Auditory- and somatosensory-evoked potentials in cerebral malaria and anaesthesia: a comparison.

BACKGROUND AND OBJECTIVE: Parallels exist between the coma associated with cerebral malaria and general anaesthesia. They both produce reversible loss of consciousness. In the case of cerebral malaria and in the absence of other complications, patients recover without sequelae. General anaesthetics are so designed that patients recover from their anaesthetics very quickly and show no 'after effects'. This study compares brain function in these two clinical conditions by examining auditory- (AEPs) and median nerve somatosensory-evoked potentials (SEPs). The AEPs studied (waves Pa and Nb) are thought to arise from the primary auditory cortex and the median nerve SEPs (waves P15, N20, P25, N35, P45) from the pons, thalamus and primary somatosensory cortices. METHODS: Six comatosed patients with malaria (three males, three females) aged between 19 and 38 yr were studied in Zimbabwe. Their Glasgow Coma Scores on admission were 4, 3, 6, 7, 7 and 11. Their AEPs and median nerve SEPs were recorded daily over 4 days. The data were compared with those previously collected in the UK on patients and volunteers anaesthetized with desflurane, isoflurane, sevoflurane and propofol. RESULTS: In general, patients with cerebral malaria showed AEPs and SEPs similar to those of light to moderate anaesthesia i.e. 0.5-1.25 measure of anaesthetic potency (MAC), where 1 MAC is the minimum alveolar concentration necessary to prevent movement to surgical incision in 50% of patients. The appearance of the AEPs and SEPs bore no relationship to the degree of coma. The auditory brainstem-evoked response was retained in all degrees of coma, as would be expected. Otherwise, it would not be possible to interpret the waveform. In most instances, the early cortical complex Pa/Nb/Pb of the AER was present. When comatose patients emerged from malarial coma or were stimulated by talking loudly to them, they showed changes in the Pa/Nb/Pb complex similar to those seen on awakening from anaesthesia. The somatosensory-evoked response showed clear P15, N20 and P25 peaks at the expected latencies, and in some instances the waveforms of cerebral malaria and lightly anaesthetized volunteers were very similar. CONCLUSIONS: The sensory-evoked responses of the cerebral malaria patients recorded in this study were not markedly different from those seen in light-to-moderately anaesthetized patients and volunteers. The profound depression of the AEPs and SEPs associated with deeper levels of anaesthesia were not seen, with the exception of one patient several hours before death.

Auditory evoked response during propofol anaesthesia after pre-induction with midazolam.

BACKGROUND: In clinical use, midazolam reduces the dose requirement for propofol. We studied the effect of midazolam given before anaesthesia on the amount of propofol needed and the time taken, to achieve loss of consciousness (LOC) in 20 patients. METHODS: We compared the auditory evoked responses (AER) in these patients with those in a group of 20 patients who were not given midazolam. RESULTS: LOC, as defined by a loss of response to verbal command and eyelash reflex, occurred after 113 (95% CI, 99-131) s in the control group and 75 (56-101) s in the midazolam group (P < 0.05). In the control group 2.3 (2.0-2.6) mg kg-1 propofol caused LOC compared with 1.3 (1.1-1.5) mg kg-1 in the group pretreated with midazolam (P < 0.001). Pa amplitude decreased by 60% in the control group and by 54% in the midazolam group while Nb latency increased by 24% in the control group and by 32% in the midazolam group following LOC. These differences were not significant. CONCLUSIONS: We confirmed that coinduction of anaesthesia with midazolam and propofol reduces the requirement of propofol. We also demonstrated that the AER reflects anaesthetic depth rather than plasma concentrations of anaesthetic drugs.

Effects of dexmedetomidine on isoflurane requirements in healthy volunteers. 2: Auditory and somatosensory evoked responses.

The anaesthetic-sparing activity of dexmedetomidine during isoflurane anaesthesia was examined, using the end-point of lack of response to tetanic nerve stimulation. Nine subjects were given two doses of dexmedetomidine (target plasma concentrations of 0.3 ng ml-1 and 0.6 ng ml-1, respectively) and saline on separate occasions. We measured auditory (AER) and somatosensory (SER) evoked responses at end-tidal isoflurane concentrations of 0.2-1.4%. Pa and P25-N35 amplitudes increased as isoflurane concentration was reduced (P < 0.001). Dexmedetomidine had no significant effect on this relationship. In contrast, P15-N20 (SER) amplitude increased (P < 0.001) as isoflurane concentration was reduced. The dose of dexmedetomidine had a significant interaction with this trend (P < 0.002). Decreasing the concentration of isoflurane at the high dose of dexmedetomidine had less impact on P15-N20 amplitude than decreasing isoflurane at the low dose or with saline. The mechanism by which dexmedetomidine spares isoflurane is discussed in the light of these evoked response changes.

Effect of remifentanil on the auditory evoked response and haemodynamic changes after intubation and surgical incision.

We have observed the effect of intubation and incision, as measured by the auditory evoked response (AER) and haemodynamic variables, in 12 patients undergoing hernia repair or varicose vein surgery who received remifentanil as part of either an inhaled anaesthetic technique using isoflurane or as part of a total i.v. technique using propofol. Anaesthesia was induced with remifentanil 1 microgram kg-1 and propofol, neuromuscular block was achieved with atracurium 0.6 mg kg-1 before intubation, and anaesthesia was maintained with a continuous infusion of remifentanil in combination with either a continuous infusion of propofol or inhaled isoflurane. The AER and haemodynamic variables were measured before and after intubation and incision. The effects of intubation and incision on the AER and haemodynamic variables were not significantly different between the remifentanil-propofol and remifentanil-isoflurane groups. However, the study had a low power for this comparison. When the data for the two anaesthetic combinations were pooled, the only significant effects were increases in diastolic arterial pressure and heart rate immediately after intubation; these were not seen 5 min after intubation. There were no cardiovascular responses to incision. There were no significant changes in the AER after intubation or incision.

Auditory evoked response, median frequency and 95% spectral edge during anaesthesia with desflurane and nitrous oxide.

We have studied in 12 patients the effect of desflurane in nitrous oxide on the electroencephalogram (EEG) and the early cortical auditory evoked response (AER). After induction with desflurane, patients' lungs were ventilated to maintain three different end-expiratory concentrations of desflurane (1.5, 3 and 6%) during four consecutive 10-min periods before surgery. As the end-expiratory concentration of desflurane was increased, Pa and Nb (AER) amplitudes decreased and their latencies increased, and spontaneous EEG showed an increase in amplitude and a slowing of frequency. A linear relationship was demonstrated between log10 concentration of desflurane and all variables (P = 0.001). Pa amplitude showed the greatest linearity followed by the derived variable F95 of the EEG. From regression slopes, mean percentage changes of each variable were calculated for a 1 MAC change in desflurane concentration, Pa amplitude showed the largest change (mean 49% (95% confidence interval 40-56%) decrease for a 1 MAC increase). This was greater than that of F95 for a similar confidence interval, indicating better resolution. This study confirms that the early cortical AER is affected by desflurane in a similar manner to that of other anaesthetic agents and as such remains the most promising EEG derived measure of depth of anaesthesia.

Spontaneous movement after injection of propofol.

Spontaneous movement following injection of propofol at induction was studied in 303 patients. Two hundred patients were Caucasians and 103 were Asians. In a pilot study carried out prior to the main study, 26% of the Asians moved at induction as compared with 6% of the Caucasians. The patients were studied in relation to a number of variables; age, sex, weight, height, race, smoker/non smoker, vegetarian/non vegetarian, alcohol consumption, premedication, use of fentanyl at induction and dose of propofol. When race was included as the sole variable there was a marginal but not significant difference between the two groups in terms of movement (p = 0.06). However, when the other recorded variables were taken into account, race was not included as a predictor of whether or not the patient moved. The best model for predicting whether the patients moved or not combines the variables weight and dose of propofol. Patients were more likely to move if they were lighter and the dose of propofol used at induction was higher.

Remifentanil reduces auditory and somatosensory evoked responses during isoflurane anaesthesia in a dose-dependent manner.

We studied 60 patients during stable isoflurane anaesthesia (0.4 MAC) after premedication with temazepam. Patients were allocated randomly to one of three dose regimens of remifentanil: 1 microgram kg-1 i.v. over 1 min and an infusion of 0.2 microgram kg-1 min-1 (low dose); 2.5 micrograms kg-1 and 0.5 microgram kg-1 min-1 (medium dose); and 5 micrograms kg-1 and 1 microgram kg-1 min-1 (high dose). The auditory (AER) and median nerve somatosensory (SER) responses were elicited throughout, and recorded before and after tracheal intubation, and surgical incision, together with systolic and diastolic arterial pressure and heart rate. Venous blood concentrations of remifentanil were measured at the above times. After administration of remifentanil, Pa and Nb amplitudes of the AER increased at the low dose, remained constant at the medium dose and decreased at the high dose. This dose-related effect was linear and significant (P = 0.012, P = 0.05). Pa amplitude correlated inversely with remifentanil blood concentrations before and after intubation and incision (P = 0.002, P < 0.001, P < 0.001 and P < 0.001). In the SER, P15-N20 amplitudes decreased after administration of remifentanil (P < 0.001), whereas P25-N35 and N35-P45 amplitudes increased at all dose concentrations (P < 0.001 and P < 0.001). After intubation, P15-N20 and N35-P45 amplitudes increased at the low dose, did not change at the medium dose and decreased at the high dose (P = 0.001, P = 0.027). After remifentanil, systolic and diastolic arterial pressure and heart rate decreased in a linearly dose-related manner (P = 0.033, P < 0.001, P < 0.001). At all doses the three variables increased after intubation (P = 0.001, P < 0.001, P < 0.01), and systolic and diastolic arterial pressure increased after incision (P = 0.027, P = 0.039).

Effect of neuromuscular block on depth of anaesthesia as measured by the auditory evoked response.

In a double-blind, randomized, controlled, prospective study, we have investigated the effects of vecuronium and laryngoscopy on the auditory evoked response (AER) of the electroencephalogram (EEG) in 40 ASA I and II patients under steady state anaesthesia. After stable anaesthesia had been achieved with 1.0 MAC of isoflurane and nitrous oxide in oxygen, patients were allocated randomly to receive two separate doses of vecuronium 0.05 mg kg-1 or saline. The AER was recorded before and after each dose and then after 20-s laryngoscopy in each group to determine any changes in the early cortical components of the AER waveform (Pa and Nb). There were no statistically significant changes between the vecuronium and saline groups. However, there was a statistically significant increase in mean Pa amplitude of 36% (P = 0.008) and a reduction in mean Nb latency of 6% (P = 0.05) after laryngoscopy in both the paralysed and unparalysed groups, and these changes did not differ significantly between groups. There were correspondingly significant haemodynamic responses to laryngoscopy in both groups. We conclude that neuromuscular block with vecuronium does not affect depth of anaesthesia as measured by the AER in either stimulated or unstimulated patients. In addition, we have demonstrated clearly the arousal effect of laryngoscopy on the AER.

Effect of suxamethonium on the auditory evoked response in humans.

We have studied the arousal effect of suxamethonium on the auditory evoked response (AER) of the electroencephalogram (EEG) in 40 ASA I and II patients during isoflurane anaesthesia. After induction of anaesthesia, the patient's lungs were ventilated for 20 min with 0.6 MAC end-expiratory isoflurane (0.59-0.77% depending on the age of the patient), and 50% nitrous oxide in oxygen. The patients were then allocated randomly to one of two groups: 21 received suxamethonium 1 mg kg-1, while 19 were given saline. The AER before and after administration of suxamethonium or saline was compared to determine the changes in Pa and Nb amplitudes and latencies. Pa amplitude after suxamethonium increased by 53% (95% confidence interval (CI) 15, 104%) compared with a reduction in Pa amplitude in the saline group of 19% (95% CI, -41, 12%) (P = 0.004) suggesting an arousal effect. Similarly, Nb amplitude increased in the suxamethonium group by 47% (95% CI, 3, 110%) and decreased in the saline group by 11% (95% CI, -33, 19%) (P = 0.03). We conclude that suxamethonium caused arousal according to the AER and postulate that this may have been caused by increased muscle afferent activity after stimulation of muscle spindles, although further studies are required to confirm this.

Monitoring evoked potentials during surgery to assess the level of anaesthesia.

The hypnotic and analgesic components of anaesthesia can be assessed using middle latency auditory evoked potentials (MLAEPs) and somatosensory evoked potentials (SEPs). To monitor these potentials reliably during clinical anaesthesia, we have developed an evoked potential (EP) system based around a portable personal computer, a DSP board and an isolated pre-amplifier unit. Unlike many currently available systems, this amplifier is largely immune to diathermy interference due to excellent isolation via a digital fibre optical link, small size and RF screening and filtering. The pre-amplifier unit has integral auditory and somatosensory stimulators, and automatic calibration and impedance checking. Stimulus intensity and profile are under software control and SEP stimulus level is constantly monitored. The unit is powered by two AA cells and battery status continuously monitored by the PC software. Up to eight channels of EEG may be recorded and displayed in a smoothly scrolling window and as moving average MLAEPs and SEPs.

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.

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 auditory evoked response as an indicator of awareness.

The latency of the early cortical wave Nb of the auditory evoked response (AER) was compared with responses to Tunstall's isolated forearm test, while the concentration of nitrous oxide was progressively reduced during light anaesthesia in seven patients. A threshold Nb latency of 44.5 ms was chosen to discriminate between an early cortical AER containing three waves and that with two waves of longer latency. When Nb latency decreased below this threshold, four of the patients has positive responses, indicating awareness. The addition of a volatile anaesthetic abolished any response, and increased Nb latency to more than 44.5 ms. The three wave AER pattern, therefore, is associated with a depth of anaesthesia at which awareness occurs.

Early cortical auditory evoked response in anaesthesia: comparison of the effects of nitrous oxide and isoflurane.

Previous studies showing graded changes in the early cortical waves Pa and Nb of the auditory evoked response (AER) with increasing concentration of volatile anaesthetic agents demonstrated high amplitudes of these waves in the period immediately following induction of anaesthesia and tracheal intubation, when the patient breathed nitrous oxide alone. These high amplitude waves were not consistent with extrapolation of the data or observations of patients under steady-state nitrous oxide anaesthesia. In order to discriminate between effects in the period immediately following induction of anaesthesia and tracheal intubation, and effects caused by nitrous oxide alone, a randomized cross-over study was performed. Eight patients breathed either nitrous oxide or isoflurane at 0.6 MAC for three consecutive 10-min periods following intubation and before surgery. The amplitudes of Pa and Nb were significantly less for isoflurane with respect to the same MAC fraction of nitrous oxide in all periods, but for both agents the amplitudes were significantly greater in the 10 min following intubation than in subsequent periods, presumably as a result of stimulation.

Increased readability improves the comprehension of written information for patients with skin disease.

Many standardized methods are available with which to evaluate the reading ease and comprehensibility of written material. Techniques depend on mechanical analysis of sentence length, multiple prepositional phrases, direct phraseology, and arrangement of printed materials on the page. Those techniques were used to analyze a pamphlet designed for patient education by the American Academy of Dermatology. The pamphlet scored a reading ease grade of 45, corresponding to what is considered difficult reading and at a level commonly found in academic journals. We rewrote the pamphlet and increased its reading ease score to 62.4, corresponding to material that appears in standard digest-type magazines. We gave both versions of the pamphlet to a group of first-year medical students and to a group of middle-class patients from a dermatology practice. In both groups the modified version led to greater understanding of the written material. We conclude that the usefulness of patient education materials now being distributed by dermatologists could be significantly improved by being rewritten according to well-recognized formulas.

A corticosterone metabolite produced by A6 (toad kidney) cells in culture: identification and effects on Na+ transport.

A6 cells form typical tight epithelia when grown in culture on permeable supports and exhibit active Na+ transport [short circuit current (Isc)], which is stimulated by aldosterone and corticosterone. Previous studies demonstrated nuclear binding of polar corticosterone metabolites produced by the cells. This study was performed to determine whether sufficient quantities of the metabolite(s) are released into the medium of A6 cells for identification and to test for agonist activity on active Na+ transport. Cells were incubated in [3H]corticosterone (10(-8)-10(-4) M) for 24 h. Approximately 25-35% of the radiolabel, recovered in ethyl acetate extracts of medium, chromatographed on reverse phase HPLC as a single peak more polar than corticosterone. This derivative cochromatographed with 6 beta-hydroxycorticosterone (6 beta-OH-corticosterone) on HPLC and normal phase high performance TLC. Mass spectroscopy of 6 beta-OH-corticosterone and the unknown yielded 10 identical molecular ions, including the molecular ion with a mass to charge ratio of 362 corresponding to the mol wt of 6 beta-OH-corticosterone stimulated Isc in A6 epithelia with a time course typical of a steroid and an EC50 of 10(-6) M. The Isc induced by 6 beta-OH-corticosterone was equivalent to net Na+ flux, indicating active Na+ transport stimulation. At maximum effective concentrations of corticosteroids, 6 beta-OH-corticosterone plus aldosterone induced a greater Isc stimulation than aldosterone alone, suggesting that at least a portion of the effect of 6 beta-OH-corticosterone is mediated by a steroidal pathway other than that used by aldosterone. Also, corticosterone produced twice the Isc increase produced by aldosterone. Thus, 6 beta-OH-corticosterone may contribute to the enhanced corticosterone effect on Isc compared to aldosterone alone.