The influence of sparse data sampling on population pharmacokinetics: a post hoc analysis of a pharmacokinetic study of morphine in healthy volunteers.

BACKGROUND: Intensive sampling of patients for drugs with complex pharmacokinetic profiles is difficult to perform in the clinic or hospitalized patient setting. We seek to address whether sparse sampling can obtain pharmacokinetic parameter values similar to those with traditional modeling from a post hoc analysis of 2 previous clinical trials. OBJECTIVE: This study investigated whether population-guided, sparse-sampling pharmacokinetic analysis of morphine in 14 healthy volunteers allowed for optimal characterization of concentration-time profiles for a validation population of 5 young male patients receiving morphine. METHODS: Data were analyzed using nonparametric adaptive grid (NPAG) population modeling to investigate optimal compartmental structure and the influence of sparse sampling (ie, 9 versus 3 samples per subject) on parameter identification. These results were compared with traditional standard 2-stage (STS) pharmacokinetic modeling. The coefficients of determination (R(2)), mean error (ME), and root-mean-square error were used to assess the predictive performance of the various sampling models against a validation population. RESULTS: Seventy-nine percent of the healthy volunteers were male, with a mean age of 36 (17) years and a mean weight of 68 (10) kg. NPAG modeling identified that intravenous morphine was best represented by a 3-compartment pharmacokinetic profile and that sparse sampling with a least 3 blood samples per subject resulted in virtually identical measures of central tendency as the more intensively sampled dataset. A validation cohort of 5 male patients undergoing elective surgery had a mean age of 26 (4) years and a mean weight of 80 (13) kg. Using mean parameter estimates generated from sparse sampling and the 3-compartment model structure, simulated profiles were compared against measured concentrations in this validation cohort. Sparse sampling using NPAG achieved similar values of predictive performance as mean parameter values from the more intensively sampled, with an ME of -1.0 ng/mL and precision of 26.2 ng/mL compared with 0.76 ng/mL and 25.8 ng/mL, respectively. Traditional (STS) modeling techniques resulted in the greatest degree of underprediction within the validation group (ME = 4.43 versus 0.76 ng/mL, STS and NPAG-9, respectively; P < 0.0001). CONCLUSIONS: This post hoc analysis suggests that intensive sampling for discerning complex, 3-compartment pharmacokinetic models, such as morphine, may not be necessary. Sparse sampling achieved accurate model structure recognition and parameter identification for predicting concentrations of very complex drug-dosage regimens.

Thoracic epidural analgesia improves pulmonary function in patients undergoing cardiac surgery.

PURPOSE: Pulmonary dysfunction commonly occurs following coronary artery bypass graft (CABG) surgery, increasing morbidity and mortality. We hypothesized that thoracic epidural anesthesia (TEA) would improve pulmonary function and would decrease complications in patients undergoing CABG surgery. METHODS: This prospective, randomized, controlled trial was conducted with Ethics Board approval. Fifty patients, undergoing CABG surgery, were randomized to the epidural group or to the patient-controlled analgesia morphine group. Patients in the epidural group received a high, thoracic epidural, preoperatively. Intraoperatively, 0.75% ropivacaine was infused, followed postoperatively, by 0.2% ropivacaine for 48 hr. Outcome measurements included: visual analogue pain scores; spirometry; atelectasis scores on chest radiographs; and the incidence of atrial fibrillation. RESULTS: Twenty-five patients were enrolled in each group. Patients in the epidural group had significantly less pain on the operative day, and for the subsequent two days. Compared to baseline, the forced expiratory volume in one second was significantly higher in the epidural group, on the first and second postoperative days (43.7 +/- 12.2% vs 36.4 +/- 12.0%, p < 0.002, and 43.3 +/- 12.5% vs 38.4 +/- 11.0%, p <0.05). There was significantly more atelectasis in the control group, four hours postoperatively (p < 0.04); however, on the third, postoperative day, the groups were similar with regards to this outcome. The incidence of atrial fibrillation was similar in both groups, and there were no complications related to the epidural. CONCLUSIONS: High TEA decreases postoperative pain and atelectasis and improves pulmonary function in patients undergoing CABG surgery. Our results support the use of TEA in this group of patients.

A comparison of aprotinin and lysine analogues in high-risk cardiac surgery.

BACKGROUND: Antifibrinolytic agents are commonly used during cardiac surgery to minimize bleeding and to reduce exposure to blood products. We sought to determine whether aprotinin was superior to either tranexamic acid or aminocaproic acid in decreasing massive postoperative bleeding and other clinically important consequences. METHODS: In this multicenter, blinded trial, we randomly assigned 2331 high-risk cardiac surgical patients to one of three groups: 781 received aprotinin, 770 received tranexamic acid, and 780 received aminocaproic acid. The primary outcome was massive postoperative bleeding. Secondary outcomes included death from any cause at 30 days. RESULTS: The trial was terminated early because of a higher rate of death in patients receiving aprotinin. A total of 74 patients (9.5%) in the aprotinin group had massive bleeding, as compared with 93 (12.1%) in the tranexamic acid group and 94 (12.1%) in the aminocaproic acid group (relative risk in the aprotinin group for both comparisons, 0.79; 95% confidence interval [CI], 0.59 to 1.05). At 30 days, the rate of death from any cause was 6.0% in the aprotinin group, as compared with 3.9% in the tranexamic acid group (relative risk, 1.55; 95% CI, 0.99 to 2.42) and 4.0% in the aminocaproic acid group (relative risk, 1.52; 95% CI, 0.98 to 2.36). The relative risk of death in the aprotinin group, as compared with that in both groups receiving lysine analogues, was 1.53 (95% CI, 1.06 to 2.22). CONCLUSIONS: Despite the possibility of a modest reduction in the risk of massive bleeding, the strong and consistent negative mortality trend associated with aprotinin, as compared with the lysine analogues, precludes its use in high-risk cardiac surgery. (Current Controlled Trials number, ISRCTN15166455 [controlled-trials.com].).

Efficacy and safety of the cyclooxygenase 2 inhibitors parecoxib and valdecoxib in patients undergoing coronary artery bypass surgery.

OBJECTIVE: Inhibition of cyclooxygenase 2 provides analgesia in ambulatory patients. We prospectively evaluated the safety and efficacy of a newly introduced cyclooxygenase 2 inhibitor in patients undergoing coronary artery bypass grafting surgery through a median sternotomy in a randomized clinical trial. METHODS: A total of 462 patients with New York Heart Association classes I to III who were less than 77 years of age and were from 58 institutions in the United States, Canada, Germany, and the United Kingdom participated in this multicenter, phase III, placebo-controlled, double-blind, randomized, parallel-group trial. Patients were allocated at a ratio of 2:1 to parecoxib/valdecoxib or standard care (control) groups, respectively. Intravenous study drug (40 mg) was administered within 30 minutes after extubation and every 12 hours for a minimum of 3 days. Subsequently, oral treatment at a dose of 40 mg every 12 hours was initiated and administered for a combined total of 14 days. Patient-controlled analgesia with morphine, oral opioids, or acetaminophen was available as required. Assessment of the analgesic efficacy of the study drug was primarily based on morphine and morphine equivalent use. Additional efficacy evaluations included daily pain intensity, patient and physician global evaluation of study medication, and pain effect on quality of life. Clinical adverse events were assessed by the principal investigator at each site from the time of the first dose through the 30-day postdosing period. RESULTS: Patients in the parecoxib/valdecoxib group received significantly less morphine or morphine equivalents than patients in the control group during the 0- to 24-hour (P =.009), 24- to 48-hour (P =.017), 72- to 96-hour (P =.002), 96- to 120-hour (P =.004), and 120- to 144-hour (P =.037) periods. Both patients (P <.001) and physicians (P <.001) evaluated the study medication as significantly better than control therapy. The modified Brief Pain Inventory questionnaire used in the oral dosing period detected significant improvements in the parecoxib/valdecoxib treatment group in 6 of 8 domains tested (eg, current pain, worst pain, and mood) beginning on day 4 and continuing for at least 4 days. Although there were no differences between the groups in overall adverse events, serious adverse events occurred twice as frequently in parecoxib/valdecoxib-treated patients (19.0%, 59/311 patients) than in control patients (9.9%, 15/151 patients; P =.015). Regarding individual serious adverse events, a greater incidence in sternal wound infection was found in the parecoxib/valdecoxib patients (10 [3.2%]) versus control patients (0 [0%]) (P =.035). The incidences of other individual serious adverse events, including cerebrovascular complications, myocardial infarction, and renal dysfunction, were proportionally greater but not significantly different between the groups. CONCLUSIONS: In patients undergoing coronary artery bypass grafting surgery, the cyclooxygenase 2 inhibitor combination, parecoxib/valdecoxib, was effective for postoperative analgesia. However, the 14-day treatment regimen also was associated with an increased incidence of serious adverse events overall and sternal wound infections in particular. Therefore our study raises important concerns requiring their comprehensive evaluation in a large-scale trial before these cyclooxygenase 2 inhibitors are used in patients undergoing coronary artery bypass grafting surgery.

Survey of the members of the cardiovascular section of the Canadian Anesthesiologists' Society on the use of perioperative transesophageal echocardiography - a brief report.

PURPOSE: Transesophageal echocardiography (TEE) is a useful diagnostic and monitoring tool in the operating room. In the United States, an increasing number of centres are training anesthesiologists to preform intraoperative TEE. In Canada, TEE has been slow to gain acceptance as an intraoperative monitor and little information is available on its use by the anesthesiologists across the country. METHODS: We surveyed all members of the cardiovascular section of the Canadian Anesthesiologists' Society, to find out how many perform TEE, how they acquired their skills and how they use TEE in their practice. RESULTS: The response rate was 48.4%. Most respondents were Canadian-trained cardiac anesthesiologists working in university centres. 91% of respondents stated that their centres offer intraoperative TEE services. Of those services, 35.1% were provided by anesthesiologists only, 13% by cardiologists only, and 51.9% by both. 53.8% of respondents have certification in intraoperative TEE (NBE/SCA, ASE or Provincial College). 90% of respondents use equipment that is less than five years old and multiplane probes are used by almost everyone. There was strong support for Canadian-based continuing medical education events in perioperative TEE. CONCLUSION: TEE appears to be available in most cardiac centres in Canada and anesthesiologists are actively involved in providing intraoperative TEE services, using state-of-the-art equipment. Many anesthesiologists have formal training in TEE.

Postoperative pulmonary function in coronary artery bypass graft surgery patients undergoing early tracheal extubation: a comparison between short-term mechanical ventilation and early extubation.

OBJECTIVE: To evaluate the effect of a short period of mechanical ventilation (3 hours) versus immediate extubation (within 1 hour of surgery) on pulmonary function, gas exchange, and pulmonary complications after coronary artery bypass graft (CABG) surgery. DESIGN: Prospective randomized study. SETTING: University teaching hospital. PARTICIPANTS: Thirty-five patients undergoing CABG surgery. INTERVENTIONS: Patients were randomized into 2 groups. Patients in group I were extubated as soon as possible after surgery. Patients in group II were ventilated for a minimum of 3 hours after surgery. Patients in both groups were extubated only after achieving predetermined extubation criteria. Patients who did not meet the criteria for extubation within the predetermined set time limit (90 minutes in group I and 6 hours in group II) were withdrawn from the study. Pulmonary function tests (vital capacity, forced expiratory volume in 1 second, total lung capacity, functional residual capacity), arterial blood gases, and chest radiographs were done preoperatively and postoperatively. Pulmonary complications were recorded. MEASUREMENTS AND MAIN RESULTS: Demographic data were similar between groups. The mean time to extubation in group I was 45.7 plus minus 27.6 minutes and in group II was 201.4 plus minus 21 minutes (p < 0.01). Two patients in group I and 1 patient in group II did not meet the extubation criteria within the predetermined set time limit and were excluded from the study. In both groups, there was a significant decline in pulmonary function but no differences between groups at 24 or 72 hours after surgery. There were no differences between groups in blood gases, atelectasis scores, or pulmonary complications. CONCLUSION: The data suggest that extending mechanical ventilation after CABG surgery does not affect pulmonary function. Provided that routine extubation criteria are met, patients can be safely extubated early (within 1 hour) after major cardiac surgery without concerns of further pulmonary derangement.