Cost-efficacy of Rofecoxib versus Acetaminophen for Preventing Pain after Ambulatory Surgery

Background: Nonsteroidal antiinflammatory drugs are commonly administered as part of a multimodal regimen for pain management in the ambulatory setting. This randomized, double-blinded, placebo-controlled study was designed to compare the analgesic effect of oral rofecoxib, a cyclooxygenase-2 inhibitor, and acetaminophen when administered alone or in combination prior to outpatient otolaryngologic surgery.

Methods: A total of 143 healthy outpatients undergoing elective otolaryngologic surgery were assigned to one of four study groups: group 1 = control (500 mg vitamin C); group 2 = 2 g acetaminophen; group 3 = 50 mg rofecoxib; or group 4 = 2 g acetaminophen and 50 mg rofecoxib. The first oral dose of the study medication was taken 15-45 min before surgery, and a second dose of the same medication was administered on the morning after surgery. Recovery times, side effects, and the need for rescue analgesics were recorded. Follow-up evaluations were performed at 24 and 48 h after surgery to assess postdischarge pain, analgesic requirements, nausea, and patient satisfaction with their postoperative pain management and quality of recovery. Peak pain scores and the need for rescue analgesic medication were used as the endpoints for estimating efficacy of the study drugs, while cost to achieve complete satisfaction with analgesia was used in the cost-effectiveness analysis.

Results: Premedication with rofecoxib (50 mg) was significantly more effective than either placebo or acetaminophen (2 g) in reducing the peak postoperative pain, the need for analgesic medication, and improving the quality of recovery and patient satisfaction. Moreover, the addition of acetaminophen failed to improve its analgesic efficacy. An expenditure for rofecoxib of $16.76 (95% confidence interval, $7.89 to 21.03) and $30.24 (95% confidence interval, $5.25 to 54.20) would obtain complete satisfaction with pain control in one additional patient who would not have been satisfied if placebo or acetaminophen, respectively, had been administered prior to surgery.     

Emergence from Anesthesia in the Prone versus Supine Position in Patients Undergoing Lumbar Surgery

Background: Conventional supine emergence in patients undergoing prone lumbar surgery frequently results in tachycardia, hypertension, coughing, and loss of monitoring as the patient is rolled supine. The prone position might facilitate a smoother emergence because the patient is not disturbed. No data describe this technique.

Methods: Fifty patients were anesthetized with fentanyl, nitrous oxide, isoflurane, and rocuronium. By the conclusion of surgery, all patients achieved spontaneous ventilation and full reversal of neuromuscular blockade in the prone position, as the volatile anesthetic level was reduced. Baseline heart rate and mean arterial pressure were recorded. Patients were then randomized at time 0 to the supine (n = 24) or prone (n = 21) position as 100% oxygen was administered. Patients in the supine position were then rolled over, while those in the prone position remained undisturbed. Heart rate, mean arterial pressure, and coughs were recorded until extubation. Tracheas were extubated on eye opening or purposeful behavior.

Results: When compared with the supine group, prone patients had significantly less increase in heart rate (P = 0.0003, maximum increase 9.3 vs. 25 beats/min), less increase in mean arterial pressure (P = 0.0063, maximum increase 4.8 vs. 19 mmHg), less coughing (P = 0.0004, 7.0 vs. 23 coughs), and fewer monitor disconnections (P < 0.0001). Time to extubation from time 0 was similar (4.0 vs. 3.7 min, prone vs. supine). No one required airway rescue. There was no significant difference in need for restraint (three prone, four supine).     

Awareness: Monitoring versus Remembering What Happened

Background: Awareness during anesthesia is foremost assessed with postoperative interviews, which may underestimate its incidence. On-line monitors such as the Bispectral Index(R) and patient response to verbal command are not necessarily commonly used. This study investigated response to command during deep sedation (Bispectral Index 60-70) and the ability of prevailing monitoring techniques to indicate awareness and predict recall.

Methods: The authors systematically assessed the response to command using the isolated forearm technique while monitoring electroencephalographic and hemodynamic variables. Fifty-six elective surgical patients were repeatedly given verbal instructions to squeeze the observer's hand during target-controlled infusion with propofol and alfentanil. After recovery, conscious recall was assessed with a short structured interview.

Results: Overall, 1,082 commands were given. No response was observed to 887 (82%) commands, an equivocal response was observed to 56 (5%) commands, and an unequivocal response was observed to 139 (13%) commands. Of the 37 patients (66%) with an unequivocal response to command ("awareness"), nine (25%) reported conscious recall after recovery. Their reports provided valuable insights as to how awareness may be adequately addressed. Hemodynamic variables poorly predicted awareness, whereas parameters derived from the encephalogram, especially the Bispectral Index, were highly significant predictors (P < 0.0001). Electroencephalographic parameters did not discriminate between patients with or without conscious recall, whereas heart rate and responsiveness to command did.     

Combined Spinal-Epidural versus Epidural Labor Analgesia

Background: Despite the growing popularity of combined spinal-epidural analgesia in laboring women, the exact role of intrathecal opioids and the needle-through-needle technique remains to be determined. The authors hypothesized that anesthetic technique would have little effect on obstetric outcome or anesthetic complications.

Methods: Data were prospectively collected from 2,183 laboring women randomly assigned to have labor analgesia induced with either 10 [mu]g intrathecal sufentanil with or without 2.0 mg bupivacaine (n = 1,071) or 10 [mu]g epidural sufentanil and 12.5-25.0 mg bupivacaine (n = 1,112). Immediately after induction, a continuous epidural infusion of 0.083% bupivacaine plus 0.3 [mu]g/ml sufentanil was begun in all patients and continued until delivery. Labor was managed by nurses, obstetricians, and obstetric residents who were unaware of the anesthetic technique used.

Results: Anesthetic technique lacked impact on our primary outcome: mode of delivery or labor duration. Infants whose mothers were allocated to the combined spinal-epidural group had a slightly higher umbilical artery carbon dioxide partial pressure (54.2 +/- 10.4 vs. 53.2 +/- 10.2 mmHg). However, only achieving at least 5 cm cervical dilation before induction of analgesia and having a cesarean delivery were independent risk factors for elevated umbilical artery carbon dioxide partial pressure. The frequencies of accidental dural puncture, failed epidural analgesia, headache, and epidural blood patch were low and similar in the two groups.     

Amitriptyline versus Bupivacaine in Rat Sciatic Nerve Blockade

Background: Amitriptyline, a tricyclic antidepressant, is frequently used orally for the management of chronic pain. To date there is no report of amitriptyline producing peripheral nerve blockade. The authors therefore investigated the local anesthetic properties of amitriptyline in rats and in vitro.

Methods: Sciatic nerve blockade was performed with 0.2 ml amitriptyline or bupivacaine at selected concentrations, and the motor, proprioceptive, and nociceptive blockade was evaluated. Cultured rat GH3 cells were externally perfused with amitriptyline or bupivacaine, and the drug affinity toward inactivated and resting Na+ channels was assessed under whole-cell voltage clamp conditions. In addition, use-dependent blockade of these drugs at 5 Hz was evaluated.

Results: Complete sciatic nerve blockade for nociception was obtained with amitriptyline for 217 +/- 19 min (5 mm, n = 8, mean +/- SEM) and for 454 +/- 38 min (10 mm, n = 7) versus bupivacaine for 90 +/- 13 min (15.4 mm, n = 6). The time to full recovery of nociception for amitriptyline was 353 +/- 12 min (5 mm) and 656 +/- 27 min (10 mm) versus 155 +/- 9 min for bupivacaine (15.4 mm). Amitriptyline was approximately 4.7-10.6 times more potent than bupivacaine in binding to the resting channels (50% inhibitory concentration [IC50] of 39.8 +/- 2.7 vs. 189.6 +/- 22.3 [mu]m) at -150 mV, and to the inactivated Na+ channels (IC50 of 0.9 +/- 0.1 vs. 9.6 +/- 0.9 [mu]m) at -60 mV. High-frequency stimulation at 3 [mu]m caused an additional approximately 14% blockade for bupivacaine, but approximately 50% for amitriptyline.     

Activation of Coagulation and Fibrinolysis during Coronary Surgery: On-pump versus Off-pump Techniques

Background : The authors studied the changes in selected hemostatic variables in patients undergoing coronary surgery with on-pump coronary artery bypass grafting (CABG) or off-pump coronary artery bypass surgery (OPCAB) techniques.

Methods : Platelet counts and plasma concentrations of antithrombin, fibrinogen, D dimer, [alpha]2 antiplasmin, and plasminogen were measured preoperatively, 5 min after administration of heparin, 10 min after arrival in the intensive care unit, and 24 h after surgery in patients scheduled to undergo OPCAB (n = 15) or CABG (n = 15). To correct for dilution, hemostatic variables and platelet counts were adjusted for the changes in immunoglobulin G plasma concentrations and hematocrit, respectively.

Results : Adjusting for dilution, antithrombin and fibrinogen concentrations decreased to a similar extent in patients undergoing OPCAB or CABG (pooled means and 95% confidence limits of the mean: 95.5% of baseline, 93-98%, P = 0.002, and 91.7% of baseline, 88-95%, P = 0.0001), respectively, whereas [alpha]2-antiplasmin concentrations were unchanged. Only CABG was associated with a reduction in platelet counts (76% of baseline, 66-85%, P = 0.0001), plasminogen concentrations (96% of baseline, 91-99%, P = 0.011), and increased D-dimer formation (476%, 309-741%, P = 0.004). Twenty-four hours after surgery, platelet counts were still lower in patients undergoing CABG (P = 0.049), but all the investigated variables adjusted for dilution were similar in the two groups.     

A Double-blind, Randomized Comparison of IV Lorazepam versus Midazolam for Sedation of ICU Patients via a Pharmacologic Model

Background: Benzodiazepines, such as lorazepam and midazolam, are frequently administered to surgical intensive care unit (ICU) patients for postoperative sedation. To date, the pharmacology of lorazepam in critically ill patients has not been described. The aim of the current study was to characterize and compare the pharmacokinetics and pharmacodynamics of lorazepam and midazolam administered as continuous intravenous infusions for postoperative sedation of surgical ICU patients.

Methods: With Institutional Review Board approval, 24 consenting adult surgical patients were given either lorazepam or midazolam in a double-blind fashion (together with either intravenous fentanyl or epidural morphine for analgesia) through target-controlled intravenous infusions titrated to maintain a moderate level of sedation for 12-72 h postoperatively. Moderate sedation was defined as a Ramsay Sedation Scale score of 3 or 4. Sedation scores were measured, together with benzodiazepine plasma concentrations. Population pharmacokinetic and pharmacodynamic parameters were estimated using nonlinear mixed-effects modeling.

Results: A two-compartment model best described the pharmacokinetics of both lorazepam and midazolam. The pharmacodynamic model predicted depth of sedation for both midazolam and lorazepam with 76% accuracy. The estimated sedative potency of lorazepam was twice that of midazolam. The predicted C50,ss (plasma benzodiazepine concentrations where P(Sedation >= ss) = 50%) values for midazolam (sedation score [SS] >= n, where n = a Ramsay Sedation Score of 2, 3, . . . 6) were 68, 101, 208, 304, and 375 ng/ml. The corresponding predicted C50,ss values for lorazepam were 34, 51, 104, 152, and 188 ng/ml, respectively. Age, fentanyl administration, and the resolving effects of surgery and anesthesia were significant covariates of benzodiazepine sedation. The relative amnestic potency of lorazepam to midazolam was 4 (observed). The predicted emergence times from sedation after a 72-h benzodiazepine infusion for light (SS = 3) and deep (SS = 5) sedation in a typical patient were 3.6 and 14.9 h for midazolam infusions and 11.9 and 31.1 h for lorazepam infusions, respectively.     

Risk Factors for Early-onset, Ventilator-associated Pneumonia in Critical Care Patients: Selected Multiresistant versus Nonresistant Bacteria

Background: Ventilator-associated pneumonia is the leading nosocomial infection in critically ill patients. The frequency of ventilator-associated pneumonia caused by multidrug-resistant bacteria has increased in recent years, and these pathogens cause most of the deaths attributable to pneumonia. The authors, therefore, evaluated factors associated with selected multidrug-resistant ventilator-associated pneumonia in critical care patients.

Methods: The authors prospectively recorded potential risk factors at the time of intensive care unit admission. An endotracheal aspirate was obtained in all patients who met clinical criteria for pneumonia. Patients were considered to have ventilator-associated pneumonia only when they met the clinical criteria and aspirate culture was positive for bacteria 48 h or more after initiation of mechanical ventilation. Pediatric patients were excluded. Adult patients with ventilator-associated pneumonia were first grouped as "early-onset" (< 5 days) and "late-onset," determined by episodes of ventilator-associated pneumonia, and then, assigned to four groups based on the bacteria cultured from their tracheal aspirates:Pseudomonas aeruginosa, Acinetobacter baumanii, methicillin-resistant staphylococci, and all others. The first three bacteria were considered to be multidrug resistant, whereas the others were considered to be antibiotic susceptible. Potential risk factors were evaluated with use of univariate statistics and multivariate regression.

Results: Among 486 consecutive patients admitted during the study, 260 adults underwent mechanical ventilation for more than 48 h. Eighty-one patients (31%) experienced 99 episodes of ventilator-associated pneumonia, including Pseudomonas (33 episodes), methicillin-resistant staphylococci (17 episodes), Acinetobacter (9 episodes), and nonresistant bacteria (40 episodes). Sixty-six of these episodes were early onset and 33 episodes were late onset. Logistic regression analysis identified three factors significantly associated with early-onset ventilator-associated pneumonia caused by any one of the multidrug-resistant bacterial strains: emergency intubation (odds ratio, 6.4; 95% confidence interval, 2.0-20.2), aspiration (odds ratio, 12.7; 95% confidence interval, 2.4-64.6), and Glasgow coma score of 9 or less (odds ratio, 3.9; 95% confidence interval, 1.3-11.3). A. baumanii-related pneumonia cases were found to be significantly associated with two of these factors: aspiration (odds ratio, 14.2; 95% confidence interval, 1.5-133.8) and Glasgow coma score (odds ratio, 6.0; 95% confidence interval, 1.1-32.6).     

Efficacy and Safety of Heparinase I versus Protamine in Patients Undergoing Coronary Artery Bypass Grafting with and without Cardiopulmonary Bypass

Background: Hemodynamic protamine reactions with heparin reversal during cardiac surgery are common and associated with adverse outcomes. As an alternative to protamine, the authors examined heparinase I reversal of heparin after aortocoronary bypass graft surgery.

Methods: In a randomized, double-blind, double-dummy trial, 167 on- and off-pump aortocoronary bypass graft surgery patients received either heparinase I (maximum 35 [mu]g/kg) or protamine (maximum 650 mg) for heparin reversal, monitored by activated clotting time values and clinical assessment. Hemodynamic parameters were recorded electronically; safety evaluation was to 30 days postoperatively. Noninferiority was predefined as 400 ml or less median 12-h chest tube drainage from intensive care unit arrival for heparinase I patients, after risk adjustment. Hemodynamic instability was defined as systemic hypotension (>= 30 mmHg decrease) and/or pulmonary hypertension (>= 40 mmHg with an increase >= 10mmHg) within 30 min of heparin reversal initiation.

Results: Patient enrollment was terminated on advisement of the Data Safety Monitoring Board. Although heparinase I was noninferior for 12-h chest tube drainage, protamine had a superior safety profile. Overall, heparinase I subjects had longer hospital stays (P = 0.04), were more likely to experience a serious adverse event (P = 0.01), and were less likely to avoid transfusion (P = 0.006). A composite morbidity score was not different (P = 0.24), and similar rates of hemodynamic instability were observed between groups. Findings were consistent in analyses stratified by on- and off-pump surgery.     

Bulleyaconitine A Isolated from Aconitum Plant Displays Long-acting Local Anesthetic Properties In Vitro and In Vivo

Background: Bulleyaconitine A (BLA) is an active ingredient of Aconitum bulleyanum plants. BLA has been approved for the treatment of chronic pain and rheumatoid arthritis in China, but its underlying mechanism remains unclear.

Methods: The authors examined (1) the effects of BLA on neuronal voltage-gated Na+ channels in vitro under the whole cell patch clamp configuration and (2) the sensory and motor functions of rat sciatic nerve after single BLA injections in vivo.

Results: BLA at 10 [mu]m did not affect neuronal Na+ currents in clonal GH3 cells when stimulated infrequently to +50 mV. When stimulated at 2 Hz for 1,000 pulses (+50 mV for 4 ms), BLA reduced the peak Na+ currents by more than 90%. This use-dependent reduction of Na+ currents by BLA reversed little after washing. Single injections of BLA (0.2 ml at 0.375 mm) into the rat sciatic notch not only blocked sensory and motor functions of the sciatic nerve but also induced hyperexcitability, followed by sedation, arrhythmia, and respiratory distress. When BLA at 0.375 mm was coinjected with 2% lidocaine (approximately 80 mm) or epinephrine (1:100,000) to reduce drug absorption by the bloodstream, the sensory and motor functions of the sciatic nerve remained fully blocked for approximately 4 h and regressed completely after approximately 7 h, with minimal systemic effects.     

Tissue Monocytes/Macrophages in Inflammation: Hyperalgesia versus Opioid-mediated Peripheral Antinociception

Background: Opioid-containing leukocytes migrate to peripheral sites of inflammation. On exposure to stress, opioid peptides are released, bind to opioid receptors on peripheral sensory neurons, and induce endogenous antinociception. In later stages of Freund's complete adjuvant-induced local inflammation, monocytes/macrophages are a major opioid-containing leukocyte subpopulation, but these cells also produce proalgesic cytokines. In this study, the role of tissue monocytes/macrophages in hyperalgesia and in peripheral opioid-mediated antinociception was investigated.

Methods: After intraplantar injection of Freund's adjuvant, leukocyte subpopulations and opioid-containing leukocytes were analyzed by flow cytometry in the inflamed paw in the presence or absence of monocyte/macrophage depletion by intraplantar injection of clodronate-containing liposomes (phosphate-buffered saline and empty liposomes served as controls). Paw volume was measured with a plethysmometer. Hyperalgesia was determined by measuring heat-induced paw withdrawal latency and paw pressure threshold. Paw pressure threshold was also measured after swim stress and injection of fentanyl.

Results: At 48 and 96 h of inflammation, it was found that (1) monocytes/macrophages were the largest leukocyte subpopulation (> 55% of all leukocytes) and the predominant producers of opioid peptides (71-77% of all opioid-containing leukocytes in the paw), (2) clodronate-containing liposomes depleted monocytes/macrophages by 30-35% (P < 0.05), (3) hyperalgesia was unaltered by liposome injection (P > 0.05), and (4) opioid-containing leukocytes and swim stress but not fentanyl-induced antinociception were significantly decreased by clodronate-containing liposomes (P < 0.05, P > 0.05, all by t test; opioid-containing cells and swim stress-induced increase of paw pressure threshold were reduced by 35-42% and 20%, respectively).     

Assessment of Depth of Anesthesia and Postoperative Respiratory Recovery after Remifentanil-versus Alfentanil-based Total Intravenous Anesthesia in Patients Undergoing Ear-Nose-Throat Surgery

Background: The authors investigated whether total intravenous anesthesia (TIVA) with precalculated equipotent infusion schemes for remifentanil and alfentanil would ensure appropriate analgesia and that remifentanil would result in better recovery characteristics.

Methods: Forty consenting patients (classified as American Society of Anesthesiologists physical status I-III) scheduled for microlaryngoscopy were randomized to receive, in a double-blind manner, either remifentanil (loading dose 1 [mu]g/kg; maintenance infusion, 0.25 [mu]g [middle dot] kg-1 [middle dot] min-1) or alfentanil (loading dose, 50 [mu]g/kg; maintenance infusion, 1 [mu]g [middle dot] kg-1 [middle dot] min-1) as the analgesic component of TIVA. They were combined with propofol (loading dose, 2 mg/kg; maintenance infusion, 100 [mu]g [middle dot] kg-1 [middle dot] min-1). To insure an equal state of anesthesia, the opioids were titrated to maintain heart rate and mean arterial pressure within 20% of baseline, and propofol was titrated to keep the bispectral index (BIS) less than 60. Neuromuscular blockade was achieved with succinylcholine. Drug dosages and the times from cessation of anesthesia to extubation, verbal response, recovery of ventilation, and neuropsychological testing, orientation, and discharge readiness were recorded.

Results: Demographics, duration of surgery, and anesthesia were similar between the two groups. Both groups received similar propofol doses. There were no difference in BIS values preoperatively (mean, 96), intraoperatively (mean, 55), and postoperatively (mean, 96). Recovery of BIS and times for verbal response did not differ. At 20, 30, and 40 min after terminating the opioid infusion, the peripheral oxygen saturation and respiratory rate were significantly higher in the remifentanil group compared with the alfentanil group.     

Pharmacokinetics and Pharmacodynamics of Inhaled versus Intravenous Morphine in Healthy Volunteers

Background: A new pulmonary drug delivery system produces aerosols from disposable packets of medication. This study compared the pharmacokinetics and pharmacodynamics of morphine delivered by an AERx prototype with intravenous morphine.

Methods: Fifteen healthy volunteers were enrolled. Two subjects were administered four inhalations of 2.2 mg morphine each at 1-min intervals or 4.4 mg over 3 min by intravenous infusion. Thirteen subjects were given twice the above doses, i.e., eight inhalations or 8.8 mg intravenously over 7 min. Arterial blood sampling was performed every minute during administration and at 2, 5, 7, 10, 15, 20, 45, 60, 90, 120, 150, 180, and 240 min after administration. The effect of morphine was assessed by measuring pupil diameter and ventilatory response to a hypercapnic challenge. Pharmacokinetic and pharmacodynamic analyses were performed simultaneously using mixed-effect models.

Results: The pharmacokinetic data after intravenous administration were described by a three-exponent decay model preceded by a lag time. The pharmacokinetic model for administration by inhalation consisted of the three-exponent intravenous pharmacokinetic model preceded by a two-exponent absorption model. The authors found that, with administration by inhalation, the total bioavailability was 59%, of which 43% was absorbed almost instantaneously and 57% was absorbed with a half-life of 18 min. The median times to the half-maximal miotic effects of morphine were 10 and 5.5 min after inhalation and intravenous administration, respectively (P < 0.01). The pharmacodynamic parameter ke0 was approximately 0.003 min-1.     

Peribulbar versus Retrobulbar Anesthesia for Ophthalmic Surgery: An Anatomical Comparison of Extraconal and Intraconal Injections

Background: Peribulbar and retrobulbar anesthesia have long been opposed on the basis of the existence of an intermuscular membrane, which is supposed to separate the intraconal from the extraconal spaces in a water-tight fashion. A local anesthetic injected outside the cone should spread through this septum to reach the nerves to be blocked. The existence of this septum is questioned. The aim of this study was to compare the spread of a colored latex dye injected intraconally or extraconally to simulate both retrobulbar and peribulbar anesthesia.

Methods: The authors used 10 heads from human cadavers. For each head, one eye was injected intraconally, and the other eye was injected extraconally. The heads were then frozen and sectioned into thin slices following various planes. They were then photographed and observed.

Results: There was no evidence of the existence of an intermuscular septum separating the intraconal and extraconal spaces. Those two spaces appeared to be part of a common spreading space, the corpus adiposum of the orbit.     

Financial Impact If Payers Use Medicare Rates: Anesthesiology versus Other Specialties

Background: In 1992, Medicare changed its method for calculating physician payments. The resulting fee schedules have contained low payments for anesthesiologists. Now, other third-party (insurance) payers are using these schedules. The financial impact on anesthesiologists if all payers pay Medicare rates is unknown.

Methods: Payments from Medicare were compared with payments from other third parties in each clinical procedural terminology (CPT) grouping used by the West Virginia University Department of Anesthesiology during 1998. Changes in total Department of Anesthesiology receipts were determined if non-Medicare third-party payers paid Medicare rates. Then, the effect of adding payments at Medicare rates from patients without insurance was determined. Finally, potential changes in receipts of the Departments of Anesthesiology, Radiology, Surgery, and Medicine were compared by considering only patients with insurance and recalculating total payments to the departments using Medicare rates.

Results: Medicare paid less than other third-party payers in every clinical procedural terminology group. Total Department of Anesthesiology payments would decrease by 31% if all non-Medicare third-parties paid Medicare rates. Adding payments at Medicare rates from patients without insurance still leads to a 21% decrease in total Department of Anesthesiology receipts. Considering only patients with third-party coverage, Medicare-rate payments would decrease total Department of Anesthesiology payments by 37%, whereas radiology, surgery, and medicine payments would decrease by 26, 22, and 13% respectively.