Additive Effects of Sevoflurane and Propofol on γ-Aminobutyric Acid Receptor Function

Background: Previous studies have shown that propofol and sevoflurane enhance the function of [gamma]-aminobutyric acid type A (GABAA) receptors. However, it is not known whether these two drugs modulate the same molecular pathways. In addition, little is known about receptor function in the presence of both propofol and sevoflurane. The aim of this study was to better understand the interactions of propofol and sevoflurane with the GABAA receptor.

Methods: Wild-type [alpha]1, [beta]2, [gamma]2s GABAA receptor subunit complementary DNAs were transfected into human embryonic kidney cells grown on glass coverslips using a calcium phosphate transfection method. After transfection (36-72 h), cells were whole cell patch clamped and exposed to combinations of the following: 0.3-1,000 [mu]m [gamma]-aminobutyric acid (GABA), 0-10 [mu]m propofol, and 0-1,650 [mu]m sevoflurane. Chemicals were delivered to the cells using two 10-channel infusion pumps and a rapid solution exchanger.

Results: Both propofol and sevoflurane alone enhanced the amplitude of GABAA receptor responses to submaximal concentrations of GABA in a dose-dependent manner. The enhancement was underpinned by an increase in the apparent affinity of the receptor for GABA. Coapplication of both anesthetics further enhanced the apparent affinity of the receptor for GABA.     

The Well-being Model: A New Drug Interaction Model for Positive and Negative Effects

Background: Drugs are routinely combined in anesthesia and pain management to obtain an enhancement of the desired effects. However, a parallel enhancement of the undesired effects might take place as well, resulting in a limited therapeutic usefulness. Therefore, when addressing the question of optimal drug combinations, side effects must be taken into account.

Methods: By extension of a previously published interaction model, the authors propose a method to study drug interactions considering also their side effects. A general outcome parameter identified as patient's well-being is defined by superposition of positive and negative effects. Well-being response surfaces are computed and analyzed for varying drugs pharmacodynamics and interaction types. In particular, the existence of multiple maxima and of optimal drug combinations is investigated for the combination of two drugs.

Results: Both drug pharmacodynamics and interaction type affect the well-being surface and the deriving optimal combinations. The effect of the interaction parameters can be explained in terms of synergy and antagonism and remains unchanged for varying pharmacodynamics. For all simulations performed for the combination of two drugs, the presence of more than one maximum was never observed.     

N-Phenylethyl Amitriptyline in Rat Sciatic Nerve Blockade

Background: The antidepressant amitriptyline is commonly used orally for the treatment of chronic pain, particularly neuropathic pain, which is thought to be caused by high-frequency ectopic discharge. Among its many properties, amitriptyline is a potent Na+ channel blocker in vitro, has local anesthetic properties in vivo, and confers additional blockade at high stimulus-discharge rates (use-dependent blockade). As with other drug modifications, adding a phenylethyl group to obtain a permanently charged quaternary ammonium derivative may improve these advantageous properties.

Methods: The electrophysiologic properties of N-phenylethyl amitriptyline were assessed in cultured neuronal GH3 cells with the whole cell mode of the patch clamp technique, and the therapeutic range and toxicity were evaluated in the rat sciatic nerve model.

Results: In vitro, N-phenylethyl amitriptyline at 10 [mu]m elicits a greater block of Na+ channels than amitriptyline (resting block of approximately 90%vs. approximately 15%). This derivative also retains the attribute of amitriptyline in evoking high-degree use-dependent blockade during repetitive pulses. In vivo, duration to full recovery of nociception in the sciatic nerve model was 1,932 +/- 72 min for N-phenylethyl amitriptyline at 2.5 mm (n = 7) versus 72 +/- 3 min for lidocaine at 37 mm (n = 4; mean +/- SEM). However, there was evidence of neurotoxicity at 5 mm.     

Poor Intraoperative Blood Glucose Control Is Associated with a Worsened Hospital Outcome after Cardiac Surgery in Diabetic Patients

Background: Tight perioperative control of blood glucose improves the outcome of diabetic patients undergoing cardiac surgery. Because stress response and cardiopulmonary bypass can induce profound hyperglycemia, intraoperative glycemic control may become difficult. The authors undertook a prospective cohort study to determine whether poor intraoperative glycemic control is associated with increased intrahospital morbidity.

Methods: Two hundred consecutive diabetic patients undergoing on-pump heart surgery were enrolled. A standard insulin protocol based on subcutaneous intermediary insulin was given the morning of the surgery. Intravenous insulin therapy was initiated intraoperatively from blood glucose concentrations of 180 mg/dl or greater and titrated according to a predefined protocol. Poor intraoperative glycemic control was defined as four consecutive blood glucose concentrations greater than 200 mg/dl without any decrease in despite insulin therapy. Postoperative blood glucose concentrations were maintained below 140 mg/dl by using aggressive insulin therapy. The main endpoints were severe cardiovascular, respiratory, infectious, neurologic, and renal in-hospital morbidity.

Results: Insulin therapy was required intraoperatively in 36% of patients, and poor intraoperative glycemic control was observed in 18% of patients. Poor intraoperative glycemic control was significantly more frequent in patients with severe postoperative morbidity (37% vs. 10%; P < 0.001). The adjusted odds ratio for severe postoperative morbidity among patients with a poor intraoperative glycemic control as compared with patients without was 7.2 (95% confidence interval, 2.7-19.0).     

Sildenafil Prevents Cardiovascular Changes after Bone Marrow Fat Embolization in Sheep

Background: Sudden, intraoperative cardiovascular deterioration as a result of pulmonary embolization of bone marrow fat is a potentially fatal complication during total hip and knee arthroplasty, intramedullary nailing, and spine surgery. Anesthetic management is challenging in the presence of increased right ventricular afterload due to pulmonary hypertension. Selective pulmonary vasodilation may be an appropriate prophylactic or therapeutic measure. The effect of sildenafil (phosphodiesterase inhibitor) on cardiovascular deterioration after bone marrow fat embolization was therefore investigated.

Methods: Bone cement (polymethylmethacrylate) was injected into three lumbar vertebrae in 12 sheep. Invasive blood pressures and heart rate were recorded continuously until 60 min after the last injection. Cardiac output and arterial and mixed venous blood gas variables were measured at selected time points. Before the first cement injection, 6 animals received a bolus injection (0.7 mg/kg) of sildenafil, with continuous infusion (0.2 mg [middle dot] kg-1 [middle dot] h-1) thereafter. Postmortem lung and kidney biopsies were taken for semiquantitative analysis of intravascular fat.

Results: Fat embolism was associated with a transient increase (21 +/- 7mmHg) in pulmonary arterial pressure. A transient decrease in arterial blood pressure and temporary increases in central venous pressure and dead space were also observed. No significant changes in any cardiovascular variable were observed after fat embolism in the sildenafil group. There was significantly (P < 0.05) less intravascular fat in the lungs of the sildenafil (median count of 5 emboli per microscopic view) compared with the control group (median count of 1).     

Effects of Intermittent Femoral Nerve Injections of Bupivacaine, Levobupivacaine, and Ropivacaine on Mitochondrial Energy Metabolism and Intracellular Calcium Homeostasis in Rat Psoas Muscle

Background: Long-acting local anesthetics cause muscle damage. Moreover, long-acting local anesthetics act as uncoupler of oxidative phosphorylation in isolated mitochondria and enhance sarcoplasmic reticulum Ca2+ release. The aim of the study was to evaluate effects of perineural injections of local anesthetics on mitochondrial energetic metabolism and intracellular calcium homeostasis in vivo.

Methods: Femoral nerve block catheters were inserted in adult male Wistar rats. Rats were randomized and received seven injections (1 ml/kg) of bupivacaine, levobupivacaine, ropivacaine, or isotonic saline at 8-h intervals. Rats were killed 8 h after the last injection. Psoas muscle was quickly dissected from next to the femoral nerve. Local anesthetic concentrations in muscle were determined. Oxidative capacity was measured in saponin-skinned fibers. Oxygen consumption rates were measured, and mitochondrial adenosine triphosphate synthesis rate was determined. Enzymatic activities of mitochondrial respiratory chain complexes were evaluated. Local calcium release events (calcium sparks) were analyzed as well as sarcoplasmic reticulum calcium content in saponin-skinned fibers.

Results: Eight hours after the last injection, psoas muscle concentration of local anesthetics was less than 0.3 [mu]g/g tissue. Adenosine triphosphate synthesis and adenosine triphosphate-to-oxygen ratio were significantly decreased in the muscle of rats treated with local anesthetics. A global decrease (around 50%) in all of the enzyme activities of the respiratory chain was observed. Levobupivacaine increased the amplitude and frequency of the calcium sparks, whereas lower sarcoplasmic reticulum calcium content was shown.     

Performance of Residents and Anesthesiologists in a Simulation-based Skill Assessment

Background: Anesthesiologists and anesthesia residents are expected to acquire and maintain skills to manage a wide range of acute intraoperative anesthetic events. The purpose of this study was to determine whether an inventory of simulated intraoperative scenarios provided a reliable and valid measure of anesthesia residents' and anesthesiologists' skill.

Methods: Twelve simulated acute intraoperative scenarios were designed to assess the performance of 64 residents and 35 anesthesiologists. The participants were divided into four groups based on their training and experience. There were 31 new CA-1, 12 advanced CA-1, and 22 CA-2/CA-3 residents as well as a group of 35 experienced anesthesiologists who participated in the assessment. Each participant managed a set of simulated events. The advanced CA-1 residents, CA-2/CA-3 residents, and 35 anesthesiologists managed 8 of 12 intraoperative simulation exercises. The 31 CA-1 residents each managed 3 intraoperative scenarios.

Results: The new CA-1 residents received lower scores on the simulated intraoperative events than the other groups of participants. The advanced CA-1 residents, CA-2/CA-3 residents, and anesthesiologists performed similarly on the overall assessment. There was a wide range of scores obtained by individuals in each group. A number of the exercises were difficult for the majority of participants to recognize and treat, but most events effectively discriminated among participants who achieved higher and lower overall scores.     

Guidelines for Cardiac Management in Noncardiac Surgery Are Poorly Implemented in Clinical Practice: Results from a Peripheral Vascular Survey in The Netherlands

Background: The American College of Cardiology (ACC)/American Heart Association (AHA) guidelines for Perioperative Cardiovascular Evaluation for Noncardiac Surgery recommend an algorithm for a stepwise approach to preoperative cardiac assessment in vascular surgery patients. The authors' main objective was to determine adherence to the ACC/AHA guidelines on perioperative care in daily clinical practice.

Methods: Between May and December 2004, data on 711 consecutive peripheral vascular surgery patients were collected from 11 hospitals in The Netherlands. This survey was conducted within the infrastructure of the Euro Heart Survey Programme. The authors retrospectively applied the ACC/AHA guideline algorithm to each patient in their data set and subsequently compared observed clinical practice data with these recommendations.

Results: Although 185 of the total 711 patients (26%) fulfilled the ACC/AHA guideline criteria to recommend preoperative noninvasive cardiac testing, clinicians had performed testing in only 38 of those cases (21%). Conversely, of the 526 patients for whom noninvasive testing was not recommended, guidelines were followed in 467 patients (89%). Overall, patients who had not been tested, irrespective of guideline recommendation, received less cardioprotective medications, whereas patients who underwent noninvasive testing were significantly more often treated with cardiovascular drugs ([beta]-blockers 43% vs. 77%, statins 52% vs. 83%, platelet inhibitors 80% vs. 85%, respectively; all P < 0.05). Moreover, the authors did not observe significant differences in cardiovascular medical therapy between patients with a normal test result and patients with an abnormal test result.     

Auricular Acupressure as a Treatment for Anxiety in Prehospital Transport Settings

Background: Auricular acupuncture at the relaxation point has been previously shown to be an effective treatment for anxiety in the preoperative setting. The purpose of this prospective, randomized, blinded study was to determine whether auricular acupressure can reduce stress and anxiety during ambulance transport.

Methods: Patients who required ambulance transport secondary to medical conditions were randomized to receive auricular acupressure at the relaxation point (n = 17) or at a sham point (n = 19). A visual analog scale was used to assess state anxiety as well as patient anticipation of hospital medical treatment (estimated waiting period for treatment, anticipated pain during treatment, attitude toward the physicians, and treatment outcomes). These variables were assessed at baseline and on arrival to the hospital.

Results: Patients in the relaxation group reported significantly less anxiety than patients in the sham group on arrival to the hospital (visual analog scale mean +/- SD: 37.6 +/- 20.6 to 12.4 +/- 7.8 mm vs. 42.5 +/- 29.9 to 46.7 +/- 25.9 mm, respectively;P = 0.002). Similarly, patient perception of pain during treatment (mean visual analog scale +/- SD: 32.7 +/- 27.7 to 14.5 +/- 8.1 mm vs. 17.2 +/- 26.1 to 28.8 +/- 21.9 mm, respectively;P = 0.006) and treatment outcomes of their illnesses (mean visual analog scale +/- SD: 46.7 +/- 29.4 to 19.1 +/- 10.4 mm vs. 35.0 +/- 25.7 to 31.5 +/- 20.5 mm, respectively;P = 0.014) were significantly more positive in the relaxation group than in the sham group. No differences were found in the other variables assessed.     

Myocardial Depressant Effects of Desflurane: Mechanical and Electrophysiologic Actions In Vitro

Background: The authors determined whether desflurane altered myocardial excitation-contraction coupling and electrophysiologic behavior in the same manner as isoflurane and sevoflurane.

Methods: The effects of desflurane on isometric force in guinea pig ventricular papillary muscles were studied in modified standard and in 26 mm K+ Tyrode solution with 0.1 [mu]m isoproterenol. Desflurane effects on sarcoplasmic reticulum Ca2+ release were also determined by examining its actions on rat papillary muscles, guinea pig papillary muscles in low-Na+ Tyrode solution, and rapid cooling contractures. Normal and slow action potentials were recorded using a conventional microelectrode technique. Ca2+ and K+ currents of guinea pig ventricular myocytes were examined.

Results: Desflurane (5.3% and 11.6%) decreased peak force to approximately 70% and 40% of the baseline, respectively, similar to the effects of equianesthetic isoflurane concentrations. With isoproterenol in 26 mm K+ Tyrode solution, desflurane markedly depressed late peaking force and modestly depressed early peak force. The rested state contractions of rat myocardium or guinea pig myocardium in low-Na+ Tyrode solution were modestly depressed, whereas rapid cooling contractures were virtually abolished after desflurane administration. Desflurane significantly prolonged the action potential duration. Desflurane reduced L-type Ca2+ current and the delayed outward K+ current but did not alter the inward rectifier K+ current.