Effect of Vorapaxar Alone and in Combination with Aspirin on Bleeding Time and Platelet Aggregation in Healthy Adult Subjects.

The effect of the protease-activated receptor-1 (PAR-1) antagonist vorapaxar on human bleeding time is not known. This was a randomized, two-period, open-label trial in healthy men (n = 31) and women (n = 5). In period 1, subjects received 81 mg aspirin q.d. or a vorapaxar regimen achieving steady-state plasma concentrations equivalent to chronic 2.5 mg q.d. doses, for 7 days. In period 2, each group added 7 days of the therapy alternate to that of period 1 without washout. Bleeding time and platelet aggregation using arachidonic acid, ADP, and TRAP agonists were assessed. Bleeding time geometric mean ratio (90% CI) for vorapaxar/baseline was 1.01 (0.88-1.15), aspirin/baseline was 1.32 (1.15-1.51), vorapaxar + aspirin/vorapaxar was 1.47 (1.26-1.70), and vorapaxar + aspirin/aspirin was 1.12 (0.96-1.30). Unlike aspirin, vorapaxar did not prolong bleeding time compared with baseline. Bleeding time following administration of vorapaxar with aspirin was similar to that following aspirin alone.

Randomized, double-blind comparison of oral aprepitant alone compared with aprepitant and transdermal scopolamine for prevention of postoperative nausea and vomiting.

BACKGROUND: Aprepitant blocks the emetic effects of substance P. Scopolamine antagonizes muscarinic type 1 and histamine type 1 receptors. This study compares monotherapy and multimodal therapy by looking at complete response, nausea, vomiting, and rescue medication in patients at high risk for postoperative nausea and vomiting (PONV) treated with oral aprepitant with or without scopolamine. METHODS: We enrolled 120 patients in this randomized, double-blind trial. Inclusion criteria were: >18 yr old, ASA I-III, two or more Apfel four-point risk factors, undergoing an elective surgical procedure with a high risk of PONV expected to last at least 60 min. The primary outcome variable was complete response, that is, no emesis and no rescue therapy from 0 to 24 h. The outcomes measured included the incidences of nausea, vomiting, their composite, and the need for rescue medication. RESULTS: The aprepitant alone and aprepitant with scopolamine did not differ in complete responses (63% vs 57%, P=0.57) or net clinical benefit (26% vs 19%, P=0.38). The number who did not experience PONV and who used rescue medication did not differ. The incidence of PONV in the post-anaesthesia care unit did not differ nor did the use of rescue medications. CONCLUSIONS: This trial evaluating the effectiveness of aprepitant alone and in combination with scopolamine showed no difference between treatment groups. The primary objective, complete response, and secondary objectives, incidences of nausea, vomiting, their composite, and the need for rescue medication, all showed no statistical difference.

Heart rate variability changes during pregnancy: an observational study.

BACKGROUND: Autonomic nervous systemic imbalance, as reflected by altered heart rate variability, is associated with adverse clinical sequelae. Before heart rate variability can predict adverse responses to interventions at delivery, changes compared to the non-pregnant state should be explored. METHODS: Twenty-four normal healthy volunteer women and 22 pregnant women at term immediately before cesarean section, underwent various analyses of heart rate variability following a standard sampling. Calculations included time domain, frequency domain and non-linear measures. To make 14 comparisons between pregnant and volunteer subjects, a significance level of 0.00357 was taken. RESULTS: Compared to volunteers, pregnant patients had higher heart rates and blood pressures, and decreases in some time domain heart rate variability parameters. Frequency domain heart rate variability parameters remained unaffected by pregnancy. Non-linear analysis results all decreased numerically, but failed to achieve statistical significance. CONCLUSIONS: Future investigations seeking associations of heart rate variability parameters with clinical events in pregnant women at term should consider time domain and non-linear analyses.

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.

Is age associated with size of adult extrahepatic bile duct: sonographic study.

PURPOSE: To determine if the size of the extrahepatic bile duct increases with age in adults. MATERIALS AND METHODS: A total of 258 consecutive patients 18 years and older, without known biliary or pancreatic disease, who were fasting to undergo routine abdominal sonography were examined. The transverse and anteroposterior dimensions of the extrahepatic bile duct were measured proximally at the porta hepatis, at the middle above the head of the pancreas, and distally at the head of the pancreas. Simple linear regression of the average of these measurements against age tested the hypothesis of a slope of 1.0 mm per decade. RESULTS: The sample included a wide variety of ages: 55 years +/- 16 (mean +/- SD), with a range of 20-92 years, including 151 men and 107 women. One-tenth of the cohort were younger than 35 years old and one-tenth were older than 77 years old. The six measurements were proximal-transverse 3.5 mm +/- 1.0, proximal-anteroposterior 2.9 mm +/- 1.1, middle-transverse 3.9 mm +/- 1.2, middle-anteroposterior 3.4 mm +/- 1.2, distal-transverse 4.1 mm +/- 1.2, distal-anteroposterior 3.5 mm +/- 1.2. Least squares regression slope differed significantly from 0.1 mm per year (95% CI; -0.000703, +0.00110) and in fact contained zero. CONCLUSION: Findings were not able to help confirm an association between age and size of the extrahepatic bile duct in an asymptomatic adult population.

Effect of propofol with and without EDTA on haemodynamics and calcium and magnesium homeostasis during and after cardiac surgery.

OBJECTIVE: To determine the effect of the addition of disodium edetate (EDTA) to propofol on haemodynamics, ionised calcium and magnesium serum concentrations, and adverse events during cardiac surgery. DESIGN: Double-blind, randomised, multicenter trial. SETTING: Operating room and intensive care unit of 5 academic health centres. PATIENTS: A total of 102 evaluable patients, aged 34 to 85 years, undergoing first-time, elective coronary artery bypass graft surgery. INTERVENTIONS: Comparison of propofol with EDTA and propofol without EDTA, each in conjunction with the opioid sufentanil, for intraoperative anaesthesia and postoperative sedation. MEASUREMENTS AND RESULTS: There were no significant differences at any time between the two formulations in any clinical chemistry measurements, including ionised calcium, ionised magnesium, total calcium, parathyroid hormone, blood urea nitrogen, creatinine, sodium, potassium, and phosphate. During bypass, the mean concentration of ionised calcium decreased to below the normal range, but the decrease was similar in both groups (propofol with EDTA, 0.98 +/- 0.07 mmol/L [N = 51]; propofol, 0.99 +/- 0.10 mmol/ L [N = 51]; p = NS). Calcium concentration returned to normal after rewarming. Mean ionised magnesium concentrations remained within normal limits in both groups. Similarly, there were no clinically meaningful differences between treatments with respect to haemodynamic variables, efficacy variables, or incidence of adverse events. CONCLUSIONS: The inclusion of EDTA in the current formulation of propofol appears to have no significant effects on calcium and magnesium profiles, renal function, haemodynamic variables, or other indicators of safety and efficacy during intraoperative anaesthesia and postoperative sedation in patients undergoing cardiac surgery.

Differences among heart rate variability measures after anesthesia and cardiac surgery.

OBJECTIVE: To determine whether there are differences among measures of heart rate variability (HRV; traditional and nonlinear) after anesthesia and cardiac surgery. DESIGN: Prospective. SETTING: University hospital. PARTICIPANTS: Patients scheduled for cardiac surgery. INTERVENTIONS: None. Medical management was not varied as part of this study. MEASUREMENTS AND MAIN RESULTS: HRV was measured in 13 patients from electrocardiograms (ECGs) recorded before anesthesia, during anesthesia but before cardiac surgery, and on the first postoperative day. Anesthesia was induced with moderate-dose fentanyl. For each ECG, HRV was measured from series of 400 heartbeat intervals using standard deviation (SD), approximate entropy (ApEn), and point correlation dimension (PD2). Multivariate repeated-measures analyses of variance on ranks and Spearman correlations were performed. All HRV measures decreased significantly with anesthesia. Postoperatively, ApEn recovered to original values. PD2 and SD did not recover with consciousness and were significantly less than original values. Correlations among ApEn, PD2, and SD were weak. CONCLUSIONS: Nonlinear measures of HRV differ among themselves after anesthesia and cardiac surgery. The use of multiple nonlinear and traditional measures may improve the effectiveness of using HRV to assess the cardiovascular system.

Noncardiogenic pulmonary edema associated with protamine administration during coronary artery bypass graft surgery.

Protamine sulfate is the only agent approved to reverse heparin-induced anticoagulation. As with any other drug, protamine has the potential to cause adverse effects that range from mild hypotension to potentially fatal events, such as noncardiogenic pulmonary edema (NCPE) and catastrophic pulmonary vasoconstriction. We report a case of NCPE after the administration of protamine to a patient undergoing coronary artery bypass graft surgery and discuss the diagnosis and management of this severe adverse event.

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

UNLABELLED: In 1995, our department of anesthesiology established an airway team to assist in treating unanticipated difficult endotracheal intubations and an airway quality improvement (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 =90% 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).

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

UNLABELLED: 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.

Heart transplantation in patients with heparin-induced thrombocytopenia on the Novacor left ventricular assist system.

We report on two patients with development of heparin-induced thrombocytopenia with thrombosis while on the Novacor left ventricular assist system. Heart transplantation was successfully performed in both patients with heparin used for cardiopulmonary bypass after careful monitoring of heparin-associated antibodies. The approach to the patients' management and potential alternatives for anticoagulation are discussed.

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.

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 microg/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 microg/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.

Upper airway closure: a primary source of difficult ventilation with sufentanil induction of anesthesia.

Large-dose opioid induction of anesthesia can lead to difficult ventilation via a mask. Poor ventilatory compliance (VC) may be secondary to "rigid" chest and abdominal wall musculature, glottic closure, or upper airway obstruction. This double-blind study assessed the contribution of the upper airway to poor VC by inducing sufentanil anesthesia in patients undergoing cardiac surgery who are ventilated via a mask (Group M) or endotracheal tube fiberoptically inserted (Group E). After induction of anesthesia with sufentanil 3 microgram/kg from time (T) = 0 min to T = 2 in Group M (n = 17) or Group E(n = 23), VC and adductor pollicis (AP) twitch tension was measured continuously. Immediately prior to muscle relaxant (pipecuronium or doxacurium) administration at T = 3, Group E demonstrated significantly better VC (46 mL/cm H2O [39-55 interquartile range (IQR)]) than Group M (19 mL/cm H2O [7-24 IQR]). The effect of muscle relaxant administration on VC preceded its effect at the AP. After complete relaxation of the AP at T = 9, both groups had similar VC. Difficult ventilation during sufentanil induction of anesthesia lies at the level of the glottis or above. Bypassing these structures with an endotracheal tube overcomes the usual decreased VC.

Activated coagulation time: one tube or two?

OBJECTIVES: To compare activated coagulation time (ACT) management directed by a single ACT determination to that of the average of two simultaneously obtained ACT values. DESIGN: Prospective study. SETTING: Cardiac operating rooms of a university hospital. PARTICIPANTS: Patients undergoing surgery requiring cardiopulmonary bypass. INTERVENTIONS: All ACT determinations were performed in duplicate; patients were managed based on the average of the duplicate values, as is customary. Results of all tests were recorded on a spreadsheet, and the management dictated by a randomly chosen single result of each pair was compared with the management directed by the average value of each pair. Predetermined criteria were set for preference of one testing method over the other. Patients were grouped according to preoperative heparin exposure, and results of the two groups were compared. MEASUREMENTS AND MAIN RESULTS: One hundred patients underwent 683 paired celite ACT determinations. In 565/683 tests (83%), both methods called for identical heparin management responses. Management by the single-tube method would have resulted in supplemental heparin administration 34% more often than management by the average method. The single-tube method would have resulted in withholding supplemental heparin 13 times when the average method called for supplemental heparin administration, a 16% occurrence. The results of the patients with and without preoperative heparin exposure were not significantly different. CONCLUSIONS: The results of this study suggest the use of a two-tube average method to guide heparin administration for cardiopulmonary bypass. Preoperative heparin exposure did not influence this outcome.

Methylene blue does not neutralize heparin after cardiopulmonary bypass.

OBJECTIVE: It was hypothesized that methylene blue could neutralize heparin in patients after cardiopulmonary bypass and become an alternative to protamine. DESIGN: This was a prospective unblinded study with patients serving as their own controls. SETTING PARTICIPANTS: A single, large university hospital. This study was conducted in patients scheduled for elective aortocoronary bypass grafting. INTERVENTIONS: When heparin was to be neutralized, patients received methylene blue, 2 to 12 mg/kg, diluted in 50 mL and infused over 20 minutes. If a clot was not observed or the activated coagulation time (ACT) remained elevated, protamine, 250 mg, was administered and the ACT was repeated. MEASUREMENTS AND MAIN RESULTS: No patient demonstrated clot after methylene blue infusion. ACT did not return to preheparin values in any patient. All patients required protamine to establish hemostasis. Protamine restored the ACT to preheparin values in every patient. The one patient who received 12 mg/kg experienced severe pulmonary hypertension. CONCLUSIONS: Methylene blue does not neutralize heparin after cardiopulmonary bypass.

Sufentanil plasma concentrations following lower extremity tourniquet release.

STUDY OBJECTIVE: To investigate whether release of a tourniquet on the lower extremity affects plasma concentrations of sufentanil, as previously demonstrated with fentanyl and midazolam. DESIGN: Prospective. SETTING: University tertiary-care institution with residency program. PATIENTS: 20 ASA status I, II, and III patients undergoing total knee arthroplasty under a tourniquet using a sufentanil, nitrous oxide, relaxant regimen. INTERVENTIONS: Each patient received sufentanil 1 to 2 micrograms/kg at induction of anesthesia and in 12.5 to 25 microgram increments as needed thereafter, until 15 minutes prior to tourniquet release. MEASUREMENTS AND MAIN RESULTS: Plasma sufentanil concentrations were determined before tourniquet inflation, immediately before tourniquet deflation, and 1, 2, 5, 10, 20, 30, and 40 minutes following deflation. A 15% elevation of plasma sufentanil concentration above that predicted by elimination pharmacokinetics defined a secondary peak. Although the aggregate data did not indicate an overall statistically significant rise in plasma concentrations after deflation, 9 (45%) patients exhibited a secondary peak in sufentanil plasma concentration following tourniquet deflation (range of secondary peaks, 16% to 89% above predicted values). No patient experienced clinically significant respiratory depression. CONCLUSION: Release of a tourniquet on the lower extremity may yield a detectable rise in plasma sufentanil concentration.