Ruth A. Reinsel

midazolam Changes Cerebral Blood Flow in Discrete Brain Regions : an H2-15o Positron Emission Tomography Study

Background: Changes in regional cerebral blood flow (rCBF) determined with H215 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 [center dot] 100 g sup ‐1 [center dot] min sup ‐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.

Thiopental and propofol affect different regions of the brain at similar pharmacologic effects.

In this study, we examined the onset and duration of local analgesic effects of bupivacaine incorporated into biodegradable microcapsules (extended-duration local anesthetic; EDLA) administered as subcutaneous infiltrations in different doses in humans. In 18 volunteers, the skin on the medial calf was infiltrated with 10 mL of EDLA, and the opposite calf was infiltrated with 10 mL of aqueous bupivacaine (5.0 mg/mL) in a double-blinded, randomized manner. Three different concentrations of EDLA were tested (6.25, 12.5, and 25 mg/mL), with 6 subjects in each group. Pain responses to mechanical and heat stimuli and sensory thresholds (touch, warm, and cold detection thresholds) were examined by von Frey hairs and contact thermodes. Assessments were made before and 2, 4, 6, 8, 24, 48, 72, 96, and 168 h after the injections. Safety evaluations were performed daily for the first week and at 2 wk, 6 wk, and 6 mo after the injections. The time to maximum effects was significantly shorter for aqueous bupivacaine (2–6 h) than for EDLA (4–24 h), but there were no significant differences between the maximum effects of EDLA and aqueous bupivacaine. From 24 to 96 h after the injections, EDLA was significantly more efficient than aqueous bupivacaine for all variables, and significant effects of EDLA were demonstrated for at least 96 h for all variables. In general, a dose-response gradient was seen in the EDLA group for 5 of 7 variables when the curves expressing effect over time for the different concentrations were evaluated. No serious side effects were observed for up to 6 mo after administration. In conclusion, bupivacaine incorporated in microcapsules provided analgesia for 96 h after subcutaneous infiltration.Propofol has a greater amnesic effect than thiopental. In this study we tested whether different brain regions were affected by propofol and thiopental at similar drug effects. Changes in regional cerebral blood flow (rCBF) were identified by using SPM99 analysis of images obtained with positron emission tomography with (15)O water. Ten right-handed male volunteers (age, 35 +/- 10 yr; weight, 74.1 +/- 7.5 kg; mean +/- sd) were randomized to receive thiopental (n = 4) or propofol (n = 6) to target sedative and hypnotic concentrations with bispectral index (BIS) monitoring. Four positron emission tomography images were obtained during various tasks at baseline and with sedative and hypnotic effects. Two participants receiving propofol were unresponsive at sedative concentrations and were not included in the final analyses. Median serum concentrations were 1.2 and 2.7 microg/mL for sedative and hypnotic propofol effects, respectively. Similarly, thiopental concentrations were 4.8 and 10.6 microg/mL. BIS decreased similarly in both groups. The pattern of rCBF change was markedly different for propofol and thiopental. Propofol decreased rCBF in the anterior (right-sided during sedation) brain regions, whereas thiopental decreased rCBF primarily in the cerebellar and posterior brain regions. At similar levels of drug effect, propofol and thiopental affect different regions of the brain. These differences may help to identify the loci of action for the nonsedative effects of propofol, such as amnesia.

Propofol-induced alpha rhythm.

The electroencephalographic effects of two intravenous sedative/hypnotic drugs, propofol and thiopental, were studied at three stable blood concentrations in 52 normal healthy volunteers. The higher concentration resulted in unresponsiveness (lack of response to auditory/tactile stimuli) in all subjects. This report describes the strong frontal-central rhythms apparent in this state using a quantitative description of oscillatory systems underlying the rhythm. These rhythms occur when sedative drug concentrations are greater than those producing the well-described increase in broadband β-power associated with many sedative drugs. Propofol induces rhythms in the α-range, while thiopental produces rhythms in the β-range. Quasistationary for a period of about 1 h, these rhythms exceed the baseline α-rhythm in power. By their resonant nature, these propofol-induced rhythms are analogous to ‘the classic α-rhythm’, but quantitative characteristics of the underlying oscillatory systems are different. Baseline properties of the oscillatory system underlying the initial resting α-rhythm recover completely as drug concentration decays to negligible values.

A neuroanatomical construct for the amnesic effects of propofol.

Background This study was designed to identify neuroanatomical locations of propofols effects on episodic memory by producing minimal and maximal memory impairment during conscious sedation. Drug-related changes in regional cerebral blood flow (rCBF) were located in comparison with rCBF increases during a simple word memory task. Methods Regional cerebral blood flow changes were assessed in 11 healthy volunteers using H215O positron emission tomography (PET) and statistical parametric mapping (SPM99) at 600 and 1,000 ng/ml propofol target concentrations. Study groups were based on final recognition scores of auditory words memorized during PET scanning. rCBF changes during propofol administration were compared with those during the word memory task at baseline. Results Nonoverlapping memory effects were evident: low (n = 4; propofol concentration 523 ± 138 ng/ml; 44 ± 13% decrement from baseline memory) and high (n = 7; 829 ± 246 ng/ml; 87 ± 6% decrement from baseline) groups differed in rCBF reductions primarily in right-sided prefrontal and parietal regions, close to areas activated in the baseline memory task, particularly R dorsolateral prefrontal cortex (Brodmann area 46; x, y, z = 51, 38, 22). The medial temporal lobe region exhibited relative rCBF increases. Conclusions As amnesia becomes maximal, rCBF reductions induced by propofol occur in brain regions identified with working memory processes. In contrast, medial temporal lobe structures were resistant to the global CBF decrease associated with propofol sedation. The authors postulate that the episodic memory effect of propofol is produced by interference with distributed cortical processes necessary for normal memory function rather than specific effects on medial temporal lobe structures.

Drug-induced amnesia is a separate phenomenon from sedation: electrophysiologic evidence.

BackgroundSedative–hypnotic drugs not only increase sedation, but also impair memory as serum concentration increases. These drugs also produce profound changes in the auditory event-related potential (ERP). The ability of various ERP components to predict changes in sedation and memory produced by various drugs was tested. MethodsSixty-five healthy volunteers randomly received intravenous placebo, midazolam, propofol, thiopental, fentanyl with ondansetron, or ondansetron alone at five different stable target concentrations (three increasing, two decreasing) using a computer-controlled infusion pump to produce varying degrees of sedation without loss of consciousness. ERPs were recorded while volunteer participants detected a deviant auditory stimulus and made a button-press response to a target tone (standard oddball paradigm, 80:20 ratio, to elicit a P3 response). At each target concentration, volunteers learned a list of 16 words. The predictive probabilities (Pk) of various ERP components were determined for word recognition at the end of the day (memory) and log reaction time to the deviant stimulus (sedation). ResultsThe N2 latency of the ERP consistently predicted log reaction time in all groups (Pk ± SE from 0.58 ± 0.04 to 0.71 ± 0.04). The N2P3 amplitude of the ERP was the best predictor of memory performance for midazolam (Pk, 0.63 ± 0.04), propofol (Pk, 0.62 ± 0.05), and thiopental (Pk, 0.66 ± 0.04). There was a differential ability to predict memory performance from sedation for midazolam and propofol. ConclusionsMidazolam and propofol affect memory differentially from their sedative effects, and these are indexed by specific components of the auditory ERP. These components of the ERP are associated with specific, but not necessarily unique, neuroanatomic structures. Thus, these drugs act by additional mechanisms beyond general central nervous system depression to produce the effects of sedation and memory impairment.

Value of perioperative Doppler echocardiography in patients undergoing major lung resection

BACKGROUND The effects of major lung resection on right heart function have not been well established. Our goal was to evaluate these effects using serial Doppler echocardiography in the perioperative period. METHODS In 86 patients undergoing lobectomy (n = 47) and pneumonectomy (n = 39), we examined the effects of pulmonary resection on perioperative changes in right heart function by transthoracic echocardiography. Serial echocardiograms were performed preoperatively, on postoperative day 1, and again between postoperative days 2 and 6 (median, 3 days) to evaluate cardiovascular function and to estimate right ventricular systolic pressure by the tricuspid regurgitation jet Doppler velocity method. RESULTS Right or left atrial size, right atrial pressure, and estimated right ventricular systolic pressure did not differ between groups on the preoperative or postoperative day 1 examinations. However, on postoperative days 2 through 6 patients who underwent pneumonectomy had higher (mean +/- standard deviation) right ventricular systolic pressure values than lobectomy patients (31 +/- 15 versus 25 +/- 10 mm Hg, respectively; p < 0.05 by analysis of variance). In the subset of patients with percent predicted forced expiratory volume in 1 second less than 60% undergoing pneumonectomy (9/39), preoperative right ventricular systolic pressure was inversely correlated with percent predicted forced expiratory volume in 1 second values (r = -0.78; p < 0.04). This correlation was not significant in corresponding lobectomy patients. Postoperative right ventricular enlargement determined by echocardiography occurred with similar frequency in both groups and was associated with poor short-term prognosis in patients in whom severe respiratory failure developed. CONCLUSIONS Preoperative indices of right heart function were within the normal range in both groups. Pneumonectomy but not lobectomy was associated with mild postoperative pulmonary hypertension that was not accompanied by significant right ventricular systolic dysfunction. Postoperative echocardiography may be useful to evaluate right heart function in critically ill patients after lung resection.

The Effects of Endobronchial Cuff Inflation on Double-Lumen Endobronchial Tube Movement After Lateral Decubitus Positioning

OBJECT This study was designed to measure changes in tracheal and bronchial lumen distances from mainstem and secondary carina with lateral positioning, and to assess whether inflation of the endobronchial cuff before lateral positioning would further secure a double-lumen endobronchial tube (DLT) and reduce movement. DESIGN Prospective study. SETTING University-affiliated cancer center. PARTICIPANTS Fifty adult patients scheduled for elective thoracic surgical procedures requiring the placement of a left DLT. INTERVENTIONS Patients were sequentially assigned to either the endobronchial cuff-inflated group or the deflated group during lateral positioning. After induction of general anesthesia, a left polyvinylchloride (PVC) DLT was placed and the position confirmed. In the supine position, the distance from the tip of the tracheal lumen to main carina was measured using a fiberoptic bronchoscope (FOB) passed through the tracheal lumen, and the distance from the bronchial lumen to secondary carina was measured with the FOB passed through the bronchial lumen. The patients were then positioned laterally and a second set of measurements taken. Overall movement was determined by increases and decreases in tracheal and bronchial distances obtained by substracting supine values from lateral values. MEASUREMENTS AND MAIN RESULTS There was significant tracheal movement in 40 of 50 patients, with a mean of 0.92 +/- 1.0 cm. This was predominantly in the upward direction, as seen in 35 of 50 patients. There was significant bronchial movement in 37 of 50 patients, with a mean of 0.92 +/- 1.15 cm. Also, predominance in the upward direction was seen in 34 of 50 patients. CONCLUSIONS DLTs move with lateral positioning, regardless of endobronchial cuff inflation. The movement is predominantly in the upward direction. Therefore, fiberoptic visualization in the supine position should be used only to confirm that the endobronchial lumen is placed on the appropriate side and the cuff is at least 1 cm inside the left mainstem bronchus. Final positioning should always be verified in the lateral position.

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.

Propofol versus midazolam for monitored sedation: a comparison of intraoperative and recovery parameters

STUDY OBJECTIVE To compare intraoperative and recovery parameters in patients who received either propofol infusion (PI), propofol bolus (PB), or midazolam bolus (MZ) for sedation. DESIGN Randomized clinical study. SETTING Medical/surgical patients in a specialized hospital. PATIENTS Ninety patients, aged 18 to 85 years, scheduled for central venous access for chemotherapy and/or total parenteral nutrition. INTERVENTIONS In 30 patients, sedation was induced with MZ 0.02 mg/kg intravenously (i.v.), repeated every 2 to 3 minutes to achieve a sedation level of 3 (eyes closed, responds to verbal stimulus) (SL3). Maintenance was with MZ 0.005 mg/kg i.v. repeated as necessary to maintain SL3. In both propofol groups (30 patients each), induction of sedation was with a bolus of propofol 0.75 to 1.0 mg/kg i.v. Maintenance in the PB group was with propofol 0.25 mg/kg IV, repeated as necessary to maintain SL3. Maintenance in the PI group was with propofol 2 to 4 mg/kg/hr or 33 to 66 micrograms/kg/min to maintain SL3. MEASUREMENTS AND MAIN RESULTS Blood pressure, heart rate, respiratory rate, oxygen saturation, and sedation level were monitored each minute for 5 minutes and then at 5-minute intervals during the procedure. A right atrial blood sample was taken for pH and partial pressure of carbon dioxide at maximum sedation. Adequate sedation was achieved in all three groups. The time to reach SL3 was significantly shorter in the PB group than in the PI and MZ groups (p < 0.05 and p < 0.01, respectively). Cardiovascular and respiratory parameters were remarkably stable. Immediate recovery, as judged by spontaneous eye opening, response to commands, and ability to state date of birth, was significantly shorter in both the PB and PI groups than in the MZ group (p < 0.0001). Intermediate recovery, as measured by sedation score at recovery entry, Aldrete score, and time to standing, was slower in the MZ group (p < 0.05 for the MZ group vs. the PB and PI groups for sedation score and Aldrete score; p < 0.05 for the MZ group vs. the PI group in time to standing). Psychomotor recovery, judged by digit symbol substitution tests, was significantly faster in the PB and PI groups (p < 0.05 vs. the MZ group). Amnesia, measured by picture recall, was significantly greater in the MZ group than in the PI and PB groups (p < 0.05). Mood changes were measured on a visual analog scale. All groups showed improvement. Nausea, headache, dizziness, blurred vision, appetite, tension, pain, depression, drowsiness, and ability to concentrate were evaluated in the preoperative and postoperative periods. The frequency did not differ significantly between groups due to confounding factors such as postoperative chemotherapy and premedicant drugs. CONCLUSION The PI, PB, and MZ groups all gave excellent sedation for patients undergoing surgical procedures with local anesthesia. Amnesia was greatest with midazolam, and recovery was more rapid with propofol.

Propofol and midazolam inhibit conscious memory processes very soon after encoding: An event related potential study of familiarity and recollection in volunteers

Background:Intravenous drugs active via &ggr;-aminobutyric acid receptors to produce memory impairment during conscious sedation. Memory function was assessed using event-related potentials (ERPs) while drug was present. Methods:The continuous recognition task measured recognition of photographs from working (6 s) and long-term (27 s) memory while ERPs were recorded from Cz (familiarity recognition) and Pz electrodes (recollection recognition). Volunteer participants received sequential doses of one of placebo (n = 11), 0.45 and 0.9 &mgr;g/ml propofol (n = 10), 20 and 40 ng/ml midazolam (n = 12), 1.5 and 3 &mgr;g/ml thiopental (n = 11), or 0.25 and 0.4 ng/ml dexmedetomidine (n = 11). End-of-day yes/no recognition 225 min after the end of drug infusion tested memory retention of pictures encoded on the continuous recognition tasks. Results:Active drugs increased reaction times and impaired memory on the continuous recognition task equally, except for a greater effect of midazolam (P < 0.04). Forgetting from continuous recognition tasks to end of day was similar for all drugs (P = 0.40), greater than placebo (P < 0.001). Propofol and midazolam decreased the area between first presentation (new) and recognized (old, 27 s later) ERP waveforms from long-term memory for familiarity (P = 0.03) and possibly for recollection processes (P = 0.12). Propofol shifted ERP amplitudes to smaller voltages (P < 0.002). Dexmedetomidine may have impaired familiarity more than recollection processes (P = 0.10). Thiopental had no effect on ERPs. Conclusion:Propofol and midazolam impaired recognition ERPs from long-term memory but not working memory. ERP measures of memory revealed different pathways to end-of-day memory loss as early as 27 s after encoding.