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Biphasic EEG changes in relation to loss of consciousness during induction with thiopental, propofol, etomidate, midazolam or sevoflurane.

The time course of four EEG effect variables, amplitude in the 2-5 Hz and in the 11-15 Hz band, spectral edge frequency 95% (SEF95), and bispectral index (BIS), in response to increasing concentrations of thiopental, propofol, etomidate, midazolam, or sevoflurane during a 10 min induction of anaesthesia was studied in 25 patients to determine the existence of a biphasic effect and to study the relationship of the EEG effect to the moment of loss of consciousness. A biphasic effect, that is, an initial increase of the effect variable followed by a decrease at higher concentrations, during the transition from consciousness to unconsciousness was found in EEG amplitude (both frequency bands) and in SEF95 for all anaesthetics except midazolam. There was a concentration-related decrease in BIS for all anaesthetics. There was no consistent relationship between the time of occurrence of the peak EEG effect, or the value of the EEG variable and the moment of loss of consciousness. With rapidly changing drug concentrations during the induction of anaesthesia, none of these EEG effect variables could be correlated to the moment of loss of consciousness.

Adolescent↗

Ketamine and thiopental sodium: individual and combined neuroprotective effects on cortical cultures exposed to NMDA or nitric oxide.

BACKGROUND: An N-methyl-D-aspartate (NMDA) blocker, ketamine, has been shown to be neuroprotective both in vivo and in vitro. However, ketamine is not commonly recommended for use in patients suffering from cerebral ischaemia because of its adverse neurological effects. We hypothesized that combined administration of ketamine and thiopental sodium (TPS) would be highly effective in protecting cerebral cortical neurones from ischaemia, with possibly reduced dosages. METHODS: We examined the degree of neuroprotection provided by various concentrations of ketamine and TPS, alone and in combination, in cortical cultures exposed to NMDA or a nitric oxide-releasing compound (NOC-5) for 24 h. The survival rate (SR) of E16 Wistar rat cortical neurones was evaluated using photomicrographs before and after exposure to these compounds. RESULTS: The SRs of cortical neurones exposed to 30 microM NMDA or NOC-5 were 15.0 (3.8)%, 12.8 (3.1)%, respectively. Higher doses (5, 10 and 50 microM) but not lower doses (<1 microM) of ketamine improved SRs [57.9 (2.2)%, 61.1 (5.4)%, 76.7 (3.0)%, respectively] against NMDA but not NOC. Enhanced survival was observed with combined administration of 5 or 10 microM ketamine and 50 microM TPS [SR 71.3 (4.8)%, 74.7 (3.7)%, respectively, P<0.05 if ketamine alone, P<0.01 if TPS alone], against NMDA-induced neurotoxicity in vitro. Only the highest dose of TPS (50 microM) improved survival after NOC exposure. This neuroprotection was not influenced by ketamine. CONCLUSIONS: These data indicate that a low, clinically relevant dose of ketamine offer significant neuroprotection during prolonged exposure to NMDA but not to NOC. Combinations of reduced doses of ketamine and TPS exhibited enhanced neuroprotection against NMDA-induced neurotoxicity. Hence, combinations of these two common i.v. anaesthetics agents could be developed to protect the brain from ischaemia.

Anesthetics, Dissociative↗

The effect of high dose sodium thiopental on brain stem auditory and median nerve somatosensory evoked responses in humans.

Median nerve somatosensory evoked potentials (MnSSEPs), brain stem auditory evoked responses (BAERs), and the cortical electro-encephalogram (EEG) were recorded in six patients during a 62-min infusion of sodium thiopental (STP) at a rate of 1.25 mg X kg-1 X min-1 (total dose, 77.5 mg/kg). The EEG became isoelectric after 22 +/- 8 (SD) min of STP infusion. Dose-related changes in the latencies and amplitudes of various evoked response wave forms were observed. However, in no instance was any component of either the MnSSEP or the BAER rendered unobtainable by STP administration. For the MnSSEP, progressive increases in the central conduction time (5.33 +/- 0.41 ms preinduction vs. 7.46 +/- 1.2 ms at t = 60 min) and in the latency of the cortical primary specific complex were observed simultaneously with significant reductions in the amplitude of the latter (2.10 +/- 0.85 muV preinduction vs. 0.85 +/- 0.55 muV at t = 60 min). Changes in the latency and amplitude of the response recorded over the upper cervical spine (C2) were not statistically significant in this small population. For the BAER, progressive and significant increases in the latencies of Waves I, III, V (e.g., Wave V latency: 6.16 +/- 0.24 vs. 6.87 +/- 0.31 ms) and in the I-III, III-V, and the I-V interwave latencies were observed. The amplitudes of the BAER components were not significantly altered. The authors conclude that the administration of a dose of STP in excess of twice that required to produce EEG isoelectricity can be compatible with effective monitoring of MnSSEPs and BAERs. However, STP produces dose-related changes in both evoked response wave forms, which must be considered in the interpretation of responses elicited during STP anesthesia.

Adult↗

Information loss over time defines the memory defect of propofol: a comparative response with thiopental and dexmedetomidine.

BACKGROUND: Sedative-hypnotic drugs impair memory, but details regarding the nature of this effect are unknown. The influences of propofol, thiopental, and dexmedetomidine on the performance of a task that isolates specific components of episodic memory function were measured. METHODS: Working (1 intervening item, 6 s) and long-term memory (10 intervening items, 33 s) were tested using auditory words in a continuous recognition task before and during drug administration. Eighty-three volunteer participants were randomly assigned to receive a constant target concentration of drug or placebo, producing sedative effects from imperceptible to unresponsiveness. Responsive participants were categorized as high or low performers, using a median split of long-term memory performance during drug administration. Recognition of words at the end of the study day was assessed. RESULTS: High performers had acquisition of material into long-term memory when drug was present at the same level as placebo. Retention of this material at 225 min was significantly less for propofol (39 +/- 23% loss of material) than for other drugs (17-23% loss; P < 0.01). Greater sedation in low performers was evident in multiple measures. Memory for words presented before drug was no different from that associated with placebo for all groups. CONCLUSIONS: Lack of retention of material acquired into long-term memory during propofol administration, associated with minimal sedation, seems to define drug-induced amnesia. Sedation seems to impair the acquisition or encoding of material into long-term memory. Therefore, the putative targets of drug-induced amnesia by propofol are processes associated with retention of material in long-term memory.

Dexmedetomidine↗

Long-term infusion of sodium thiopental: hemodynamic and respiratory effects.

To establish the possible advantages of ultrashort acting barbiturates administered in continuous infusion as the only sedative agent for mechanically ventilated patients, sodium thiopental was given to 30 subjects for periods ranging from 2--14 days. Plasma levels were maintained at approximately 15 microgram/ml, using both laboratory determinations and clinical judgment. This technique proved effective for patients requiring either controlled ventilation or intermittent mandatory ventilation. None of the hemodynamic and respiratory variables studied was significantly altered during the infusion, with the exception of decreased heart rates. In view of these results, the technique is considered both expedient and safe for prolonged sedation of patients requiring ventilatory support.

Clinical Trials as Topic↗

Rectal thiopental for sedation of children for computed tomography.

Rectally administered thiopental was evaluated for sedation in pediatric computed tomography and compared with "cardiac cocktail" sedation. The drug produced sedation as effective as the "cocktail" with easier administration, more rapid onset, and shorter duration of sedation. Although no complications were observed, careful observation for respiratory depression is suggested.

Anesthesia, General↗

A comparison of the electrophysiologic characteristics of EEG burst-suppression as produced by isoflurane, thiopental, etomidate, and propofol.

Electroencephalogram (EEG) burst-suppression can be produced with several anesthetic agents. Discussions of burst-suppression suggest that it has been viewed by many as a relatively uniform physiologic state independent of the agent used to produce it. This view may be an oversimplification. In this study, relatively deep EEG burst-suppression (suppression to burst time ratio, 4:1) was induced in rats with isoflurane (I), thiopental (T), etomidate (E), and propofol (P). Burst duration, maximum peak-to-peak voltage, area under the curve, and the ratio of power in high versus low frequencies of EEG recorded in both cortex and subcortex (thalamus) were determined. Analysis of the bursts revealed significant differences in duration [I, 1.4 +/- 0.4 (SD); T, 0.8 +/- 0.5; E, 0.3 +/- 0.1; P, 0.4 +/- 0.1 seconds], peak-to-peak voltage (I, 488 +/- 146; T, 285 +/- 106; E, 310 +/- 87; P, 249 +/- 50 muV), and area under the curve (I, 111 +/- 24; T, 35 +/- 31; E, 17 +/- 7; P, 21 +/- 4 muV-s) for all agent pairs except etomidate and propofol. Suppression phase analysis revealed considerable residual activity with all four agents, although peak-to-peak voltage (I, 129 +/- 29; T, 64 +/- 20; E, 62 +/- 11; P, 40 +/- 15 muV) and area under the curve (I, 73 +/- 17; T, 37 +/- 14; E, 30 +/- 5; P, 22 +/- 10 muV-s) were greatest with isoflurane. The cortical versus subcortical comparison revealed, for all agents, greater peak-to-peak voltage and area under the curve in the subcortex. The data indicate that the electrophysiologic characteristics of burst-suppression vary among the four agents, with the possible exception of etomidate and propofol. The data suggest that the neurophysiologic states associated with burst-suppression produced by various anesthetics should not be assumed to be uniform.

Anesthetics, Inhalation↗

Suppression of cerebral metabolic rate for oxygen (CMRO2) by mild hypothermia compared with thiopental.

If the efficacy of hypothermia and barbiturates in ameliorating ischemic brain injury lies in reducing the cerebral metabolic rate of oxygen (CMRO2), the greater efficacy of mild hypothermia (34 degrees C) compared with barbiturates is inconsistent with the 15-20% reduction of CMRO2 caused by mild hypothermia compared with 50% caused by barbiturates. This paradox, we hypothesized, derives from the fact that whereas barbiturates lower CMRO2 associated with EEG activity or thiopental (TP)-suppressible CMRO2, not essential for cellular viability, hypothermia lowers CMRO2 associated with providing energy, i.e., adenosine triphosphate, to maintain transmembrane ion gradients or TP-nonsuppressible CMRO2, essential for neuronal viability. To test this hypothesis, we measured whole brain cerebral blood flow (CBF) and CMRO2 in two groups of rats mechanically ventilated with 70% N2O/30% O2 before and after TP-induced isoelectric EEG. In the normothermic group (n = 7), measurements were made at a brain temperature (Tb) of 38 degrees C, while in the hypothermic group (n = 7), they were made at 34 degrees C. In the normothermic group, TP-induced isoelectric EEG reduced CMRO2 by 50%, from 7.92 +/- 1.05 to 3.95 +/- 0.70 ml 100 g-1 min-1 (mean +/- = SD). Thus, at 38 degrees C, TP-suppressible and TP-nonsuppressible CMRO2 were both 50 +/- 4% of total CMRO2. In the hypothermic group, decreasing Tb from 38 to 34 degrees C caused a 17% decline in CMRO2, from 7.62 +/- 1.92 to 6.28 +/- 1.22 ml 100 g-1 min-1 (p > 0.05). AT 34 degrees C, TP infusion lowered CMRO2 to 2.15 = 0.46 ml 100 g-1 min-1. At 34 degrees C, TP-suppressible and TP-nonsuppressible CMRO2 values were 64 +/- 7% and 36 +/- 8% of total CMRO2, respectively. TP lowered CBF by 50% at both 38 and 34 degrees C. In conclusion, mild hypothermia selectively lowers TP-nonsuppressible CMRO2 associated with the maintenance of viability rather than EEG-associated or TP-suppressible CMRO2.

Anesthetics, Intravenous↗

Computer simulation of intracranial pressure changes during induction of anesthesia: comparison of thiopental, propofol, and etomidate.

We have developed a computer model of cerebrovascular hemodynamics that interacts with a pharmacokinetic drug model. We used this model to examine the effects of various stimuli occurring during anesthesia on cerebral blood flow (CBF) and intracranial pressure (ICP). The model is a seven-compartment constant-volume system. A series of resistances and compliances relate blood and cerebrovascular fluid fluxes to pressure gradients between compartments. Variable arterial-arteriolar resistance (Ra-ar) and arteriolar-capillary resistance (Rar-c) simulate autoregulation and drug effects, respectively. Rar-c is also used to account for the effect of CO2 on the cerebral circulation. A three-compartment pharmacokinetic model predicts concentration-time profiles of intravenous induction agents. The effect-site compartment is included to account for disequilibrium between drug plasma and biophase concentrations. The simulation program is written in VisSim dynamic simulation language for an IBM-compatible personal computer. Using the model, we have predicted ICP responses during induction of anesthesia for a simulated patient with normal as well as elevated ICP. Simulation shows that the induction dose of intravenous anesthetic reduces ICP up to 30% (propofol > thiopental > etomidate). The duration of this effect is limited to less than 5 minutes by rapid drug redistribution and cerebral autoregulation. Subsequent laryngoscopy causes acute intracranial hypertension, exceeding the initial ICP. ICP elevation is more pronounced in a nonautoregulated cerebral circulation. Simulation results are in good agreement with the available experimental data. The presented model allows comparison of various drug administration schedules to control ICP.

Anesthetics, Intravenous↗

Hemodynamics during superficial thiopental anesthesia in the dog.

Radioactive microspheres, labeled withe ytterbium (169Yb), strontium (85Sr) and cerium (141Ce) were used in an investigation of the cardiovascular response to superficial thiopental anesthesia. The course was followed for 90 min and measurements were carried out 30, 60 and 90 min, respectively. Between 30 and 60 min of anesthesia there was a slight decrease in cardiac output and left ventricular work. The blood flow was reduced to the lungs, kidneys and the liver. Between 60 and 90 min there were, except for the coeliac artery and total liver, no further changes, which indicated a circulatory steady state.

Anesthesia, Intravenous↗

Minimum cerebral blood flow and metabolism during craniotomy. Effect of thiopental loading.

Cerebral blood flow and metabolism were measured repeatedly during surgery for cerebral tumours by a modification of the classical Kety & Schmidt method using 133Xe infusion intravenously. Our standard procedure for neuroanaesthesia (pentobarbitone-fentanyl induction, halothane-nitrous oxide maintenance) reduced blood flow from 47.1 to 24.2 ml X 100 g X ml-1 and metabolism from 3.30 to 1.83 ml O2 X 100 g-1 X ml-1. PaCO2 was reduced by hyperventilation from 5.3 to 3.6 kPa. Additional thiopental loading and maintenance using 4 + 4 mg X kg-1 (n = 5) or 8 + 8 mg X kg-1 (n = 5) reduced cerebral metabolism by an additional 15% (P less than 0.01) and blood flow by 16.5% (P less than 0.01), while mean arterial blood pressure fell from 11.0 to 9.9 kPa (P less than 0.05). PaCO2 remained unchanged. This additional reduction in cerebral metabolism and blood flow is small, but we nevertheless conclude that it may well be of clinical interest to the problem of protecting the brain in case of episodes of focal cerebral ischaemia which may arise peroperatively during intracranial surgery.

Adult↗

In vitro effect of etomidate and thiopental on granulocyte migration.

An increased mortality has been reported during long-term etomidate infusion. Inhibition of adrenal corticosteroid synthesis has been incriminated - but other factors related to host defence cannot be excluded. Using an under-agarose assay, we investigated the effect of etomidate on in vitro granulocyte migration. Unlike thiopental (50 micrograms/ml), etomidate (4-32 micrograms/ml) did not affect either spontaneous or directed migration. Impaired granulocyte migration is an unlikely cause of morbidity during long-term etomidate infusion.

Cell Movement↗

Propofol-fentanyl anesthesia compared to thiopental-halothane with special reference to recovery and vomiting after pediatric strabismus surgery.

Forty-four children, ASA physical status I or II, aged 1.5-14 years and admitted for strabismus surgery, were studied. The study compared the postoperative condition after two different anesthesia methods. All children were premedicated with midazolam rectally, received glycopyrrolate i.v. and were then randomised to one of two anesthetic methods: 1) induction with thiopental, maintenance with halothane or 2) induction with propofol supplemented with fentanyl, maintenance with propofol infusion. In both groups, tracheal intubation was performed after vecuronium i.v. and the children were ventilated manually. Peroperatively, patients receiving propofol/fentanyl had more episodes of bradycardia (P less than 0.001). Times to spontaneous breathing and extubation were shorter in the propofol/fentanyl group (P less than 0.05) and there was also a lesser degree of sedation during the first 2 h postoperatively (P less than 0.01). Fewer children in the propofol/fentanyl group vomited postoperatively (P less than 0.05). The apprehension score was higher in the propofol/fentanyl group compared to the thiopental/halothane group (P less than 0.05). We conclude that children undergoing strabismus surgery anesthetized with propofol/fentanyl had more episodes of peroperative bradycardia, a lower incidence of postoperative vomiting and a shorter recovery time, and were more apprehensive during the initial postoperative period than children anesthetized with thiopental/halothane.

Adolescent↗

Sevoflurane and oxygen anaesthesia following administration of atropine-xylazine-guaifenesin-thiopental in spontaneously breathing horses.

The effects of sevoflurane-oxygen anaesthesia at a light-surgical depth on clinically important features were evaluated in spontaneously breathing horses that received atropine, xylazine, and guaifenesin-thiopental. Mean end-tidal concentrations of sevoflurane ranged from 1.6 to 2.3% during 90 min maintenance. Recovery from anaesthesia was extremely rapid and smooth. Heart rates did not significantly change after anaesthesia. Arrhythmia was not observed. Mean arterial pressure (mean +/- SD) ranged from 86 +/- 17 to 98 +/- 5 mmHg during anaesthesia. Minute ventilation was low due to decreased respiratory rates during anaesthesia. Changes in arterial blood gases and pH demonstrated respiratory acidosis during anaesthesia. Haematological findings revealed haemodilution during anaesthesia. Serum potassium decreased slightly during anaesthesia, but other serum biochemical values did not significantly change for 7 days post-anaesthesia. These results suggest that sevoflurane may be an effective inhalant anaesthetic which produces a rapid recovery from anaesthesia in horses.

Anesthesia, Inhalation↗

Quantitative comparison of cell loss and thiopental-induced EEG changes in human epileptic hippocampus.

Thiopental-induced EEG beta activity recorded from mesial and lateral temporal lobe sites was analyzed both visually and by computer in 30 patients with complex partial seizures. All patients later received anterior temporal lobectomy. Volumetric cell densities and percentage of principal cell loss relative to normal controls were determined in several different areas of each resected temporal lobe. The percentage of drug-induced beta activity was then compared with the percentage of cell loss by (a) making precise topographic correlations between induced beta and cell loss, (b) relating the overall degree of left/right beta asymmetry to cell loss averaged over wide regions, and (c) comparing the likelihood of left/right beta asymmetries in patients with and without extreme cell loss. The results obtained were consistently negative and were unaffected by whether EEG data were analyzed by computer or visual inspection. These results indicate that the well-known loss of drug-induced beta activity found in epileptogenic regions is not an indicator of the degree of cell loss or sclerosis. The underlying focal dysfunction measured by EEG beta activity remains unknown, and factors such as focal hypoperfusion, hypometabolism, and the microanatomic features of the cells remaining in the focus should be investigated.

Beta Rhythm↗

Erythrocyte ghost--buffer partition coefficients of phenobarbital, pentobarbital, and thiopental support the pH-partition hypothesis.

The partition coefficient (lambda) between red cell ghosts and buffer has been determined for three barbiturates over a range of pH. Experimental partition coefficients were linearly proportional to the calculated degree of association of the barbiturates. Lambda was 9.5 +/- 0.52 for phenobarbital, 12.7 +/- 0.91 for pentobarbital, and 27 +/- 4.9 for thiopental in their acid forms. Lambda for all three barbiturates in their anionic forms was zero. Our data support the assumption of the pH-partition hypothesis that the dependence of lambda on pH in biological membranes behaves essentially like that in organic solvents. However, the relative magnitudes of the erythrocyte partition coefficients correlate much more closely with the physiological permeability constants than do those of organic solvents, which tend to overestimate the differences between these compounds.

Buffers↗

Effects of thiopental anesthesia on local rates of cerebral protein synthesis in rats.

We have examined the effects of a surgical level of thiopental anesthesia in adult male rats on local rates of cerebral protein synthesis with the quantitative autoradiographic L-[1-14C]leucine method. The relative contribution of leucine derived from protein breakdown to the intracellular precursor amino acid pool for protein synthesis was found to be statistically significantly decreased in the anesthetized rats compared with controls. In the brain as a whole and in 30 of the 35 brain regions examined, rates of protein synthesis were decreased (1-11%) in the anesthetized rats. Decreases were statistically significant (P < or = 0.05) in the brain as a whole and in six of the regions, and they approached statistical significance in an additional 13 regions, indicating a tendency for a generalized but small effect.

Amino Acids↗

Respiratory mechanics in recumbent dogs anesthetized with thiopental sodium.

Pressure-volume (PV) and conductance-volume (GV) curves were obtained in trained dogs awake and then anesthetized with thiopental sodium, in the prone left lateral decubitus, and supine positions. By paired analyses, induction of anesthesia had no significant effect on lung volumes, static PV curves of the lung or chest wall, or static compliance of the lung or chest wall. In addition, change of posture had little effect on these variables in either the awake or the anesthetized state. Frequently, however, individual dogs showed changes in lung PV curves after induction of anesthesia or change of posture. These PV curve shifts were not accompanied by predictable changes in GV relations. Therefore, we concluded that such changes in the lung PV curve reflect either local artifacts or local deformation of the respiratory system.

Anesthesia↗