0.05). The C1-C2 angle was, on average, 9.3 degrees greater in the protrusion position than in the flat pillow position (P < 0.05). CONCLUSION: This study showed that the protrusion position using a flat pillow and a donut-shaped pillow during general anesthesia reduced the anterior atlantodental interval and increased the posterior atlantodental interval in RA patients with atlantoaxial subluxation. This suggests that the protrusion position, which involves support of the upper cervical spine and extension at the craniocervical junction, might be advantageous for these patients.