The effect of ultrafiltration with cardiopulmonary bypass on the removal of dabigatran from the circulation of adult pigs.

OBJECTIVE: Dabigatran etexilate is a direct thrombin inhibitor approved for use in patients with non-valvular atrial fibrillation. There is no currently available pharmacological therapy to reverse this renally cleared anticoagulant. Dabigatran has a low level of plasma protein binding and has been considered dialyzable. We used a pig model with renal artery ligation to exclude intrinsic drug excretion to examine the efficacy of ultrafiltration (UF) during cardiopulmonary bypass (CPB) for dabigatran removal. METHOD: Dabigatran was intravenously infused (20 mg) in Yorkshire pigs (male, n=7, 70±1 kg) following renal artery ligation. CPB with UF was initiated after heparinization and continued until a total volume of 6 liters of UF effluent was removed. Serial labs, including dabigatran concentration, activated coagulation times (ACT), hematocrit and creatinine were drawn at intervals before the start of CPB and then incrementally during UF (0, 2, 4 and 6 L removed). Hemodialysis (HD) was performed on one animal following UF. RESULTS: Dabigatran concentration (ng/mL) rose from undetectable levels at baseline to 296±70 (p<0.05) at the conclusion of infusion, but dropped significantly upon administration of heparin (178±40, p<0.05). A further decrement in dabigatran concentration was observed from the administration of heparin to the start of CPB (to 135±28, p<0.05). Once on CPB, dabigatran remained stable, with the end UF (eUF) dabigatran concentration being 133±34. Dabigatran concentration in the UF effluent was measured in one animal and was 98.8, with 6 L of effluent having been removed. The total recovery of dabigatran was calculated to be less than 5%. Dabigatran concentrations also did not decrease appreciably with HD on CPB following UF. CONCLUSIONS: UF in conjunction with CPB was ineffective at removing dabigatran. Heparin demonstrated a dabigatran-lowering effect, suggesting a possible drug interaction or assay impairment. Based on these findings, emergent cardiac surgery with UF on cardiopulmonary bypass to remove dabigatran is not advisable. Alternative forms of drug removal or reversal must be identified.

Predicting adult perfusion practice trends and the adoption of evidence-based practice.

In an effort to provide optimal patient care, perfusionists should rely on information provided by current research. Present statistics, however, document a substantial underuse of evidence-based clinical practice and therapies not only in perfusion, but throughout the entire medical field. This investigation applied a statistical method--binomial proportion analysis--to aid in uncovering the trends in perfusion practice from 2004 to 2011. Through the analysis of national adult perfusion practice surveys, the feasibility of using binomial proportion statistical analysis is assessed in its ability to track adult perfusion practice proportional differentials over time and evaluate the adoption and attitudes toward the compliance of evidence-based practice within the field of perfusion. Surveys conducted in 2004 and 2006 on adult perfusion practice in the United States--although not published--are compared with data obtained by a similar survey distributed in 2011 through an international perfusion network system and perfusion mailing system, Perflist and Perfmail. The increase of perfusionists who practice retrograde and antegrade autologous priming (R/A AP) seen from 2004 to 2006 (35-50%) was statistically significant (Z(cal) = -2.30, p < .05) and from 2006 to 2011 (Z(calc) = -5.23; p < .05). Although the increase in biocompatible circuit (BC) use by perfusionists from 2004-2006 (53-64%) was not statistically significant (Z(calc) = -1.69, p < .05), the use of BCs did continue to increase (86%) significantly from 2006 to 2011 (Z(calc) = -9.15, p < .05). Other trends were observed; however, statistical significance was variable. This investigation demonstrates that binomial proportion statistical analysis is an effective method of evaluating perfusion practice trends and adoptions based on increasing or decreasing perfusion population proportion compliance over time.

Effect of New Heparin Potency on Activated Clotting Time during Pediatric Cardiac Surgery: A Retrospective Chart Review.

In 2009, the U.S Food and Drug Administration (FDA) announced a two-phase change in unfractionated heparin to reduce contamination and create a new potency reference. The FDA announced the change would bring about a 10% decrease in potency from the old heparin (OH) to new heparin (NH). The purpose of this article is to compare heparin in pediatric patients undergoing cardiac surgery before and after the FDA changes. After Institutional Review Board approval, a retrospective chart review was conducted with pediatric patients (n = 266) undergoing cardiac surgery. All patients received a heparin loading dose of 400 IU/kg and data collected included patient demographics, baseline activated clotting time (ACT), ACT after initial heparin dose, and heparin dose-response. These data were then further broken down into age blocks consisting of neonates (< 1 month), 1-12 months, 1-5 years old, and older than 5 years old. In 17.3% of cases in the NH group, the ACT after the initial heparin dose did not reach the critical value of 400 seconds necessary for initiation of cardiopulmonary bypass (CPB). This is significantly higher than the 8.9% of cases in the OH group (p < .05). There was an overall trend among age groups that the NH was less potent than OH. However, only the 1-5 years of age group showed significance at p < .05. Given the median ACTs 591 seconds for OH and 484 seconds for NH, the calculated percentage difference was 18.1%. The results from this retrospective pediatric chart review indicate that the change in heparin potency greatly deviates from the 10% change reported by the FDA. In conclusion, NH has a trend of lower potency and frequent monitoring is necessary to maintain a safe level of anticoagulation during CPB.

A meta-analysis of renal benefits to pulsatile perfusion in cardiac surgery.

Multiple studies have evaluated the efficacy of pulsatile flow during cardiopulmonary bypass (CPB) showing controversial results. Suggested benefits to pulsatile perfusion include reducing the systemic inflammatory response syndrome associated with bypass, decreased need for inotropic support, shortened hospital stay, and superior organ preservation. This study aims to compare prior studies to determine if there is a significant difference in post-operative renal function with pulsatile perfusion compared to non-pulsatile perfusion during cardiac surgery. Studies included in the analysis were identified by searching keywords--pulsatile perfusion, pulse, pulsatile flow, cardiopulmonary bypass, and cardiac surgery. To maintain a homogenous sample, manuscripts were included if they met the following criteria: research was prospective in nature, subjects were human, paper contained documented baseline demographics, outcome data included markers of renal function. A meta-analysis was performed to compare post-op renal function between pulsatile and non-pulsatile perfusion groups. A total of 298 articles were screened. Ten articles met the criteria, of these, 477 patients underwent non-pulsatile perfusion while 708 received pulsatile perfusion during CPB. There was insufficient evidence to show a difference in mean postoperative creatinine or BUN between the groups, however, the pulsatile perfusion group had significantly higher creatinine clearance (standardized difference in means = 2.48, p = .004) and lower serum lactate levels (standardized difference in means = -2.08, p = .012) in the intensive care unit. This study found that there is great variability among pulsatile perfusion research. The methods to create and assess effective pulsatility on bypass varied widely among manuscripts. This analysis suggests that pulsatile perfusion during CPB is beneficial in renal preservation and should be considered.

Improvement in long-term ECMO by detailed monitoring of anticoagulation: a case report.

INTRODUCTION: The use of unfractionated heparin (UFH) as an anticoagulant during long-term extracorporeal support presents a unique challenge for the clinician in balancing the amount of anticoagulant to maintain adequate anticoagulation without causing excessive bleeding. Activated clotting times (ACT) and activated partial thromboplastin times (aPTT) are the most common modality to monitor UFH on extracorporeal membrane oxygenation (ECMO). Limitations to these tests include consumptive coagulopathies, clotting factor deficiencies, platelet dysfunction, and fibrinolysis. The following case report describes the use of alternative monitoring strategies to assess more accurately anticoagulation during ECMO. CASE REPORT: A 20-month-old female presented to the emergency department with a 5-6 day history of cough, fever, tachypnea, and respiratory distress. She was diagnosed with influenza A and B with pneumonia. The patient was placed on veno-venous ECMO (V-V ECMO) after mechanical ventilation failed. On ECMO day eight, the patient developed a thrombus in her inferior vena cava and pleural effusions, obstructing cannula flow. Laboratory tests revealed the ACT was within range, yet the aPTT was dropping, despite increased heparin. Heparin levels were low and antithrombin-III (AT) concentrations were 40%. Recombinant AT was given and subsequent aPTTs were within the therapeutic range. Later, the aPTT decreased to <50 sec, heparin levels were within the therapeutic range, while fibrinogen was >475 mg/ dL, and Factor VIII >150 IU/dL, suggesting an acute phase reaction or ongoing systemic inflammation, increasing the risk for thrombosis. We maintained heparin assays between 0.5-0.7 IU/mL and AT >60% to assure heparin's effect. The patient showed no signs of excess bleeding, blood product administration, or clots in the circuit, suggesting proper anticoagulation. The patient was successfully weaned on day 33 and is currently alive and at home. CONCLUSION: Monitoring of anti-Xa UFH and AT proved effective for measuring anticoagulation and detecting inconsistencies in other anticoagulation parameters, leading to steady levels of heparin without further complications.

Gaseous microemboli in a pediatric bypass circuit with an unprimed venous line: an in vitro study.

Miniaturizing cardiopulmonary bypass (CPB) circuits to reduce hemodilution and allogenic blood product administration is common in cardiac surgery. One major concern associated with smaller CPB circuits is a possible increase in gaseous microemboli (GME) sent to the cerebral vasculature, which is exacerbated by vacuum-assisted venous drainage (VAVD). The use of VAVD has increased with smaller venous line diameter and venous cannulae. This study examines the effects of CPB initiation with an unprimed venous line and VAVD in a pediatric circuit. A CPB circuit was set up with reservoir, oxygenator, and arterial filter with a bag reservoir to simulate the patient. All trials were done in vitro, and GME were measured using the EDAC Quantifier by Luna Innovations. EDAC sensors were placed proximal and distal to the oxygenator and distal to the arterial filter. Group 1 was the control group with no VAVD and a primed venous line. Groups 2, 3, and 4 used an unprimed venous line and VAVD of -40, -20, and -10 mmHg, respectively. Total microemboli counts and total embolic load in micrometers were measured at each sensor. Groups 2 (12,379.00 +/- 3180.37) and 3 (8296.67 +/- 2818.76) had significantly more microemboli than group 1 (923.33 +/- 796.08, p < .05) at the pre-oxygenator sensor. Group 2 (57.33 +/- 25.01, p < .05) had significantly more microemboli than group 1 (5.33 +/- 3.21) at the post-oxygenator sensor. No other findings were statistically significant. The results suggest that, if an oxygenator and arterial filter with sufficient air handling capabilities are used, this method to reduce prime volume may not increase GME in the arterial line distal to the arterial filter.

Trends and emerging technologies in extracorporeal life support: results of the 2006 ECLS survey.

Extracorporeal life support (ECLS) is a procedure used to support the failing heart and/or lungs via a heart lung machine. Over 145 institutions perform this practice in the United States with more than 24,000 ECLS cases recorded. While many articles are published each year on common perfusion practice, little information is shared on emerging technologies in ECLS and common practices among perfusionists and ECLS specialists. This article presents our 2006 ECLS survey results and discusses emerging technologies and management topics new to the ECLS arena. ECLS specialists were asked to participate in an online survey. Two hundred twenty-two ECLS specialists responded. This survey suggests positive displacement roller pumps are still the leading pump used for ECLS 122/188 (64.9%). Silicone membrane oxygenators are used by responders 75% of the time for long-term use, while hollow fiber membrane oxygenators are used 44%. Forty-five percent of responders are using heparin or biocoated circuits exclusively, while 14.6% restrict their use to specific subpopulations. The most common coating is heparin coating (67.9%). Activated clotting time (ACT) management is still standard of care for coagulation monitoring (98%), while partial thromboplastin time (PTT) follows at 71.7%. The interquartile range for ACTs is 160-220 seconds and 160-200 seconds with active bleeding. This article suggests ECLS specialists are beginning to incorporate different technology into their practice, such as centrifugal pumps with hollow fiber oxygenators and coated-circuits.

Use of aprotinin during cardiopulmonary bypass in a patient with protein C deficiency.

This case study reviews cardiopulmonary bypass (CPB) management in a Protein C deficient patient undergoing reoperation for an atrioventricular (AV) valve replacement with the use of aprotinin. Protein C inhibits factors Va and VIIIa in the coagulation cascade and inactivates tissue plasminogen activator inhibitor, thus maintaining hemostasis. Protein C deficiency can cause hypercoagulability and may result in thrombotic episodes, especially in areas of low blood flow or during activation of the coagulation cascade. A 17-year-old male presented with a functional single ventricle and AV valve regurgitation. The patient had a history of three previous AV valve replacements. Protein C deficiency was first diagnosed after thrombosis of the first valve prosthesis. Other case studies in protein C deficient patients suggested the use of fresh frozen plasma (FFP) before bypass to restore protein C levels, ATIII replacement before heparin administration, and avoidance of aprotinin because of its known competitive inhibition of activated protein C. Two units of FFP were given by anesthesia before the administration of aprotinin, and two units of FFP were added to the pump prime. The full Hammersmith loading dose of aprotinin was administered just before initiation of CPB. The same dose of aprotinin was added to the pump prime just before initiation of CPB. Additional heparin (100 U/kg) was administered every hour during bypass. Activated clotting time tests (ACTs) were performed every 15 min, and thromboelastographs (TEGs) were performed every hour. The patient recovered from surgery without major complications, and there were no perioperative thrombotic events. The patient was discharged on day 41 and is doing well. Postoperative atrial arrhythmias were a contributing factor to his delayed discharge. The use of aprotinin in a protein C deficient patient undergoing open-heart surgery may be safe if protein C levels are restored before administration of aprotinin, and anticoagulation is carefully monitored.

Leukocyte depletion as a mechanism for reducing neutrophil-mediated ischemic-reperfusion injury during transplantation.

Patients undergoing transplantation are at high risk for leukocyte-mediated morbidity because of activated neutrophils and oxygen free radicals. This type of injury is most prominent during the reperfusion stage of transplantation. When tissue becomes ischemic, normal oxidation is altered. As oxygen is reintroduced to the system, oxygen free radical formation occurs via the oxidation of hypoxanthine by xanthine oxidase, causing destruction of the endothelium, increased permeability, and decreased organ function. In addition, neutrophils that may have already been activated by contact activation from the cardiopulmonary bypass circuit, accumulate in the ischemic organ at reperfusion. Activated neutrophils then release oxygen metabolites and proteolytic enzymes, which further destroy the integrity of the vascular endothelium. This insult can cause edema, capillary plugging, and poor graft function. Recent attempts have been made to decrease the mediators of ischemic-reperfusion injury. Perhaps the most advantageous of these attempts is the removal of leukocytes during reperfusion. This has been successfully achieved using leukocyte-depleting filters before exposing the organ to systemic blood flow. This article is a review of ischemic-reperfusion injury and the use of leukocyte depletion during reperfusion of transplanted organs.