The effect of three different doses of tranexamic acid on blood loss after cardiac surgery with mild systemic hypothermia (32 degrees C).

OBJECTIVE: Prophylactic administration of tranexamic acid (TA), an antifibrinolytic agent, decreases bleeding after cardiac surgery with systemic hypothermia (25 degrees C to 29 degrees C). Warmer systemic temperatures during cardiopulmonary bypass (CPB) may reduce bleeding and thus alter the requirement for TA. The effect of three different doses of TA on bleeding after cardiac surgery with mild systemic hypothermia (32 degrees C) is evaluated. DESIGN: Double-blind, prospective, randomized study. SETTING: University hospital. PARTICIPANTS: One hundred fifty adult patients undergoing aortocoronary bypass or valvular cardiac surgery. INTERVENTIONS: Patients received TA, 50 (n = 50), 100 (n = 50), or 150 (n = 50) mg/kg intravenously before CPB with mild systemic hypothermia. MEASUREMENTS AND MAIN RESULTS: Blood loss through chest drains over 6, 12, and 24 hours after surgery and total hemoglobin loss were measured. Autotransfused blood, transfused banked blood and blood products, and coagulation profiles were measured. Analysis of variance on log-transformed data for blood loss and confidence intervals (CIs) of 0.95 were calculated and transformed to milliliters of blood. No patient was re-explored for bleeding. Blood loss at 6 hours was statistically greater in the 50-mg/kg group compared with the other two groups (p = 0.03; p = 0.02). Total hemoglobin loss was statistically greater in the 50-mg/kg group compared with the 150-mg/kg group (p = 0.04). There was no statistical difference in blood tranfusion rate or coagulation profiles among the three groups. However, preoperative hemoglobin level was statistically lower in the 150-mg/kg group compared with the other two groups (p = 0.01). CONCLUSION: Of the three doses of TA studied, the most efficacious and cost-effective dose to reduce bleeding after cardiac surgery with mild hypothermic systemic perfusion is 100 mg/kg.

Do prescribing formularies help GPs prescribe from a narrower range of drugs? A controlled trial of the introduction of prescribing formularies for NSAIDs.

BACKGROUND: Previous studies have suggested that prescribing formularies may promote rational prescribing. The range of drugs prescribed may be one aspect of rational prescribing. AIM: To determine whether the introduction of prescribing formularies helps general practitioners (GPs) to prescribe from a narrower range of non-steroidal anti-inflammatory drugs (NSAIDs). METHOD: General practices in Lincolnshire were offered help in developing prescribing formularies. Ten practices decided to develop a formulary for NSAIDs. Level 3 PACT data were used to determine whether changes in prescribing had occurred with the introduction of the formulary. Matched controls were used to determine whether similar changes had occurred in other practices. RESULTS: Between April and June 1992, and during the same period in 1993, practices that introduced a formulary for NSAIDs reduced the mean number of different drugs used (14.3 versus 13.1, P = 0.04) and increased the percentage of NSAID-defined daily doses coming from the three most commonly used drugs (70.1% versus 74.8%, P = 0.02). Similar changes were not seen in control practices. CONCLUSION: Following the development of a formulary for NSAIDs, practices prescribed from a narrower range of drugs and focused a greater proportion of their prescribing on their three most commonly used drugs.

Prevention of bleeding after cardiopulmonary bypass with high-dose tranexamic acid. Double-blind, randomized clinical trial.

This prospective, double-blind, randomized trial assessed the effectiveness of high-dose tranexamic acid given in the preoperative period on blood loss in patients undergoing cardiopulmonary bypass. One hundred fifty patients scheduled to undergo cardiac operations with cardiopulmonary bypass were randomized into three groups of equal size. The first group received 10 gm of tranexamic acid intravenously over 20 minutes before sternotomy and a placebo infusion over 5 hours. The second group received 10 gm of tranexamic acid over 20 minutes and then another 10 gm infused intravenously over 5 hours. The control group received a placebo bolus and a placebo infusion over 5 hours (0.9% normal saline solution). The blood loss after the operation was measured at 6 hours and 24 hours. The homologous blood and blood products given during and up to 48 hours after operation were recorded. Eighteen percent of the control group patients shed more than 750 ml blood in 6 hours compared with only 2% in both tranexamic acid groups. Patients who shed more than 750 ml blood required 93% more red blood cell transfusions than patients without excessive bleeding. Tranexamic acid (10 gm) given intravenously in the period before cardiopulmonary bypass reduced blood loss over 6 hours by 50% and over 24 hours by 35%. Continued tranexamic acid infusion (10 gm over 5 hours) did not reduce bleeding further. There was no difference in the coagulation profile before operation between patients with and without excessive bleeding. However, coagulation tests done in the postoperative period indicated ongoing fibrinolysis and platelet dysfunction in patients with excessive bleeding.

Prevention of postbypass bleeding with tranexamic acid and epsilon-aminocaproic acid.

In this institution, two antifibrinolytic agents have been in routine use before cardiopulmonary bypass (CPB) to prevent bleeding due to fibrinolysis; epsilon-aminocaproic acid (EACA) or tranexamic acid (TA) are administered as intravenous infusions over 2 hours, from the time of anesthetic induction until the onset of CPB. TA is 10 times more potent and binds more strongly to plasminogen than EACA. Data were collected retrospectively on 411 patients undergoing first-time coronary artery bypass grafting with cardiopulmonary bypass who had received one of four therapy regimens: 10 g of EACA (65 patients), 15 g of EACA (60 patients), 6 g of TA (100 patients), or 10 g of TA (75 patients). Patients who did not receive any drug (91) served as controls. Anesthetic technique and the heparin/protamine protocol did not differ. Blood collected by mediastinal and pleural tubes was autotransfused up to 6 hours postoperatively. Both TA and EACA reduced post-CPB bleeding in the first 24 hours. Ten grams of TA was the most effective, resulting in a 52% and 36% reduction in blood loss over controls at 6 and 24 hours, respectively. Although 10 g of TA was more effective than 6 g of TA in blood loss control for the first 6 hours, the difference was not significant at 24 hours. A significantly lower number of patients in the 10 g TA group received blood products than in control (28% v 49%) patients (P = 0.02). Pretreatment with 10 g of TA prevented excessive (over 750 mL in 6 hours) bleeding after CPB.

The effect of warm heart surgery on postoperative bleeding.

The effects of normothermic systemic perfusion (35 degrees to 37 degrees C; n = 73) were compared with those of moderately hypothermic systemic perfusion (25 degrees to 29 degrees C; n = 73) with respect to blood loss, transfusion requirements, and platelet levels in 146 patients undergoing isolated, primary coronary artery bypass grafting. In addition, most patients were given an antifibrinolytic medication during operation as follows: tranexamic acid (10 gm intravenously; n = 63), epsilon-aminocaproic acid (15 gm intravenously; n = 63), or no drug as a control. (n = 20). Normothermic patients tended to bleed less at 24 hours (warm, 864 +/- 42 ml and cold, 918 +/- 68 ml), but these differences were not statistically significant. Patients receiving either tranexamic acid or epsilon-aminocaproic acid, regardless of perfusion temperature, bled less after 6, 12, and 24 hours than did cold control patients (p less than 0.05). Warm control patients also bled less than did cold control patients after 6 or 12 hours (p less than 0.05), and neither drug further reduced blood loss in these patients. Circulating platelet levels were better preserved in patients receiving either tranexamic acid or epsilon-aminocaproic acid and in patients with warm perfusion and no drug than in cold control patients. Normothermic systemic perfusion, tranexamic acid, and epsilon-aminocaproic acid each reduced postoperative blood loss and preserved platelets.

Dipyridamole for coronary artery bypass surgery.

A randomized trial to compare the effects of oral and intravenous dipyridamole was conducted in 58 patients undergoing coronary artery bypass graft (CABG) surgery. Preoperative oral administration of dipyridamole resulted in lower plasma drug concentrations in the early postoperative period than perioperative intravenous administration. Postoperative platelet counts were highest in the patients receiving intravenous dipyridamole, intermediate in those receiving oral dipyridamole and lowest in the control group. Postoperative blood loss was significantly reduced with both oral and intravenous dipyridamole. A second randomized trial was conducted in an additional 40 patients undergoing CABG surgery to evaluate the effects of dipyridamole on myocardial platelet and leukocyte deposition and the cardiac release of thromboxane. Twenty patients received intravenous dipyridamole perioperatively. Autologous platelets and leukocytes were labeled with 111In and 99mTc respectively and were infused before release of the crossclamp. Myocardial biopsies were obtained after aortic declamping and indicated that platelets and leukocytes were deposited in the myocardium during reperfusion. Dipyridamole reduced both platelet and leukocyte deposition. Cardiac release of thromboxane B2 occurred in the early postoperative period and was reduced by dipyridamole. In conclusion, dipyridamole preserved platelets and reduced postoperative bleeding and blood product transfusions in patients undergoing CABG surgery. Dipyridamole also reduced cardiac platelet deposition and thromboxane release and may reduce perioperative ischemic injury.

Ancrod (Arvin) as an alternative to heparin anticoagulation for cardiopulmonary bypass.

Heparin is the anticoagulant used during cardiopulmonary bypass (CPB). Both the use of heparin and the reversal of its effect with protamine have well-documented complications. Ancrod is a defibrinogenating enzyme that has been used as an anticoagulant in humans, but its use as an anticoagulant for CPB has been limited to studies in animals. Twenty patients for elective aortocoronary bypass surgery were anticoagulated by means of an intravenous infusion of ancrod pre-operatively. Target plasma fibrinogen concentrations of 0.40-0.80 g/l were achieved within 13.3 +/- 2.5 h using an average dose of ancrod of 1.65 +/- 0.55 U/g. All perfusions were without incident. Postoperative blood loss (2286 +/- 1311 cc) was compared to that of 20 matched controls (1737 +/- 973 cc), as was blood product use; 4.1 +/- 2.1 U of packed cells versus 2.5 +/- 2.3 U (P less than 0.05) and 5.6 +/- 3.1 U of plasma versus 2.6 +/- 2.9 U (P less than 0.05) in the ancrod and heparin-treated groups, respectively. There were no differences in the postoperative courses or recovery periods of the ancrod-treated and control patients. This study confirms the efficacy and feasibility of ancrod as an alternative form of anticoagulation for CPB.

Hormonal and metabolic responses during coronary artery bypass surgery: role of infused glucose.

Anesthesia, surgery, and hypothermia are conventionally considered the major stress factors in the metabolic and hormonal responses to cardiac surgery. We compared these responses in 14 nondiabetics during and for 24 h after coronary artery bypass surgery; 8 received cardioplegic solutions (C+), and 6 did not (C-). The mean intraoperative glucose load in C+ was 106 g compared to 32 g in C-; postoperatively both groups received 50 g. Marked hyperglycemia (31.8 +/- 4.8 mmol/L) occurred during hypothermia in C+, but dropped to 18.9 mmol/L before surgery ended and to 11.2 +/- 1.1 mmol/L by 2 h postop. In contrast, C- showed constant mild hyperglycemia of 8.3-9.8 mmol/L throughout, significantly less than C+ until 1 h postop. Insulin was suppressed by 55% only during hypothermia, peaking with rewarming in C+ at 2,849 +/- 911 vs. 639 +/- 251 pmol/L in C- (P less than 0.05); as with glycemia, values were comparable after 2 h postop. The pancreatic beta-cell thus responded to hyperglycemia during restoration of normothermia, resulting in a rapid decline in glycemia. This occurred despite elevations in antiinsulin factors in both groups; GH was 14 +/- 4 micrograms/L, cortisol was 607 +/- 38.6 nmol/L, norepinephrine was 11.5 +/- 3.7 nmol/L, epinephrine was 13,863 +/- 3,875 pmol/L, and FFA were 0.36 +/- 0.05 g/L. Early postop, a secondary rise in stress hormones occurred in both groups. Maximal cortisol values were at 4 h (1,186 +/- 140 nmol/L) and peaks of norepinephrine (6.50 +/- 1.66 nmol/L), epinephrine (7,969 +/- 3,602 pmol/L), and FFA (0.27 +/- 0.03 g/L) occurred. The only significant glucagon elevation was at 24 h (C+, 464 +/- 53 ng/L; C-, 350 +/- 241 ng/L; P less than 0.02), Thus, 1) many metabolic responses during coronary artery bypass surgery are influenced by the glucose-containing cardioplegic solution; 2) hypothermia suppresses insulin secretion, but it responds thereafter despite marked elevations of catecholamines, and is associated with decreasing glycemia despite elevated antiinsulin factors; 3) a lesser but highly significant stress response corresponds to awakening from anesthesia; and 4) glucagon plays a minor role in intraoperative hyperglycemia; the rise at 24 h is unexplained.

Ancrod anticoagulation for cardiopulmonary bypass in heparin-induced thrombocytopenia and thrombosis.

Heparin-induced thrombocytopenia and thrombosis was diagnosed in a 50-year-old man undergoing a repeat heart operation after heparinization led to microemboli and an eventual left transmetatarsal amputation. A third heart operation was aborted when anticoagulation with low molecular weight heparin produced intraoperative thrombi. The patient was referred to Toronto where ancrod (Arvin) was used to lower plasma fibrinogen level, allowing successful repair of a ventricular septal defect using cardiopulmonary bypass support. The patient made an uneventful recovery.

Postoperative hypertension: a comparison of diltiazem, nifedipine, and nitroprusside.

In previous studies, the treatment of postoperative hypertension with sodium nitroprusside induced ischemic metabolism without a decrease in coronary sinus blood flow. In contrast, the calcium antagonists diltiazem and nifedipine reduce blood pressure and may improve myocardial metabolism. A prospective randomized trial was performed in 62 patients, in whom hypertension developed (mean arterial pressure greater than 95 mm Hg) after coronary bypass procedures, to compare diltiazem (n = 22), nifedipine (n = 20), and nitroprusside (n = 20). All three agents reduced blood pressure equally (p less than 0.0001, by analysis of variance). Heart rate decreased with diltiazem (p = 0.006) but increased with nifedipine and nitroprusside (p less than 0.05). Left ventricular diastolic function (the relation between left atrial pressure and left ventricular end-diastolic volume) was not changed with the three drugs. Systolic function (the relation between systolic blood pressure and left ventricular end-systolic volume) was depressed with diltiazem (p = 0.05 by analysis of covariance) and nifedipine (p = 0.05) but not with nitroprusside. Myocardial performance (the relation between left ventricular stroke work index and end-diastolic volume) was depressed most by diltiazem (p = 0.001 by analysis of covariance), and to a lesser extent with nifedipine (p = 0.03), but not with nitroprusside. Myocardial lactate flux in response to the stress of atrial pacing decreased with nitroprusside but not with diltiazem or nifedipine (p = 0.03 by analysis of variance). Diltiazem and nifedipine are effective agents for treating postoperative hypertension after coronary artery bypass operations.

Effects of anesthetic induction on myocardial function and metabolism: a comparison of fentanyl, sufentanil and alfentanil.

Anaesthetic induction may induce myocardial ischaemia. A prospective randomized trial was instituted to compare the effect on ventricular function and myocardial metabolism of induction with fentanyl (FEN) or its analogues sufentanil (SUF) or alfentanil (ALF) in 96 patients undergoing elective coronary artery bypass grafting (CABG). Haemodynamic, metabolic (coronary sinus oxygen and lactate extraction) and gated ventriculographic measurements were made awake pre-induction (PRE), after induction (IND) and after intubation (INT). Induction was performed with FEN 75 micrograms.kg-1, SUF 15 micrograms.kg-1 or ALF 125 micrograms.kg-1 and metocurine. Fentanyl induction was associated with the greatest stability of mean arterial pressure (MAP), cardiac performance, and systolic function without associated myocardial lactate production. SUF produced the greatest depression of systolic function (p less than 0.05) but without haemodynamic instability or myocardial lactate production in all but one patient. Induction with ALF produced the greatest reduction in MAP (p less than 0.05) associated with the greatest decrease in diastolic compliance (p less than 0.05) and 50 per cent incidence of myocardial lactate production (p less than 0.05) with no significant change in coronary blood flow or myocardial oxygen consumption.

Cardiac release of prostacyclin and thromboxane A2 during coronary revascularization.

Cardiac surgery stimulates the systemic synthesis of prostacyclin and thromboxane A2, but the cardiac release of these prostanoids has been reported infrequently. Fifty-four patients undergoing elective coronary artery bypass had coronary sinus catheters inserted to evaluate the cardiac release of the stable metabolites of prostacyclin (6-keto-prostaglandin F1 alpha) and thromboxane A2 (thromboxane B2). Arterial concentrations of 6-keto-prostaglandin F1 alpha and thromboxane B2 were elevated after cardiac cannulation and during cardiopulmonary bypass. The cardiac release of 6-keto-prostaglandin F1 alpha was observed after cannulation and during, but not after, cardiopulmonary bypass. Cardiac thromboxane B2 release was detected after cross-clamp release and persisted during the early postoperative period when cardiac 6-keto-prostaglandin F1 alpha release was no longer detectable. Cardiopulmonary bypass stimulated the systemic production of thromboxane and prostacyclin. The cardiac release of thromboxane was unopposed by cardiac prostacyclin production in the early postoperative period and may contribute to reperfusion injury.

Cardiac dysfunction during abdominal aortic operation: the limitations of pulmonary wedge pressures.

The mortality rate for elective abdominal aortic operations remains between 3% and 8% despite careful hemodynamic monitoring, and half of these deaths are cardiac in origin. An extensive evaluation of ventricular function was performed during abdominal aortic operation to detect subtle abnormalities in systolic or diastolic ventricular function that could precipitate progressive ischemic cardiac injury. Twenty-three patients undergoing elective abdominal aortic operations (14 patients with abdominal aortic aneurysm [AAA] and nine patients with aortoiliac occlusive disease [AIOD] ) had hemodynamic and nuclear ventriculographic measurements performed preoperatively, during aortic clamping, and immediately after aortic declamping. No differences were found in the hemodynamic response to operation between patients with AAA or AIOD. Volume loading was performed at each time period to assess ventricular function. Myocardial performance (the relation between cardiac index and end-diastolic volume index) and systolic function (the relation between systolic blood pressure and end-systolic volume index) were depressed during aortic clamping (p less than 0.05), suggesting decreased contractility, but returned to baseline values after declamping. Diastolic compliance (the relation between pulmonary capillary wedge pressure and end-diastolic volume index) decreased after declamping (p less than 0.05), suggesting early myocardial ischemia. The decrease in diastolic compliance rendered pulmonary capillary wedge pressure a poor index of left ventricular preload after declamping. Higher pressures were required to maintain adequate diastolic volumes. Despite careful hemodynamic monitoring, potentially ischemic ventricular dysfunction was found during abdominal aortic operation.

Anaesthesia and amiodarone.

Two recent reports support and one report disputes the existence of dangerous interactions between the new benzofuran antiarrhythmic amiodarone and the anaesthetic state. We have reviewed our experience with 17 anaesthetics administered to 16 patients taking amiodarone. Haemodynamics and serum amiodarone levels were evaluated where available. Twelve cases involved cardio-pulmonary bypass; of these, three patients died. There were no deaths in the non-cardio-pulmonary bypass group. The charts of 30 patients with poor left ventricular function, who were not receiving amiodarone but who were undergoing coronary artery bypass surgery, were reviewed to establish a comparison group. Interactions were manifested in three forms: nodal rhythm and/or complete heart block developed in ten of 15 patients (one patient had a preoperative pacemaker inserted for the sick sinus syndrome), poor cardiac output requiring intra-aortic balloon pump augmentation developed in six of 12 cardio-pulmonary bypass patients, or, a state of alpha adrenergic blockade leading to a low systemic vascular resistance despite alpha agonist therapy developed in two of 16 patients. We conclude that dangerous, fatal interactions may occur in patients taking amiodarone who undergo general anaesthesia with cardio-pulmonary bypass. Anaesthesia for non-cardiac surgery may be associated with haemodynamically significant bradyarrhythmias. We recommend aggressive invasive monitoring, including pulmonary artery catheterization and consideration of an atrio-ventricular pacemaker in high risk patients.

Hemodynamic and myocardial metabolic consequences of PEEP.

The cardiac effects of positive end expiratory pressure (PEEP) were examined in 50 patients six hours after elective coronary bypass surgery. Increasing the level of PEEP from 5 to 10 to 15 cm H2O decreased cardiac index (evaluated by thermodilution), stroke index and left ventricular end diastolic volume index without a change in left ventricular ejection fraction (evaluated by nuclear ventriculography). Right ventricular end diastolic volume index remained unchanged. Coronary sinus blood flow (measured by the continuous thermodilution technique) and myocardial oxygen and lactate consumption were unchanged with the application of 15 cm H2O PEEP. In 21 patients, volume loading (250 ml [mL] of plasma) was performed at 5 cm, and again at 15 cm H2O PEEP. Volume loading produced a similar increase in cardiac volumes and cardiac index at 5 and 15 cm H2O PEEP. Right and left ventricular performance and left ventricular systolic function were not altered by PEEP (by analyses of covariance). Coronary sinus blood flow and myocardial oxygen consumption increased with volume loading at 5 and 15 cm H2O of PEEP, but myocardial lactate utilization tended to increase at 5 cm, and decrease at 15 cm H2O PEEP (p = 0.08). Of the 33 patients who underwent complete hemodynamic and metabolic measurements, 16 increased cardiac lactate utilization at 15 cm H2O PEEP and 17 decreased cardiac lactate utilization at 15 cm H2O PEEP. PEEP decreased cardiac index, perhaps by reducing left but not right ventricular volumes. Volume loading during PEEP restored cardiac index and revealed no depression in myocardial performance or systolic function. With the application of PEEP, myocardial metabolism was maintained in half the patients, but ischemic metabolism was observed in the other half.

A comparison of nitroglycerin and nitroprusside: I. Treatment of postoperative hypertension.

Nitroglycerin improves perfusion to ischemic myocardial regions and therefore has theoretical advantages over sodium nitroprusside to treat hypertension (mean arterial pressure [MAP] greater than 95 mm Hg) following coronary bypass operation. Thirty-three hypertensive patients were randomized to an initial infusion of either nitroglycerin or nitroprusside in a crossover trial designed to reduce MAP to 85 mm Hg. Thermodilution cardiac output measurements permitted calculation of left ventricular stroke work index (LVSWI), and nuclear ventriculograms permitted estimation of left ventricular ejection fraction, left ventricular end-diastolic volume index (LVEDVI), and left ventricular end-systolic volume index (LVESVI). Coronary sinus blood flow was measured by the continuous thermodilution technique, and arterial and coronary sinus lactate measurements permitted calculation of myocardial lactate flux (MVL). Both nitroglycerin and nitroprusside reduced MAP (-25 +/- 12 mm Hg and -20 +/- 10 mm Hg, respectively; not significant [NS]). Nitroglycerin reduced LVSWI more than did nitroprusside (-15 +/- 13 gm-m/m2 and -7 +/- 9 gm-m/m2, respectively; p less than 0.01). Both agents increased left ventricular ejection fraction (nitroglycerin, +8 +/- 8%, and nitroprusside, +10 +/- 7%; NS), and decreased LVEDVI (-20 +/- 22 ml/m2 and -11 +/- 17 ml/m2, respectively; NS) and LVESVI (-13 +/- 14 ml/m2 and -10 +/- 12 ml/m2, respectively; NS). Coronary sinus blood flow decreased with both drugs (NS), but MVL increased with nitroglycerin (+0.02 +/- 0.14 mmol/min) and decreased with nitroprusside (-0.02 +/- 0.02 mmol/min) (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)