Christoph H. Kindler

The Visual Analog Scale Allows Effective Measurement of Preoperative Anxiety and Detection of Patients' Anesthetic Concerns

The advent of managed care, reduction of costs, and advances in medical technology place increasing demands on anesthesiologists. Preoperative anxiety may go unnoticed in an environment that stresses increased productivity. The present study compares different methods for measuring preoperative anxiety, identifies certain patient characteristics that predispose to high anxiety, and describes the quantity and quality of anxiety that patients experience preoperatively. Seven hundred thirty-four patients participated in the study. We assessed aspects of anxiety by means of visual analog scales (VAS) and the State Anxiety Score of the Spielberger State-Trait Anxiety Inventory (STAI). The mean STAI anxiety score was 39 ± 1 (n = 486) and the mean VAS for fear of anesthesia was 29 ± 1 (n = 539). Patients feared surgery significantly more than anesthesia (P < 0.001). The VAS measuring fear of anesthesia correlated well with the STAI score (r = 0.55;P < 0.01). Young patients, female patients, and patients with no previous anesthetic experience or a previous negative anesthetic experience had higher anxiety scores. Patients worried most about the waiting period preceding surgery and were least concerned about possible awareness intraoperatively. Factor analysis of various anxiety items showed three distinct dimensions of fear: 1) the fear of the unknown 2) the fear of feeling ill, and 3) the fear for one’s life. Among these dimensions, fear of the unknown correlated highest with the anxiety measuring techniques STAI and VAS. The simple VAS proved to be a useful and valid measure of preoperative anxiety. Implications: The study of qualitative aspects of anxiety reveals three distinct dimensions of preoperative fear: fear of the unknown, fear of feeling ill, and fear for one’s life. Groups of patients with a higher degree of preoperative anxiety and their specific anesthetic concerns can be identified using the visual analog scale.

TWIK-2, a new weak inward rectifying member of the tandem pore domain potassium channel family.

Potassium channels are found in all mammalian cell types, and they perform many distinct functions in both excitable and non-excitable cells. These functions are subserved by several different families of potassium channels distinguishable by primary sequence features as well as by physiological characteristics. Of these families, the tandem pore domain potassium channels are a new and distinct class, primarily distinguished by the presence of two pore-forming domains within a single polypeptide chain. We have cloned a new member of this family, TWIK-2, from a human brain cDNA library. Primary sequence analysis of TWIK-2 shows that it is most closely related to TWIK-1, especially in the pore-forming domains. Northern blot analysis reveals the expression of TWIK-2 in all human tissues assayed except skeletal muscle. Human TWIK-2 expressed heterologously in Xenopus oocytes is a non-inactivating weak inward rectifier with channel properties similar to TWIK-1. Pharmacologically, TWIK-2 channels are distinct from TWIK-1 channels in their response to quinidine, quinine, and barium. TWIK-2 is inhibited by intracellular, but not extracellular, acidification. This new clone reveals the existence of a subfamily in the tandem pore domain potassium channel family with weak inward rectification properties.

Local Anesthetic Inhibition of Baseline Potassium Channels with Two Pore Domains in Tandem

BACKGROUND Recently, a new structural family of potassium channels characterized by two pore domains in tandem within their primary amino acid sequence was identified. These tandem pore domain potassium channels are not gated by voltage and appear to be involved in the control of baseline membrane conductances. The goal of this study was to identify mechanisms of local anesthetic action on these channels. METHODS Oocytes of Xenopus laevis were injected with cRNA from five cloned tandem pore domain baseline potassium channels (TASK, TREK-1, TOK1, ORK1, and TWIK-1), and the effects of several local anesthetics on the heterologously expressed channels were assayed using two-electrode voltage-clamp and current-clamp techniques. RESULTS Bupivacaine (1 mM) inhibited all studied tandem pore potassium channels, with TASK inhibited most potently. The potency of inhibition was directly correlated with the octanol: buffer distribution coefficient of the local anesthetic, with the exception of tetracaine, to which TASK is relatively insensitive. The approximate 50% inhibitory concentrations of TASK were 709 microM mepivacaine, 222 microM lidocaine, 51 microM R(+)-ropivacaine, 53 microM S(-)-ropivacaine, 668 microM tetracaine, 41 microM bupivacaine, and 39 microM etidocaine. Local anesthetics (1 mM) significantly depolarized the resting membrane potential of TASK cRNA-injected oocytes compared with saline-injected control oocytes (tetracaine 22+/-6 mV rs. 7+/-1 mV, respectively, and bupivacaine 31+/-7 mV vs. 6+/-4 mV). CONCLUSIONS Local anesthetics inhibit tandem pore domain baseline potassium channels, and they could depolarize the resting membrane potential of cells expressing these channels. Whether inhibition of these channels contributes to conduction blockade or to the adverse effects of local anesthetics remains to be determined.

Volatile anesthetics activate the human tandem pore domain baseline K+ channel KCNK5.

Background Previous studies have identified a volatile anesthetic–induced increase in baseline potassium permeability and concomitant neuronal inhibition. The emerging family of tandem pore domain potassium channels seems to function as baseline potassium channels in vivo. Therefore, we studied the effects of clinically used volatile anesthetics on a recently described member of this family. Methods A cDNA clone containing the coding sequence of KCNK5 was isolated from a human brain library. Expression of KCNK5 in the central nervous system was determined by Northern blot analysis and reverse-transcription polymerase chain reaction. Functional expression of the channel was achieved by injection of cRNA into Xenopus laevis oocytes. Results Expression of KCNK5 was detected in cerebral cortex, medulla, and spinal cord. When heterologously expressed in Xenopus oocytes, KCNK5 currents exhibited delayed activation, outward rectification, proton sensitivity, and modulation by protein kinase C. Clinical concentrations of volatile general anesthetics potentiated KCNK5 currents by 8–30%. Conclusion Human KCNK5 is a tandem pore domain potassium channel exhibiting delayed activation and sensitivity to volatile anesthetics and may therefore have a role in suppressing cellular excitability during general anesthesia.

Two-Pore Domain Potassium Channels: New Sites of Local Anesthetic Action and Toxicity

Potassium (K+) channels form the largest family of ion channels with more than 70 such genes identified in the human genome. They are organized in 3 superfamilies according to their predicted membrane topology: (1) subunits with 6 membrane-spanning segments and 1-pore domain, (2) subunits with 2 membrane-spanning segments and 1-pore domain, and (3) subunits with 4 membrane-spanning segments and 2-pore domains arrayed in a tandem position. The last family has most recently been identified and comprises the so-called 2-pore domain potassium (K2P) channels, believed responsible for background or leak K+ currents. Despite their recent discovery, interest in them is growing rapidly with more than 270 references in the literature reported (http://www.ipmc.cnrs.fr/~duprat/2p/ref2p.htm#2P, accessed October 30, 2004). K2P channels are widely expressed in the central nervous system and are involved in the control of the resting membrane potential and the firing pattern of excitable cells. This article will therefore review recent findings on actions of local anesthetics with respect to K2P channels. It begins with an overview of the role of background K+ channels in neuronal excitability and nerve conduction and is followed by a description of the K2P channel family including experimental evidence for the contribution of K2P channels to the mechanism of action and toxicity of local anesthetics.

Volatile anesthetics increase intracellular calcium in cerebrocortical and hippocampal neurons.

BACKGROUND An increase in intracellular calcium concentration ([Ca2+]i) in neurons has been proposed as an important effect of volatile anesthetics, because they alter signaling pathways that influence neurotransmission. However, the existing data for anesthetic-induced increases in [Ca2+]i conflict. METHODS Changes in [Ca2+]i were measured using fura-2 fluorescence spectroscopy in rat cortical brain slices at 90, 185, 370, and 705 microM isoflurane. To define the causes of an increase in [Ca2+]i, slices were studied in Ca2+-free medium, in the presence of Ca2+-channel blockers, and in the presence of the Ca2+-release inhibitor azumolene. The authors compared the effect of the volatile anesthetic with that of the nonanesthetic compound 1,2-dichlorohexafluorocyclobutane. Single-dose experiments in CA1 neurons in hippocampal slices with halothane (360 microM) and in acutely dissociated CA1 neurons with halothane (360 microM) and isoflurane (445 microM) also were performed. RESULTS Isoflurane at 0.5, 1, and 2 minimum alveolar concentrations increased basal [Ca2+]i in cortical slices in a dose-dependent manner (P < 0.05). This increase was not altered by Ca2+-channel blockers or Ca2+-free medium but was reduced 85% by azumolene. The nonanesthetic 1,2-dichlorohexafluorocyclobutane did not increase [Ca2+]i. In dissociated CA1 neurons, isoflurane reversibly increased basal [Ca2+]i by 15 nM (P < 0.05). Halothane increased [Ca2+]i in dissociated CA1 neurons and CA1 neurons in hippocampal slices by approximately 30 nM (P < 0.05). CONCLUSIONS (1) Isoflurane and halothane reversibly increase [Ca2+]i in isolated neurons and in neurons within brain slices. (2) The increase in [Ca2+]i is caused primarily by release from intracellular stores. (3) Increases in [Ca2+]i occur with anesthetics but not with the nonanesthetic 1,2-dichlorohexafluorocyclobutane.

Small-dose intrathecal clonidine and isobaric bupivacaine for orthopedic surgery : a dose-response study

We examined the dose-response relationship of intrathecal clonidine at small doses (≤150 &mgr;g) with respect to prolonging bupivacaine spinal anesthesia. We aimed for establishing doses of intrathecal clonidine that would produce clinically relevant prolongation of spinal anesthesia and pain relief without significant side effects. Eighty orthopedic patients were randomly assigned to intrathecally receive isobaric 0.5% bupivacaine, 18 mg, plus saline (Group 1), clonidine 37.5 &mgr;g (Group 2), clonidine 75 &mgr;g (Group 3), and clonidine 150 &mgr;g (Group 4). Duration of the sensory block (regression below level L1) was increased in patients receiving intrathecal clonidine: 288 ± 62 min (Group 1, control), 311 ± 101 min in Group 2 (+8%), 325 ± 69 min in Group 3 (+13%), and 337 ± 78 min in Group 4 (+17%) (estimated parameter for dose 0.23 [95% confidence interval −0.05–0.50]). Duration of pain relief from intrathecal clonidine administration until the first request for supplemental analgesia was significantly prolonged: 295 ± 80 min (Group 1, control), 343 ± 75 min in Group 2 (+16%), 381 ± 117 min in Group 3 (+29%), and 445 ± 136 min in Group 4 (+51%) (estimated parameter for dose 1.02 [95% confidence interval 0.59–1.45]). Relative hemodynamic stability was maintained and there were no between-group differences in the sedation score. We conclude that small doses of intrathecal clonidine (≤150 &mgr;g) significantly prolong the anesthetic and analgesic effects of bupivacaine in a dose-dependent manner and that 150 &mgr;g of clonidine seems to be the preferred dose, in terms of effect versus unwarranted side effects, when prolongation of spinal anesthesia is desired.

Postoperative patient complaints: a prospective interview study of 12,276 patients

STUDY OBJECTIVE To evaluate the incidence of perioperative minor adverse events and to analyze patient satisfaction based on potential explanatory variables. DESIGN Structured, face-to-face interview of 25% of all patients undergoing surgery during the period from January 2003 through June 2006. SETTING Academic university medical center. PATIENTS 12,276 patients (5,793 men and 6,483 women) from all surgical disciplines: 7,440 patients had general anesthesia, 4,236 patients had regional anesthesia, and 600 patients had a combined general-regional anesthetic technique. MEASUREMENTS Occurrence of perioperative minor adverse events was assessed during the interview. Patient satisfaction was measured with a 4-point Likert scale. MAIN RESULTS 3,652 (30%) patients reported at least one perioperative complaint and 737 (6%) patients reported multiple minor adverse events. Overall, a total of 4,475 minor adverse events were reported. Leading adverse events included postoperative nausea and vomiting (1,705 complaints), sore throat (1,228 complaints), and hoarseness (802 complaints). Patient satisfaction with anesthetic care was generally high (97% satisfied or highly satisfied). Patients were significantly more satisfied following regional than general anesthesia (P < 0.001). Patient dissatisfaction was also associated with the occurrence of at least one minor adverse event (P < 0.001) or with increasing ASA physical status (P < 0.001). CONCLUSION Minor events occur with a surprisingly high incidence and are significantly associated with patient dissatisfaction. Regional anesthesia is associated with fewer patient complaints and significantly higher postoperative patient satisfaction.

Anaesthetic mechanisms: update on the challenge of unravelling the mystery of anaesthesia

General anaesthesia is administered each day to thousands of patients worldwide. Although more than 160 years have passed since the first successful public demonstration of anaesthesia, a detailed understanding of the anaesthetic mechanism of action of these drugs is still lacking. An important early observation was the Meyer–Overton correlation, which associated the potency of an anaesthetic with its lipid solubility. This work focuses attention on the lipid membrane as a likely location for anaesthetic action. With the advent of cellular electrophysiology and molecular biology techniques, tools to dissect the components of the lipid membrane have led, in recent years, to the widespread acceptance of proteins, namely receptors and ion channels, as more likely targets for the anaesthetic effect. Yet these accumulated data have not produced a comprehensive explanation for how these drugs produce central nervous system depression. In this review, we follow the story of anaesthesia mechanisms research from its historical roots to the intensely neurophysiological research regarding it today. We will also describe recent findings that identify specific neuroanatomical locations mediating the actions of some anaesthetic agents.

Additive Inhibition of Nicotinic Acetylcholine Receptors by Corticosteroids and the Neuromuscular Blocking Drug Vecuronium

Background: Neuromuscular disorders associated with muscular weakness and prolonged paralysis are common in critically ill patients. Acute myopathy has been described in patients receiving a combination therapy of corticosteroids and nondepolarizing neuromuscular blocking drugs for treatment of acute bronchospasm. The cause of this myopathy is not fully established and may involve drug interactions that perturb neuromuscular transmission. To investigate the interaction of corticosteroids with neuromuscular blocking drugs, the authors determined the effects of methylprednisolone and hydrocortisone alone and in combination with vecuronium on fetal (&ggr;-subunit containing) and adult (&egr;-subunit containing) subtypes of the muscle-type nicotinic acetylcholine receptor. Methods: Functional channels were expressed in Xenopus laevis oocytes and activated with 1 &mgr;M acetylcholine. The resulting currents were recorded using a whole cell two-electrode voltage clamp technique. Results: Both forms of the muscle-type acetylcholine receptor were potently inhibited by methylprednisolone and hydrocortisone, with concentrations producing 50% inhibition in the range of 400–600 &mgr;M and 1–2 mM, respectively. The corticosteroids produced noncompetitive antagonism of the muscle-type nicotinic acetylcholine receptor at clinical concentrations. Both receptor forms were also inhibited, even more potently, by vecuronium, with a concentration producing 50% inhibition in the range of 1–2 nM. Combined application of vecuronium and methylprednisolone showed additive effects on both receptor forms, which were best described by a two-site model, with each site independent. Conclusions: The enhanced neuromuscular blockade produced when corticosteroids are combined with vecuronium may augment pharmacologic denervation and contribute to the pathophysiology of prolonged weakness observed in some critically ill patients.