The sedative effects of climazolam and climazolam with fentanyl-fluanisone in rats (Rattus norvegicus)

A trial of the sedative effects of a novel benzodiazepine, climazolam, and of a mixture of climazolam and fentanyl-fluanisone was undertaken in male and female Sprague Dawley and Lewis strain rats (Rattus norvegicus) of different ages. At the recommended intravenous therapeutic dosage of 0.25 mg/kg, climazolam sedated the rats but failed to inhibit the righting reflex or responses to painful stimuli. Even at 25 times the recommended dosage, there was no anaesthetic effect. Predictable and satisfactory surgical anaesthesia was not obtained with the mixture of climazolam and fentanyl-fluanisone administered intraperitoneally. In contrast with diazepam and midazolam, climazolam failed to potentiate the sedative analgesic properties of fentanyl-fluanisone: indeed many animals retained their tail and pedal pinch reflexes. The results also revealed significant differences in effect related to strain and age but not to sex.     

Large slow potential shifts occur during halothane anaesthesia in gerbils

Continuous recordings were made of slow potential shift activity occurring at six locations on the surface of the cerebral cortex of seizure-prone and non seizure-prone gerbils. Measurements were made for 80-s epochs of recordings of frequency, maximum and minimum slow shift amplitude and baseline potential of the brain during periods of normal inactivity and subsequently during halothane anaesthesia. Induction of anaesthesia initially provoked large (millivolt) slow (3–4 s) oscillations in all animals, larger in amplitude than any recorded prior to anaesthesia. With increasing depth of anaesthesia, all animals also showed a reduction in the amplitude of this spontaneous slow potential shift activity. The effect was most pronounced in seizure-prone animals, and subsequent to anaesthetic-induced behavioural immobility, these animals also showed a regional resistance to the depression of spontaneous slow potential shift oscillations. Slow potential shift activity during anaesthesia represents ionic fluxes which may normally be involved in modulation of neuronal responsiveness. It was suggested that glia may be targets for anaesthetics and that seizure susceptibility may confer some degree of resistance to the depressant effects of such substances. Accepted: 25 January 1998     

Plastic,inquisitive roots and intelligent plants in the light of some new vistas in plant biology

Abstract

Metaphors, such as those used in the title of this article, are often useful for the comprehension of specialised topics in plant biology. A brief attempt is made to elucidate one of these metaphors, plant “intelligence”, as it relates to the plastic responses of roots and root systems to their environment. Tropisms and nastic movements of root apices are two expressions of an inherent plasticity of form exhibited by roots. In soil, roots are exposed to multiple stimuli, many of which can potentially elicit such movements. Hence, a key question is how roots respond to and process the different stimuli which simultaneously reach their surfaces. Assuming that roots always use the same site along their length to express their movement responses, and that they also use an auxin‐based information‐transduction pathway, the most evident choices for the processing of stimuli are that roots either prioritise the various incoming stimuli and respond only to the strongest or they amalgamate stimuli and mount an averaged compromise response to all of them. The proposal that plants may be “intelligent”, especially in respect to their plastic growth responses, is one that draws upon knowledge of this faculty from animal biology. Also implied is that plants and animals are sufficiently similar to share usage of this term “intelligence”. But an alternative view is that plants and animals are sufficiently different and so intelligence is an unfitting term. Following the line of enquiry into creative evolution initiated by Henri Bergson, plants can be viewed differently to animals. The tendency of plants is towards instinctive behaviour rather than intelligent behaviour.     

Effects of surgery and epidural or general anaesthesia on testosterone, 17-hydroxyprogesterone and cortisol plasma levels in prepubertal boys

Testosterone (T), 17-hydroxyprogesterone (17P) and cortisol (F) plasma levels have been measured in two groups of prepubertal boys before and during surgery under general anaesthesia (Group 1) and epidural anaesthesia (Group 2) respectively. The mean plasma levels of T, 17P and F increased significantly (P less than 0.05; P less than 0.001; P less than 0.005, respectively) during surgery in Group 1; in Group 2 the plasma levels of T and F did not show any significant variation, whereas 17P significantly increased (P less than 0.05). However the mean level reached by 17P in Group 2 was significantly lower (P less than 0.005) than that observed in Group 1. No significant variation of LH and FSH plasma levels was observed in either group. Our report suggests that the modifications of T and 17P plasma levels observed during surgery under general anaesthesia (GA) are probably due to the stress induced adrenal response. This response can be inhibited or reduced by epidural anaesthesia (EA).     

Role of tricyclic antidepressants in the central regulation of hyperalgesia and stress analgesia

The effect of hypophysectomy (HE) on pain thresholds was studied in female noninbred rats. Hyperalgesia was observed after HE since the first till the sixth day of the observation period. Droperidol (1 mg/kg i.p.) and amitryptyline (5 mg/kg i.p.) produced hyperalgesia in sham-operated rats, which was potentiated in hypophysectomized animals. In rats taken into the experiment 3 days after operation, no increase in the pain threshold was recordable during the 30-minute painful stress, and poststress autoanalgesia did not develop subsequently. The opposing data were obtained in sham-operated animals. On intraperitoneal administration of phentanyl (25 micrograms/kg) after the 30-minute painful stress hypophysectomized rats did not manifest any potentiation of its analgesic effect in contradistinction to sham-operated animals. Simultaneous administration of phentanyl at the same dose and melipramine (5 mg/kg i.p.) produced considerable potentiation of analgesia if administered after stress. In hypophysectomized rats, that effect was somewhat reduced.     

Effects of anaesthesia on blood gases, acid-base status and ions in the toad Bufo marinus

It is common practice to chronically implant catheters for subsequent blood sampling from conscious and undisturbed animals. This method reduces stress associated with blood sampling, but anaesthesia per se can also be a source of stress in animals. Therefore, it is imperative to evaluate the time required for physiological parameters (e.g. blood gases, acid-base status, plasma ions, heart rate and blood pressure) to stabilise following surgery. Here, we report physiological parameters during and after anaesthesia in the toad Bufo marinus. For anaesthesia, toads were immersed in benzocaine (1 g l(-1)) for 15 min or until the corneal reflex disappeared, and the femoral artery was cannulated. A 1-ml blood sample was taken immediately after surgery and subsequently after 2, 5, 24 and 48 h. Breathing ceased during anaesthesia, which resulted in arterial Po(2) values below 30 mmHg, and respiratory acidosis developed, with arterial Pco(2) levels reaching 19.5+/-2 mmHg and pH 7.64+/-0.04. The animals resumed pulmonary ventilation shortly after the operation, and oxygen levels increased to a constant level within 2 h. Acid--base status, however, did not stabilise until 24 h after anaesthesia. Haematocrit doubled immediately after cannulation (26+/-1%), but reached a constant level of 13% within 24 h. Blood pressure and heart rate were elevated for the first 5 h, but decreased after 24 h to a constant level of approximately 30 cm H2O and 35 beats min(-1), respectively. There were no changes following anaesthesia in mean cellular haemoglobin concentration, [K+], [Cl-], [Na+], [lactate] or osmolarity. Toads fully recovered from anaesthesia after 24 h.     

Changes in plasma IL-1beta, TNF-alpha and IL-6 after total hip replacement surgery in general or regional anaesthesia

Different anaesthetic methods influence the neuro-immuno-endocrine biologic responses to surgery and may thus possibly interfere with the postoperative course and development of complications. The neuroendocrine system is closely related to the cytokine network. In this study, the effects of general anaesthesia (n=6) and regional spinal/epidural anaesthesia (n=6) on the cytokine response (IL-1beta, TNFalpha, IL-6) to uncemented total hip replacement surgery were evaluated. The postoperative clinical course was uneventful in every case. In both groups, only very low values of plasma IL-beta were measured perioperatively, whereas plasma IL-6 increased postoperatively with peak values 4 h after surgery. The changes in plasma TNF-alpha were not significant. No significant differences in plasma TNF-alpha or IL-6 were found between patients operated in general or in regional anaesthesia. This suggests minor influence of plasma cytokines on the possible beneficial effects of regional anaesthesia on the clinical course after surgery in low risk patients. There were slightly higher TNF-alpha and IL-6 levels after the operation and significantly lower cortisol levels during the operation in the regional anaesthesia group compared to the general anaesthesia group, giving rise to a significant inverse correlation between peak values of IL-6 and peak values of cortisol. This supports the theory that after surgery the inhibitory effect of cortisol on monocyte cytokine production overrides adrenergic stimulation.     

Phasic and Tonic Pain Differentially Impact the Interruptive Function of Pain

The interruptive effect of painful experimental stimulation on cognitive processes is a well-known phenomenon. This study investigated the influence of pain duration on the negative effects of pain on cognition. Thirty-four healthy volunteers performed a rapid serial visual presentation task (RSVP) in which subjects had to detect (visual detection task) and count the occurrence of a target letter (working memory task) in two separate sessions while being stimulated on the left volar forearm with either short (2 sec) or long (18 sec) painful heat stimuli of equal subjective intensity. The results show that subjects performed significantly worse in the long pain session as indexed by decreased detection and counting performance. Interestingly, this effect on performance was also observed during control trials of the long pain session in which participants did not receive any painful stimulation. Moreover, subjects expected long painful stimulation to have a greater impact on their performance and individual expectation correlated with working memory performance. These findings suggest that not only the length of painful stimulation but also its expected ability to impair cognitive functioning might influence the interruptive function of pain. The exact relevance of expectation for the detrimental effects of pain on cognitive processes needs to be explored in more detail in future studies.     

Dynamics of nociceptive sensitivity and blood levels of steroid hormones in Wistar rats

Changes in nociceptive sensitivity and the level of steroid hormones (corticosterone and testosterone) in the plasma of male Wistar rats were studied in repeatedly applied painful stimuli. According to the changes in nociceptive sensitivity the animals were divided into 6 groups. A reliable corticosterone increment and testosterone decrement in the plasma were caused by repeatedly applied painful stimuli. The data observed could be used as individual indices characteristic of animals of this strain.     

EFFECTS OF EXCITATION AND ANAESTHESIA ON THE GLUTAMINE CONTENT OF THE RAT BRAIN WITH A REFERENCE TO THE ADMINISTRATION OF GLUTAMINE

Abstract— A study of the factors affecting the ghtamine content in brain of rats showed that it was significantly decreased by intraperitoneal injection of physiological saline and by the stimulus of decapitation. It fell markedly at the stage of delirium (excitement) of pentobarbitone sodium anaesthesia and returned to the original value in light and deep surgical anaesthesia; after pentylenetetrazol injection the glutamine content showed a tendency to decrease but this change was only significant in relation to its post-saline level when the convulsant and 0.9 % NaCl were given to lightly-anaesthetized animals.
The i.p. administration of glutamine temporarily abolished the decrease in its concentration in the brain caused by injection and decapitation but never raised it above the original level. Many rats previously treated with glutamine showed no signs of excitement during the induction period of pentobarbitone sodium anaesthesia, and those which were excited showed a comparatively smaller decrease of brain glutamine content. whereas in the anaesthetic state there was no change in the content of brain glutamine after glutamine had been administered. Pentylenetetrazol given at the dose level of 200 mg/kg, but not at that of 100 mg/kg, resulted in the uptake of the added glutamine by the brain up to its normal concentration. Hence, the added glutamine did not readily enter normal or anaesthetized brain, but did penetrate the hyperactive brain where its level had fallen.
The brain levels of free glutamic and aspartic acids were not affected, in general, by procedures which increased cerebral activity. Glutamate was decreased by deep anaesthesia, whereas aspartate was not significantly altered in any of the conditions which were tested.
The significance of these results in relation to cerebral ammonia metabolism and possible changes of the permeability of the tissue to glutamine in different functional states is discussed.     

Electroencephalogram-based anaesthetic depth monitoring in laboratory animals

Objective measurements of physiological parameters controlled by the autonomic nervous system such as blood pressure, heart rate and respiration are easily obtained nowadays during anaesthesia by the use of monitors: oscillometers, pulseoximeters, electrocardiograms and capnographs are available for laboratory animals. However, the effect-site of hypnotic drugs that cause general anaesthesia is the central nervous system (the brain). In the present, the adjustment of hypnotic drugs in veterinary anaesthesia is performed according to subjective evaluation of clinical signs which are not direct reflexes of anaesthetic effects on the brain, making depth of anaesthesia (DoA) assessment a complicated task. The difficulties in assessing the real anaesthetic state of a laboratory animal may not only result in welfare-threatening situations, such as awareness and pain sensation during surgery, but also in a lack of standardization of experimental conditions, as it is not easy to keep all animals from an experiment in the same DoA without a measure of anaesthetic effect. A direct measure of this dose-effect relationship, although highly necessary, is still missing in the veterinary market. Meanwhile, research has been intense in this subject and methods based on the brain electrical activity (electroencephalogram) have been explored in laboratory animal species. The objective of this review is to explain the achievements made in this topic and clarify how far we are from an objective measure of DoA for animals.     

An evaluation of three anaesthetic regimes in the gray short-tailed opossum (Monodelphis domestica)

The effect of several anaesthetic agents on the gray short-tailed opossum (Monodelphis domestica) was investigated. Pentobarbitone sodium at a dose of 50 mg/kg sedated the animals but did not produce analgesia or anaesthesia. A combination of ketamine hydrochloride and xylazine at 40 mg/kg and 5 mg/kg, respectively, sedated the animals, but anaesthetic levels were not attained. Halothane was most effective in producing anaesthesia in Monodelphis domestica. Hypothermia was a major side effect with all three anaesthetic regimes.     

Responses of Neurons of the Extrastriate Area 21b of the Cat Brain Cortex to Changes in Orientation of Moving Visual Stimuli

We studied the responses of neurons of the extrastriate cortical area 21b of the cat to changes in orientation of the movements of visual stimuli within the receptive field (RF) of the neuron under study. Our experiments demonstrated that 24 of 108 cells (22%) responded differentially to a certain extent to orientation of the movements of visual stimuli. As a whole, neurons of the area 21b did not demonstrate fine tuning on the optimum angle of orientation. In many cases, neuronal responses to different orientations of the movement of visual stimulus depended significantly on specific parameters of this stimulus (its shape, dimensions, and contrast). Some directionally sensitive neurons responded to a change in orientation of the movement of visual stimuli by modification of the index of directionality. We also studied spatial organization of the RF of neurons with the presentation of stationary visual stimuli. Comparison of the neuronal responses to a change in orientation of the movements of stimuli and to presentation of stationary stimuli showed that the correlation between the orientation sensitivity of the neuron under study and the stationary functional organization of its RF was insignificant. We hypothesize that inhibitory processes and subthreshold influences from a space surrounding the RF play a special role in the formation of the neuronal responses generated in the associative visual cortical regions to visual stimulation.     

Utility of nociceptive flexion reflex threshold and bispectral index to predict movement responses under propofol anaesthesia

Introduction: The nociceptive flexion reflex threshold (NFRT) is a promising tool to monitor analgesia during general anaesthesia. Clinical studies have shown that the NFRT allows to predict movement responses to painful stimuli under a combined anaesthetic regime of sedative and opioid agents. Experimental studies indicated that the NFRT is also able to predict such movement responses under an exclusively sedative regime like propofol mono-anaesthesia. Therefore, we performed this study to investigate the ability of the NFRT to predict movement responses to painful stimuli in patients during a clinical propofol mono-anaesthesia.

Methods: We investigated 140 cardiac surgery patients during their postoperative phase under propofol mono-anaesthesia. NFRT and bispectral index (BIS) were determined in each patient right before endotracheal suctioning or painful electrical test stimulation. Prediction probabilities were calculated to quantify how accurate each measure is able to predict movement responses to the stimuli.

Results: The 124 patients included in the analysis received a median propofol dosage of 3.2 (2.5–3.9) [median (IQR)] mg/kg/h. The included patients showed 287 movement responses after a total of 725 investigated stimuli. The prediction probabilities for positive movement responses were 0.63 (95%CI: 0.59–0.67) for the NFRT and 0.69 (95%CI: 0.65–0.73) for the BIS.

Conclusions: The NFRT allows the prediction of movement responses under propofol mono-anaesthesia, which confirms its utility as a monitor to predict movement responses under general anaesthesia. The BIS allows an even more accurate prediction, although it does not reflect the physiological structures of movement suppression, but correlates closely with the dose of propofol.

Trial registration: German clinical trial register (DRKS00003062, Deutsches Register Klinischer Studien).     

Thoughts of Death Modulate Psychophysical and Cortical Responses to Threatening Stimuli

Existential social psychology studies show that awareness of one''s eventual death profoundly influences human cognition and behaviour by inducing defensive reactions against end-of-life related anxiety. Much less is known about the impact of reminders of mortality on brain activity. Therefore we explored whether reminders of mortality influence subjective ratings of intensity and threat of auditory and painful thermal stimuli and the associated electroencephalographic activity. Moreover, we explored whether personality and demographics modulate psychophysical and neural changes related to mortality salience (MS). Following MS induction, a specific increase in ratings of intensity and threat was found for both nociceptive and auditory stimuli. While MS did not have any specific effect on nociceptive and auditory evoked potentials, larger amplitude of theta oscillatory activity related to thermal nociceptive activity was found after thoughts of death were induced. MS thus exerted a top-down modulation on theta electroencephalographic oscillatory amplitude, specifically for brain activity triggered by painful thermal stimuli. This effect was higher in participants reporting higher threat perception, suggesting that inducing a death-related mind-set may have an influence on body-defence related somatosensory representations.     

Investigation of long term problems after obstetric epidural anaesthesia.

OBJECTIVE--To examine the association between obstetric epidural anaesthesia and subsequent long term problems. DESIGN--Postal questionnaire on health problems after childbirth linked to maternity case note data. SETTING--Maternity hospital in Birmingham. SUBJECTS--11701 women who delivered their most recent child during 1978-85 and who returned completed questionnaires. MAIN OUTCOME MEASURES--Frequencies of long term symptoms after childbirth. RESULTS--Compared with the 6935 women who did not have epidural anaesthesia the 4766 women who did more commonly experienced backache (903 (18.9%) with epidural v 731 (10.5%) without epidural), frequent headaches 220 (4.6%) v 199 (2.9%)), migraine (92 (1.9%) v 73 (1.1%)), neckache (116 (2.4%) v 112 (1.6%)), and tingling in hands or fingers (143 (3.0%) v 150 (2.2%)). The results could not be explained by correlated social or obstetric factors. The associations with head, neck, and hand symptoms were found only in women who reported backache. An excess of visual disturbances among women who had epidural anaesthesia (83 (1.7%) v 91 (1.3%)) was present only in association with migraine, but excess of dizziness or fainting (102 (2.1%) v 109 (1.6%)) was independent of other symptoms. 26 women had numbness or tingling in the lower back, buttocks, and leg, of whom 23 had had epidural anaesthesia. Of 34 women with spinal headache, nine (five after accidental dural puncture; four after spinal block) reported long term headaches. CONCLUSIONS--These associations may indicate a causal sequence, although this cannot be proved from this type of study. Randomised trials of epidural anaesthesia are required to determine whether causal relations exist.     

Suppression of F-VEP during isoflurane-induced EEG suppression

We recorded visual evoked potentials (VEPs) to flash stimuli in moderately deep anaesthesia when EEG showed burst suppression pattern. Flash VEPs could consistently be recorded in all 8 test subjects during bursts but not during suppressions. We conclude that during isoflurane-induced EEG suppression VEPs to flash stimuli are also suppressed. This effect should be taken into account in evoked potential testing during anaesthesia.     

Modification of Plasma Corticosteroid Concentrations during and after Surgery by Epidural Blockade

The adrenocortical response to major surgery was assessed by the measurement of plasma corticosteroid concentrations in patients receiving either a general anaesthetic alone or in combination with an epidural block. The expected increase in plasma corticosteroid concentration seen in the general anaesthesia group was significantly inhibited by epidural block. The inhibition was related to the duration of the epidural block. The lack of the normal adrenocortical response to surgery was not associated with cardiovascular collapse and indeed did not seem detrimental in any way. These findings question the need for corticosteroid “cover” for the stress of surgery in patients who have been taking corticosteroid drugs.     

Studies on the hormonal regulation of fuel metabolism in the human newborn infant undergoing anaesthesia and surgery

Little is known of the endocrine and metabolic milieu in preterm and term neonates exposed to surgical stress. In order to define the effects of anaesthesia and surgery on the hormonal regulation of intermediary metabolism, the levels of plasma insulin, glucagon, adrenaline and noradrenaline were measured in addition to blood glucose, lactate, pyruvate, alanine, acetoacetate, hydroxybutyrate, glycerol and plasma-free fatty acids in 38 neonates (23 term, 15 preterm) undergoing surgery. Blood samples were drawn pre-operatively, at the end of surgery, and at 6, 12 and 24 h post-operatively. Plasma levels of adrenaline and noradrenaline increased significantly in response to surgery. In term neonates, plasma insulin concentrations were unaltered at the end of surgery, but were significantly increased throughout the post-operative period; plasma glucagon levels were unchanged at the end of surgery but had significantly decreased by 24 h after surgery. Insulin levels in preterm neonates remained unchanged during surgery as well as in the post-operative period. All neonates developed a significant peri-operative hyperglycaemia which persisted up to 12 h after surgery. Blood lactate and pyruvate increased during surgery, accompanied by significant increases in plasma free fatty acids, total ketone bodies and glycerol concentrations by the end of surgery. Blood glucose concentrations were significantly correlated with plasma adrenaline levels at the end of surgery and with plasma glucagon at 6 h post-operatively. The insulin/glucose ratio was significantly decreased at the end of surgery in term and preterm neonates. Further analysis showed that total parenteral nutrition given just before surgery and thiopentone anaesthesia given during surgery significantly augmented the peri-operative hyperglycaemic response of term neonates. Thus, stress-related hormonal changes in preterm and term neonates may precipitate a catabolic state characterized by glycogenolysis, gluconeogenesis, lipolysis and mobilization of gluconeogenic substrates in the post-operative period. Prevention of these metabolic derangements by anaesthetic or hormonal manipulation may possibly help to improve the clinical outcome of neonates undergoing surgery.