Comparison of Blood Concentration and Weight-Based Heparin and Protamine Dosing Strategies for Cardiopulmonary Bypass: A Systematic Review and Meta-Analysis.

BACKGROUND:  The conventional method of heparin and protamine management during cardiopulmonary bypass (CPB) is based on total body weight which fails to account for the heterogeneous response to heparin in each patient. On the other hand, the literature is inconclusive on whether individualized anticoagulation management based on real-time blood heparin concentration improves post-CBP outcomes. METHODS:  We searched databases of Medline, Excerpta Medica dataBASE (EMBASE), PubMed, Cumulative Index to Nursing and Allied Health Literature (CINHL), and Google Scholar, recruiting randomized controlled trials (RCTs) and prospective studies comparing the outcomes of dosing heparin and/or protamine based on measured heparin concentration versus patient's total body weight for CPB. Random effects meta-analyses and meta-regression were conducted to compare the outcome profiles. Primary endpoints include postoperative blood loss and the correlation with heparin and protamine doses, the reversal protamine and loading heparin dose ratio; secondary endpoints included postoperative platelet counts, antithrombin III, fibrinogen levels, activated prothrombin time (aPTT), incidences of heparin rebound, and re-exploration of chest wound for bleeding. RESULTS:  Twenty-six studies, including 22 RCTs and four prospective cohort studies involving 3,810 patients, were included. Compared to body weight-based dosing, patients of individualized, heparin concentration-based group had significantly lower postoperative blood loss (mean difference (MD)=49.51 mL, 95% confidence interval (CI): 5.33-93.71), lower protamine-to-heparin dosing ratio (MD=-0.20, 95% CI: -0.32 ~ -0.12), and higher early postoperative platelet counts (MD=8.83, 95% CI: 2.07-15.59). The total heparin doses and protamine reversal were identified as predictors of postoperative blood loss by meta-regression. CONCLUSIONS:  There was a significant correlation between the doses of heparin and protamine with postoperative blood loss; therefore, précised dosing of both could be critical for reducing bleeding and transfusion requirements. Data from the enrolled studies indicated that compared to conventional weight-based dosing, individualized, blood concentration-based heparin and protamine dosing may have outcome benefits reducing postoperative blood loss. The dosing calculation of heparin based on the assumption of a one-compartment pharmacokinetic/pharmacodynamic (PK/PD) model and linear relationship between the calculated dose and blood heparin concentration may be inaccurate. With the recent advancement of the technologies of machine learning, individualized, precision management of anticoagulation for CPB may be possible in the near future.

Algorithmic and consultative integration of transfusion medicine and coagulation: a personalized medicine approach with reduced blood component utilization.

BACKGROUND: Therapy customized for the individual patient defines personalized medicine. Current transfusion therapy is performed primarily using general guidelines such as keeping the platelet count at >100,000/µL, the INR at ≤ 1.7 and fibrinogen at >100mg/dL for patients undergoing surgery. OBJECTIVE: The purpose of this report is to provide an algorithmic and consultative approach for the delivery of personalized and targeted blood component, blood derivative, and recombinant therapies in order to minimize unnecessary exposure to such therapies and to deliver an optimal risk-benefit ratio for a particular patient. METHODS: The initiative involved a step-wise process that included: 1. establishing "triggers" to alert and permit the clinical pathologist to intervene in the utilization of blood components for a given patient in the context of the blood bank inventory; 2. developing algorithms for the assessment of the patient's procoagulant/anticoagulant status so that appropriate blood component, derivative, and/or recombinant therapies could be instituted while minimizing the risk of thrombophilia; 3. a real time assessment and interpretation of the coagulation data so that dialogue between the pathologist and the patient's clinical team could be effected 24 hours a day, 7 days a week; and 4. monitoring the outcome of these efforts by comparing blood component utilization prior to or during development, early implementation and following full implementation of the program. RESULTS: "Triggers" (i.e., administration of six units of fresh frozen plasma [FFP] or ten units of cryoprecipitate or two single donor [apheresis] platelets in a 24-hour period) were approved. A diagnostic and therapeutic algorithm was constructed, with multidisciplinary input to assist in defining the coagulopathy contributing to the patient's microvascular bleeding in the adult cardiac surgery/cardiac intensive care unit (CICU) and the adult intensive care unit (AICU). Monitoring of utilization, prior to or during development, early implementation and following full implementation of this initiative, revealed a decline in the number of units of FFP, cryoprecipitate and single donor (apheresis) platelets administered. CONCLUSION: We report on the successful development of a model - based on the algorithmic and consultative integration of transfusion medicine and coagulation - that customizes blood component, derivative, and recombinant therapies appropriate for an individual patient's need, resulting in targeted transfusion therapy and associated with reduced blood component utilization.

Soluble fibrin monomer complex and cardiopulmonary bypass.

Soluble fibrin monomer complexes (SFMCs) are precursors of fibrin polymer formation. Laboratory tests can be used to detect SFMCs in plasma. The purpose of this study was to determine whether a positive SFMC test is associated with pre-operative, intra-operative, and post-operative variables for patients that have undergone cardiopulmonary bypass (CPB). Pre-operative, operative, post-operative, and laboratory data from 120 consecutive adults patients (July 3, 2006 to June 29, 2007) that had undergone cardiac surgery with the use of CPB were obtained from a prospective quality control database. Two groups were created. Group 1 was all negative (NEG). This group had no SFMC test with a positive result (n=60) and no positive SFMCs (POS, n=60). Group 2 was any positive (POS). This group had at least one positive SFMC test (n=60). The POS group had more patients with endocarditis (11.7% vs. 3.3%, p < .001), chronic obstructive pulmonary disease (COPD) (18% vs. 8.3%, p = .005), longer CPB time (172 +/- 64 vs. 151 +/- 53 minutes, p = .047), and fewer minimally invasive procedures (31.7% vs. 51.7%, p = .002). The POS group required intraoperative (70.0% vs. 53.3%, p = .010) and post-operative (75.5% vs. 45.0%, p < .001) transfusions more frequently than the NEG group, despite similar amounts of blood loss. SFMC tests in CPB may be associated with patient pre-operative status and an increase in transfusion requirements.

Autologous platelet gel: fad or savoir? Do we really know?

Autologous platelet-gel (APG) is the process of harvesting ones own cells (platelets), concentrating them most often through centrifugation, exposing them to an agonist which induces activation which releases intrinsic substances, and applying them to a target area to accelerate wound healing. APG is attractive because it concentrates a large number of biologically active substances, which are primarily proteins that participate in complex series of mechanisms involved in inflammation and wound healing. It has been used in numerous applications including sports medicine, dermatology, and surgery. However, there are few prospective randomized trials that have compared it in a rigorous manner to other techniques or to placebo. The following report is a review of APG, which includes a description of its perceived benefit, identification of the various modalities where it has been used, and criticisms concerning its use.

Perfusion quality improvement and the reduction of clinical variability.

The purpose of this study was to describe the development and utilization of a perfusion quality improvement program to reduce perfusion-to-perfusion variability in a large multi-center perfusion practice. Phase I of the study included the establishment of a perfusion database using standard spreadsheet format to serve multiple administrative functions including patient and procedure sequencing, predictive algorithms for yearly caseload, summary statistics, and inter-perfusionist comparison. The database used 236 separate variables, including demographic and clinical procedure-related categories. Forty of these variables are modifiable by perfusion interaction as established via protocol and algorithm. Phase II of the study used a perfusion electronic data recording system to automatically obtain patient data from physiologic monitors and the heart-lung machine. Data were transferred to a central database for perfusionist comparison. Data analysis used logical functions and macros programming, and statistical analysis used both parametric and non-parametric models within the program. Each quarter all variables underwent analysis with summary data established for the most recent 225 patients undergoing CPB. Twenty-five cases from each perfusionist (n = 9) were compared with the aggregate data of the entire staff, with reference to previous quarter's summary statistics. The results were discussed in monthly staff meetings and methods for improving compliance were discussed. Individual variation (p < .01) varied in 17 of 40 variables (26.0 +/- 8.6), with quarterly improvement (27.4 +/- 2.3 vs. 24.2 +/- 2.1 vs. 17.0 +/- 2.1) demonstrated in seven of nine individuals. In Phase II, performance was analyzed using the same variables as in Phase I but it also included the electronically recorded data from which 27 core measures were derived. All results were discussed with the staff at monthly departmental quality improvement meetings. The perfusion quality improvement program has evolved from a simple descriptive listing of cases to a quantitative instrument used to reduce variability amongst perfusionists and assure compliance with policies and standards of care.

Characteristics of uncontrolled hemorrhage in cardiac surgery.

Patients with uncontrolled hemorrhage require massive transfusion therapy and consume a large fraction of blood bank resources. Institutional guidelines have been established for treatment, but early identification and prevention in susceptible patients remains challenging. Uncontrolled hemorrhage was defined as meeting institutional guidelines for recombinant FVIIa administration. Patients who received rFVIIa were compared with patients who did not require the therapy but who were operated on during the same time period. After institutional review board approval, demographic, operative, and transfusion data were analyzed from a prospective database. Patients receiving rFVIIa were more likely to undergo multiple procedures (2.6 +/- 0.8 vs. 1.8 +/- 0.8; p < .001); aortic surgery (59% vs. 11%; p < .005); have a higher Cleveland Clinic Clinical Severity score (7.8 +/- 2.7 vs. 5.5 +/- 4.0; p < .005); require longer bypass (265 +/- 92 min vs. 159 +/- 63 min; p < .001), cross-clamp (182 +/- 68 min vs. 112 +/- 56 min; p < .001), and circulatory arrest (15 +/- 24 min vs. 2 +/- 7 min; p < .05) times; and require more autotransfusion (2580 +/- 1847 mL vs. 690 +/- 380 mL; p < .05). Uncontrolled hemorrhage is associated with more complex surgery requiring longer bypass times and more autotransfusion.

Factors that influence the ability to perform autologous priming.

The purpose of this study was to determine which factors impact the ability to perform autologous priming (AP) of the extracorporeal circuit. Second, the effects of differential AP on transfusion and volume requirements were evaluated. After institutional review board approval, demographic, operative, volumetric, and transfusion data were prospectively collected on 100 adult patients undergoing cardiopulmonary bypass (CPB). Two analyses were conducted: AP Taken and percent AP Given. For each analysis, three groups were created based on standard distribution. Group A included patients within less than mean--1 SD (< or = 500 mL AP Taken or > or = 90% AP Given back), group B included patients within mean +/- 1 SD (501-1299 mL AP Taken or 11%-89% AP Given back), and group C included patients greater than mean + 1 SD (> or = 1300 mL AP Taken or < or = 10% AP given back). Weight, pre-CPB hematocrit, clinical severity, and pre-CPB volume balance did not differ between the groups. Significant differences existed in AP Taken and percent AP Given between individual perfusionists. More AP was given back with higher urine output (group A: 846 +/- 700 mL, group B: 613 +/- 414 mL, group C: 384 +/- 272 mL; p = .004), more autotransfusion [group A: 0 (0,1300 mL), group B: 0 (0,500 mL), group C: 0 (0,250 mL); p = .008], and less AP Taken [group A: 800 (0,1300 mL), group B: 1000 (200,1600 mL), group C: 1000 (800,1600 mL); p = .001]. When more AP was taken, CPB hematocrit was higher (group A: 22.3% +/- 4.8%, group B: 25.6% +/- 4.7%, group C: 26.6% +/- 4.3%; p = .032), and fewer patients received red blood cells (group A: 64.3%, group B: 28.3%, group C:14.3%; p = .017). Some perfusionists were able to remove more AP before CPB. When more AP was taken, CPB hematocrit was higher, fewer patients received a transfusion, and less AP was given back. More AP was also given back with higher urine output and higher blood loss to the autotransfusion device.

A novel calculation to estimate blood volume and hematocrit during bypass.

Patient blood volume impacts most facets of perfusion care, including volume management, transfusion practices, and pharmacologic interventions. Unfortunately, there is a wide variability in individual blood volumes, and experimental measurement is not practical in the clinical environment. The purpose of this study was to evaluate a mathematical algorithm for estimating individual blood volume. After institutional review board approval, volumetric and transfusion data were prospectively collected for 165 patients and applied to a series of calculations. The resultant blood volume estimate (BVE) was used to predict the first and last bypass hematocrit. The estimated hematocrits using both BVE and 65 mL/kg were compared with measured hematocrits using the Pearson moment correlation coefficient and the Bland Altman measures of accuracy and precision. There was a wide range of BVE (minimum, 35 mL/kg; mean +/- SD, 64 +/- 22 mL/kg; maximum, 129 mL/kg). Using BVE, the estimated hematocrit was similar to the measured first (24.7 +/- 6.4% vs. 24.5 +/- 6.2%, r = 0.9884, p > .05) and last (24.5 +/- 5.9% vs. 25.1 + 5.7%, r = 0.9001, p > .05) bypass hematocrit. Using 65 mL/kg resulted in a larger difference between estimated and measured hematocrits for the first (25.6 +/- 4.5% vs. 24.5 +/- 6.2%, r = 0.6885, p = .030) and last (23.8 +/- 3.6% vs. 25.1 +/-5.7%, r = 0.5990, p = .001) bypass hematocrits. Compared with using 65 mL/kg for blood volume, the BVE allowed for a more precise estimated hematocrit during CPB.

Use of a multi-modality life support system.

The purpose of this study was to describe the design and utilization of a multi-modality life support system (MMLSS), which is used to provide extracorporeal support for cases such as left heart bypass (LHB), extracorporeal life support (ECLS), veno-venous bypass, and hypothermic resuscitation. The design of the MMLSS consisted of a mobile cart outfitted with a centrifugal pump, heater cooler, an in-line blood gas monitor, oxygen blender/flow meter, and assorted safety devices (pressure sensors and level and bubble detectors). A single disposable circuit was used for all procedures and designed to be easily modifiable to support a variety of clinical scenarios, with and without the use of an oxygenator. The system was designed for rapid deployment throughout the hospital. From January 1, 2006 to December 31, 2007, the MMLSS has been used in three LHB procedures (63 +/- 72 minutes), four adult ECLS cases (57.2 +/- 56.9 hours), four veno-venous bypasses (72 +/- 35 minutes), and one hypothermic resuscitation (182 minutes). The MMLSS was designed to be used in patients > 20 kg and could achieve flows in the range of 1-5.5 L. There were no complications associated with the device. The MMLSS is a versatile system that can be used throughout the hospital with a single disposable circuit, accommodating a diverse caseload in a safe and reproducible manner.

Dose titration of recombinant factor VIIa using thromboelastograph monitoring in a child with hemophilia and high titer inhibitors to factor VIII: a case report and brief review.

The administration of recombinant factor VIIa (rFVIIa) is complicated by a wide inter-subject variation in response, a short half-life, evolving indications for use, and the absence of a test that has been shown to correlate with clinical effect. This report describes a method used to titrate rFVIIa to thromboelastography (TEG) parameters in a difficult to manage hemophilic patient with high titer inhibition to factor VIII. The current concepts of monitoring rFVIla administration in hemophiliacs and uncontrolled hemorrhage in cardiac surgery are briefly reviewed.

Autologous platelet concentrate and vacuum-assisted closure device use in a nonhealing total knee replacement.

Following a total knee replacement surgery, a 51-year-old insulin-dependent patient presented with complications of impaired healing and postoperative trauma to the wound site. The inability of this leg wound to heal placed this patient at risk of amputation. Vacuum-assisted closure therapy was initiated at postoperative day 53; after 100 days of protracted wound history a series of treatments with topical platelet concentrates were added to the vacuum assisted closure therapy and conventional wound care therapy. The previous nonhealing wound presented with good granulation and margination that enabled a skin graft with good take on postoperative day 150.

Improved outcomes during cardiac surgery: a multifactorial enhancement of cardiopulmonary bypass techniques.

Patients presenting for cardiac surgery with cardiopulmonary bypass (CPB) are more likely to have pre-existing comorbidities, which has resulted in a steady increase in the risk associated with CPB. The resulting challenge has mandated the optimization of perfusion care. The purpose of this study was to retrospectively evaluate the impact of a number of simultaneous, evidence based perfusion care changes on patient outcome. After Institutional Review Board approval, two groups of patients were compared. The control group (n = 317) included all patients undergoing CPB in a 12-month period preceding a multifaceted change in perfusion techniques. The treatment group (n = 259) included all patients undergoing CPB in the 12-month period after the changes, which included the incorporation of updated continuous blood gas monitoring, biocompatible circuitry, updated centrifugal blood propulsion, continuous autotransfusion technology, new generation myocardial protection instrumentation, plasmapheresis, topical platelet gel application, excluding hetastarch while increasing the use of albumin, viscoelastographic coagulation monitoring, and implementing a quantitative quality improvement program. After univariate analysis, propensity scoring and multiple conditional logistical regression were used to control for demographic, preoperative, operative, and postoperative parameters. Results of the primary endpoints revealed a lower mortality rate in the treatment group (4% vs. 9% [95% confidence interval 1.33, 7.72], p = 0.009), lower transfusion rate (51% vs. 59% [1.00, 2.11], p = 0.048), and lower complication rate (55% vs. 65% [1.06,2.19], p = 0.025) despite having similar predicted mortality (11 [2,22] vs. 11[3,22], p = NS) and other preoperative and operative parameters. The lower mortality rate was concurrent with a trend towards a lower incidence of complications, consistent with the differences in primary outcomes. In conclusion, the patients treated after the implementation of a multifactorial improvement plan using evidence based changes in CPB care had decreased complication and mortality rates.

Use of the Quest Myocardial Protection System (MPS) for modified ultrafiltration during pediatric cardiac surgery.

Modified ultrafiltration generally is considered a standard of care for treating children undergoing cardiopulmonary bypass for congenital heat surgery. Different methods, incorporating a variety of devices and technologies, have been described. The present report describes a technique of modified ultrafiltration using arterial-venous flow with the Quest Myocardial Protection System (MPS).

Utilization of rapid-infuser devices for massive blood loss.

Rapid volume replacement for severe hemorrhage continues to challenge the clinician involved in the care of the patient suffering hemorrhagic shock. We report on the development and utilization of two rapid-infuser systems for volume replacement in critically ill patients presenting in extremis. We have developed rapid-infusion circuits by using commercially available devices available at our institution. The primary pumping mechanism is either a centrifugal pump (Revolution--COBE Cardiovascular, Arvada, CO, USA), or the Myocardial Protection System (MPS Quest Medical, Allen, TX, USA), and offers advantages over commercially available devices. Both circuits consist of a cardiotomy reservoir, a cardioplegia delivery set, assorted tubing and connectors, and a heater-cooler system. Between January and October of 2003, 15 procedures were performed which utilized one of these two devices. There were nine ruptured aneurysms, five traumas and one radical nephrectomy. The rapid infusion time averaged 228.5 +/- 105.7 min where 10.4 +/- 9.4 L of autotransfusion volume was processed, with 3.9 +/- 4.2 L of red cell volume reinfused. The allogeneic blood products that were transfused included packed red blood cells and fresh frozen plasma, as well as 5% albumin. There were no intraoperative deaths and the rapid-infuser was considered lifesaving in all instances. Mechanical rapid infusion systems may be lifesaving when severe hypovolemia or hemorrhagic shock is encountered. While both devices are able to meet the requirements of rapid fluid replacement, the MPS offers the most safety features and has become the standard of care at our institution.

Coagulation management of a patient with factor V Leiden mutation, lupus anticoagulant, and activated protein C resistance: a case report.

Although patients undergoing cardiac surgery often present with diverse comorbidities, those with coagulation derangements are especially challenging. The present report describes the management of a patient who presented with a Factor V Leiden mutation, lupus anticoagulant, and acquired activated protein C resistance. A 42-year-old female presented with acute shortness of breath and chest pain. She was otherwise healthy 1 month prior to admission when she presented with dysfunctional uterine bleeding, resulting in the transfusion of three units of packed red blood cells. Coagulation evaluation revealed that the patient had lupus anticoagulant, factor V Leiden mutation and an activated protein C resistance. The patient presented with an acute myocardial infarction and was found to have 90% stenosis of her left main coronary artery, moderate mitral and tricuspid regurgitation, and a left ventricular ejection fraction of 25%. An emergent off-pump coronary artery bypass procedure with placement of a vein graft to the left anterior descending artery was completed. Intraoperative thrombophilia was encountered as evidenced by both an elevated thromboelastograph coagulation index (+3.6) and an acquired antithrombin-III deficiency. Postoperatively, the patient was placed on low molecular weight heparin, but developed heparin-induced thrombocytopenia and was switched to a direct thrombin inhibitor, argatroban. The following case report describes the coagulation management of this patient from the time of admission to discharge 43 days later, and the unique challenges this combination of hemostatic defects present to the clinicians.

Use of platelet gel and its effects on infection in cardiac surgery.

The use of plasmapheresis in cardiac surgery has failed to show an unequivocal benefit. However, the further processing of plasmapheresed blood to obtain a platelet-rich concentrate, termed platelet gel, may reduce patient susceptibility to infection through poorly understood mechanisms related to a combination of platelets, white blood cell content, and expedited wound healing. The purpose of the study was to retrospectively evaluate the incidence wound infections in patients undergoing cardiac surgery. Platelet gel (PG) patients (n = 382) received topical administration of a mixture of platelet concentrated plasma, 10% calcium chloride (5 mL), and bovine thrombin (5000 units). A control group (NoPG, n = 948) operated on concurrently with the treatment group did not receive PG, but otherwise received similar wound care. A historical control (HC, n = 929) included patients operated on before the availability of PG. After Institutional Review Board approval, 20 factors reported in the literature to predispose individuals for increased infection were recorded along with infections classified either as superficial or deep sternal according to the Society of Thoracic Surgeon criteria. All data were obtained from our institutional contribution to the Society of Thoracic Surgeon database. All adult (>19 years of age) patients undergoing cardiac surgery at our institution between October 2002 and June 2005 were included in this study (n = 2259). The incidence of superficial infection was significantly lower in the PG group (0.3%) compared both with the NoPG (1.8%) and HC (1.5%) groups (p < .05). There was a similar relationship found when comparing deep sternal wound infections (PG, 0.0% vs. NoPG, 1.5%; p < .029 and PG vs. HC, 1.7%;p < .01). In conclusion, the application of PG in patients undergoing cardiac surgery seems to confer a level of protection against infection, although the mechanisms of action remain to be elucidated.

Selective deep spinal hypothermia with vacuum-assisted cerebral spinal fluid drainage for thoracoabdominal aortic surgery.

Recent experiences from several centers indicate that the overall risk of spinal cord ischemia during thoracoabdominal aortic aneurysm repair has decreased to 5-8%. The results from these centers are rather consistent, despite the use of a variety of spinal protection strategies. An alternative to the various distal aortic perfusion techniques is selective spinal cooling by cold saline lavage. The principle advantage of selective hypothermia is the avoidance systemic heparinization and extracorporeal by-passes, while affording comparable spinal protection. The primary method of spinal cooling was pioneered by Cambria et al. at Massachusetts General Hospital. In their experience, paraplegia or paresis occurred in 6.9% of patients (5-year period, 170 cases). An alternative to the Cambria method utilizes readily available perfusion supplies and offers the potential advantages of lower cerebral spinal fluid-systemic blood pressure differences, more expedient cooling, and deeper spinal hypothermia. This report describes this method and the clinical course of a patient treated with it.