Auditory evoked response and awareness: a study in volunteers at sub-MAC concentrations of isoflurane.

We have investigated the relationship between the auditory evoked response (AER) and simple tests of conscious awareness at four end-expiratory concentrations (0.0, 0.1, 0.2 and 0.4 MAC) of isoflurane in oxygen in each of eight anaesthetist volunteers, in random order, at least 1 week apart. The early cortical AER was recorded from electrodes at the vertex and inion. Amplitudes of the waves Pa, Nb and Pc and latencies of the waves Na, Pa, Nb, Pb and Nc were measured. All the AER variables were highly significantly related to end-expiratory anaesthetic concentration. Amplitudes decreased and latencies increased progressively with increasing anaesthetic concentration. The AER variables were also highly significantly related to the level of response. Amplitudes were greatest and the latencies shortest when there was full response to command. (Nb latency increased from 47.5 to 54.5 ms between partial and no response.) The close correlation between the effects of concentration and level of response, and between concentration and the AER implied that it was difficult to demonstrate those changes in the AER which specifically relate to changes in response. At 0.2 MAC, however, which was the concentration at which all subjects showed some deficit, the response to a shock word was distinguished clearly by Nb latency. In eight of 24 possible comparisons (eight AER variables and three types of psychological test) the AER fitted the response more closely than concentration.

Somatosensory and auditory evoked responses recorded simultaneously: differential effects of nitrous oxide and isoflurane.

Auditory (AER) and somatosensory evoked responses (SSER) were recorded simultaneously in eight patients under anaesthesia before surgery. We studied the effects of equi-MAC end-expiratory concentrations of isoflurane (0.65-0.75%) and nitrous oxide (60-65%). The anaesthetics were changed at random in three consecutive 10-min periods so that each patient received both drugs. From the AER recorded from the vertex and inion, Pa and Nb latency and amplitude were measured. N13, P20 latency and N13 amplitude were measured from SSER recordings from the neck and P15, N20, P25, N35, P45 latency and P15-N20, N20-P25, P25-N35 and N35-P45 amplitude from the scalp over the hand area of the sensory cortex. Compared with nitrous oxide, isoflurane significantly increased the latencies of the AER waves Pa (P = 0.02) and Nb (P = 0.02), and the SSER waves N20 (P = 0.001) and P25 (P = 0.04). We were unable to demonstrate significant differences in Pa and Nb amplitude between isoflurane and nitrous oxide that we had seen previously. However, the amplitude of the SSER wave N20 was reduced significantly by nitrous oxide compared with isoflurane (P = 0.0004). This wave (N20) is thought to emanate from the thalamo-cortical radiations, and our findings may be explained by an analgesic effect of nitrous oxide mediated by endogenous opioids.

The effects of the competitive NMDA receptor antagonist CPP on the high pressure neurological syndrome in a primate model.

Neurophysiological interactions between the competitive N-methyl-D-aspartate (NMDA) preferring receptor antagonist, CPP (3-((+-)-2-carboxypiperazine-4-yl)-propyl-1-phosphonate) and the high pressure neurological syndrome (HPNS) have been investigated in the non-human primate Papio anubis. Eight animals were exposed on two occasions to environmental pressures of 81 atmospheres absolute (ATA) in a hyperbaric chamber, using helium and oxygen. One exposure followed pretreatment with CPP (either 5 or 10 mg/kg i.v. plus 5 mg/kg/hr infusion), the other a saline control. Pretreatment with CPP delayed moderate signs of face tremor and myoclonus and abolished severe signs of whole body tremor and seizure activity. By 81 ATA, scores representing severity of HPNS were significantly reduced by CPP to a mean score, reflecting a level of just mild to moderate limb tremoring (P less than 0.001). Changes in the EEG were observed in channels associated with the frontal, parietal and occipital regions of the left cortex. Amplitude and frequency spectra were calculated and changes with pressure in the 4 conventional wavebands were analysed. The most striking change was the complete prevention by CPP of the 100% increase in the amplitude of alpha waves at 81 ATA in the frontal region (P less than 0.001). It is concluded that NMDA transmission has a major role in the expression of HPNS.

Evaluation of the Lamtec anaesthetic agent monitor.

The Lamtec agent monitor is a compact anaesthetic analyser designed to measure halothane, isoflurane and enflurane. It shows good linearity and stability. The faster model can be used for end-tidal measurements up to 25 breaths per minute. Calibration using a standard of the gas to be measured is recommended.

A chamber system for maintaining a hyperbaric environment for long-term animal studies.

An experimental hyperbaric chamber system is described whereby animals, including nonhuman primates, can be cared for under altered environmental conditions for periods in excess of 1 wk. The chamber itself is capable of a working pressure of 200 atm abs, used with various mixtures of gases which can be varied independently. The novel approach of vertical mounting enables cages to be lowered into position, and food and water can be supplied from above while excreta can be removed from below, irrespective of the internal pressure. The chamber has an integrated life support system such that temperature, both of the chamber and of the mass of gas inside, humidity, oxygen, carbon dioxide, and noise levels can be accurately and finely controlled, all within a pathogen-free environment.

Levels of consciousness in volunteers breathing sub-MAC concentrations of isoflurane.

Eight volunteers inhaled isoflurane in concentrations of 0.1, 0.2 and 0.4 MAC, and 100% oxygen as control in separate sessions more than 1 week apart. When the end-expiratory isoflurane concentration was stable, response to verbal commands was tested, and the subjects were read 30 words in two lists. Response to the commands was impaired at 0.1 MAC in three subjects and lost at 0.2 MAC in two subjects. No subject responded at 0.4 MAC. When the subjects were questioned 1 h after exposure, memory of response to commands was lost also at these concentrations. Frequently, those who responded to the command "open your eyes" failed to remember having done so; non-responders remembered nothing. At the time of that test, at 0.4 MAC, five of eight subjects had no eyelash reflex. Both recall and recognition of neutral words was lost at 0.2 MAC and greater, but the effect of attention was demonstrated by the memory of a "shock" word by four of eight subjects at 0.2 MAC.

The effects of MK801 on the high pressure neurological syndrome in the baboon (Papio anubis).

The in vivo neurophysiological interactions of the non-competitive NMDA receptor antagonist MK801 with the High Pressure Neurological Syndrome have been investigated in the primate Papio anubis. A hyperbaric chamber was used to achieve environmental pressures of 61 ATA (atmospheres absolute) over a period of 5 hr. Eight animals underwent 2 compressions each, one following pretreatment with 0.03 mg/kg (i.v.) MK801, the other a control. Half of the animals received MK801 on their first exposure. Mild signs of the high pressure neurological syndrome, e.g. paw and limb tremor were first observed between 10 and 20 ATA and more severe signs, e.g. whole body tremor, myoclonus and vomiting, appeared after 50 ATA. The onset pressures for the various signs were increased by 10-17 ATA when the animals received MK801 (P = 0.06) and the severity of the signs, over the whole range of pressures at which they appeared, was significantly reduced (P less than 0.001). Additional experiments showed that MK801 afforded considerable protection, at pressures up to 81 ATA, but doses larger than those used for the main experiment produced signs of tranquilisation and sedation. Changes in the EEG were observed in channels associated with the frontal, parietal and occipital regions. Amplitude and frequency spectra were calculated and trends with pressure in the 4 conventional wavebands were analysed. The most striking change was a decrease in amplitude of delta waves (P less than 0.001), which was ameliorated by MK801 (P less than 0.001).

A method of remote physiological monitoring of a fully mobile primate in a single animal cage.

A system was designed to allow the physiological monitoring of a fully mobile, unstressed baboon (Papio anubis) in a single animal cage for the purpose of measuring the changes occurring in a hyperbaric environment. It was required to operate for at least three months, both inside a pressure chamber and outside, and to measure the following parameters: electroencephalogram (EEG, three channels), electrooculogram (EOG), electromyelogram (EMG, two channels), electrocardiogram (ECG), arterial blood pressure, respiration and body temperature. Also in the system were catheters through which blood samples could be taken and intravenous drugs given. The overall system consisted of a harness and jacket, an umbilical and back pack, a combined electrical and fluid transmission swivel and a monitoring implant and catheters.

Sodium valproate interactions with the HPNS: EEG and behavioral observations.

A new baboon model was used to investigate the therapuetic effect of sodium valproate on the high pressure neurologic syndrome (HPNS). A hyperbaric chamber was used to achieve environmental pressures of 61 ATA, over a 5-h period. Eight animals underwent two compressions, a control and a valproate-treated compression (half the animals had valproate on the first compression). Mild signs of HPNS (e.g., paw and limb tremor) were first observed at approximately 20 ATA. More severe signs (e.g., whole body tremor, myoclonus, and vomiting) were observed above 40 ATA. Sodium valproate was administered during the compression phase and for 2 wk previously. It was effective at the higher pressures above 41 ATA in reducing the severity of the signs of HPNS. The major effect of pressure on the EEG was to increase alpha and theta wave amplitude in a linear manner. Alpha wave amplitude was reduced by sodium valproate.

Cochlear degeneration in minipigs after repeated hyperbaric exposures.

Auditory function and cochlear pathology were investigated in 4 minipigs subjected to compression to 4 ATA, held for 1 h, and decompressed using a standard schedule (Blackpool Tables) on 21 occasions. Three minipigs were used as controls. Brainstem auditory evoked response testing was carried out after the last hyperbaric exposure and showed no response bilaterally in 3 and unilaterally in 1 of the test animals. Light microscopy demonstrated a loss of hair cells throughout the cochlea in all the compressed animals; in one the tectorial membrane was detached and adherent to Reissner's membrane. Vestibular changes were confined to the saccule. Hemorrhage was not a prominent feature. On scanning electron microscopy the pathologic changes included missing hair cells and fused and giant stereocilia. Possible causes of the pathology include barotrauma or direct effects of repeated compression and decompression on the inner ear, or both. The compression-decompression profile used was one that is thought to be safe for compressed air workers who are repeatedly exposed to hyperbaric conditions.

Regional amino acid concentration in the brains of rats exposed to high pressures.

Regional amino acid concentrations were measured in rat brain fixed by microwave irradiation at three levels of elevated atmospheric pressure corresponding to different phases of the high-pressure neurological syndrome [20 atmospheres absolute (ATA), no clinical signs; 60 ATA, tremor; 85 ATA, severe tremor and myoclonic jerks]. No changes in amino acid content occurred at 20 or 60 ATA. At 85 ATA glutamine content increased in hippocampus, striatum, cerebellum, and substantia nigra, and gamma-aminobutyric acid content increased in hippocampus. It is suggested that enhanced glutamate release in various subcortical structures contributes to the myoclonic activity observed at 85 ATA.

Evaluation of the Datex 'Normac' anaesthetic agent monitor.

The Datex 'Normac' infrared anaesthetic agent monitor has been evaluated for accuracy of calibration, stability and speed of response. Accuracy was assessed by comparing with a gas chromatograph calibrated using volumetric standards and was found to be very good for isoflurane and enflurane but was slightly less accurate for halothane, due to a low signal: noise ratio. The stability of the instrument was found to be exceptionally good. The response time is dependent on the sampling rate and we found that, in practice, the instrument would record the end expired anaesthetic concentration on patients breathing up to 15 breaths/minute. The instrument is compact and convenient for use in operating theatres.

Fluid and electrolyte homeostasis during prolonged exercise at altitude.

The combined effect of exercise and altitude on fluid and electrolyte homeostasis was studied over 13 days on six male subjects eating a diet with constant sodium and potassium content. During the first 4 and last 4 days subjects were semisedentary at an altitude of 900 m. In the middle 5 days subjects exercised by hill walking for about 7 h daily at altitudes between 2,678 and 3,629 m. There was a retention of sodium (mean of 202 mM by the end of the exercise-altitude period) and a small retention of water (mean of 0.49 liters). Plasma volume increased by 0.76 liters and packed cell volume fell from a mean of 44.5 to 41.8%. There was no change in plasma sodium concentration. The retention of sodium implies an expansion in the extracellular space of 1.44 liters at the expense of the intracellular space, which decreased by a calculated 1.05 liters. These changes are similar to those resulting from comparable exercise at sea level and opposite to the effect of altitude on resting subjects.

Chronic exposure of rats to enflurane 200 p.p.m.: no evidence of toxicity or teratogenicity.

Adult male or female rats were exposed either to enflurane 200 p.p.m. or to air for up to 63 days before mating and subsequently throughout the pregnancy of the females. The treated animals were exposed for 8 h per day, 5 days per week for a maximum total of 100 days. The parents and progeny-were studied. Additional positive controls with vitamin A palmitate demonstrated that the strain of animals was susceptible to a known teratogen. No abortifacient effect was observed with these conditions of exposure to enflurane. Skeletal examination of the fetuses failed to reveal any major teratogenic effect. The parents remained healthy clinically, whilst autopsy and histopathological examination failed to reveal any consistent organ injuries which could be blamed on exposure to enflurane. In rats at least, environmental pollution with enflurane appears not to be associated with significant toxicity or teratogenicity.

Maternal and paternal chronic exposure to enflurane and halothane: fetal and histological changes in the rat.

Adult male and female rats were exposed chronically to halothane 10 p.p.m., enflurane 20 p.p.m. or air for up to 64 days before mating and subsequently throughout the pregnancy of the females. The parents, progeny and, in a few cases, the subsequent generation, were studied. No abortifacient effect was seen with either agent. The groups exposed to anaesthetic had larger litters with lighter fetuses compared with their control groups. Skeletal examination did not reveal any major teratological effects for either agent. No consistent organ injury could be associated with chronic exposure to the agents under the conditions of this study.