The effects of isoflurane minimum alveolar concentration on withdrawal reflex activity evoked by repeated transcutaneous electrical stimulation in ponies

The aim of this study was to quantify the effects of isoflurane at approximately the minimum alveolar concentration (peri-MAC) on the temporal summation (TS) of reflex activity in ponies. TS was evoked by repeated electrical stimulations applied at 5 Hz for 2 s on the digital nerve of the left forelimb of seven ponies. Surface electromyographic activity was recorded from the deltoid and common digital extensor muscles. TS thresholds and amplitude of response to stimulations of increasing intensities were assessed during anaesthesia at 0.85, 0.95 and 1.05 times the individual MAC, and after anaesthesia in standing animals. Under isoflurane anaesthesia, TS thresholds increased significantly in a concentration-dependent fashion and at each isoflurane MAC, the responses increased significantly for increasing stimulation intensities. A concentration-dependent depression of evoked reflexes with a reduction in the slopes of the stimulus-response function was observed for both muscles. The results demonstrated that with this model it is possible to describe and quantify the effects of anaesthetics on spinal sensory-motor processing in ponies.

Quantitative assessment of nociceptive processes in conscious dogs by use of the nociceptive withdrawal reflex

OBJECTIVE: To investigate the feasibility of evoking the nociceptive withdrawal reflex (NWR) from fore and hind limbs in conscious dogs, score stimulus-associated behavioral responses, and assess the canine NWR response to suprathreshold stimulations. ANIMALS: 8 adult Beagles. PROCEDURE: Surface electromyograms evoked by transcutaneous electrical stimulation of ulnaris and digital plantar nerves were recorded from the deltoideus, cleidobrachialis, biceps femoris, and tibialis cranialis muscles. Train-of-five pulses (stimulus(train)) were used; reflex threshold (I(t train)) was determined, and recruitment curves were obtained at 1.2, 1.5, and 2 x I(t train). Additionally, a single pulse (stimulus(single)) was given at 1, 1.2, 1.5, 2, and 3 x I(t train). Latency and amplitude of NWRs were analyzed. Severity of behavioral reactions was subjectively scored. RESULTS: Fore- and hind limb I(t train) values (median; 25% to 75% interquartile range) were 2.5 mA (2.0 to 3.6 mA) and 2.1 mA (1.7 to 2.9 mA), respectively. At I(t train), NWR latencies in the deltoideus, cleidobrachialis, biceps femoris, and cranial tibialis muscles were not significantly different (19.6 milliseconds [17.1 to 20.5 milliseconds], 19.5 milliseconds [18.1 to 20.7 milliseconds], 20.5 milliseconds [14.7 to 26.4 milliseconds], and 24.4 milliseconds [17.1 to 40.5 milliseconds], respectively). Latencies obtained with stimulus(train) and stimulus(single) were similar. With increasing stimulation intensities, NWR amplitude increased and correlated positively with behavioral scores. CONCLUSIONS AND CLINICAL RELEVANCE: In dogs, the NWR can be evoked from limbs and correlates with behavioral reactions. Results suggest that NWR evaluation may enable quantification of nociceptive system excitability and efficacy of analgesics in individual dogs.

Evaluation of administration of isoflurane at approximately the minimum alveolar concentration on depression of a nociceptive withdrawal reflex evoked by transcutaneous electrical stimulation in ponies

OBJECTIVE: To investigate effects of isoflurane at approximately the minimum alveolar concentration (MAC) on the nociceptive withdrawal reflex (NWR) of the forelimb of ponies as a method for quantifying anesthetic potency. ANIMALS: 7 healthy adult Shetland ponies. PROCEDURE: Individual MAC (iMAC) for isoflurane was determined for each pony. Then, effects of isoflurane administered at 0.85, 0.95, and 1.05 iMAC on the NWR were assessed. At each concentration, the NWR threshold was defined electromyographically for the common digital extensor and deltoid muscles by stimulating the digital nerve; additional electrical stimulations (3, 5, 10, 20, 30, and 40 mA) were delivered, and the evoked activity was recorded and analyzed. After the end of anesthesia, the NWR threshold was assessed in standing ponies. RESULTS: Mean +/- SD MAC of isoflurane was 1.0 +/- 0.2%. The NWR thresholds for both muscles increased significantly in a concentration-dependent manner during anesthesia, whereas they decreased in awake ponies. Significantly higher thresholds were found for the deltoid muscle, compared with thresholds for the common digital extensor muscle, in anesthetized ponies. At each iMAC tested, amplitudes of the reflex responses from both muscles increased as stimulus intensities increased from 3 to 40 mA. A concentration-dependent depression of evoked reflexes with reduction in slopes of the stimulus-response functions was detected. CONCLUSIONS AND CLINICAL RELEVANCE: Anesthetic-induced changes in sensory-motor processing in ponies anesthetized with isoflurane at concentrations of approximately 1.0 MAC can be detected by assessment of NWR. This method will permit comparison of effects of inhaled anesthetics or anesthetic combinations on spinal processing in equids.

Do transsexuals have micturition disorders?

OBJECTIVE: Transsexualism occurs with an estimated prevalence of 2.4:100,000 male-to-female (MTF) and 1:100,000 female-to-male (FTM) transsexuals. As sex reassignment surgery involves surgery of the urethra and transsexuals are substituted life-long with the cross gender hormones there could possibly arise micturition disorders. Aim of the study was to determine if transsexuals have an increased risk of micturition disorders and if so which. STUDY DESIGN: Between January and July 2003 we examined 25 transsexuals whereof 18 were MTF and 7 were FTM transsexuals using King's Health Questionnaire, visual analogue scale for patient's well being, perineal and transabdominal ultrasound, urine dipstick and uroflow measurement. RESULTS: 17 out of 25 patients considered themselves very happy. In MTF transsexuals, a diverted stream, overactive bladder and stress urinary incontinence was a common problem. Prostate volume was small with 20 g and palpation did not confirm and solid or suspicious lesions. None of the patients had significant residual urine but MTF transsexuals had a reduced urinary flow. We could not detect a current urinary tract infections in any of the patients. CONCLUSION: Transsexuals have an increased risk for the development of micturition disorders including stress urinary incontinence and overactive bladder compared to age-matched control groups and should be counselled preoperatively. Reasons for the development of incontinence might be surgery including pudendal nerve damage, hormonal reasons and ageing.

Effects of butorphanol on the withdrawal reflex using threshold, suprathreshold and repeated subthreshold electrical stimuli in conscious horses

OBJECTIVE: To assess the effects of a single intravenous dose of butorphanol (0.1 mg kg(-1)) on the nociceptive withdrawal reflex (NWR) using threshold, suprathreshold and repeated subthreshold electrical stimuli in conscious horses. STUDY DESIGN: 'Unblinded', prospective experimental study. ANIMALS: Ten adult horses, five geldings and five mares, mean body mass 517 kg (range 487-569 kg). METHODS: The NWR was elicited using single transcutaneous electrical stimulation of the palmar digital nerve. Repeated stimulations were applied to evoke temporal summation. Surface electromyography was performed to record and quantify the responses of the common digital extensor muscle to stimulation and behavioural reactions were scored. Before butorphanol administration and at fixed time points up to 2 hours after injection, baseline threshold intensities for NWR and temporal summation were defined and single suprathreshold stimulations applied. Friedman repeated-measures analysis of variance on ranks and Wilcoxon signed-rank test were used with the Student-Newman-Keul's method applied post-hoc. The level of significance (alpha) was set at 0.05. RESULTS: Butorphanol did not modify either the thresholds for NWR and temporal summation or the reaction scores, but the difference between suprathreshold and threshold reflex amplitudes was reduced when single stimulation was applied. Upon repeated stimulation after butorphanol administration, a significant decrease in the relative amplitude was calculated for both the 30-80 and the 80-200 millisecond intervals after each stimulus, and for the whole post-stimulation interval in the right thoracic limb. In the left thoracic limb a decrease in the relative amplitude was found only in the 30-80 millisecond epoch. CONCLUSION: Butorphanol at 0.1 mg kg(-1) has no direct action on spinal Adelta nociceptive activity but may have some supraspinal effects that reduce the gain of the nociceptive system. CLINICAL RELEVANCE: Butorphanol has minimal effect on sharp immediate Adelta-mediated pain but may alter spinal processing and decrease the delayed sensations of pain.

Identification of brain structures involved in micturition with functional magnetic resonance imaging (fMRI)

OBJECTIVE: The voluntary control of micturition is believed to be integrated by complex interactions among the brainstem, subcortical areas and cortical areas. Several brain imaging studies using positron emission tomography (PET) have demonstrated that frontal brain areas, the limbic system, the pons and the premotor cortical areas were involved. However, the cortical and subcortical brain areas have not yet been precisely identified and their exact function is not yet completely understood. MATERIALS AND METHODS: This study used functional magnetic resonance imaging (fMRI) to compare brain activity during passive filling and emptying of the bladder. A cathetherism of the bladder was performed in seven healthy subjects (one man and six right-handed women). During scanning, the bladder was alternatively filled and emptied at a constant rate with bladder rincing solution. RESULTS: Comparison between passive filling of the bladder and emptying of the bladder showed an increased brain activity in the right inferior frontal gyrus, cerebellum, symmetrically in the operculum and mesial frontal. Subcortical areas were not evaluated. CONCLUSIONS: Our results suggest that several cortical brain areas are involved in the regulation of micturition.

Psychologic factors are related to some sensory pain thresholds but not nociceptive flexion reflex threshold in chronic whiplash

OBJECTIVES: Sensory hypersensitivity, central hyperexcitability [lowered nociceptive flexion reflex (NFR) thresholds], and psychologic distress are features of chronic whiplash. However, relationships between these substrates are not clear. This study tested the hypothesis that psychologic distress and catastrophization are correlated with sensory hypersensitivity and NFR responses in chronic whiplash. METHODS: Pressure and thermal pain thresholds (mean values across 3 body sites), NFR threshold, and pain at threshold Visual Analog Scale were measured in 30 participants with chronic whiplash and 30 asymptomatic controls. Pain and disability levels Neck Disability Index, psychologic distress (GHQ-28), and catastrophization (PCS) were also measured in the whiplash group. RESULTS: Whiplash injured participants demonstrated lowered pain thresholds to pressure and cold (P<0.05); lowered NFR thresholds (P=0.003), and demonstrated above threshold levels of psychologic distress (GHQ-28) and levels of catastrophization comparable with other musculoskeletal conditions. There were no group differences for heat pain thresholds or pain at NFR threshold. In the whiplash group, PCS scores correlated moderately with cold pain threshold (r=0.51, P=0.01). In contrast, there were no significant correlations between GHQ-28 scores and pain threshold measures or between psychologic factors and NFR responses in whiplash participants. There were no significant correlations between psychologic factors and pain thresholds or NFR responses in controls. DISCUSSION: We have demonstrated that psychologic factors have some association with sensory hypersensitivity (cold pain threshold measures) in chronic whiplash but do not seem to influence spinal cord excitability. This suggests that psychologic disorders are important, but not the only, determinants of central hypersensitivity in whiplash patients.

Integrity of venoarteriolar reflex determines level of microvascular skin flow enhancement with intermittent pneumatic compression

OBJECTIVE: To investigate whether intermittent pneumatic compression (IPC) augments skin blood flow through transient suspension of local vasoregulation, the veno-arteriolar response (VAR), in healthy controls and in patients with peripheral arterial disease (PAD). METHODS: Nineteen healthy limbs and twenty-two limbs with PAD were examined. To assess VAR, skin blood flow (SBF) was measured using laser Doppler fluxmetry in the horizontal and sitting positions and was defined as percentage change with postural alteration [(horizontal SBF--sitting SBF)/horizontal SBF x 100]. On IPC application to the foot, the calf, or both, SBF was measured with laser Doppler fluxmetry, the probe being attached to the pulp of the big toe. RESULTS: Baseline VAR was higher in the controls 63.8 +/- 6.4% than in patients with PAD (31.7 +/- 13.4%, P = .0162). In both groups SBF was significantly higher with IPC than at rest (P < .0001). A higher percentage increase with IPC was demonstrated in the controls (242 +/- 85% to 788 +/- 318%) than in subjects with PAD, for each one of the three different IPC modes investigated (98 +/- 33% to 275 +/- 72%) with IPC was demonstrated. The SBF enhancement with IPC correlated with VAR for all three compression modes (r = 0.58, P = .002 for calf compression, r = 0.65, P < .0001 for foot compression alone, and r = 0.64, P = .0002 for combined foot and calf compression). CONCLUSION: The integrity of the veno-arteriolar response correlates with the level of skin blood flow augmentation generated with intermittent pneumatic compression, indicating that this may be associated with a transient suspension of the autoregulatory vasoconstriction both in healthy controls and in patients with PAD.

New method for quantification and statistical analysis of nociceptive reflex receptive fields in humans

A method for quantifying nociceptive withdrawal reflex receptive fields in human volunteers and patients is described. The reflex receptive field (RRF) for a specific muscle denotes the cutaneous area from which a muscle contraction can be evoked by a nociceptive stimulus. The method is based on random stimulations presented in a blinded sequence to 10 stimulation sites. The sensitivity map is derived by interpolating the reflex responses evoked from the 10 sites. A set of features describing the size and location of the RRF is presented based on statistical analysis of the sensitivity map within every subject. The features include RRF area, volume, peak location and center of gravity. The method was applied to 30 healthy volunteers. Electrical stimuli were applied to the sole of the foot evoking reflexes in the ankle flexor tibialis anterior. The RRF area covered a fraction of 0.57+/-0.06 (S.E.M.) of the foot and was located on the medial, distal part of the sole of the foot. An intramuscular injection into flexor digitorum brevis of capsaicin was performed in one spinal cord injured subject to attempt modulation of the reflex receptive field. The RRF area, RRF volume and location of the peak reflex response appear to be the most sensitive measures for detecting modulation of spinal nociceptive processing. This new method has important potential applications for exploring aspects of central plasticity in volunteers and patients. It may be utilized as a new diagnostic tool for central hypersensitivity and quantification of therapeutic interventions.

Effects of a low dose infusion of racemic and S-ketamine on the nociceptive withdrawal reflex in standing ponies

OBJECTIVE: To investigate the effect of plasma concentrations obtained by a low dose constant rate infusion (CRI) of racemic ketamine or S-ketamine on the nociceptive withdrawal reflex (NWR) in standing ponies. STUDY DESIGN: Prospective, blinded, cross-over study. ANIMALS: Six healthy 5-year-old Shetland ponies. METHODS: Ponies received either 0.6 mg kg(-1) racemic ketamine (group RS) or 0.3 mg kg(-1) S-ketamine (group S) intravenously (IV), followed by a CRI of 20 microg kg(-1)minute(-1) racemic ketamine (group RS) or 10 microg kg(-1)minute(-1) S-ketamine (group S) for 59 minutes. The NWR was evoked by transcutaneous electrical stimulation of a peripheral nerve before drug administration, 15 and 45 minutes after the start of the bolus injection and 15 minutes after the end of the CRI. Electromyographic responses were recorded and analysed. Arterial blood was collected before stimulation and plasma concentrations of ketamine and norketamine were measured enantioselectively using capillary electrophoresis. Ponies were video recorded and monitored to assess drug effects on behaviour, heart rate (HR), mean arterial blood pressure (MAP) and respiratory rate. RESULTS: The NWR was significantly depressed in group RS at plasma concentrations between 20 and 25 ng mL(-1) of each enantiomer. In group S, no significant NWR depression could be observed; plasma concentrations of S-ketamine (9-15 ng mL(-1)) were lower, compared to S-ketamine concentrations in group RS, although this difference was not statistically significant. Minor changes in behaviour, HR and MAP only occurred within the first 5-10 minutes after bolus drug administration in both groups. CONCLUSION: Antinociceptive activity in standing ponies, demonstrated as a depression of the NWR, could only be detected after treatment with racemic ketamine. S-ketamine may have lacked this effect as a result of lower plasma concentrations, a more rapid metabolism or a lower potency of S-ketamine in Equidae so further investigation is necessary.

Comparison of the effects of the alpha-2 agonists detomidine, romifidine and xylazine on nociceptive withdrawal reflex and temporal summation in horses

OBJECTIVE: To evaluate and compare the antinociceptive effects of the three alpha-2 agonists, detomidine, romifidine and xylazine at doses considered equipotent for sedation, using the nociceptive withdrawal reflex (NWR) and temporal summation model in standing horses. STUDY DESIGN: Prospective, blinded, randomized cross-over study. ANIMALS: Ten healthy adult horses weighing 527-645 kg and aged 11-21 years old. METHODS: Electrical stimulation was applied to the digital nerves to evoke NWR and temporal summation in the left thoracic limb and pelvic limb of each horse. Electromyographic reflex activity was recorded from the common digital extensor and the cranial tibial muscles. After baseline measurements a single bolus dose of detomidine, 0.02 mg kg(-1), romifidine 0.08 mg kg(-1), or xylazine, 1 mg kg(-1), was administered intravenously (IV). Determinations of NWR and temporal summation thresholds were repeated at 10, 20, 30, 40, 60, 70, 90, 100, 120 and 130 minutes after test-drug administration alternating the thoracic limb and the pelvic limb. Depth of sedation was assessed before measurements at each time point. Behavioural reaction was observed and recorded following each stimulation. RESULTS: The administration of detomidine, romifidine and xylazine significantly increased the current intensities necessary to evoke NWR and temporal summation in thoracic limbs and pelvic limbs of all horses compared with baseline. Xylazine increased NWR thresholds over baseline values for 60 minutes, while detomidine and romifidine increased NWR thresholds over baseline for 100 and 120 minutes, respectively. Temporal summation thresholds were significantly increased for 40, 70 and 130 minutes after xylazine, detomidine and romifidine, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: Detomidine, romifidine and xylazine, administered IV at doses considered equipotent for sedation, significantly increased NWR and temporal summation thresholds, used as a measure of antinociceptive activity. The extent of maximal increase of NWR and temporal summation thresholds was comparable, while the duration of action was drug-specific.

The influence of a continuous rate infusion of dexmedetomidine on the nociceptive withdrawal reflex and temporal summation during isoflurane anaesthesia in dogs

Objective To examine the influence of a low dose dexmedetomidine infusion on the nociceptive withdrawal reflex and temporal summation in dogs during isoflurane anaesthesia. Study design Prospective experimental blinded cross-over study. Animals Eight healthy mixed breed dogs, body weight Mean +/- SD 26.5 +/- 8.4 kg and age 25 +/- 16 months. Methods Anaesthesia was induced with propofol and maintained with isoflurane (Fe'ISO 1.3%) delivered in oxygen and air. After stabilization, baseline recordings (time 0) were obtained, then a dexmedetomidine bolus (1 mug kg(-1) IV) followed by a continuous rate infusion (1 mug kg(-1) hour(-1) ) or saline placebo were administered. At times 10, 30 and 60 minutes after the initial bolus, electrical stimulations of increasing intensity were applied over the lateral plantar digital nerve, and administered both as single and as repeated stimuli. The resulting reflex responses were recorded using electromyography. Data were analysed using a multivariable linear regression model and a Kruskal Wallis test for single stimulation data, and repeated measures anova and paired t-test for repeated stimulation data. Results The AUC for the stimulus-response curves after single stimulation were similar for both treatments at time 0. At times 10, 30 and 60 the AUCs for the stimulus-response curves were significantly lower with dexmedetomidine treatment than with placebo. Temporal summation was evident in both treatments at times 0, 10, 30 and 60 starting from a stimulation intensity of 10 mA. The magnitude of temporal summation was smaller in dexmedetomidine than in placebo treated dogs at time 10, 30 and 60, but not at time 0. Conclusions During isoflurane anaesthesia, low dose dexmedetomidine suppresses the nociceptive reflex responses after single and repeated electrical stimulation. Clinical relevance This experimental study confirms previous reports on its peri-operative efficacy under clinical conditions, and further indicates that dexmedetomidine might reduce the risk of post-operative chronic pain development.

Quantitative assessment of the nociceptive withdrawal reflex in healthy, non-medicated experimental sheep

This study aimed to characterize the nociceptive withdrawal reflex (NWR) and to define the nociceptive threshold in 25 healthy, non-medicated experimental sheep in standing posture. Electrical stimulation of the dorsal lateral digital nerves of the right thoracic and the pelvic limb was performed and surface-electromyography (EMG) from the deltoid (all animals) and the femoral biceps (18 animals) or the peroneus tertius muscles (7 animals) was recorded. The behavioural reaction following each stimulation was scored on a scale from 0 (no reaction) to 5 (strong whole body reaction). A train-of-five 1 ms constant-current pulse was used and current intensity was stepwise increased until NWR threshold intensity was reached. The NWR threshold intensity (It) was defined as the minimal stimulus intensity able to evoke a reflex with a minimal Root-Mean-Square amplitude (RMSA) of 20 μV, a minimal duration of 10 ms and a minimal reaction score of 1 (slight muscle contraction of the stimulated limb) within the time window of 20 to 130 ms post-stimulation. Based on this value, further stimulations were performed below (0.9It) and above threshold (1.5It and 2It). The stimulus-response curve was described. Data are reported as medians and interquartile ranges. At the deltoid muscle It was 4.4 mA (2.9–5.7) with an RMSA of 62 μV (30–102). At the biceps femoris muscle It was 7.0 mA (4.0–10.0) with an RMSA of 43 μV (34–50) and at the peroneus tertius muscle It was 3.4 mA (3.1–4.4) with an RMSA of 38 μV (32–46). Above threshold, RMSA was significantly increased at all muscles. Below threshold, RMSA was only significantly smaller than at It for the peroneus tertius muscle but not for the other muscles.