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Biomedical subjects

R A Veselis

Publications and source records attributed to R A Veselis.

At least 19 recordsLinked to original sources
PubMed2000

Isoflurane pretreatment ameliorates postischemic neurologic dysfunction and preserves hippocampal Ca2+/calmodulin-dependent protein kinase in a canine cardiac arrest model.

BACKGROUND: Inhalational anesthetics are neuroprotective in rat models of global ischemia. To determine whether isoflurane at a clinically relevant concentration is neuroprotective in a canine model of cardiac arrest, we measured neurologic function and hippocampal Ca2+/calmodulin-dependent protein kinase II (CaMKII) content 20 h after cardiac arrest. METHODS: We tested the neuroprotective effect of 30 min of 1.5% isoflurane exposure before 8 min of global ischemia induced with ventricular fibrillation. Animals were randomized to four groups: control, isoflurane-control, ischemia, and isoflurane-ischemia. After resuscitation and 20 h of intensive care, each animal's neurologic deficit score was determined by two blinded evaluators. The hippocampal content of CaMKII, determined by immunoblotting, was measured by an individual blinded to the treatment groups. CaMKII activity was measured in samples from the cortex, hippocampus, and striatum of animals in each group. RESULTS: Isoflurane-ischemic animals had a median neurologic deficit score of 22.6% compared with 43.8% for the ischemic animals (P < 0.05). Hippocampal levels of the beta-subunit of CaMKII (CaMKIIbeta) were relatively preserved in isoflurane-ischemic animals (68 +/- 4% of control) compared with ischemic animals (48 +/- 2% of control; P < 0.001), although both groups were statistically significantly lower than control (P < 0. 001 ischemia vs. control and P < 0.05 isoflurane-ischemia vs. control). CONCLUSIONS: Isoflurane is an effective neuroprotective drug in a canine cardiac arrest model in terms of both functional and biochemical criteria.

Anesthetics, Inhalation↗
PubMed1997

Performance of computer-assisted continuous infusion at low concentrations of intravenous sedatives.

We studied the performance of a target-controlled drug infusion device, computer-assisted continuous infusion (CACI). Forty-one volunteers received one of midazolam (n = 11), propofol (n = 10), thiopental (n = 10), or fentanyl (n = 10) in sedative concentrations. Concentrations were kept constant for 45-70 min at five sequential target concentrations in each subject. Twenty-six subjects had arterial sampling and 15 had venous sampling to determine drug concentrations. Median performance errors, median absolute performance error (MDAPE), wobble, divergence, and median absolute constancy error (MDACE), defined as error around mean actual concentration at each target, were calculated. CACI demonstrated significant performance errors, which were different among drugs. MDAPE (5%-95% confidence interval) ranged from 22.9% (12.1%-39.6%) for propofol to 82.2% (36.0%-183.0%) for midazolam. Although performance errors could be large, CACI was able to maintain a constant serum concentration over time very successfully. The MDACE ranged from 5.6% (3.9%-17.3%) for fentanyl to 11.2% (8.9%-20.4%) for propofol. Few differences occurred between arterial and venous sampling, although when they occurred, arterial samples indicated larger errors. It is concluded that CACI is very successful at maintaining constant serum concentrations of these drugs at sedative concentrations. Arterial sampling should be used when the performance characteristics of an infusion device are being tested. However, venous sampling may be adequate to determine serum concentrations when a pseudo-steady state has been achieved.

Adult↗
PubMed1997

The comparative amnestic effects of midazolam, propofol, thiopental, and fentanyl at equisedative concentrations.

BACKGROUND: The authors evaluated the effects of midazolam, propofol, thiopental, and fentanyl on volunteer participants' memory for words and pictures at equisedative concentrations. METHODS: Sixty-seven healthy volunteers were randomized to receive intravenous infusions of midazolam (n = 11), propofol (n = 11), thiopental (n = 10), fentanyl with ondansetron pretreatment (n = 11), ondansetron alone (n = 8), or placebo (n = 16) in a double-blind design. Three increasing and then two decreasing sedative concentrations were achieved by computer-controlled infusion in each volunteer. Measures of sedation, memory, and drug concentration were obtained at each target concentration. Drug concentrations were normalized to equisedative effects using both Emax and logistic regression methods of pharmacodynamic modeling. The serum concentrations at 50% memory effect (Cp50s) were determined using four different memory end points. The relative potencies compared with midazolam for memory impairment were determined. RESULTS: Equisedative concentrations were midazolam, 64.5 +/- 9.4 ng/ml; propofol, 0.7 +/- 0.2 microg/ml; thiopental, 2.9 /- 1.0 microg/ml; and fentanyl, 0.9 +/- 0.2 ng/ml. The Cp50s for 50% loss of memory for words were midazolam, 56 +/- 4 ng/ml; propofol, 0.62 +/- 0.04 microg/ml; thiopental, 4.5 +/- 0.3 microg/ml; and fentanyl, 3.2 +/- 0.4 ng/ml. Compared with midazolam, relative potencies (with 95% confidence intervals) were propofol, 0.96 (0.44-1.78); thiopental, 0.76 (0.52-0.94); and fentanyl, 0.34 (0.05-0.76). Large effects on memory were only produced by propofol and midazolam. CONCLUSIONS: At equal sedation, propofol produces the same degree of memory impairment as midazolam. Thiopental has mild memory effects whereas fentanyl has none. Ondansetron alone has no sedative or amnesic effects.

Adult↗
PubMed1997

Midazolam changes cerebral blood flow in discrete brain regions: an H2(15)O positron emission tomography study.

BACKGROUND: Changes in regional cerebral blood flow (rCBF) determined with H2(15)O positron emission tomographic imaging can identify neural circuits affected by centrally acting drugs. METHODS: Fourteen volunteers received one of two midazolam infusions adjusted according to electroencephalographic response. Low or high midazolam effects were identified using post-hoc spectral analysis of the electroencephalographic response obtained during positron emission tomographic imaging based on the absence or presence of 14-Hz spindle activity. The absolute change in global CBF was calculated, and relative changes in rCBF were determined using statistical parametric mapping with localization to standard stereotactic coordinates. RESULTS: The low-effect group received 7.5 +/- 1.7 mg midazolam (serum concentrations, 74 +/- 24 ng/ml), and the high-effect group received 9.7 +/- 1.3 mg midazolam (serum concentrations, 129 +/- 48 ng/ml). Midazolam decreased global CBF by 12% from 39.2 +/- 4.1 to 34.4 +/- 6.1 ml x 100 g(-1) x min(-1) (P < 0.02 at a partial pressure of carbon dioxide of 40 mmHg). The rCBF changes in the low-effect group were a subset of the high-effect group. Decreased rCBF (P < 0.001) occurred in the insula, the cingulate gyrus, multiple areas in the prefrontal cortex, the thalamus, and parietal and temporal association areas. Asymmetric changes occurred, particularly in the low-effect group, and were more significant in the left frontal cortex and thalamus and the right insula. Relative rCBF was increased in the occipital areas. CONCLUSION: Midazolam causes dose-related changes in rCBF in brain regions associated with the normal functioning of arousal, attention, and memory.

Adult↗
PubMed1997

Comparison of the EEG effects of midazolam, thiopental, and propofol: the role of underlying oscillatory systems.

The EEG effects of 3 intravenous sedative drugs from different chemical families were studied during conscious sedation in 47 normal volunteers. The drugs studied were midazolam (a benzodiazepine), propofol (an alkylphenol) and thiopental (a barbiturate). Though these drugs cause different degrees of amnesia, they have the common EEG effects of suppressing alpha-rhythm and increasing total beta-power. A large portion of the increase in beta-power can be accounted for by beta-rhythms. We used the UNIFAC-EEG technique to differentiate oscillatory systems underlying the rhythms induced by these drugs in a quantitative fashion. While thiopental induced beta-rhythms which were similar to those appearing during drowsiness, midazolam and propofol induced beta-rhythms with substantially different characteristics. The differences between the beta-rhythms induced by drug infusion and previously described 'sleep spindles' are discussed. We conclude that a quantitative analysis of beta-rhythms can differentiate the effects of these drugs on the EEG.

Adult↗
PubMed1995

The P300 event-related potential during propofol sedation: a possible marker for amnesia?

We have studied the effects of conscious sedation with propofol on long latency components of the auditory event-related potential (ERP) in 10 normal volunteers (aged 21-41 yr) receiving propofol 75 micrograms kg-1 min-1 i.v. We examined the effects of propofol on ERP amplitudes and latencies, and their relationship to delayed recognition performance using a verbal memory test, a selective attention task (button pushing) and serum concentrations of propofol. During infusion of propofol, subjects were mildly sedated, oriented and readily responsive to verbal commands. ERP were recorded from monopolar FZ, CZ and PZ electrodes. We used a standard paradigm requiring selective attention to randomly occurring stimuli associated with a task (button push). The peak-to-peak amplitudes and latencies of the N2 and P3 waves were obtained before and during infusion, and 15, 100 and 170 min after infusion. Propofol produced a 70% decrease in the amplitude of P3 (P < 0.0001) from baseline and a 50% increase in reaction time. The differential response to target compared with non-target stimuli was maintained during infusion for both N2 and P3. Memory performance correlated more strongly with changes in P3 amplitude (r = 0.59) than with serum propofol concentrations (r = -0.07), although this correlation with memory did not reach statistical significance (P = 0.08). We conclude that P3 amplitude was profoundly affected by propofol given in sedative concentrations.

Adult↗
PubMed1995

Brain tumors do not affect thiopental dosing requirements.

We used the biphasic electroencephalographic (EEG) response to increasing concentrations of thiopental to measure regional brain responses to thiopental. Eight patients with cortical parietal brain tumors, 3.3 (SD 1.3) cm in diameter, and eight control patients with lung cancer and normal brain computed tomography scans received thiopental by infusion (50-75 mg/min) until burst suppression (50% isoelectric activity) on the EEG occurred. Infusion lasted 10.7 (SD 2.4) min, and the average dose of thiopental administered was 810 (SD 170) mg [11.2 (SD 1.9) mg/kg]. During infusion the EEG was continuously recorded from the F3, F4, P3, and P4 electrodes. On-line power spectral analysis was performed, and data were saved for later analysis. Four EEG parameters [log beta (15-30 Hz) power, percent beta power, spectral edge 95% and spectral edge 70%] were plotted against calculated brain concentration of thiopental [using an assumed plasma-effect site rate constant (ke0) of 0.58] for each individual. Three points were measured on each curve (50% upslope, peak, and zero intercept) to quantitate the EEG response. Statistical comparisons were performed between the following sets of data: EEG response at electrode closest to brain tumor versus electrode farthest from tumor (in the same patient); and electrodes closest to brain tumors (parietal P3 and P4) versus same electrode pair in control patients (patients with thoracic tumors) using analysis. No differences were found in any comparison. Thus, the presence of a brain tumor does not affect the response of the brain in this region to thiopental as measured using EEG.

Aged↗
PubMed1994

Impaired memory and behavioral performance with fentanyl at low plasma concentrations.

Fentanyl is commonly administered to conscious patients by continuous epidural or intravenous (i.v.) infusions, or by the transdermal route, which result in relatively constant, low, concentrations of the drug. Previous studies of memory and cognitive effects have not been performed at constant plasma concentrations of fentanyl. Based on simulated infusions using the pharmacokinetic modeling program IV-SIM, we administered fentanyl or placebo to nine healthy volunteers (aged 21-45 yr) by continuous i.v. infusion, targeting plasma concentrations of 1, 1.5, and 2.5 ng/mL in succession. A battery of memory and psychomotor tasks was administered at each plasma concentration of fentanyl, and at two points in the recovery phase while drug levels were decreasing. At increasing plasma concentrations of fentanyl, we found the following effects on memory (in comparison with placebo): a progressive decline in verbal learning (P < 0.03); decreased delayed recognition of words presented at different test times (P < 0.02); and decreased spontaneous recall of pictures shown during infusion (P < 0.03). Fentanyl at concentrations above 2.5 ng/mL caused a performance decrement of 15%-30% relative to baseline on all the psychomotor tests administered. Plasma concentrations less than 2.25 ng/mL had negligible effects on performance with the exception of the critical flicker fusion frequency, which decreased by 5 Hz at plasma concentrations between 1.5 and 2.25 ng/mL. Visual analog scale (VAS) measures of mental and physical sedation were significantly affected by fentanyl, but euphoria was not demonstrable. All subjects receiving fentanyl experienced severe nausea and four of six had one or more episodes of emesis (P < 0.03).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Analytical methods to differentiate similar electroencephalographic spectra: neural network and discriminant analysis.

Differences in electroencephalographic (EEG) power spectra obtained under similar, but not identical, conditions may be difficult to discern using standard techniques. Statistical analysis may not be useful because of the large number of comparisons necessary. Visual recognition of differences also may be difficult. A new technique, neural network analysis, has been used successfully in other problems of pattern recognition and classification. We examined a number of methods of classifying similar EEG data: standard statistical analysis (analysis of variance), visual recognition, discriminant analysis, and neural network analysis. Twenty-nine volunteers received either thiopental (n = 9), midazolam (n = 10), or propofol (n = 10) in sedative doses in 3 different studies. These drugs produced very similar changes in the EEG power spectra. Except for beta 2 power during thiopental infusion, differences between drugs could not be detected using analysis of variance. Visual categorization was correct in 72% of the baseline EEGs, 70% of thiopental EEGs, 27% of propofol EEGs, and 46% of midazolam EEGs. A classification neural network (Learning Vector Quantization network) containing a Kohonen hidden layer was able to successfully classify 57 of 58 EEG samples (of 4 minutes' duration). Discriminant analysis had a similar rate of success. This level of performance was achieved by dividing the EEG power spectrum from 1 to 30 Hz into 15 2-Hz bandwidths. When the EEG power spectrum was divided into the "classical" frequency bandwidths (alpha, beta 1, beta 2, theta, delta), both neural network and discriminant analysis performance deteriorated. By training the network using only certain inputs we were able to identify drug-specific bandwidths that seemed to be important in correct classification. We conclude that propofol, thiopental, and midazolam produce different effects on the EEG and that both neural network and discriminant analysis are useful in identifying these differences. We also conclude that EEG spectra should be analyzed without using classical EEG bands (alpha, beta, etc.). Additionally, neural networks can be used to identify frequency bands that are "important" in specific drug effects on the EEG. Once a classification algorithm is obtained using either a neural network or discriminant analysis, it could be used as an on-line monitor to recognize drug-specific EEG patterns.

Adult↗
PubMed1993

The effects of midazolam on the EEG during sedation of critically ill patients.

Patients who require mechanical ventilation are often sedated with midazolam. As clinical signs of sedation are often confusing or nonexistent, and there are few adverse side effects when large doses are infused over a period of days, substantial drug accumulation can result in these critically ill patients, despite the short half-life of midazolam. An objective monitor of sedation would help maintain sedation at a constant level despite changing pharmacokinetic values in patients. We undertook this study to describe the electroencephalographic changes which occur with intravenous midazolam in critically ill patients, and to determine if a relationship exists between these changes and the depth of sedation as measured using a clinical scoring method. A series of 31 critically ill patients who required intravenous midazolam during mechanical ventilation were studied. Four different levels of sedation were defined ranging from execution of verbal commands to no response to suctioning through the tracheal tube or sternal rub. Electroencephalographic recordings were obtained in patients on a daily basis and a concurrent sedation level was determined. High frequency electroencephalogram activity decreased as sedation level increased. This was reflected in decreases in the spectral edge (17.61 to 10.56 Hz (p = 0.0024)), the median frequency (4.27 to 2.56 Hz (p = 0.0278)), and the logarithm of the absolute power in the beta 1 (p = 0.0012), and beta 2 (p < 0.0001) bands. An incidental finding of asymmetry in power between right and left frontal electrodes was observed, with right-sided power being 9-18% greater (p < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

EEG and memory effects of low-dose infusions of propofol.

The purpose of this study was to identify EEG changes associated with low-dose propofol infusion producing only sedative effects, and to describe the memory effects of low-dose propofol infusion. Ten healthy volunteers underwent EEG monitoring (at Fz, Cz, Pz and Oz electrode sites) before, during and after propofol 0.5 mg kg-1 i.v. bolus and 75 micrograms kg-1 min-1 as an infusion. Mean serum concentration of propofol during infusion was 0.86 (SD 0.14) micrograms ml-1. The EEG changed significantly during infusion, with increased power in the beta 1 (15-20 Hz), beta 2 (20.5-30 Hz) and delta (1-3.5 Hz) frequencies. Beta 1 and beta 2 power changes were most marked at the Fz and Cz electrodes. Subjects were sedated, but able to complete cognitive tasks. Visual analogue scales of attention and sleepiness were obtained throughout the study and demonstrated a sedative effect during propofol infusion, but were not a significant factor in memory performance or EEG changes. A verbal learning task (Rey Auditory-Verbal Learning Task) administered before, during and after infusion showed a marked reduction in short-term memory capacity and dramatically impaired free recall and recognition during infusion. Nine of 10 subjects had partial amnesia for complex visual scenes presented during infusion, recalling less than 50% of the material. Stronger cueing was required to retrieve information presented during propofol infusion, with an increase in mean retrieval time from 95.4 (41.2) s to 426.8 (83.1) s. EEG and memory effects resolved quickly after the end of infusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

Use of neural network analysis to classify electroencephalographic patterns against depth of midazolam sedation in intensive care unit patients.

The electroencephalographic (EEG) analog signal is complex and cannot easily be described by univariate variables. Clear visual changes in the EEG power spectrum can be present with little or no change in univariate variable values. A method that could produce a single value based on the total data available in the EEG power spectrum would be very useful in monitoring EEG changes. Neural network analysis is a technique that can take multiple inputs and produce a single output value using complicated processing patterns that require training to establish. We examined the usefulness of a series of neural network models to classify 63 EEG patterns against sedation level in 26 mechanically ventilated patients requiring midazolam for long-term sedation. During a stable period of sedation, a 4- to 60-minute period of EEG data was obtained concurrently with a sedation level from 1 (follows commands) to 7 (no or gag response to suctioning of the endotracheal tube). The EEG power spectrum was divided into equal frequency bands, and the log absolute powers in each of these bands were used as inputs for a series of neural network models. The output target was the sedation level associated with each set of EEG data. Networks were trained on a subset of EEG power/sedation score data pairs, and the ability to classify the remaining data pairs was tested. Using a t-test comparison with a random set of sedation levels, we found that trained neural network models classified EEG patterns against sedation level successfully (p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗