Jan C. Horrow

A Multicenter, Double-Blind, Placebo-Controlled Trial of Aprotinin for Reducing Blood Loss and the Requirement for Donor-Blood Transfusion in Patients Undergoing Repeat Coronary Artery Bypass Grafting

BACKGROUND Aprotinin is a serine protease inhibitor that reduces blood loss and transfusion requirements when administered prophylactically to cardiac surgical patients. To examine the safety and dose-related efficacy of aprotinin, a prospective, multicenter, placebo-controlled trial was conducted in patients undergoing repeat coronary artery bypass graft (CABG) surgery. METHODS AND RESULTS Two hundred eighty-seven patients were randomly assigned to receive either high-dose aprotinin, low-dose aprotinin, pump-prime-only aprotinin, or placebo. Drug efficacy was determined by the reduction in donor-blood transfusion up to postoperative day 12 and in postoperative thoracic-drainage volume. The percentage of patients requiring donor-red-blood-cell (RBC) transfusions in the high- and low-dose aprotinin groups was reduced compared with the pump-prime-only and placebo groups (high-dose aprotinin, 54%; low-dose aprotinin, 46%; pump-prime only, 72%; and placebo, 75%; overall P = .001). The number of units of donor RBCs transfused was significantly lower in the aprotinin-treated patients compared with placebo (high-dose aprotinin, 1.6 +/- 0.2 U; low-dose aprotinin, 1.6 +/- 0.3 U; pump-prime-only, 2.5 +/- 0.3 U; and placebo, 3.4 +/- 0.5 U; P = .0001). There was also a significant difference in total blood-product exposures among treatment groups (high-dose aprotinin, 2.2 +/- 0.4 U; low-dose aprotinin, 3.4 +/- 0.9 U; pump-prime-only, 5.1 +/- 0.9 U; placebo, 10.3 +/- 1.4 U). There were no differences among treatment groups for the incidence of perioperative myocardial infarction (MI). CONCLUSIONS This study demonstrates that high- and low-dose aprotinin significantly reduces the requirement for donor-blood transfusion in repeat CABG patients without increasing the risk for perioperative MI.

Protamine: a review of its toxicity.

The prospective human studies considered above reveal that in some patients protamine is associated with decreases in SBP and SVR, especially when administered rapidly. Cardiac output increases reflexly, except perhaps in patients with less compliant ventricles, which are more dependent on preload to maintain stroke volume. In the latter, decreases in filling volume associated with protamine can lower CO. Regardless of the rate of administration, protamine does not produce predictable, acute increases in PAP, although increases in PAP may occur during idiosyncratic reactions (see the section on idiosyncratic reactions below). Left atrial or aortic administration of protamine may not confer protection from its hemodynamic or idiosyncratic sequelae (see below). Little evidence exists to conclude that protamine directly depresses contractility of the human heart.

The dose-response relationship of tranexamic acid.

Background: Prophylactic administration of the autifibrinolytic drug tranexamic acid decreases bleeding and transfusions after cardiac operations. However, the best dose of tranexamic acid for this purpose remains unknown. This study explored the dose-response relationship of tranexamic acid for hemostatic efficacy after cardiac operation. Methods: In prospective, randomized, double-blinded fashion, 148 patients undergoing cardiac operation with extracorporeal circulation were divided into six groups: a placebo group and five groups receiving tranexamic -acid in loading doses before incision (range 2.5 to 40 mg-kg -1 ) and one-tenth the loading dose hourly for 12 h. The mass of blood collected by chest tubes over 12 h represented blood loss. Allogeneic transfusions within 12 h and within 5 d of surgery were tallied. Results: The six groups presented similar demographics. Patients receiving placebo had increased postoperative D-dimer concentration compared to groups receiving tranexamic acid. Patients receiving at least 10 mg-kg -1 tranexamic acid followed by 1 mg-kg -1 -h -1 bled significantly less (365, 344, and 369 g-12 h -1 , respectively, for those three groups) compared with patients who received placebo (552 g, P<0.05). Tranexamic dose did not affect transfusions. Only initial hematocrit affected whether a patient received an allogeneic transfusion within 5 days of operation (odds ratio 2.08 for each 3% absolute decrease in hematocrit). Conclusions: Prophylactic tranexamic acid, 10 mg-kg -1 followed by 1 mg-kg -1 -h -1 , decreases bleeding after extracorporeal circulation. Larger doses do not provide additional hemostatic benefit

The laryngeal mask airway reliably provides rescue ventilation in cases of unanticipated difficult tracheal intubation along with difficult mask ventilation.

In 1995, our department of anesthesiology established an airway team to assist in treating unanticipated difficult endotracheal intubations and an airway quality im-provement (QI) form to document the use of emergency airway techniques in airway crises (laryngeal mask airway [LMA], flexible fiberoptic bronchoscopy, retrograde intubation [RI], transtracheal jet ventilation [TTJV], and cricothyrotomy). Over a 2-yr period, team members and staff anesthesiologists completed airway QI forms to document the smallest peripheral SpO2 during an airway crisis, the number of direct laryngoscopies (DL) performed before using an emergency airway technique, and the emergency airway technique that succeeded in rescue ventilation. Team members agreed to use the LMA as the first emergency airway technique to treat the difficult ventilation/difficult intubation scenario. A SpO2 value <or=to90% during mask ventilation defined difficult ventilation. Inability to perform tracheal intubation by DL defined difficult intubation. An increase in the SpO2 value >90% defined rescue ventilation. Review of airway QI forms from October 1, 1995 until October 1, 1997 revealed 25 cases of difficult ventilation/difficult intubation. Before airway rescue, the median SpO2 was 80% (range 50%-90%), and there were four median attempts at DL (range one to nine). The LMA had a success rate of 94% (95% confidence interval [CI] 77-100). Flexible fiberoptic bronchoscopy, TTJV, RI, and surgical cricothyrotomy had success rates of 50% (95% CI 0-100), 33% (95% CI 0-100), 100% (95% CI 37-100), and 100% (95% CI 37-100), respectively. LMA insertion as the first alternative airway technique was useful in dealing with unanticipated instances of simultaneous difficulty with mask ventilation and tracheal intubation. Implications: Twenty-five cases of simultaneous difficulty with mask ventilation and tracheal intubation occurred after the induction of general anesthesia during the study period. The laryngeal mask was used in 17 cases, and it provided rescue ventilation without complication in 94% of these cases (95% confidence interval 77-100). (Anesth Analg 1998;87:661-5)

Hemostatic effects of tranexamic acid and desmopressin during cardiac surgery.

Background Desmopressin-induced release of tissue plasminogen activator from endothelial cells may explain the absence of its hemostatic effect in patients undergoing cardiac surgery. Prior administration of the antifibrinolytic drug tranexamic acid might unmask such an effect, and combination therapy might thereby improve postoperative hemostasis. Methods and Results A double-blinded design randomly allocated 163 adult patients undergoing coronary revascularization, valve replacement, both procedures, or repair of atrial septal defect to four treatment groups: placebo, tranexamic acid given as 10 mg/kg over 30 minutes followed by 1 mg. kg−1. hr−1 for 12 hours initiated before skin incision, desmopressin given as 0.3 μg/kg over 20 minutes after protamine infusion, and both drugs. One surgeon performed all operations. Blood loss consisted of mediastinal tube drainage over 12 hours. Follow-up visits sought evidence of myocardial infarction and stroke. Desmopressin decreased neither the 12-hour blood loss nor the amount of homologous red cells transfused. Tranexamic acid alone significantly reduced 12-hour blood loss, by 30%1 (mean, 318 versus 453 ml; Conclusions Desmopressin exerts no hemostatic effect, with or without prior administration of antifibrinolytic drug. Prophylactic tranexamic acid alone appears economical and safe in decreasing blood loss and transfusion requirement after cardiac surgery.

Difficult or Impossible Ventilation after Sufentanil-induced Anesthesia Is Caused Primarily by Vocal Cord Closure

Introduction: Opioid‐induced rigidity often makes bag‐mask ventilation difficult or impossible during induction of anesthesia. Difficult ventilation may result from chest wall rigidity, upper airway closure, or both. This study further defines the contribution of vocal cord closure to this phenomenon. Methods: With institutional review board approval, 30 patients undergoing elective cardiac surgery participated in the study. Morphine (0.1 mg/kg) and scopolamine (6 micro gram/kg) given intramuscularly provided sedation along with intravenous midazolam as needed. Lidocaine 10% spray provided topical anesthesia of the oropharynx. A fiberoptic bronchoscope positioned in the airway photographed the glottis before induction of anesthesia. A second photograph was obtained after induction with 3 micro gram/kg sufentanil administered during a period of 2 min. A mechanical ventilator provided 10 ml/kg breaths at 10/min via mask and oral airway with jaw thrust. A side‐stream spirometer captured objective pulmonary compliance data. Subjective airway compliance was scored. Pancuronium (0.1 mg/kg) provided muscle relaxation. One minute after the muscle relaxant was given, a third photograph was taken and compliance measurements and scores were repeated. Photographs were scored in a random, blinded manner by one investigator. Wilcoxon signed rank tests compared groups, with Bonferroni correction. Differences were considered significant at P <0.05. Results: Twenty‐eight of 30 patients exhibited decreased pulmonary compliance and closed vocal cords after opioid induction. Two patients with neither objective nor subjective changes in pulmonary compliance had open vocal cords after opioid administration. Both subjective and objective compliances increased from severely compromised values after narcotic‐induced anesthesia to normal values (P = 0.000002) after patients received a relaxant. Photo scores document open cords before induction, progressing to closed cords after the opioid (P = 0.00002), and opening again after a relaxant was administered (P = 0.00005). Conclusion: Closure of vocal cords is the major cause of difficult ventilation after opioid‐induced anesthesia.

Emboli Observed with Use of Transesophageal Echocardiography Immediately after Tourniquet Release during Total Knee Arthroplasty with Cement

The right atrium and the right ventricle of fifty-five patients were imaged with transesophageal echocardiography during fifty-nine total knee arthroplasties performed with cement and the use of general anesthesia. The patients ranged in age from thirty-two to eighty-three years (mean, 65.5 years). Cardiopulmonary parameters were measured with use of hemodynamic monitoring systems, such as pulse oximeters, pulmonary artery catheters, and radial artery catheters. In addition, a femoral vein catheter was inserted on the side of the operation in ten of the fifty-five patients. Showers of echogenic material traversing the right atrium, the right ventricle, and the pulmonary artery after the tourniquet was deflated were observed to various degrees in all patients and lasted three to fifteen minutes. The mean peak intensity occurred within thirty seconds (range, twenty-four to forty-five seconds) after the tourniquet was released. The mean mixed venous oxygen saturation (and standard error of the mean) decreased (from 83 ± 0.9 to 72 ± 1.5 per cent) and the mean pulmonary arterial pressure increased (from 20 ± 1.0 to 27 ± 1.0 millimeters of mercury [2.67 ± 0.13 to 3.60 ± 0.13 kilopascals]), compared with the values before the tourniquet was released, in all patients. The pulmonary vascular resistance index increased after release of the tourniquet (to a maximum of 328 ± 29 dyne·s·cm-5·m2; p = 0.00002) only in the patients who had echogenic material that was at least 0.5 centimeter in diameter. Clinical pulmonary embolism developed postoperatively in three patients; all three had had echogenic particles that were more than 0.5 centimeter in maximum diameter on imaging. Blood aspirated from one of the pulmonary artery catheters and from five of the ten femoral vein catheters demonstrated fresh venous thrombus. Histological evaluation of the aspirates failed to demonstrate fat, marrow, or particles of polymethylmethacrylate. Surgeons should consider acute pulmonary embolism as a diagnosis when evaluating a patient who has hemodynamic collapse during total knee arthroplasty performed with cement.

Echogenic emboli upon tourniquet release during total knee arthroplasty: pulmonary hemodynamic changes and embolic composition.

Echogenic venous emboli accompany tourniquet deflation during total knee arthroplasty. The associated pulmonary hemodynamic alterations and determined embolic composition were measured in 34 patients, undergoing 35 procedures. Ten patients received a femoral venous catheter on the operative side. Hemodynamic variables, heart rate and mixed venous oximetry, end-tidal CO2 and nitrogen tensions, and transesophageal echocardiograms were recorded after induction of anesthesia (baseline), after tourniquet inflation, after cementing, and for 15 min after tourniquet deflation. Echocardiograms revealed either showers of miliary echogenic material (Group S, 9 patients), or large echogenic masses superimposed on the showers (Group MS, 26 patients). In Group MS only, pulmonary vascular resistance index increased above baseline (205±6 [sem] dyne·s·cm−2) beginning 5 min after tourniquet deflation (maximum 328±29, P < 0.05). Mean pulmonary arterial pressure increased above baseline (20±1.0 mm Hg) for both Groups S and MS beginning 3 min after tourniquet deflation (27±1.0, P < 0.05). Cardiac index did not change. Five of 10 patients demonstrated fresh thrombus from the catheter in the operative limb. Echogenic emboli occurred in all patients upon tourniquet deflation during knee arthroplasty. Pulmonary vascular resistance index increased only in patients with large echogenic material. Our data suggest that these emboli represent fresh thrombus formation during tourniquet inflation. Heparin administration prior to tourniquet inflation may diminish embolic showers.

The Incidence of large venous emboli during total knee arthroplasty without pneumatic tourniquet use

Echogenic venous emboli accompany tourniquet deflation during total knee arthroplasty.Two types of echogenic emboli appear in the central circulation: small venous emboli (miliary emboli) and large venous emboli (masses of echogenic material superimposed on miliary emboli). Presumably, medullary cavity trespass releases small and large echogenic emboli. However, patients undergoing lower extremity procedures with a tourniquet have large echogenic emboli regardless of medullary cavity invasion. Avoiding tourniquet inflation may decrease the release of large venous emboli. Thirteen patients undergoing total knee arthroplasty without pneumatic tourniquet received intramedullary guides and 11 patients received tibial extramedullary guides. Recordings of hemodynamic variables, mixed venous oximetry, end-tidal CO2, and echocardiographic images were made after the induction of anesthesia and for 15 min after femoral prosthesis cementing. Mean arterial pressure did not change during the study, and mean pulmonary arterial pressure increased minimally. Large venous emboli appeared in eight patients, small venous emboli appeared in 12 patients, and no emboli appeared in four patients. Compared with previous investigations of large venous emboli during total knee arthroplasty with a pneumatic tourniquet, multiple logistic regression analysis discloses a 5.33-fold greater risk of large venous embolism accompanied the use of a tourniquet during total knee arthroplasty. Implications: One third of knee replacements performed without a tourniquet demonstrated large emboli. Reducing marrow cavity invasion did not decrease the release of large emboli. Compared with knee replacement without tourniquet, tourniquet use places patients at a 5.33-fold greater risk of having a large emboli. (Anesth Analg 1998;87:439-44)

A controlled comparison of techniques for locating the internal jugular vein using ultrasonography.

Fifteen techniques for localization of the internal jugular vein (IJV) were evaluated in each of 25 subjects using ultrasonography to simulate actual cannulation. Ultrasound images were used to determine puncture of the IJV, puncture of the carotid artery (CA), the distance from the skin to the center of the IJV, the width of the IJV lumen, the relationship of the CA to the IJV, and the lateral distance of the IJV from the axis of the sound beam. No technique proved best in successful IJV puncture. Techniques did differ statistically in rates of CA puncture. Techniques using the CA pulse as a landmark had lower CA puncture rates. Rotation of the head, extension of the neck, and breathholding had no influence on IJV cannulation rates. It is concluded that no one technique is clearly superior to the others. Facility with one technique may be more critical to successful cannulation than the technique itself.