Pharmacological and toxicological activity of RSD921, a novel sodium channel blocker.

BACKGROUND: RSD921, the R,R enantiomer of the kappa (k) agonist PD117,302, lacks significant activity on opioid receptors. METHODS: The pharmacological and toxicological actions were studied with reference to cardiovascular, cardiac, antiarrhythmic, toxic and local anaesthetic activity. RESULTS: In rats, dogs and baboons, RSD921 dose-dependently reduced blood pressure and heart rate. In a manner consistent with sodium channel blockade it prolonged the PR and QRS intervals of the ECG. Furthermore, in rats and NHP, RSD921 increased the threshold currents for induction of extra-systoles and ventricular fibrillation (VFt), and prolonged effective refractory period (ERP). In rats, RSD921 was protective against arrhythmias induced by electrical stimulation and coronary artery occlusion. Application of RSD921 to voltage-clamped rat cardiac myocytes blocked sodium currents. RSD921 also blocked transient (ito) and sustained (IKsus) outward potassium currents, albeit with reduced potency relative to sodium current blockade. Sodium channel blockade due to RSD921 in myocytes and isolated hearts was enhanced under ischaemic conditions (low pH and high extracellular potassium concentration). When tested on the cardiac, neuronal and skeletal muscle forms of sodium channels expressed in Xenopus laevis oocytes, RSD921 produced equipotent tonic block of sodium currents, enhanced channel block at reduced pH (6.4) and marked use-dependent block of the cardiac isoform. RSD921 had limited but quantifiable effects in subacute toxicology studies in rats and dogs. Pharmacokinetic analyses were performed in baboons. Plasma concentrations producing cardiac actions in vivo after intravenous administration of RSD921 were similar to the concentrations effective in the in vitro assays utilized. CONCLUSIONS: RSD921 primarily blocks sodium currents, and possesses antiarrhythmic and local anaesthetic activity.

Group II metabotropic glutamate receptor antagonism prevents the antiallodynic effects of R-isovaline.

We previously showed that isovaline is a peripheral analgesic which acts in vivo and in brain slices as an atypical metabotropic GABA(B) agonist. Peripheral inhibitory group II and III metabotropic glutamate receptors (mGluRs) belong to the same family C as GABA(B) receptors; therefore, we hypothesized that isovaline's analgesic effects could include their activation. We examined the effects of R-isovaline on mechanical allodynia produced by prostaglandin E2 in the mouse paw. Subcutaneous R-isovaline produced dose-dependent antiallodynia restricted to the injected hindlimb. This antiallodynia was blocked by co-injection with a selective group II mGluR antagonist, LY341495, but not a group III mGluR antagonist (MAP-4). The antiallodynic effect of R-isovaline was potentiated by co-administration of a group II mGluR-positive allosteric modulator, LY487379. Injection of a group II mGluR agonist (LY354740) produced an antiallodynic effect which was completely reversed by group II antagonism, but was not affected by group III or GABA(B) (CGP35348) antagonism. Similarly, group II mGluR antagonism did not alter the antiallodynia produced by the prototypical GABA(B) agonist, baclofen. Hence, there was no apparent crosstalk between group II mGluRs and GABA(B) receptors. Previous studies have demonstrated that peripheral GABA(B) receptor activation by isovaline produces antiallodynia. In addition, the present results indicate that activation of peripheral group II mGluRs by R-isovaline produces antiallodynia.

GABA(B) receptor-mediated selective peripheral analgesia by the non-proteinogenic amino acid, isovaline.

Peripherally restricted analgesics are desirable to avoid central nervous system (CNS) side effects of opioids. Nonsteroidal anti-inflammatory drugs produce peripheral analgesia but have significant toxicity. GABA(B) receptors represent peripheral targets for analgesia but selective GABA(B) agonists like baclofen cross the blood-brain barrier. Recently, we found that the CNS-impermeant amino acid, isovaline, produces analgesia without apparent CNS effects. On observing that isovaline has GABA(B) activity in brain slices, we examined the hypothesis that isovaline produces peripheral analgesia mediated by GABA(B) receptors. We compared the peripheral analgesic and CNS effect profiles of isovaline, baclofen, and GABA (a CNS-impermeant, unselective GABA(B) agonist). All three amino acids attenuated allodynia induced by prostaglandin E2 injection into the mouse hindpaw and tested with von Frey filaments. The antiallodynic actions of isovaline, baclofen, and GABA were blocked by the GABA(B) antagonist, CGP52432, and potentiated by the GABA(B) modulator, CGP7930. We measured Behavioural Hyperactivity Scores and temperature change as indicators of GABAergic action in the CNS. ED(95) doses of isovaline and GABA produced no CNS effects while baclofen produced substantial sedation and hypothermia. In a mouse model of osteoarthritis, isovaline restored performance during forced exercise to baseline values. Immunohistochemical staining of cutaneous layers of the analgesic test site demonstrated co-localization of GABA(B1) and GABA(B2) receptor subunits on fine nerve endings and keratinocytes. Isovaline represents a new class of peripherally restricted analgesics without CNS effects, mediated by cutaneous GABA(B) receptors.

Modelling for computer controlled neuromuscular blockade.

In this paper we present data collection and methods for the selection of a model class with the goal of automated neuromuscular blockade (NMB). Neuromuscular response was measured in the presence of rocuronium in rabbits (N=5) and humans (N=14). An average response was formed and used to determine optimal ARX and Laguerre representations for a wide range of orders and parameters. A 6th order Laguerre model was selected based on its accuracy and simplicity. Models were identified for each subject. For each group, variation was measured by comparison to the average response. The standard deviation of the average impulse response static gain was 45.4 and 45.8% of the mean for the rabbit and human models, respectively. The range of static gain was 121 and 159% of the mean for the rabbit and human datasets. Frequency domain analysis showed differences in gain of 12 and 15dB, and phase of 45 and 75° for the rabbit and human models respectively. With this knowledge, design and development of appropriate controllers for NMB will proceed.

Use of a cardiocerebral-protective drug cocktail prior to countershock in a porcine model of prolonged ventricular fibrillation.

OBJECTIVES: This was the third study in a series exploring whether the use of combination pharmacotherapy with delayed countershock would produce higher rates of return of spontaneous circulation (ROSC) and one-hour survival when compared with standard advanced cardiac life support (ACLS) therapy in prolonged ventricular fibrillation (VF). METHODS: Twenty-four female, mixed-breed, domestic swine (ranging in mass from 22 to 25 kg) were used in this prospective, blinded, randomized, experimental trial. Animals were sedated (ketamine/xylazine), anesthetized (alpha-chloralose), paralyzed (pancuronium), mechanically ventilated with room air, and monitored with electrocardiography, arterial pressure, and Swan-Ganz catheters. VF was induced with a 3 s, 60 Hz, 100 mA transthoracic shock, and remained untreated for 8 min. One minute of basic life support followed (standardized by use of a mechanical device). At 9 min, animals were treated with one of three regimes: Group 1, cardiocerebral-protective cocktail (antioxidant U-74389G (3.0 mg/kg), epinephrine (0.2 mg/kg), lidocaine (1.0 mg/kg), bretylium (5.0 mg/kg), magnesium (2.0 g), and propranolol (1.0 mg)); Group 2, magnesium (2.0 g); and Group 3, standard ACLS. Groups 1 and 2 received drugs at minute nine (first countershock at minute 11), while Group 3 received first countershock at minute nine. Data were analyzed with two-tailed Fisher's exact tests. RESULTS: ROSC was achieved in Group 1, 7/7 (100%); Group 2, 3/9 (33%, P versus Group 1=0.01); and Group 3, 3/8 (38%; P versus Group 1=0.02). One-hour survival was attained in Group 1, 7/7 (100%); Group 2, 3/9 (33%; P versus Group 1=0.01), and Group 3, 1/8 (13%; P versus Group 1=0.001). CONCLUSIONS: Combination pharmacotherapy with a cardiocerebral-protective drug cocktail prior to countershock produced superior rates of ROSC and one-hour survival when compared with singular drug therapy (Group 2) and standard ACLS (Group 3) in this porcine model of prolonged VF.

Combined pre- and post-surgical bupivacaine wound infiltrations decrease opioid requirements after knee ligament reconstruction.

PURPOSE: To test the efficacy of a combination of selective pre- and post-surgical local anesthetic infiltrations of the knee, compared with standard intra-articular injection at the end of surgery alone, to reduce postoperative opioid requirements following arthroscopic cruciate ligament reconstruction (ACLR). METHODS: In a double-blind, randomized, controlled trial, we studied 23 patients (ASA I or II) scheduled for elective ACLR under general anesthesia. The treatment group (n = 12) received infiltrations with bupivacaine 0.25% with epinephrine 1:200,000 presurgically (10 ml into the portals, 10 ml at the medial tibial incision site, 10 ml at the lateral femoral incision site, and 10 ml intra-articularly) and postsurgically (5 ml at the medial tibial incision and 10 ml at the lateral femoral incision). The control group (n = 11) received infiltrations with saline 0.9% in the same manner. All patients received a standard intra-articular local anesthetic instillation of the knee (25 ml of bupivacaine 0.25% with epinephrine 1:200,000) at the completion of surgery. RESULTS: Postoperative opioid requirements were lower in the treatment group (5.8 +/- 2.9 mg morphine equivalent) than in the control group ( 13.7 +/- 5.8 mg; P = 0.008). Treatment patients were ready for discharge approximately 30 min earlier than control patients (P = 0.046). There were no adverse events in the treatment group. In the control group, 2/11 patients vomited and a third experienced transient postoperative diaphoresis, dizziness and pallor. CONCLUSION: We conclude that a combination of selective pre- and post-surgical wound infiltration with bupivacaine 0.25% provides superior analgesia compared with a standard post-surgical intra-articular injection alone.

The development and evaluation of a new aerosol irritant assay with minimal animal stress.

Current aerosol irritant assays trap animals in noxious atmospheres and put a lot of stress on them. For this reason, the Minimal Animal Stress Irritant Assay Chamber (MASIAC) was developed based on the principle of avoidance, and evaluated. The MASIAC reproducibly detected citric acid with more sensitivity than conventionally used assays. With a group of mice tested simultaneously, the responses were not significantly affected by the presence of other mice. In addition, following multiple exposures to citric acid, the mice either sensitized to the irritant, or learned to avoid it. This suggests a number of areas where the MASIAC could be applied, including behavioral and asthma research. If this new method turns out to be as good as currently used assays, it could provide investigators with an alternative, more humane method of evaluating pulmonary irritants.

RSD1019 suppresses ischaemia-induced monophasic action potential shortening and arrhythmias in anaesthetized rabbits.

The electrophysiological actions of lidocaine, tedisamil and RSD1019 were assessed on normal and ischaemic cardiac tissue using monophasic action potentials (MAPs) recorded from the epicardium of anaesthetized rabbits. Drug effects on ischaemia-induced arrhythmias were assessed simultaneously in the same rabbits. Lidocaine, infused at 2.5, 5 and 10 micromol kg(-1) min(-1) i.v., accelerated and worsened the electrophysiological derangement caused by ischaemia, had profibrillatory actions and reduced the time to the occurrence of ventricular fibrillation (VF) relative to controls. Tedisamil, infused at 0.063, 0.125 and 0.25 micromol kg(-1) min(-1) i.v., prolonged MAP duration at 90% repolarization (MAPD(90%)) before induction of ischaemia in a dose-related manner; however, this effect was not maintained 5 min after induction of ischaemia. Tedisamil had no significant antiarrhythmic actions over the dose-range tested. RSD1019, infused at 2, 4 and 8 micromol kg(-1) min(-1) i.v., produced a small increase in MAPD(90%) before induction of ischaemia and only at the highest dose tested. In contrast to tedisamil, RSD1019 suppressed ischaemia-induced MAP shortening assessed 5 min after induction of ischaemia. This effect was dose-related. RSD1019 completely prevented ischaemia-induced tachyarrhythmias at the mid and highest infusion levels tested. The results of this study illustrate a pathologically targeted approach for preventing ischaemia-induced arrhythmias. Suppression of ischaemia-induced MAP shortening, demonstrated herein for RSD1019, represents a novel antifibrillatory approach.

Effect of an administrative intervention on rates of screening for domestic violence in an urban emergency department.

OBJECTIVES: This study measured the effects of an administrative intervention on health care provider compliance with universal domestic violence screening protocols. METHODS: We used a simple, interrupted-time-series design in a stratified random sample of female emergency department patients 18 years or older (n = 1638 preintervention, n = 1617 postintervention). The intervention was a 4-tiered hospital-approved disciplinary action, and the primary outcome was screening compliance. RESULTS: Preintervention and postintervention screening rates were 29.5% and 72.8%, respectively. Before the intervention, screening was worse on the night shift (odds ratio [OR] = 0.46, 95% confidence interval [CI] = 0.31, 0.68) and with psychiatric patients (OR = 0.34, 95% CI = 0.14, 0.85); after the intervention, no previous screening barriers remained significant. CONCLUSIONS: An administrative intervention significantly enhanced compliance with universal domestic violence screening.

Combination pharmacotherapy with delayed countershock vs standard advanced cardiac life support after prolonged ventricular fibrillation.

OBJECTIVE: To test the hypothesis that combination pharmacotherapy with delayed countershock would produce higher rates of return of spontaneous circulation (ROSC) and one-hour survival when compared with standard Advanced Cardiac Life Support (ACLS) therapy. METHODS: A prospective, block-randomized, blinded, laboratory experiment was conducted in an established swine model of prolonged ventricular fibrillation (VF). Fifty-six female domestic swine were anesthetized, instrumented, and shocked into VF with a bipolar pacing catheter. The VF was untreated for 8 minutes, then basic CPR was done mechanically for 1 minute. At 9 minutes of VF, the animals were randomized to treatment with one of seven therapies: group 1, combination pharmacotherapy with epinephrine (0.20 mg/kg), lidocaine (1.0 mg/kg), bretylium (5.0 mg/kg), propranolol (1.0 mg), and U-74389G (3.0 mg/kg); group 2, epinephrine (0.20 mg/kg); group 3, lidocaine (1.0 mg/kg) and bretylium (5.0 mg/kg); group 4, propranolol (1.0 mg); group 5, U-74389G (3.0 mg/kg); group 6, normal saline solution (volume equal to that for group 1); and group 7, standard ACLS (first countershock at 9 minutes of VF). Initial countershocks for groups 1-6 were given after 11 minutes of VF. Data were analyzed with two-tailed Fisher's exact test, with alpha set at 0.05. RESULTS: Return of spontaneous circulation occurred in group 1 = 8/8 (100%); group 2 = 7/8 (88%); group 3 = 3/8 (38%); group 4 = 3/8 (38%); group 5 = 5/8 (63%); group 6 = 4/8 (50%); and group 7 = 3/8 (38%). One-hour survival occurred in group 1 = 8/8 (100%); group 2 = 5/8 (63%); group 3 = 2/8 (25%); group 4 = 2/8 (25%); group 5 = 3/8 (38%); group 6 = 2/8 (25%); and group 7 = 1/8 (13%). CONCLUSIONS: Combination pharmacotherapy with delayed countershock (group 1) produced significantly higher rates of ROSC (p = 0.03) and one-hour survival (p = 0.001) when compared with standard ACLS in this porcine model of prolonged VF.

Cost comparison of sevoflurane with isoflurane anesthesia in arthroscopic menisectomy surgery.

PURPOSE: To determine the "real world" cost of sevoflurane compared with isoflurane in balanced general anesthesia for daycare arthroscopic menisectomy, we prospectively investigated perioperative drug requirement and expense as well as recovery time. METHODS: Following intravenous induction, 40 consenting adult patients randomly received either sevoflurane- or isoflurane-based anesthesia with a standardized gas inflow rate of 3 l x min. Recovery was assessed in the postanesthetic recovery room (PARR) in a double-blind manner at 15 min intervals using the Aldrete scoring system until patients met discharge criteria. RESULTS: Patient demographics, anesthetic duration, volatile potency and adjunct drug requirements were similar in the two groups. Total perioperative drug cost per patient was CAN$38.10+/-10.13 (mean +/- SD) for the sevoflurane group and $23.87+/-6.59 for the isoflurane group (P<0.01). Although the nonvolatile drug cost was comparable between the two groups, the volatile drug cost per patient was $19.40+/-8.80 for sevoflurane and $4.50+/-1.90 for isoflurane (P<0.01). This four-fold sevoflurane-to-isoflurane cost difference was the product of two ratios, both based on the volume of liquid anesthetic: the ratio of consumption, 2.1; and the ratio of institutional price, 2.1. Intraoperative hemodynamic response, time until discharge from the PARR and incidences of postoperative nausea and vomiting did not significantly differ between the two groups. CONCLUSIONS: When used to maintain equipotent balanced general anesthesia for daycare arthroscopic menisectomy, volatile consumption and cost were greater for sevoflurane compared with isoflurane. Nonvolatile perioperative drug cost and recovery times were similar, however, in the two groups.

Addition of femoral 3-in-1 blockade to intra-articular ropivacaine 0.2% does not reduce analgesic requirements following arthroscopic knee surgery.

PURPOSE: To test the hypothesis that the addition of a preincisional femoral 3-in-1 block to intra-articular instillation with ropivacaine 0.2% at the end of surgery improves postoperative pain control in patients undergoing arthroscopic anterior cruciate ligament reconstruction (ACLR) under general anesthesia. METHODS: In a prospective, randomized, placebo-controlled, double-blind trial, we studied 44 patients scheduled for inpatient ACLR. Prior to incision, the treatment group (n = 22) received a femoral 3-in-1 block with 40 ml ropivacaine 0.2%, augmented by infiltrations of the lateral and anteromedial incisions with 20 ml ropivacaine 0.2% at the end of the procedure. The control group (n = 22) received saline 0.9% instead of ropivacaine. All patients received an intra-articular instillation with 30 ml ropivacaine 0.2% at the end of surgery. The primary efficacy variable was 24 hr morphine consumption postoperatively standardized by weight, administered intravenously via a patient-controlled analgesia (PCA) pump. RESULTS: There was no difference between both groups in 24 hr PCA morphine consumption postoperatively (control, 0.45 +/- 0.44 [mean +/- SD] mg x kg(-1); treatment, 0.37 +/- 0.50 mg x kg(-1); p = 0.55). No difference was found in postoperative visual analog scale pain scores, adverse events, or vital signs. In the treatment group, R = 10/22 patients did not require postoperative morphine compared with R = 6/22 in the control group (P = 0.35). CONCLUSION: We found no effect of a femoral 3-in-1 block with ropivacaine 0.2% on postoperative analgesic consumption, compared to intra-articular instillation with ropivacaine 0.2% alone, in patients undergoing ACLR under general anesthesia.

Universal screening for intimate partner violence in the emergency department: importance of patient and provider factors.

STUDY OBJECTIVE: Screening for intimate partner violence has been widely advocated in the health care setting, but efforts to assess effectiveness and ensure adequacy of universal screening are largely untested. We sought to identify barriers to screening of female emergency department patients for intimate partner violence during the first year of implementation of a screening protocol. METHODS: A retrospective, structured medical chart review of 1,638 randomly identified visits included demographic factors of age, race, marital status, employment status, insurance status, arrival mode, mechanism of presenting complaint, severity of condition, presentation time, and nurse gender. The study was conducted an an inner-city Level I trauma center with 43,000 annual ED visits and universal procedures for screening for intimate partner violence in place since February 1994. The participants were a cohort of 1,509 female patients, 18 years of age or older, who were discharged from the ED between July 1994 and June 1995. The main outcome measure was the odds of being screened as a function of patient and provider variables. Statistical analyses involved univariate and multivariate logistic regression on screening rates (Yes/No) as derived from universal screening instrument variables. RESULTS: Of 1,638 records reviewed, 483 patients (29.5%) were screened for intimate partner violence. Univariate analyses revealed that women presenting with nonpsychiatric, less acute complaints and those who presented during daylight hours were more likely to be screened than women who presented with psychiatric or more acute complaints, or during the night shift. Male and female nurse providers were equally likely to screen for intimate partner violence. Step-down multivariate analyses agreed with these findings. CONCLUSION: In this random sample of female patients, screening rates varied by severity of the patient's condition, type of presenting complaint, and presentation time.

Correlation between triage nurse and physician ordering of ED tests.

Triage nurse ordering of tests can reduce patient time in the emergency department. This benefit must be balanced with the extra expense and potential morbidity of unnecessary tests. This study examined whether triage nurse ordering of lab tests and X-rays correlated with physician ordering. In Phase I, a prospective study, triage nurses completed an order form for each patient triaged during randomly selected 2-hour blocks over a 3-week period. In Phase II, Phase I was repeated with test ordering guidelines derived from Phase I results. Correlations of nurse and physician orders were analyzed by kappa statistics and paired t tests. In Phase I, 176 patients were enrolled of a possible 204 (82%). In Phase II, 350 patients were enrolled of a possible 418 (84%). The percentage of nurse overordering of tests in Phase I was 35%; In Phase II, it was 34% (P NS). Kappa values were determined for blood testing (Phase I, 0.48; Phase II, 0.54 [P = .048]), for X-ray (Phase I, 0.68; Phase II, 0.65 [P = .523]), for urinalysis (Phase I, 0.76; Phase II, 0.67 [P = .338]), and for electrocardiogram (Phase I, 0.78; Phase II, 0.77 [P = .438]). The improved lab correlation in Phase II resulted from the nurses ordering fewer tests (P = .046). Nurses deviated from the test ordering guidelines in 37% of patients. Triage nurse ordering of X-rays, electrocardiogram, and urinalysis has moderate to substantial correlation with physician ordering. Correlation of triage nurse and physician ordering of tests can be improved with the use of test ordering guidelines.

A model of myocardial ischemia for the simultaneous assessment of electrophysiological changes and arrhythmias in intact rabbits.

A method of recording epicardial monophasic action potentials (MAPs) and ischemia-induced arrhythmias following coronary artery ligation in intact rabbits is described. It is expected that this model will have utility in analyzing drug effects and mechanisms of ischemic arrhythmogenesis. Rabbits were found to have two arrhythmic phases following coronary artery occlusion which correspond to phase Ia and Ib arrhythmias in other species. Epicardial MAPs recorded from ischemic tissue allowed electrophysiological effects to be correlated with these phases. Phase Ia arrhythmias occurred within the first 2 min of coronary artery occlusion and were associated with a reduction in the maximum upstroke velocity of MAPs and changes in MAP duration, including the occurrence of alternans in duration. Phase Ib arrhythmias occurred between 8 and 15 min after coronary artery occlusion. These arrhythmias were associated with a decrease in MAP duration and amplitude, alternans in MAP duration as well as conduction block. Coronary artery occlusion reliably induced arrhythmias in rabbits if the left branch of the coronary artery and the left anterior descending artery were occluded. There was a 95% incidence of premature ventricular contractions, 38% of ventricular tachycardia, and 48% of ventricular fibrillation (n = 21). The results of this study show that epicardial MAPs can be used to aid in the characterization of the electrophysiological mechanisms of ischemia-induced arrhythmias in vivo.

Liposomal bupivacaine. Extended duration nerve blockade using large unilamellar vesicles that exhibit a proton gradient.

BACKGROUND: There is a clinical requirement for longer-acting local anesthetics, particularly for the management of post-operative and chronic pain. In this regard, liposomes have been suggested to represent a potentially useful vehicle for sustained drug release after local administration. In the current study, the authors used a transmembrane pH gradient to efficiently encapsulate bupivacaine within large unilamellar vesicles. They report on the kinetics of drug uptake and release and the duration of nerve blockade. METHODS: The rate and extent of bupivacaine uptake into large unilamellar vesicles that exhibit a pH gradient (interior acidic) were determined and compared to drug association with control liposomes that did not exhibit a proton gradient. In subsequent studies, researchers examined the kinetics of bupivacaine release from these liposome systems in vitro. Using the guinea pig cutaneous wheal model, the rate of clearance of the liposome carrier was monitored after intradermal administration, using a radiolabelled lipid marker, and the duration of nerve blockade produced by free and liposomal bupivacaine was compared. RESULTS: Bupivacaine was rapidly and efficiently accumulated within liposomes that exhibited a pH gradient (interior acidic) with trapping efficiencies of 64-82% of total drug, depending on the initial bupivacaine:phospholipid ratio. Little uptake was seen, however, for control vesicles that did not exhibit a transmembrane proton gradient. Using an in vitro model of drug clearance, liposomally encapsulated bupivacaine was found to be slowly released for a longer period of time compared with either the free drug or bupivacaine associated with control (no pH gradient liposomes). In the guinea pig cutaneous wheal model, more than 85% of the liposomal carrier was found to remain at the site of administration for 2 days. The sustained drug release afforded by liposomes that exhibited a pH gradient resulted in an increase in the duration of nerve blockade of as much as threefold compared with either the free drug or bupivacaine in the presence of control (no pH gradient) liposomes. Recovery of half maximal response (R2.5) after administration of 0.75% free bupivacaine, for example, was approximately 2 h, whereas the same dose of bupivacaine in pH gradient liposomes exhibited a R2.5 of approximately 6.5 h. CONCLUSIONS: Large unilamellar vesicles that exhibit a pH gradient can efficiently encapsulate bupivacaine and subsequently provide a sustained-release system that greatly increases the duration of neural blockade.

Anaesthesia by intravenous emulsified isoflurane in mice.

An emulsion of isoflurane in Intralipid for intravenous (iv) injection was formulated and its anaesthetic properties determined in mice. The major advantage of iv delivery of volatile agents is to accelerate the induction of anaesthesia by circumventing the anesthetic circuitry and the lung's functional residual capacity. Isoflurane was added to Intralipid in varying concentrations. The ED50 (n = 34) and LD50 (n = 20) were determined by a single iv bolus injection. Anaesthesia was also induced and maintained for 30 min (n = 5) by continuous infusion and the time to emergence was measured. The ED50 and LD50 were 0.7 +/- 0.2 microliter and 2.4 +/- 0.2 microliter of isoflurane equivalent respectively. An average infusion rate of 1.6 +/- 0.4 microliters.min-1 of isoflurane equivalent was required for maintenance following which the average emergence time was 193 +/- 35 secs. The only negative effect was local skin ulceration with an inadvertent interstitial injection. We conclude that iv induction and maintenance with emulsified isoflurane in Intralipid can be carried out with safety and reproducibility in the mouse. Further larger animal studies are warranted assessing the haemodynamic, toxicological, physiochemical and pharmacokinetic characteristics of these and other similar preparations.

Pregnancy in the emergency department: risk factors and prevalence among all women.

STUDY OBJECTIVE: To determine the prevalence of unrecognized pregnancy in the emergency department and to ascertain if patient history can effectively detect unrecognized pregnancies. DESIGN: Prospective study. SETTING: Urban ED with annual census of 40,000. PARTICIPANTS: One hundred ninety-one consecutive women meeting inclusion criteria. INTERVENTIONS: All participants completed a menstrual/sexual history questionnaire and had a urine pregnancy test. RESULTS: Overall, we found a 6.3% prevalence of unrecognized pregnancy. Women with abdominal/pelvic complaints had a 13% prevalence; those with other complaints had a 2.5% prevalence. Two historical risk factors, the patient's suspicion that she might be pregnant and an abnormal last menstrual period, had a statistically significant correlation with unrecognized pregnancy. A third risk factor, the presence of abdominal/pelvic complaints, nearly achieved statistical significance. These risk factors detected all unrecognized pregnancies with a sensitivity of 100% and a specificity of 54%. CONCLUSION: The prevalence of unrecognized pregnancy in our ED was 6.3%. Historical risk factors detected all of them.

Improved peribulbar anaesthesia with alkalinization and hyaluronidase.

A prospective double-blind randomized study was carried out to determine the effect of pH and the addition of hyaluronidase to a mixture of lidocaine and bupivacaine on the efficacy of peribulbar anaesthesia. One hundred patients were assigned to one of five groups. All groups received a solution of two parts bupivacaine (0.75%) and one part lidocaine (2%) (with 1:100,000 adrenaline) as the base components of their anaesthesia. Group 1 received only the bupivacaine-lidocaine mixture, pH 3.9. Group 2 received a solution supplemented with hyaluronidase (ten units.ml-1), pH of 5.1. Group 3 received the bupivacaine-lidocaine mixture alkalinized with sodium bicarbonate to a pH of 5.1, the same as solution 2. Group 4 received the mixture with hyaluronidase alkalinized to pH of 6.7. Group 5 received the bupivacaine-lidocaine mixture alkalinized to a pH of 6.7. Efficacy of each block was graded according to the degree of residual movement 30 min following injection, as described by House et al. The solution containing hyaluronidase and pH adjusted to 6.7 was found to be the most effective (P < 0.025). The presence of hyaluronidase without alkalinization did not improve the efficacy of the mixture; and similarly, alkalinization in the absence of hyaluronidase was ineffective. These results reflected the pH- and temperature-dependent thermodynamic properties of local anaesthetics, and the pH-dependent activity of hyaluronidase.