Steven B. Backman

Brain Mechanisms of Propofol-Induced Loss of Consciousness in Humans: a Positron Emission Tomographic Study

In the present study, we used positron emission tomography to investigate changes in regional cerebral blood flow (rCBF) during a general anesthetic infusion set to produce a gradual transition from the awake state to unconsciousness. Five right-handed human volunteers participated in the study. They were given propofol with a computer-controlled infusion pump to achieve three stable levels of plasma concentrations corresponding to mild sedation, deep sedation, and unconsciousness, the latter defined as unresponsiveness to verbal commands. During awake baseline and each of the three levels of sedation, two scans were acquired after injection of an H215O bolus. Global as well as regional CBF were determined and correlated with propofol concentrations. In addition, blood flow changes in the thalamus were correlated with those of the entire scanned volume to determine areas of coordinated changes. In addition to a generalized decrease in global CBF, large regional decreases in CBF occurred bilaterally in the medial thalamus, the cuneus and precuneus, and the posterior cingulate, orbitofrontal, and right angular gyri. Furthermore, a significant covariation between the thalamic and midbrain blood flow changes was observed, suggesting a close functional relationship between the two structures. We suggest that, at the concentrations attained, propofol preferentially decreases rCBF in brain regions previously implicated in the regulation of arousal, performance of associative functions, and autonomic control. Our data support the hypothesis that anesthetics induce behavioral changes via a preferential, concentration-dependent effect on specific neuronal networks rather than through a nonspecific, generalized effect on the brain.

Physostigmine Reverses Propofol-induced Unconsciousness and Attenuation of the Auditory Steady State Response and Bispectral Index in Human Volunteers

BACKGROUND It is postulated that alteration of central cholinergic transmission plays an important role in the mechanism by which anesthetics produce unconsciousness. The authors investigated the effect of altering central cholinergic transmission, by physostigmine and scopolamine, on unconsciousness produced by propofol. METHODS Propofol was administered to American Society of Anesthesiologists physical status 1 (n = 17) volunteers with use of a computer-controlled infusion pump at increasing concentrations until unconsciousness resulted (inability to respond to verbal commands, abolition of spontaneous movement). Central nervous system function was assessed by use of the Auditory Steady State Response (ASSR) and Bispectral Index (BIS) analysis of electrooculogram. During continuous administration of propofol, reversal of unconsciousness produced by physostigmine (28 microgram/kg) and block of this reversal by scopolamine (8.6 microgram/kg) were evaluated. RESULTS Propofol produced unconsciousness at a plasma concentration of 3.2 +/- 0.8 (+/- SD) microgram/ml (n = 17). Unconsciousness was associated with reductions in ASSR (0.10 +/- 0.08 microV [awake baseline 0.32 +/- 0.18 microV], P < 0.001) and BIS (55.7 +/- 8.8 [awake baseline 92.4 +/- 3.9], P < 0.001). Physostigmine restored consciousness in 9 of 11 subjects, with concomitant increases in ASSR (0.38 +/- 0.17 microV, P < 0.01) and BIS (75.3 +/- 8.3, P < 0.001). In all subjects (n = 6) scopolamine blocked the physostigmine-induced reversal of unconsciousness and the increase of the ASSR and BIS (ASSR and BIS during propofol-induced unconsciousness: 0.09 +/- 0.09 microV and 58.2 +/- 7.5, respectively; ASSR and BIS after physostigmine administration: 0.08 +/- 0.06 microV and 56.8 +/- 6.7, respectively, NS). CONCLUSIONS These findings suggest that the unconsciousness produced by propofol is mediated at least in part via interruption of central cholinergic muscarinic transmission.

Cortical Processing of Complex Auditory Stimuli during Alterations of Consciousness with the General Anesthetic Propofol

Background: The extent to which complex auditory stimuli are processed and differentiated during general anesthesia is unknown. The authors used blood oxygenation level–dependent functional magnetic resonance imaging to examine the processing words (10 per period; compared with scrambled words) and nonspeech human vocal sounds (10 per period; compared with environmental sounds) during propofol anesthesia. Methods: Seven healthy subjects were tested. Propofol was given by a computer-controlled pump to obtain stable plasma concentrations. Data were acquired during awake baseline, sedation (propofol concentration in arterial plasma: 0.64 ± 0.13 &mgr;g/ml; mean ± SD), general anesthesia (4.62 ± 0.57 &mgr;g/ml), and recovery. Subjects were asked to memorize the words. Results: During all periods including anesthesia, the sounds conditions combined elicited significantly greater activations than silence bilaterally in primary auditory cortices (Heschl gyrus) and adjacent regions within the planum temporale. During sedation and anesthesia, however, the magnitude of the activations was reduced by 40–50% (P < 0.05). Furthermore, anesthesia abolished voice-specific activations seen bilaterally in the superior temporal sulcus during the other periods as well as word-specific activations bilaterally in the Heschl gyrus, planum temporale, and superior temporal gyrus. However, scrambled words paradoxically elicited significantly more activation than normal words bilaterally in planum temporale during anesthesia. Recognition the next day occurred only for words presented during baseline plus recovery and was correlated (P < 0.01) with activity in right and left planum temporale. Conclusions: The authors conclude that during anesthesia, the primary and association auditory cortices remain responsive to complex auditory stimuli, but in a nonspecific way such that the ability for higher-level analysis is lost.

Dose-dependent effects of propofol on the central processing of thermal pain

BackgroundAnatomic and physiologic data show that multiple regions of the forebrain are activated by pain. However, the effect of anesthetic level on nociceptive input to these regions is not well understood. MethodsThe authors used positron emission tomography to measure the effect of various concentrations of propofol on pain-evoked changes in regional cerebral blood flow. Fifteen volunteers were scanned while warm and painful heat stimuli were presented to the volar forearm using a contact thermode during administration of target propofol concentrations of 0.0 &mgr;g/ml (alert control), 0.5 &mgr;g/ml (mild sedation), 1.5 &mgr;g/ml (moderate sedation), and 3.5 &mgr;g/ml (unconsciousness). ResultsDuring the 0.5-&mgr;g/ml target propofol concentration (mild sedation), the subjects’ pain ratings increased relative to the alert control condition; correspondingly, pain-evoked regional cerebral blood flow increased in the thalamus and the anterior cingulate cortex. In contrast, when subjects lost consciousness (3.5 &mgr;g/ml), pain-evoked responses in the thalamus and the anterior cingulate cortex were no longer observed, whereas significant pain-evoked activation remained in the insular cortex. ConclusionThese data show that propofol has a dose-dependent effect on thalamocortical transfer of nociceptive information but that some pain-evoked cortical activity remains after loss of consciousness.

Effect of Isoflurane on the Auditory Steady-state Response and on Consciousness in Human Volunteers

Background The auditory steady state response (ASSR) is a sustained electrical response of the brain to auditory stimuli delivered at fast rates (30 ‐ 50 responses/s). The aim of this study was to evaluate the effect of 0.26‐0.50% isoflurane on the ASSR and on consciousness, defined as responsiveness to verbal commands. Methods Ten volunteers (21 ‐ 31 yr) participated. Isoflurane was administered at three stable, end‐tidal concentrations: 0.26%, 0.38%, and 0.50%. The ASSR in response to 18,000 stimuli (500‐Hz tonebursts, 10 ms, 82‐dB, the right ear, 35 ‐ 45 bursts/s) was recorded from the vertex with reference to the right mastoid. Recordings were made during baseline, at each isoflurane concentration, and during recovery. Results The mean (SD) ASSR amplitudes were 0.32 (0.23) [micro sign]V during baseline, 0.24 (0.17) [micro sign]V during 0.26% isoflurane, 0.09 (0.05) [micro sign]V during 0.38% isoflurane, 0.04 (0.03) [micro sign]V during 0.50% isoflurane, and 0.29 (0.33) [micro sign]V during recovery. The amplitude during baseline and recovery was larger than during 0.38% and 0.50% isoflurane (P < 0.001). The amplitude at 0.26% was larger than at the other concentrations (P < 0.025). The logarithm of the ASSR amplitude was related linearly to the concentration of isoflurane (r = 0.85; P < 0.0001). The prediction probability (Pk) for loss of consciousness was 0.95 for both ASSR and measured isoflurane concentration. An ASSR amplitude < 0.07 [micro sign]V was always associated with unconsciousness. Conclusions The ASSR is attenuated in a concentration‐dependent manner by isoflurane. Suppression of consciousness and maximal attenuation of ASSR occur in the same isoflurane concentration range. Profound attenuation of ASSR appears to reflect unconsciousness, defined as unresponsiveness to verbal commands.

Critical involvement of the thalamus and precuneus during restoration of consciousness with physostigmine in humans during propofol anaesthesia: a positron emission tomography study

BACKGROUND Functional brain imaging offers a way to investigate how general anaesthetics impair consciousness. However, functional imaging changes may result from drug effects unrelated to hypnosis. Establishing a causal link with loss of consciousness is thus difficult. METHODS To identify changes of neuronal activity functionally linked to the level of consciousness, physostigmine was used to restore consciousness without changing the anaesthetic concentration in 11 subjects anaesthetized with propofol. Eight subjects (responders) regained consciousness after physostigmine and three did not (non-responders). Positron emission tomography was used to measure regional cerebral blood flow (rCBF); during baseline (awake), after anaesthesia-induced loss of consciousness, after physostigmine administration, and recovery. In addition to subtraction analyses, we used conjunction analysis in the responders to identify changes common to the baseline-anaesthesia and physostigmine-anaesthesia contrasts. RESULTS Complete data were available for seven subjects (four responders and three non-responders). The analyses revealed that unconsciousness was associated with rCBF decreases in the thalamus and precuneus. Restoration of consciousness by physostigmine was associated with rCBF increases in these same structures, with the strongest effect in the thalamus. CONCLUSIONS The results provide strong evidence that reductions in rCBF in the thalamus and precuneus are functionally related to propofol-induced unconsciousness independently of any non-specific effects of propofol. These observations confirm that the thalamus and precuneus are key elements to understand how general anaesthetics cause unconsciousness and how patients wake up from anaesthesia. Furthermore, they are consistent with the notion that anaesthetic-induced unconsciousness is associated with reduced cholinergic activation.

Patient controllediv analgesia is an acceptable pain management strategy in morbidly obese patients undergoing gastric bypass surgery. A retrospective comparison with epidural analgesia

PurposeTo examine the hypothesis that pain treatment with patient controlled analgesia (PCA) usingiv morphine is a suitable and safe alternative to epidural analgesia in morbidly obese patients undergoing gastric bypass surgery. We retrospectively compared the postoperative periods in all patients undergoing this procedure in our institution between November 1999 and November 2001.MethodsAccording to their perioperative pain treatment, patients were assigned to a PCA group (withiv morphine) or an epidural analgesia group, in which patients received either intermittent doses of morphine or continuous infusions of bupivacaine/fentanyl. Study endpoints included quality of pain control, incidence of cardiovascular and respiratory complications, analgesia related side effects, time to ambulation and first flatus, length of hospital stay, and wound infections.ResultsData from 86 patients were analyzed with 40 patients in the PCA group and 46 patients in the epidural group. Groups were similar with respect to age, body mass index, and gender. The type of analgesia did not affect the quality of pain control at rest, the frequency of nausea and pruritus, the time to ambulation and return of gastrointestinal function, and the length of hospital stay. Patients receiving epidural analgesia had a greater risk of wound infection than subjects with PCA (epidural group: 39%, PCA group: 15%,P = 0.01).ConclusionWe conclude that in grossly obese patients undergoing gastric bypass surgery PCA withiv morphine is an acceptable strategy for pain management and may confer some advantages when compared to epidural analgesia.RésuméObjectifVérifier l’hypothèse voulant que le traitement de la douleur par l’analgésie autocontrôlée (AAC), avec de la morphine iv soit appropriée et sans risque pour remplacer l’analgésie péridurale chez les patients atteints d’obésité morbide qui subissent un pontage gastrique.MéthodeNous avons comparé, rétrospectivement, la période postopératoire pour tous les patients qui ont subi cette intervention à notre institution entre novembre 1999 et novembre 2001. Selon l’analgésie périopératoire reçue, les patients ont été assignés à un groupe d’AAC (avec de la morphine iv ) ou à un groupe d’analgésie péridurale, soit avec des doses de morphine intermittentes, soit des perfusions continues de bupivacaïne/fentanyl. Les paramètres étudiés ont été la qualité de l’analgésie, l’incidence de complications cardiovasculaires et respiratoires, les effets secondaires reliés à l’analgésie, la durée écoulée avant le premier lever et le retour du péristaltisme gastrointestinal, la durée du séjour hospitalier et les infections de la plaie chirurgicale.RésultatsLes données de 86 patients ont été analysées, 40 du groupe d’AAC et 46 du groupe d’analgésie péridurale. Les groupes étaient comparables quant à l’âge, l’index de masse corporelle et le sexe. Le type d’analgésie n’a pas affecté la qualité de l’analgésie au repos, la fréquence de nausée et de prurit, le temps écoulé avant de pouvoir se lever et avant le retour du péristaltisme gastrointestinal, et la longueur du séjour hospitalier. Les patients sous analgésie péridurale présentaient un risque plus élevé d’infection de la plaie que les sujets sous AAC (péridurale : 39%, AAC : 15%, P = 0,01).ConclusionChez les patients très obèses, devant subir un pontage gastrique, l’AAC avec de la morphine iv est une stratégie d’analgésie acceptable et peut présenter certains avantages par rapport à l’analgésie péridurale.

Neostigmine decreases heart rate in heart transplant patients

PurposeThis study evaluated the effect of neostigmine on heart rate in cardiac transplant patients.MethodsNeostigmine (2.5–50 μg · kg−1) was administered to ASA 1 or 2 patients with normally innervated hearts (controls), and to patients who had undergone recent (<six months before study) or remote (> six months before study) cardiac transplantation.ResultsBaseline heart rate was 66 ± 3 beats · min−1 in controls (n = 10, mean ± SEM), which was slower than that observed in recently (95 ± 4 beats · min−1, n = 15, P < 0.001) and in remotely (88 ± 3 beats · min−1, n = 16, P < 0.001) transplanted patients. Neostigmine produced a dose-dependent decrease in heart rate in all patients. Controls were the most sensitive to neostigmine, with a 10% decrease in heart rate produced by an estimated dose of 5.0 ± 1.0 μg · kg−1. The recently transplanted group was the least sensitive, with the maximum dose producing only an 8.3 ± 0.9% reduction. The response to neostigmine of the remotely transplanted patients was variable. The estimated dose to produce a 10% decrease in heart rate in this group was 24 ± 6 μg · kg−1 which was greater than that for controls (P = 0.008). Administration of atropine (1.2 mg) reversed the neostigmine-induced bradycardia in all three groups. Reversal of the bradycardia consisted of a transient peak increase in heart rate in controls to 145 ± 6% of baseline, a value which was greater than that observed in recent (103 ± 1%, P < 0.001) and in remote (109 ± 3%, P < 0.001) transplants.ConclusionsNeostigmine produces a dose-dependent brady-cardia in heart transplant patients. Some remotely transplanted patients may be particularly sensitive to the bradycardic effects of neostigmine.RésuméObjectifEvaluer les effets de la néostigmine sur les transplantés cardiaques.MéthodesDe la néostigmine (2,5–50 μg · kg−1) a été administrée à des patients ASA 1 ou 2 dont le coeur était innervé normalement (contrôles) et à des patients qui avaient subi une transplantation cardiaque récente (<six mois) ou plus ancienne.RésultatsLa fréquence cardiaque de base était de 66 ± 3 b · min−1 (n = 10, moyenne ± SEM) laquelle était inférieure à celle des transplantés récents (95 ± 4 b · min−1, n = 15, P < 0,001). La néostigmine a produit une baisse de la fréquence proportionnelle à la dose chez tous les patients. Les contrôles ont été plus sensibles à la néostigmine, avec une baisse de 10% produite par une dose estimée de 5,0 ± 1,0 μg · kg−1. Les transplantés récents ont été les moins sensibles, alors que la dose maximale ne produisait qu’une baisse de 8,3 ± 0,9%. La réponse à la néostigmine des transplantés plus anciens a été variable. La dose estimée, pour produire une baisse de 10% de la fréquence cardiaque, plus élevée que pour les contrôles, était de 24 ± 6 μg · kg−1 (P = 0,008). L’administration d’atropine a neutralisé la bradycardie induite par le néostigmine chez les trois groupes. L’antagonisme de la bradycardie a été caractérisé par une augmentation transitoire de la fréquence cardiaque à 145 ± 6% de la valeur initiale dans le groupe contrôle, valeur plus importante que chez les transplantés récents (103 ± 1%, P < 0,001) et anciens (108 ± 3%, P < 0,001).ConclusionsLe néostigmine produit une bradycardie proportionnelle à la dose chez le transplanté cardiaque. Quelques uns des transplantés plus anciens peuvent être plus particulièrement sensibles aux effets bradycardisants de la néostigmine.

Autonomic Nervous System Response to Epidural Analgesia in Laboring Patients by Wavelet Transform of Heart Rate and Blood Pressure Variability

Background:Epidurals are effective in relieving labor pain but result in a sympathectomy that may compromise maternal hemodynamic stability and fetal perfusion. Decreases in blood pressure and heart rate can be corrected, but markers of autonomic activity would be useful to predict and prevent such changes. The goal of this study was to find markers describing the changes in autonomic nervous system activity with epidural anesthesia in laboring patients. Methods:The authors analyzed heart rate variability and blood pressure variability in 13 laboring patients using wavelet transform, a time-frequency analysis that accommodates rapid changes in autonomic activity. Heart rate and blood pressure variability were obtained 5 min before and 10 min after injection of 20 ml bupivacaine, 0.125%, and 50 &mgr;g fentanyl in the epidural space. Results:Blood pressure and heart rate were not affected by epidural analgesia. However, high-frequency power of heart rate variability increased after epidural (increase in parasympathetic drive). The ratio of low-frequency:high-frequency power of heart rate variability decreased. High- and low-frequency power of blood pressure variability decreased (decrease in sympathetic outflow). Conclusions:Indices of parasympathetic and sympathetic activity after neuraxial blockade in laboring patients can be obtained by analysis of both heart rate variability and blood pressure variability. The analysis by wavelet transform can discern changes in autonomic activity when values of blood pressure and heart rate do not vary significantly. Whether this technique could be used to predict and prevent hemodynamic compromise after neuraxial blockade merits further studies.

Attenuation of the 40-hertz auditory steady state response by propofol involves the cortical and subcortical generators.

Background:The 40-Hz auditory steady state response (40-Hz ASSR) provides a reliable marker of anesthetic-induced unconsciousness. Brain electric source analysis indicates that the 40-Hz ASSR arises from cortical and subcortical generators. The authors used source analysis to assess the effect of propofol anesthesia on the cerebral generators of the 40-Hz ASSR. They also examined the effect of propofol on two auditory evoked potentials of cortical origin: the N1 and the sustained potential. Methods:Eleven healthy human volunteers were anesthetized with propofol given in target-concentration mode at the minimal concentration causing unconsciousness. The 40-Hz ASSR was recorded before, during, and after anesthesia. The source model consisted of five concurrently active generator dipoles: two in the contralateral auditory cortex (one tangentially oriented, one radially oriented), two in the ipsilateral auditory cortex (same orientations), and one in the midline brainstem. Results:During anesthesia, the strength of the cortical and brainstem dipoles was reduced to the same extent (to 54% of baseline for the four cortical dipoles pooled vs. 53% for the brainstem dipole). Dipole strength during anesthesia was significantly less (P < 0.01) than during baseline and recovery for both cortical and brainstem dipoles. The N1 and sustained potential were no longer recordable during anesthesia. Conclusions:The attenuation of the 40-Hz ASSR during propofol anesthesia results from a reduction of similar magnitude of the activity of the cortical and brainstem generators. The N1 and sustained potential are so profoundly attenuated during propofol anesthesia that they are no longer recordable from the scalp.