Alex M. Zbinden

Central hypersensitivity in chronic pain after whiplash injury.

ObjectiveThe mechanisms underlying chronic pain after whiplash injury are usually unclear. Injuries may cause sensitization of spinal cord neurons in animals (central hypersensitivity), which results in increased responsiveness to peripheral stimuli. In humans, the responsiveness of the central nervous system to peripheral stimulation may be explored by applying sensory tests to healthy tissues. The hypotheses of this study were: (1) chronic whiplash pain is associated with central hypersensitivity; (2) central hypersensitivity is maintained by nociception arising from the painful or tender muscles in the neck. DesignComparison of patients with healthy controls. SettingPain clinic and laboratory for pain research, university hospital. PatientsFourteen patients with chronic neck pain after whiplash injury (car accident) and 14 healthy volunteers. Outcome MeasuresPain thresholds to: single electrical stimulus (intramuscular), repeated electrical stimulation (intramuscular and transcutaneous), and heat (transcutaneous). Each threshold was measured at neck and lower limb, before and after local anesthesia of the painful and tender muscles of the neck. ResultsThe whiplash group had significantly lower pain thresholds for all tests, except heat, at both neck and lower limb. Local anesthesia of the painful and tender points affected neither intensity of neck pain nor pain thresholds. ConclusionsThe authors found a hypersensitivity to peripheral stimulation in whiplash patients. Hypersensitivity was observed after cutaneous and muscular stimulation, at both neck and lower limb. Because hypersensitivity was observed in healthy tissues, it resulted from alterations in the central processing of sensory stimuli (central hypersensitivity). Central hypersensitivity was not dependent on a nociceptive input arising from the painful and tender muscles.

Anesthetic depth defined using multiple noxious stimuli during isoflurane/oxygen anesthesia. I. Motor reactions.

BackgroundPotency of inhaled anesthetics usually is defined by determining the minimal alveolar concentration (MAC) that prevents movement in 50% of patients in response to skin incision. Skin incision, however, is usually only a single event and, thus, determination of potency cannot be repeated in one patient. Traditional MACskin incision cannot be used to predict response to other noxious stimuli. The aim of this study was to investigate the effects of other noxious stimulation patterns and then compare these to MACskin incision measuring the end-tidal isoflurane concentrations with the corresponding arterial concentrations. MethodsIn 26 patients, the end-tidal and corresponding arterial isoflurane concentrations needed to suppress eye opening to verbal command and motor response after trapezius squeeze, 50 Hz electric tetanic stimulation, laryngoscopy, skin incision, and tracheal intubation in 50% of all patients were determined. ResultsThe end-tidal (equivalent arterial) isoflurane concentrations (mean ± SE, adjusted to sea level) expressed in vol% (to allow comparison) increased in the following order (mean ± SE): vocal command 0.37 ± 0.09 (0.36 ± 0.09); trapezius squeeze 0.84 ± 0.07 (0.65 ± 0.07); laryngoscopy 1.00 ± 0.12 (0.78 ± 0.09); tetanic stimulation 1.03 ± 0.09 (0.80 ± 0.06); skin incision 1.16 ± 0.10 (0.97 ± 0.17); and intubation 1.76 ± 0.13 (1.32 ± 0.11). ConclusionsDifferent stimuli require different isoflurane concentrations to suppress motor responses. Tetanic stimulation and, to some extent, trapezius squeeze are reproducible and noninvasive stimulation patterns that can be used as an alternative to skin incision when evaluating potency of an anesthetic agent. In contrast to skin incision, they can be repeated.

Anesthetic depth defined using multiple noxious stimuli during isoflurane/oxygen anesthesia. II. Hemodynamic responses.

BackgroundThe hemodynamic effects of isoflurane have been studied extensively. However, most data are obtained from volunteers or patients in the absence of surgical stimulation. The hemodynamic responses to various stimulation patterns of different intensity have not been evaluated. MethodsIn 26 patients, the ability of isoflurane to suppress motor and hemodynamic reactions in response to noxious stimulations of variable degree (trapezius squeeze, tetanic stimulation, laryngoscopy, skin incision, and laryngoscopy plus intubation) was evaluated by measuring arterial blood pressure and heart rate before and after stimulation. ResultsAt concentrations that inhibited motor response to these stimuli in 50% of all patients, systolic blood pressure increased by 9 (trapezius squeeze), 15 (tetanic stimulation), 23 (laryngoscopy), 35 (skin incision) and 49 (intubation) mmHg, and heart rate by 5 (trapezius squeeze), 15 (tetanic stimulation), 17 (laryngoscopy), 36 (skin incision), and 36 (intubation) min-1 compared to the prestimulation values. An analysis using multiple regression showed that blood pressure response was influenced most by the type of stimulation followed by the concomitantly occurring motor reaction, the anesthesia time, and least by the isoflurane concentration per se. A high isoflurane concentration had no influence on the magnitude of blood pressure or heart rate increase to stimulation, but it decreased the prestimulation blood pressure and slightly increased the prestimulation heart rate. Heart rate responses were less consistent than those of blood pressure. ConclusionsIsoflurane used as a sole agent is unable to suppress hemodynamic reactions (blood pressure and heart rate) to painful stimuli. A “normal” blood pressure following stimulation can be achieved only if prestimulation blood pressure is depressed to levels that may be clinically unacceptable. The lack of motor response is not an accurate predictor of the ability of an agent to depress hemodynamic reaction.

The analgesic effect of oral delta-9-tetrahydrocannabinol (THC), morphine, and a THC-morphine combination in healthy subjects under experimental pain conditions

From folk medicine and anecdotal reports it is known that Cannabis may reduce pain. In animal studies it has been shown that delta‐9‐tetrahydrocannabinol (THC) has antinociceptive effects or potentiates the antinociceptive effect of morphine. The aim of this study was to measure the analgesic effect of THC, morphine, and a THC‐morphine combination (THC‐morphine) in humans using experimental pain models. THC (20 mg), morphine (30 mg), THC‐morphine (20 mg THC+30 mg morphine), or placebo were given orally and as single doses. Twelve healthy volunteers were included in the randomized, placebo‐controlled, double‐blinded, crossover study. The experimental pain tests (order randomized) were heat, cold, pressure, single and repeated transcutaneous electrical stimulation. Additionally, reaction time, side‐effects (visual analog scales), and vital functions were monitored. For the pharmacokinetic profiling, blood samples were collected. THC did not significantly reduce pain. In the cold and heat tests it even produced hyperalgesia, which was completely neutralized by THC‐morphine. A slight additive analgesic effect could be observed for THC‐morphine in the electrical stimulation test. No analgesic effect resulted in the pressure and heat test, neither with THC nor THC‐morphine. Psychotropic and somatic side‐effects (sleepiness, euphoria, anxiety, confusion, nausea, dizziness, etc.) were common, but usually mild.

Modeling and closed-loop control of hypnosis by means of bispectral index (BIS) with isoflurane

A model-based closed-loop control system is presented to regulate hypnosis with the volatile anesthetic isoflurane. Hypnosis is assessed by means of the bispectral index (BIS), a processed parameter derived from the electroencephalogram. Isoflurane is administered through a closed-circuit respiratory system. The model for control was identified on a population of 20 healthy volunteers. It consists of three parts: a model for the respiratory system, a pharmacokinetic model and a pharmacodynamic model to predict BIS at the effect compartment. A cascaded internal model controller is employed. The master controller compares the actual BIS and the reference value set by the anesthesiologist and provides expired isoflurane concentration references to the slave controller. The slave controller maneuvers the fresh gas anesthetic concentration entering the respiratory system. The controller is designed to adapt to different respiratory conditions. Anti-windup measures protect against performance degradation in the event of saturation of the input signal. Fault detection schemes in the controller cope with BIS and expired concentration measurement artifacts. The results of clinical studies on humans are presented.

A new closed-loop control system for isoflurane using bispectral index outperforms manual control

Background: Automatic control of depth of hypnosis using the Bispectral Index (BIS) can help to reduce phases of inadequate control. Automated BIS control with propofol or isoflurane administration via an infusion system has recently been described, a comparable study with isoflurane administration via a vaporizer had not been conducted yet. Our hypothesis was that our new model based closed-loop control system can safely be applied clinically and maintains the BIS within a defined target range better than manual control. Methods: Twenty-three patients, American Society of Anesthesiologists risk class I–III, scheduled for decompressive spinal surgery were randomized into groups with either closed-loop or manual control of BIS using isoflurane. An alfentanil target-controlled infusion was adjusted according to standard clinical practice. The BIS target was set to 50 during the operation. The necessity of human intervention in the control system and events of inadequate sedation (BIS <40 or BIS >60) were counted. The number of phases of inadequate control, defined as BIS ≥65 for more than 3 min, were recorded. The performance of the controller was assessed by several indicators (mean absolute deviation and median absolute performance error) and measured during the skin incision phase, the subsequent low flow phase, and the wound closure phase. Recovery profiles of both groups were compared. Results: No human intervention was necessary in the closed-loop control group. The occurrence of inadequate BIS was quantified with the mean and median values of the area under the curve and amounted to 0.360 and 0.088 for the manual control group and 0.049 and 0.017 for the closed-loop control group, respectively. In the manual control group nine phases of inadequate control were recorded, compared with one in the closed-loop control group, 10.3% to 0.5% of all observed anesthesia time. During all phases the averages of the performance parameters (mean absolute deviation and median absolute performance error) were more than 30% smaller in closed-loop control than in manual control (P < 0.05 between groups). Conclusions: Closed-loop control with BIS using isoflurane can safely be applied clinically and performs significantly better than manual control, even in phases with abrupt changes of stimulation that cannot be foreseen by the control system.

Epidural Epinephrine and Clonidine: Segmental Analgesia and Effects on Different Pain Modalities

Background: It is not known whether epidural epinephrine has an analgesic effect per se. The segmental distribution of clonidine epidural analgesia and its effects on temporal summation and different types of noxious stimuli are unknown. The aim of this study was to clarify these issues. Methods: Fifteen healthy volunteers received epidurally (L2‐L3 or L3‐L4) 20 ml of either epinephrine, 100 micro gram, in saline; clonidine, 8 micro gram/kg, in saline; or saline, 0.9%, alone, on three different days in a randomized, double‐blind, cross‐over fashion. Pain rating after electrical stimulation, pinprick, and cold perception were recorded on the dermatomes S1, L4, L1, T9, T6, T1, and forehead. Pressure pain tolerance threshold was recorded at S1, T6, and ear. Pain thresholds to single and repeated (temporal summation) electrical stimulation of the sural nerve were determined. Results: Epinephrine significantly reduced sensitivity to pinprick at L1‐L4‐S1. Clonidine significantly decreased pain rating after electrical stimulation at L1‐L4 and sensitivity to pinprick and cold at L1‐L4‐S1, increased pressure pain tolerance threshold at S1, and increased thresholds after single and repeated stimulation of the sural nerve. Conclusions: Epidural epinephrine and clonidine produce segmental hypoalgesia. Clonidine bolus should be administered at a spinal level corresponding to the painful area. Clonidine inhibits temporal summation elicited by repeated electrical stimulation and may therefore attenuate spinal cord hyperexcitability.

Isoflurane Minimum Alveolar Concentration Decreases during Anesthesia and Surgery

BackgroundIt generally is assumed that the potency of inhalational anesthetics remains unchanged during the course of the administration of an anesthetic. Only one study has indicated a decrease of minimum alveolar concentration with time. In this study, an effect of the duration of anesthesia administration and surgery on the potency of isoflurane was investigated by determining MACtetanus (the minimum alveolar concentration that prevents movement in response to electrical tetanic stimulation in 50% of patients) before and after surgery. MethodsTen patients who underwent removal of a herniated intervertebral disc were anesthetized with isoflurane only. Reaction to a standardized electrical stimulation applied to the forearm was observed and was graded as movement or no-movement. The isoflurane concentration was increased in steps of 0.10 vol% if the patient moved and decreased in steps of 0.10 vol% if no reaction was seen, until a “movement/nomovement/movement” or “no-movement/movement/no-movement” pattern, respectively, was achieved. ResultsMACtetanus decreased in all patients from 1.28 ± 0.22 vol% (mean ± SD) before surgery to 1.04 ± 0.22 vol% after surgery (P < 0.01). When the prestimulation arterial blood pressure or the maximal increase in blood pressure caused by stimulation at the individual MACtetanus before surgery were compared to the corresponding values at the individual MACtetanus after surgery, no significant difference could be found. The prestimulation heart rate and the maximal increase in heart rate were significantly lower after surgery, even though the end-tidal isoflurane concentration was 0.24 vol% lower at the individual MACtetanus after surgery. ConclusionThe authors conclude that MACtetanus decreases during the administration of anesthesia and the performance of surgery.

Different benefit of bispectal index (BIS™) in desflurane and propofol anesthesia

Background: Bispectal index (BIS™) monitoring may reduce drug usage and hasten recovery in propofol and inhalation anesthesia. The faster emergence profile of desflurane may reduce the effect of BIS monitoring on recovery from desflurane compared with propofol. This study compared hypnotic drug usage, recovery, patient satisfaction and incidence of inadequate sedation in BIS monitored and nonmonitored women anesthetized with desflurane or propofol.

A direct search procedure to optimize combinations of epidural bupivacaine, fentanyl, and clonidine for postoperative analgesia.

Background The authors applied an optimization model (direct search) to find the optimal combination of bupivacaine dose, fentanyl dose, clonidine dose, and infusion rate for continuous postoperative epidural analgesia. Methods One hundred ninety patients undergoing 48-h thoracic epidural analgesia after major abdominal surgery were studied. Combinations of the variables of bupivacaine dose, fentanyl dose, clonidine dose, and infusion rate were investigated to optimize the analgesic effect (monitored by verbal descriptor pain score) under restrictions dictated by the incidence and severity of side effects. Six combinations were empirically chosen and investigated. Then a stepwise optimization model was applied to determine subsequent combinations until no decrease in the pain score after three consecutive steps was obtained. Results Twenty combinations were analyzed. The optimization procedure led to a reduction in the incidence of side effects and in the mean pain scores. The three best combinations of bupivacaine dose (mg/h), fentanyl dose (&mgr;g/h), clonidine dose (&mgr;g/h), and infusion rate (ml/h) were: 9-21-5-7, 8-30-0-9, and 13-25-0-9, respectively. Conclusions Given the variables investigated, the aforementioned combinations may be the optimal ones to provide postoperative analgesia after major abdominal surgery. Using the direct search method, the enormous number of possible combinations of a therapeutic strategy can be reduced to a small number of potentially useful ones. This is accomplished using a scientific rather than an arbitrary procedure.