A dose-determining trial of heparinase-I (Neutralase) for heparin neutralization in coronary artery surgery.

UNLABELLED: Heparinase-I, a specific heparin-degrading enzyme, may represent an alternative to protamine. We explored the dose of heparinase-I for efficacy and safety in patients undergoing coronary artery surgery. At the conclusion of cardiopulmonary bypass, subjects received 5, 7, or 10 microg/kg of open-label heparinase-I instead of protamine. Activated clotting time (ACT) and its difference from a contemporaneous heparin-free sample (DeltaACT) at 3 min before and 3, 6, and 9 min after heparinase-I determined reversal efficacy. After surgery, we recorded hourly chest tube drainage. Systemic and pulmonary arterial blood pressure and cardiac output measurements before and immediately after heparinase-I were used to evaluate hemodynamic safety. Coagulation measurements included anti-factor Xa and anti-factor IIa activities. Forty-nine patients from seven institutions participated: 12 received 5 microg/kg, 21 received 7 microg/kg, 4 received two doses of 7 microg/kg, 8 received 10 microg/kg, and 4 received two doses of 10 microg/kg. Treatment groups did not differ demographically. Median DeltaACT 9 min later was 11, 7, and 4 s for the 5, 7, and 10 microg/kg groups, respectively. No adverse hemodynamic changes occurred with heparinase-I administration. The authors conclude that heparinase-I effectively restored the ACT after cardiopulmonary bypass. This effect appeared to be dose dependent. IMPLICATIONS: Heparinase-I (Neutralase(TM)) successfully restored activated coagulation time with no adverse hemodynamic events in patients undergoing coronary artery surgery with cardiopulmonary bypass in an open-label dose-determining trial.

The clinical onset of heparin is rapid.

This study used the activated clotting time (ACT) to determine the clinical onset of four different doses of heparin after bolus injection into the central circulation. Ten consenting adults (Group A) undergoing coronary artery bypass grafting were given 350 U/kg of bovine lung heparin and had simultaneous duplicate arterial and venous ACT determinations at baseline and at 30, 60, 90, 120, 180, and 600 s after heparin injection. Twenty additional coronary artery bypass grafting patients were alternately assigned to one of two 10-patient groups (B and C), which were given 200 and 300 U/kg of bovine lung heparin, respectively. Group D consisted of 10 abdominal aortic aneurysmectomy patients who received 70 U/kg of bovine lung heparin. In Groups B, C, and D, duplicate ACT measurements were taken from an indwelling arterial catheter at baseline and at 30, 60, 90, 120, 180, and 300 s after completion of a bolus injection of heparin into the central circulation. After a 70 U/kg heparin dose, all patients had significant ACT prolongation within 30 s, and 8 of 10 had effectively achieved their peak anticoagulation response by that time. In all patients receiving 200, 300, and 350 U/kg of heparin, arterial anticoagulation (ACT > 300 s) occurred and in most patients peaked within 30 s after heparin administration (P < 0.05). Arterial and venous ACTs did not differ significantly from each other at any measurement period, but venous ACTs peaked slightly later than arterial ACTs (within 60 s in 9 of 10 patients). When 200 U/kg or more of heparin is administered into the central venous circulation in hemodynamically stable anesthetized patients, peak arterial ACT prolongation occurs within 30 s and peak venous ACT prolongation within 60 s.

Update on cardiopulmonary bypass.

Investigations into cardiopulmonary bypass continue to refine knowledge and clinical practice. Recent investigations have emphasized neurological complications, introducing the possibility of genetic predisposition as a risk factor. Appropriate flows, pressures, and hematocrit levels during cardiopulmonary bypass continue to create controversy. Whereas previous debate has centered around appropriate temperature management, recent discussions consider the possibility that mild hypothermia after cardiopulmonary bypass might be neuroprotective. Meta-analyses and prospective investigations continue to suggest the virtual equivalence of aprotinin and lysine analogues in reducing bleeding and transfusion after cardiopulmonary bypass. Several recent studies identified the mechanisms and severity of the inflammatory response to cardiopulmonary bypass, as well as possible techniques for attenuating inflammation.

Anticoagulation monitoring during cardiac surgery: a review of current and emerging techniques.

The literature does not consistently support the importance of anticoagulation monitoring techniques during CPB. This is best reflected by studies that have evaluated the impact of the ACT method on blood loss and transfusion outcomes. Inconsistent findings from studies that evaluated the impact of ACT monitoring may be related to either suboptimal study design (i.e., retrospective, unblinded, nonrandomized) or possibly the diagnostic inprecision of the ACT method used in these studies. There are a small number of well-controlled studies, some of which suggest that bleeding and transfusion outcomes can be improved by refining heparin monitoring techniques, either by sustaining better anticoagulation during CPB or by optimizing protamine doses (i.e., when empiric protocols result in excessive protamine doses). More well-controlled studies are needed to better define the importance of anticoagulation management during CPB.

Minimally invasive direct coronary artery bypass: anesthetic, monitoring, and pain control considerations.

OBJECTIVE: Minimally invasive direct coronary artery bypass (MIDCAB) provides many anesthetic challenges including monitoring, managing myocardial ischemia, and pain control. The objective was to evaluate the monitoring requirements and the potential benefits of preischemic conditioning and intrathecal morphine sulfate in MIDCAB patients. DESIGN AND SETTING: This review was retrospective and unrandomized and was conducted at Allegheny University Hospitals, Allegheny General, Pittsburgh, PA. PARTICIPANTS: Sixty-four patients with single coronary artery lesions (> 70% obstruction) underwent attempted MIDCAB during a 1-year period between November 1995 and November 1996. Seven patients required conversion to conventional coronary artery bypass grafting (CABG) with cardiopulmonary bypass (CPB) and two patients required extended thoracotomy incisions. This report describes the remaining 55 patients who underwent MIDCAB. INTERVENTIONS: Some of the MIDCAB patients received intrathecal morphine before anesthetic induction. Ischemic preconditioning was assessed in a subset of patients. RESULTS: MIDCAB was performed in 55 of 64 patients. Transesophageal echocardiography (TEE) was used in all patients and a pulmonary artery catheter was used in 43% of patients. Esmolol was used in 25% of patients to reduce motion of the left ventricle (LV) during the left internal mammary artery (LIMA)-LAD anastomosis, but was used less often as the surgeons adapted to the use of a retractor that stabilized the ventricular wall adjacent to the site of the LIMA-LAD anastomosis. LAD occlusion caused reversible, regional systolic dysfunction by TEE in the anterior and apical LV segments. During LAD occlusion, nitroglycerin was used in 61% of patients and phenylephrine in 24%. Ischemic preconditioning did not prevent increases in systemic or pulmonary artery pressures during LAD occlusion. Most (85%) patients were extubated in the operating room. Intrathecal morphine decreased postoperative analgesic requirements. The mean hospital length of stay (LOS) was 4.0 +/- 1.7 days (range, 1 to 10 days). CONCLUSIONS: MIDCAB may reduce hospital LOS for patients with single vessel coronary artery lesions when compared with median sternotomy with a LIMA-LAD graft performed on cardiopulmonary bypass. Pharmacologic heart rate control during the LIMA-LAD anastomosis is not critical with the use of a surgical retractor which diminishes ventricular motion. A single 5-minute test LAD occlusion did not protect against subsequent regional ischemic dysfunction in our subset of patients with normal baseline function.

Tranexamic acid reduces bleeding after cardiopulmonary bypass when compared to epsilon aminocaproic acid and placebo.

UNLABELLED: Perioperative bleeding following coronary artery bypass grafting (CABG) is associated with increased blood product usage. Although aprotonin is effective in reducing perioperative blood loss, excessive cost prohibits routine utilization. Epsilon aminocaproic acid (EACA) and tranexamic acid (TA) are inexpensive antifibrinolytic agents, which, when given prophylactically, may reduce blood loss. The present study was undertaken to compare the efficacy of TA and EACA in reducing perioperative blood loss. METHODS: The study population consisted of first-time CABG patients. Patients were allocated in a prospective double-blind fashion: (1) group EACA (loading dose 15 mg/kg, continuous infusion 10 mg/kg per hour for 6 hours, N = 20); (2) group TA (loading dose 15 mg/kg, continuous infusion 1 mg/kg per hour for 6 hours, N = 20); (3) control group (infusion of normal saline for 6 hours, N = 19). RESULTS: Treatment groups were similar preoperatively. No significant difference in intraoperative blood loss or perioperative use of blood products was noted. D-dimer concentration was elevated in the control group compared to the EACA and TA groups (p < 0.05). Group TA had less postoperative blood loss than the EACA and control groups at 6 and 12 hours postoperatively (p < 0.05). TA had reduced total blood loss (600 +/- 49 mL) postoperatively compared to EACA (961 +/- 148 mL) and control (1060 +/- 127 mL, p < 0.05). CONCLUSION: TA and EACA effectively inhibited fibrinolytic activity intraoperatively and throughout the first 24 hours postoperatively. TA was more effective in reducing blood loss postoperatively following CABG. This suggests that TA may be beneficial as an effective and inexpensive antifibrinolytic in first-time CABG patients.

Effectiveness of intraoperative autologous whole blood and platelet-rich plasma in cardiac surgery.

Autologous whole blood and platelet-rich plasma harvested intraoperatively before cardiopulmonary bypass have been used by many in an effort to reduce the use of allogeneic blood transfusions during cardiac surgery. This brief review analyses the literature published concerning those two techniques. Although theoretically appealing, neither technique appears at present to withstand close scrutiny because of limitations in the design of many clinical studies. Efforts at blood transfusion avoidance during cardiac surgery may be best directed toward the salvage of intraoperative blood (including the residual oxygenator circuit contents), selective acceptance of low haemoglobin concentrations, and prophylactic administration of antifibrinolytic drugs.

Predictive value of blood clotting tests in cardiac surgical patients.

This study prospectively evaluated numerous tests of clotting function in 897 consecutive adult cardiac surgical patients over 18 months. This included coronary operation, valve replacement, and reoperative patients. The tests included activated clotting time, activated partial thromboplastin time, prothrombin time, thrombin time, fibrinogen, fibrin/fibrinogen degradation products, platelet count, and Duke's earlobe bleeding time. Other variables such as age, sex, and cardiopulmonary bypass duration were included in the multivariate analysis. Statistically significant correlations were found between 16-hour mediastinal drainage and activated partial thromboplastin time, fibrinogen, activated clotting time, fibrin/fibrinogen degradation products, platelet count, and prothrombin time. Scatter plots indicate that these relationships, although statistically significant, had little predictive value and were largely significant as a result of the large number of patients in each group, which permitted weak correlations to reach statistical significance. The best multivariate model constructed could explain only 12% of the observed variation in postoperative blood loss. Because the predictive values of the tests are so low, it does not appear sensible to screen patients routinely using these clotting tests shortly after cardiopulmonary bypass.

Heparin-coated cardiopulmonary bypass circuits.

The indications for heparin-coated extracorporeal circuits cannot be defined or limited at present. Clinical investigation remains at an early stage of development. In situations where the risk of systemic anticoagulation is high, this technology would seem to hold great promise. Examples include extracorporeal lung assist and resuscitation from accidental hypothermia. Some have also suggested the use of heparin-coated circuits for percutaneous bypass in cardiopulmonary resuscitation. A significant advantage might also accrue in noncardiac surgical procedures requiring cardiopulmonary bypass, such as complex cerebral aneurysm or arteriovenous malformation resections, resections of the tracheal carina, or bilateral lung transplantations. Its role in routine cardiac surgical procedures remains uncertain, but the work of von Segesser et al suggests a need for continued investigation in that setting using reduced levels of systemic anticoagulation. That endeavor will be greatly assisted by the recent development of heparin-coated cardiotomy reservoirs. Although heparin-coated circuits have been safely used for extracorporeal lung assist with little or no systemic anticoagulation, prospective studies are clearly needed to determine if this approach is advantageous, and it would seem appropriate to develop heparin coating for silicone-based membrane oxygenators.

Hemodynamic and pharmacodynamic comparison of doxacurium and pipecuronium with pancuronium during induction of cardiac anesthesia: does the benefit justify the cost?

We compared the pharmacodynamic effects and hospital costs of three long-acting neuromuscular blocking drugs in a prospective, randomized, double-blind manner. Each neuromuscular blocking drug was administered with fentanyl (50 micrograms/kg) for intravenous induction of anesthesia for coronary artery bypass surgery. Each patient received twice the 95% effective dose (ED95) of either pancuronium (0.14 mg/kg, n = 10), pipecuronium (0.10 mg/kg, n = 10), or doxacurium (0.05 mg/kg, n = 10). Hemodynamic measurements were recorded at baseline, 5 min after completion of anesthetic induction, immediately after endotracheal intubation, and 5 min after intubation. Only small hemodynamic differences between neuromuscular blocking drugs were observed. Doxacurium (but not pancuronium or pipecuronium) significantly decreased mean arterial blood pressure (from 94 +/- 4 mm Hg before induction to 83 +/- 3 mm Hg 5 min after intubation); nevertheless, there were no significant between-group differences at any time. Pancuronium increased heart rate (from 68 +/- 4 beats/min before induction to 76 +/- 5 beats/min 5 min after intubation); however, pancuronium differed significantly from doxacurium and pipecuronium only 5 min after induction and 5 min after intubation. Central venous pressure, pulmonary artery occlusion pressure, cardiac index, and systemic and pulmonary vascular resistance indices did not change. Electrocardiographic abnormalities were observed in two pipecuronium patients: ST segment depression in one and premature ventricular contractions in another. No other electrocardiographic changes were observed. There were no significant between-group differences in the need for hemodynamic interventions.(ABSTRACT TRUNCATED AT 250 WORDS)

Heparin content of washed red blood cells from the cardiopulmonary bypass circuit.

Reinfusion of red blood cells (RBC) from the extracorporeal circuit following cardiopulmonary bypass (CPB) reduces patient exposure to homologous blood. Because infusing unneutralized heparin might exacerbate postoperative bleeding, this study examines the heparin content of the washed packed RBC produced by a commonly used autotransfusion device. This RBC product was derived from the residual whole blood in the oxygenator circuit after CPB. A wash volume of 750 mL of normal saline produced heparin concentrations below 0.04 USP U/mL. A 500 mL wash volume yielded heparin concentrations ranging from 0.08 to 0.22 USP U/mL, and could be used if time did not permit an additional wash. RBCs produced by the usual complete wash cycle do not contain clinically significant amounts of heparin; thus, they would not require a supplemental protamine dose.

Heparin management protocol for cardiopulmonary bypass influences postoperative heparin rebound but not bleeding.

A group of 63 adult patients undergoing cardiac surgical procedures requiring cardiopulmonary bypass (CPB) were studied to examine the relationship between heparin doses administered and postoperative bleeding. Patients were randomly assigned either to receive heparin 200 U/kg and additional heparin as needed to reach and maintain an activated clotting time (ACT) greater than 400 s for CPB (group A, n = 30), or to receive heparin 400 U/kg and additional heparin as needed to reach and maintain a whole blood heparin concentration greater than 4.0 U/ml for CPB (group H, n = 33). Groups were compared for the amount of postoperative bleeding, heparin rebound, homologous transfusion requirements, and standard laboratory coagulation tests. In the last 33 patients studied, additional tests of platelet aggregation and plasma levels of beta thromboglobulin (BTG), antithrombin III, and several markers of fibrinolysis were measured and compared by group. The mean heparin dose was 28,000 +/- 4,800 U for group A and 57,000 +/- 10,700 U for group H (P less than 0.05 for group A vs. group H). At 8 and 24 h postoperatively, mediastinal drainage did not differ significantly between groups (mean 24-h drainage +/- SD = 901 +/- 414 ml in group A, 1035 +/- 501 ml in group H), nor did the incidence of transfusion with homologous blood products.(ABSTRACT TRUNCATED AT 250 WORDS)