Early hemostatic responses to trauma identified with hierarchical clustering analysis.

BACKGROUND: Trauma-induced coagulopathy is a complex multifactorial hemostatic response that is poorly understood. OBJECTIVES: To identify distinct hemostatic responses to trauma and identify key components of the hemostatic system that vary between responses. PATIENTS/METHODS: A cross-sectional observational study of adult trauma patients at an urban level I trauma center emergency department was performed. Hierarchical clustering analysis was used to identify distinct clusters of similar subjects according to vital signs, injury/shock severity, and comprehensive assessment of coagulation, clot formation, platelet function, and thrombin generation. RESULTS: Among 84 total trauma patients included in the model, three distinct trauma clusters were identified. Cluster 1 (N = 57) showed platelet activation, preserved peak thrombin generation, plasma coagulation dysfunction, a moderately decreased fibrinogen concentration and normal clot formation relative to healthy controls. Cluster 2 (N = 18) showed platelet activation, preserved peak thrombin generation, and a preserved fibrinogen concentration with normal clot formation. Cluster 3 (N = 9) was the most severely injured and shocked, and showed a strong inflammatory and bleeding phenotype. Platelet dysfunction, thrombin inhibition, plasma coagulation dysfunction and a decreased fibrinogen concentration were present in this cluster. Fibrinolytic activation was present in all clusters, but was particularly increased in cluster 3. Trauma clusters were most noticeably different in their relative fibrinogen concentration, peak thrombin generation, and platelet-induced clot contraction. CONCLUSIONS: Hierarchical clustering analysis identified three distinct hemostatic responses to trauma. Further insights into the underlying hemostatic mechanisms responsible for these responses are needed.

Intravenous perfluorocarbon emulsion increases nitrogen washout after venous gas emboli in rabbits.

Intravenous perfluorocarbon emulsion (IV-PFC) has been shown to provide hemodynamic protection from gas embolism (Venous-VGE or arterial-AGE). The objective of this study was to investigate the mechanism of PFC protection from controlled VGE by quantifying the effects of IV-PFC emulsion on pulmonary elimination of nitrogen (N2). All rabbits received an intravenous pretreatment of PFC emulsion (Oxygent, 2.7 g/kg) or saline, then either a continuous room air infusion (0.25 ml/kg for 10 minutes) or a bolus of air (0.8 ml/kg within 10 seconds) through the femoral vein. Expiratory N2 peaked higher with PFC infusion immediately after air injection. The recovery to baseline of end tidal N2 was faster for PFC-treated animals (40 +/- 4.7 vs. 58 +/- 6.5 minutes). In PFC-treated animals, expired CO2, O2, arterial pressure and central venous pressure returned to baseline faster than the saline group. This study demonstrated that PFC increased pulmonary N2 washout. Correspondingly, PFC treatment better preserved the animals' hemodynamics after VGE injury. The use of IV-PFC promises to be a breakthrough non-recompression therapy for gas embolism in the treatment of Decompression Sickness (DCS) and in surgery.

Onset of force development as a marker of thrombin generation in whole blood: the thrombin generation time (TGT).

Prothrombin activation requires the direct interplay of activated platelets and plasma clotting factors. Once formed, thrombin causes profound, irreversible activation of platelets and reinforces the platelet plug via fibrin formation. Delayed or deficient thrombin production increases bleeding risk. Commonly employed coagulation assays, the prothrombin and partial thromboplastin times, use clot formation as a surrogate marker of thrombin generation. These assays routinely utilize platelet-poor plasma and completely miss the effects of platelets. Other markers of thrombin generation, prothrombin fragment 1 + 2 (F1 + 2) and thrombin-antithrombin complex, are typically measured after the fact. We report a simple assay, which employs the onset of platelet contractile force (PCF) as a surrogate marker of thrombin generation. PCF generation occurs concomitant with the burst of F1 + 2 release. The time between assay start and PCF onset is termed the thrombin generation time (TGT). TGT is prolonged in clotting factor deficiencies and in the presence of direct and indirect thrombin inhibitors. TGT shortens to normal with clotting factor replacement and shortens with administration of recombinant factor VIIa. TGT is short in thrombophilic states such as coronary artery disease, diabetes and thromboangiitis obliterans and prolongs toward normal with oral and intravenous anticoagulants.

Comparison of bioimpedance versus thermodilution cardiac output during cardiac surgery: evaluation of a second-generation bioimpedance device.

OBJECTIVE: To compare a second-generation thoracic electrical bioimpedance (TEB) hemodynamic monitoring system with the clinically used pulmonary artery catheter thermodilution (TD-PAC) system. DESIGN: Blinded, simultaneous measurements at specified key time points during surgery. SETTING: University teaching hospital cardiac surgical operating rooms. PARTICIPANTS: Forty-seven patients undergoing primary elective coronary artery bypass surgery. INTERVENTIONS: Timed cardiac output measurements by thermodilution and continuous monitoring of bioimpedance were performed. MEASUREMENTS AND MAIN RESULTS: Cardiac index (TEB and TD-PAC) and other hemodynamic parameters were measured at 4 time points: (1) after anesthesia induction, (2) with the mediastinum open, (3) immediately after cardiopulmonary bypass, and (4) at the end of the case. Pearson's correlation and Bland-Altman analysis were carried out. Cardiac index by TEB and TD-PAC had an overall correlation of r = 0.71 (p < 0.0001). The Bland-Altman statistics showed a mean difference of -0.28 L/min/m2 and precision of 0.67 L/min/m2. The best correlation was at time 1, and the lowest correlation was at time 4. Mediastinal opening and cardiopulmonary bypass had little or no effect on the correlation between technologies. CONCLUSION: TEB reporting of cardiac index during coronary artery surgery generally agreed with TD-PAC cardiac index except at the end of the case (time 4).

Blood transfusion: the silent epidemic.

Blood transfusion has been widely studied and the risk/benefit ratio remains unclear. Focus historically has been upon viral transmission, particularly hepatitis and HIV. Today, with advanced screening for these viruses, the risk for such transmission has become vanishingly small. Immunosuppression, with consequent postoperative bacterial infection and ABO incompatibility are now risks that physicians should consider as associated with allogeneic blood transfusion. Other inflammatory events, such as transfusion associated acute lung injury, also occur. The benefits of transfusion have never been well studied and there is scant literature on that area. Therefore, in an evidence-based medical practice the physician should regard transfusion with a skewed risk/benefit ratio. The following article examines that risk/benefit ratio in the post-AIDS era.

Factor XIIIA and clot strength after cardiopulmonary bypass.

Reduced factor XIIIA levels and decreased clot strength have been associated with increased bleeding after cardiopulmonary bypass (CPB). The purpose of this study was to evaluate the relationship between hemostatic factors, including factor XIIIA, and clot strength before, during and after CPB. Factor XIIIA antigen, platelet counts, fibrinogen, factor V activity, tissue plasminogen activator and clot strength (by thromboelastograph) were measured at baseline, after 45 min of CPB, at the end of CPB and 4 h post-operatively in 34 patients. Baseline factor XIIIA antigen was 5.2 +/- 1.4 mg/l. On average, factor XIIIA levels dropped to 64% and clot strength to 77% of baseline values after 45 min on CPB and remained below baseline during the immediate post-operative period. Clot strength was significantly correlated (r = 0.81) with platelet count and fibrinogen but not plasma factor XIIIA levels. Addition of 10 mg/l recombinant factor XIII[a2] significantly increased clot strength. Postoperative bleeding at 2 h was inversely correlated with platelet count, factor XIIIA antigen and clot strength measured at the end of CPB. Maintenance of adequate platelet counts and factor XIIIA levels at the end of CPB may play a role in maintaining clot strength and reducing blood loss.

Institutional variability in red blood cell conservation practices for coronary artery bypass graft surgery. Institutions of the MultiCenter Study of Perioperative Ischemia Research Group.

OBJECTIVE: To assess whether substantial institutional variability exists in red blood cell conservation practices associated with coronary artery bypass graft (CABG) surgery. DESIGN: Prospective, randomized patient enrollment and data collection. SETTING: Twenty-four U.S. academic institutions participating in the Multicenter Study of Perioperative Ischemia. PARTICIPANTS: A well-defined subset of primary CABG surgery patients (n = 713) expected to be at low risk for bleeding and exposure to allogeneic transfusion. INTERVENTIONS: None (observational study). MEASUREMENTS AND MAIN RESULTS: Frequency of use of red blood cell conservation techniques was determined among institutions. Correlation was determined between use of each technique and transfusion of allogeneic red blood cells and between use of each technique and median institutional blood loss. Significant variability (p < 0.01) was detected in institutional transfusion practice with respect to the use of predonated autologous whole blood, normovolemic hemodilution, red cell salvage, and reinfusion of shed mediastinal blood. The frequency of institutional use of these techniques was not associated with allogeneic transfusion (r2 < 0.15) or blood loss (r2 < 0.10) in the low-risk population of patients examined. CONCLUSIONS: Institutions vary significantly in perioperative blood conservation practices for CABG surgery. Further study to determine the appropriate use of these techniques is warranted.

A second-generation blood substitute (Perfluorodichlorooctane emulsion) generates spurious elevations in platelet counts from automated hematology analyzers.

UNLABELLED: Perfluorocarbon emulsions (PFEs) appear as platelets in automated cell counters, which may affect samples from thrombocytopenic patients (less than 100,000/microL). Therefore, we mixed clinically relevant concentrations of perfluorodichlorooctane (Oxyfluor(R); Hemagen, Inc., St. Louis, MO) in vitro with whole blood samples ranging from 0 to 150,000 platelets/microL and compared a new counter that uses optical platelet recognition (Abbott CellDyn 3200; Santa Clara, CA) with conventional electroimpedance-based counters (Abbott CellDyn 3500 and CellDyn 1700). We found that emulsion particles appear as small-sized platelets either in diluent or in blood. The emulsion results in a reproducible overestimate of the platelet counts, of greater importance as PFE concentration increases, and as the actual platelet count of the blood samples decreases. The new optical technology yields smaller overestimates but, even at low PFE concentrations, gives an unacceptable relative error at platelet counts near the transfusion thresholds recommended by the American Society of Anesthesiologists guidelines for blood component therapy. Unexpected interference in the leukocyte and erythrocyte channels is also reported. Experimental limitations preclude extrapolation of these findings to other automated cell counters, because differences in technology or software may affect their capacity to separate PFE particles from platelets. IMPLICATIONS: Perfluorocarbons are being investigated under conditions in which thrombocytopenia is likely to occur. In this in vitro study, we demonstrate significant overestimates in platelet counts from automated cell counters at clinically relevant perfluorocarbon concentrations in thrombocytopenic blood samples.

Maintenance of homeostasis in coagulation during cardiopulmonary bypass.

Cardiopulmonary bypass (CPB) represents a massive stimulus that overwhelms the body's homeostatic ability to buffer. Contact activation, the extrinsic cascade, and ongoing cellular interactions all must be considered to understand the coagulation dysfunction that occurs in CPB. Various aspects and the specific effects of these factors as well as their interrelationships are still poorly understood. Since we are dealing with a complex system, the way we approach our investigations must become more rather than less complex. Simply measuring peripheral blood levels of various proteins throughout CPB levels does not fit the important physiologic processes governing homeostasis, as production, clearance, redistribution, and dilution are all constantly at play. A recent study of prothrombin fragment F1.2 levels during CPB is provided as an illustration. Our increasing understanding of aprotinin's mechanisms of action has furthered our basic understanding of coagulation dysfunction in CPB. Further progress requires new thinking, more research, and increasingly complex approaches to the understanding of what drives homeostasis.

Safety and efficacy of shed mediastinal blood transfusion after cardiac surgery: a multicenter observational study. Multicenter Study of Perioperative Ischemia Research Group.

OBJECTIVE: To examine the efficacy and safety of shed mediastinal blood (SMB) transfusion in preventing allogenic red blood cell (RBC) transfusion. DESIGN: An observational clinical study. SETTING: Twelve US academic medical centers. PARTICIPANTS: Six hundred seventeen patients undergoing elective primary coronary artery bypass grafting. INTERVENTIONS: Patients were administered SMB transfusion or not, according to institutional and individual practice, without random assignment. MEASUREMENTS AND RESULTS: The independent effect of SMB transfusion on postoperative RBC transfusion was examined by multivariable modeling. Potential complications of SMB transfusion, such as bleeding and infection, were examined. Three hundred twelve of the study patients (51%) received postoperative SMB transfusion (mean volume, 554 +/- 359 mL). Patients transfused with SMB had significantly lower volumes of RBC transfusion than those not receiving SMB (0.86 +/- 1.50 v 1.08 +/- 1.65 units; p < 0.05). However, multivariable analysis showed that SMB transfusion was not predictive of postoperative RBC transfusion. Demographic factors (older age, female sex), institution, and postoperative events (greater chest tube drainage, lower hemoglobin level on arrival to the intensive care unit, and use of inotropes) were significant predictors of RBC transfusion. The volume of chest tube drainage on the operative day (707 +/- 392 v 673 +/- 460 mL; p = 0.30), reoperation for hemorrhage (3.1% v2.5%; p = 0.68), and overall frequency of infection (5.8% v 6.6%; p = 0.81) were similar between patients receiving and not receiving SMB, respectively. However, in patients who did not receive allogenic RBC transfusion, there was a significantly greater frequency of wound infection in the SMB group (3.6% v0%; p = 0.02). CONCLUSION: These data suggest that SMB is ineffective as a blood conservation method and may be associated with a greater frequency of wound infection.

Angiographic and histological evaluation of porcine retinal vascular damage and protection with perfluorocarbons after massive air embolism.

BACKGROUND AND PURPOSE: We have previously shown that perfluorocarbon emulsions (PFEs) reduce the severity of cerebral injury (indicated by infarct, reduced blood flow, and depressed EEG) induced by air embolism during cardiopulmonary bypass (CPB). This study used retinal fluorescein angiography to define the mechanisms of cerebral injury and to determine the efficacy of PFEs in cerebral protection. These angiographic findings were correlated to previously reported histologic findings. METHODS: Twenty domestic pigs underwent CPB with a prime of standard crystalloid or PFE (5 mg/kg) and crystalloid. After 10 minutes on CPB, a single (5 mL/kg) or double (2x2.5 mL/kg) bolus of room air or saline (control) was delivered via the right carotid artery. Retinal fluorescein angiograms were captured at 4 time points: baseline, air insult, postbypass, and postreperfusion. Following euthanasia, both eyes were removed and the retinas isolated for histological analysis with horseradish peroxidase (HRP), as previously reported. RESULTS: In control pigs, postreperfusion angiograms showed small nonperfused areas, and retinal whole mounts demonstrated vascular damage as previously reported. In 5 PFE-primed animals, postreperfusion angiograms showed hyperfluorescence, but angiograms and HRP mounts were otherwise not significantly different from baseline. Severely hyperfluorescent vessels observed angiographically also showed a correlation with HRP extravasation but were not consistently indicative of severe vascular damage. CONCLUSIONS: Retinal fluorescein angiography and retinal staining with HRP indicate that mechanisms of cerebral air embolism include nonperfusion, vascular leakage and spasm, red blood cell sludging, and hemorrhage. Priming with PFE prevented many of the sequelae associated with air embolism.

Hematocrit value on intensive care unit entry influences the frequency of Q-wave myocardial infarction after coronary artery bypass grafting. The Institutions of the Multicenter Study of Perioperative Ischemia (McSPI) Research Group.

OBJECTIVES: No data exist regarding "the best" hematocrit value after coronary artery bypass graft surgery. Transfusion practice varies, because neither an optimal hematocrit value nor a uniform transfusion trigger criterion has been determined. METHODS: To investigate the optimal hematocrit value, we studied 2202 patients undergoing coronary bypass. The hematocrit value on entry into the intensive care unit (IHCT) was categorized into three groups: high (> or = 34%), medium (25% to 33%), and low (< or = 24%). Characteristics and adverse events (outcomes) were compared, and the effect of IHCT on the risk of myocardial infarction was determined by logistic regression. RESULTS: High IHCT (> or = 34%) was associated with an increased rate of myocardial infarction (8.3% vs 5.5% vs 3.6%; p < or = 0.03, high, medium vs low) and with more severe left ventricular dysfunction (11.7% vs 7.4% and 5.7%; p=0.006, high, medium vs low). Mortality rate increased with higher IHCT when all the high-risk subgroups were combined (8.6% vs 4.5% vs 3.2%; p < 0.001, high, medium vs low). By multivariate analysis, IHCT remained the most significant predictor of adverse outcomes (relative risk high vs low 2.22, 95% confidence interval: 1.04 to 4.76). No characteristic, event, medication, or transfusion therapy confounded the relationship between IHCT and outcome. CONCLUSION: High IHCT is associated with a higher rate of myocardial infarction and is an independent predictor of infarction. On the basis of the risk of myocardial infarction, there is no rationale for transfusion to an arbitrary level after coronary artery bypass grafting.

A second-generation blood substitute (perfluorodichlorooctane emulsion) does not activate complement during an ex vivo circulation model of bypass.

OBJECTIVES: To examine whether a second-generation perfluorocarbon (PFC) blood substitute added to the cardiopulmonary bypass (CPB) prime influences complement production. DESIGN: A prospective, randomized, single-blinded, ex vivo model. SETTING: A university hospital, laboratory, and clinics. PARTICIPANTS: Ten healthy adult consented volunteer blood donors (five men, five women). INTERVENTIONS: Ex vivo closed-loop extracorporeal circuit including membrane oxygenator, tubing, and filter primed with crystalloid or crystalloid plus PFC was circulated for 1 hour with the addition of 500 mL of heparinized fresh human whole blood. MEASUREMENTS AND MAIN RESULTS: Laboratory specimens were drawn from the circuit at 10-minute intervals for 1 hour and measured for complement (C3a, Bb fragment) concentrations, blood gases, fibrinogen concentration, platelet count, and hematocrit. In the PFC group, C3a and Bb fragments were equal to or less than those in the group that received crystalloid alone. CONCLUSION: The second-generation PFC added to the prime of a CPB circuit does not independently increase complement production.

Heparin-coated bypass circuits (Carmeda) suppress the release of tissue plasminogen activator during normothermic coronary artery bypass graft surgery.

OBJECTIVES: To study fibrinolysis in a homogeneous first-time coronary artery bypass surgery (CABG) population in whom heparin-coated circuits were used. DESIGN: A prospective, blinded, randomized, placebo-controlled study. SETTING: A university hospital, tertiary care, intraoperative and postoperative intensive care unit. PARTICIPANTS: Twenty-one adult elective primary CABG patients. INTERVENTIONS: Randomized circuit-type centrifugal pump, membrane oxygenator, rigid cardiotomy reservoir, either placebo (n = 10) or heparin-coated (n = 11) (Carmeda; Medtronic Inc., Anaheim, CA). MEASUREMENTS AND MAIN RESULTS: Blood samples were analyzed for tissue plasminogen activator (TPA) activity, TPA antigen, plasminogen activator inhibitor-1 (PAI-1) activity, prothrombin complex F1.2, and antithrombin III (AT-III) at the following times: before cardiopulmonary bypass (CPB), during CPB (30 and 60 minutes), post-CPB, and day 1 postsurgery. TPA activity and antigen increased fivefold in the placebo group during CPB, whereas it did not even double in the heparin-coated group. PAI-1, F1.2, and AT-III were not different between groups. CONCLUSIONS: Heparin-coated CPB circuits reduced TPA release in this homogeneous CABG population with routine heparin/protamine management.

Variability in transfusion practice for coronary artery bypass surgery persists despite national consensus guidelines: a 24-institution study. Institutions of the Multicenter Study of Perioperative Ischemia Research Group.

BACKGROUND: An estimated 20% of allogeneic blood transfusions in the United States are associated with cardiac surgery. National consensus guidelines for allogeneic transfusion associated with coronary artery bypass graft (CABG) surgery have existed since the mid- to late 1980s. The appropriateness and uniformity of institutional transfusion practice was questioned in 1991. An assessment of current transfusion practice patterns was warranted. METHODS: The Multicenter Study of Perioperative Ischemia database consists of comprehensive information on the course of surgery in 2,417 randomly selected patients undergoing CABG surgery at 24 institutions. A subset of 713 patients expected to be at low risk for transfusion was examined. Allogeneic transfusion was evaluated across institutions. Institution as an independent risk factor for allogeneic transfusion was determined in a multivariable model. RESULTS: Significant variability in institutional transfusion practice was observed for allogeneic packed red blood cells (PRBCs) (27-92% of patients transfused) and hemostatic blood components (platelets, 0-36%; fresh frozen plasma, 0-36%; cryoprecipitate, 0-17% of patients transfused). For patients at institutions with liberal rather than conservative transfusion practice, the odds ratio for transfusion of PRBCs was 6.5 (95% confidence interval [CI], 3.8-10.8) and for hemostatic blood components it was 2 (95% CI, 1.2-3.4). Institution was an independent determinant of transfusion risk associated with CABG surgery. CONCLUSIONS: Institutions continue to vary significantly in their transfusion practices for CABG surgery. A more rational and conservative approach to transfusion practice at the institutional level is warranted.