Pierre Fiset

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.

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.

Oxygen venous embolism after the use of hydrogen peroxide during lumbar discectomy

PurposeThe knee-prone position is commonly used for patients undergoing spinal surgery. Venous air embolism m such a position may be produced by the negative venous pressure gradient between the ambient air and the venous plexuses of the spinous process. When hydrogen peroxide is used to deanse the wound, oxygen is produced. We report a case of suspected oxygen venous embolism during lumbar discectomy in the knee-prone position after use of H2O2.Clinical FeaturesImmediately after irngation of a discectomy wound with H2O2. a dramatic decrease of the PETCO2, blood pressure and oxygen saturation coincident with ST segment elevation occurred suggesting a coronary gas embolism. Symptomatic treatment was initiated immediately and the patient recovered without any sequelae.ConclusionAlthough hydrogen peroxide has an innocuous reputation, cases of accidental ingestion or massive gas embolism after wound irngation leading to death have been reported. A review of the literature suggests that many of the clinical and physiopathological features of air and oxygen emboli are similar. For both, measures of prevention and treatment of complications are similar. We argue that the use of hydrogen peroxide should be avoided during procedures where the position of the patient (sitting, knee-prone) increases the risk of gas embolism and that hydrogen peroxide is a potentially dangerous solution.RésuméObjectifLa position genupectorale est fréquemment utilisée pour la chirurgie de la colonne vertébrale. Dans cette position, l’embolie gazeuse peut être causée par la création d’un gradient veineux négatif entre l’air ambiant et les plexus des apophyses épineuses. Nettoyer une plaie avec du peroxyde d’hydrogène dégage de l’oxygène. Nous rapportons un cas d’embolie veineuse causée par de l’oxygène associé à l’utilisation de H2O2 pendant une discoïdectomie lombaire en position genupectorale.Éléments cliniquesImmédiatement après l’irngation d’une plaie de discoïdectomie avec du H2O2, une chute dramatique de la PETCO2, de la pression arténelle et de la saturation en oxygène est survenue en même temps qu’une dépression du segment ST suggérant une embolie gazeuse coronanenne. Le traitement symptomatique a été initié immédiatement et le patient a récupéré sans aucune séquelle.ConclusionMalgré sa réputation d’innocuité, on a rapporté des cas d’embolies massives fatales après l’mgestion accidentelle de peroxyde d’hydrogène ou après une irrigation de plaie avec ce produit. Une revue de la littérature suggère que plusieurs des caractéristiques cliniques et physiopathologiques des embolies aériennes et d’oxygène sont identiques. Dans les deux cas, les mesures préventives et curatives sont les mêmes. Nous croyons qu’il faut éviter d’utiliser le peroxyde d’hydrogène pendant des interventions où la position du patient (assise, genupectorale) augmente le nsque d’embolie gazeuse et qu’une solution de peroxyde d’hydrogène pourrait être dangereuse sous ces conditions.

Brain imaging in research on anesthetic mechanisms: studies with propofol.

Brain imaging helps to refine our understanding of the anesthetic effect and is providing novel information that result in the formulation of hypotheses. They have shown that anesthetics act on specific structures that have been known to be important for consciousness at large. They have also helped to show that anesthetics act on specific structures regionally, rather than being non-specific, general depressant of the central nervous system (CNS). A constant finding is that the drugs that we use seem to exert their action on specific sites within the CNS. This is true for a wide variety of drugs like midazolam, anesthetic vapors and opiates. The thalamus has consistently shown marked deactivation coincident with the anesthesia-induced loss of consciousness, appearing to be a very important target of anesthetic effect. Additionally, when vibro-tactile or pain stimulation is given, anesthetics significantly effect cortical structures even before loss of consciousness while loss of transmission at the thalamic level seems to coincide with loss of consciousness. Finally, the use of radioligands allow in vivo characterization of anesthetic effects on neurotransmitter systems.

Cholinergic mechanisms mediating anesthetic induced altered states of consciousness

Publisher Summary A host of central neurotransmitter systems subserving γ-aminobutyric acid (GABA)ergic, glutamatergic, adrenergic, serotonergic, and cholinergic transmission are likely affected by anesthetics. Anesthetic drugs interfere with cholinergic processes associated with altered states of consciousness. For example, administration of opiates, halothane, isoflurane, and enflurane are associated with decreased acetylcholine (ACh) release from neurones in the laterodorsal and pedunculopontine tegmental (LDT/PPT) nuclei projecting to the medial pontine reticular formation. Conversely, drugs that directly affect cholinergic activity also influence minimum alveolar concentration (MAC). There is one possibility that general anesthetics interfere directly with cholinergic transmission to produce unconsciousness. A series of experiments presented focuses on a hypothesis that the loss of consciousness produced by anesthetic drugs involves depression, directly or indirectly, of central cholinergic transmission. It was investigated whether physostigmine, a centrally-acting anticholinesterase, reverses the loss of consciousness produced by continuous administration of anesthetic drugs. In addition, it was determined whether the reversal was blocked by scopolamine, a nonselective centrally-acting muscarinic antagonist.

Ectomesenchymal Chondromyxoid Tumour of the Posterior Tongue

Ectomesenchymal chondromyxoid tumor (ECMT) is a rare benign neoplasm arising in the tongue. With only 45 cases reported in the literature, there are several unique features defining this lesion. Firstly, almost all patients present with an asymptomatic slow growing mass on the anterior dorsum of the tongue. At the microscopic level, it is recognizable as a well-circumscribed unencapsulated proliferation of uniform round to fusiform cells embedded in a chondromyxoid matrix. Lastly, the immunohistochemistry profile is characterised by positivity for glial fibrillary acidic protein and frequent positivity for S-100 and cytokeratins. We report a case of a mass located on the posterior dorsum of the tongue and meeting the aforementioned morphological and immunohistochemical criteria of ECMT.

Local induction of a specific Th1 immune response by allergen linked immunostimulatory DNA in the nasal explants of ragweed-allergic subjects.

BACKGROUND Allergen immunotherapy is effective in allergic individuals however efforts are being made to improve its safety, convenience, and efficacy. It has recently been demonstrated that allergen-linked immunostimulatory DNA (ISS) is effective in stimulating an allergen-specific Th1 response with decreased allergenicity. The objective of this study is to investigate whether ISS linked to purified ragweed allergen Amb-a-1 (AIC) can inhibit local allergen-specific Th2 and induce allergen-specific Th1 responses in explanted nasal mucosa of ragweed-sensitive subjects. In addition, we set out to determine whether AIC is more effective compared to stimulation with unlinked Amb a 1 and ISS. METHODS Tissue from ragweed-sensitive patients (n=12) was cultured with whole ragweed allergen (RW), Amb-a-1, AIC, Amb-a-1 and ISS (unlinked), or tetanus toxoid (TT) for 24 hours. IL-4, -5, -13, TNF-α and IFN-γ mRNA-positive cells were visualized by in situ hybridization and T cells, B cells and neutrophils were enumerated using immunocytochemistry. RESULTS RW or Amb-a-1 increased the number of IL-4, IL-5, and IL-13 mRNA+cells in the tissue compared to medium alone. AIC had similar cytokine mRNA reactivity as control tissue. AIC and TT increased IFNγ-mRNA expression. Unlinked Amb-a-1 and ISS showed similar effects to AIC, however this response was weaker. The number of TNF mRNA+ cells, T cells, B cells and neutrophils remained unchanged. CONCLUSIONS AIC is effective in stimulating a local allergen-specific Th1- and abolishing Th2-cytokine mRNA reactivity in the nose and may be considered as a strong candidate for an improved approach to immunotherapy in ragweed-sensitive individuals.BACKGROUND Allergen immunotherapy is effective in allergic individuals however efforts are being made to improve its safety, convenience, and efficacy. It has recently been demonstrated that allergen-linked immunostimulatory DNA (ISS) is effective in stimulating an allergen-specific Th1 response with decreased allergenicity. The objective of this study is to investigate whether ISS linked to purified ragweed allergen Amb-a-1 (AIC) can inhibit local allergen-specific Th2 and induce allergen-specific Th1 responses in explanted nasal mucosa of ragweed-sensitive subjects. In addition, we set out to determine whether AIC is more effective compared to stimulation with unlinked Amb a 1 and ISS. METHODS Tissue from ragweed-sensitive patients (n = 12) was cultured with whole ragweed allergen (RW), Amb-a-1, AIC, Amb-a-1 and ISS (unlinked), or tetanus toxoid (TT) for 24 hours. IL-4, -5, -13, TNF-alpha and IFN-gamma mRNA-positive cells were visualized by in situ hybridization and T cells, B cells and neutrophils were enumerated using immunocytochemistry. RESULTS RW or Amb-a-1 increased the number of IL-4, IL-5, and IL-13 mRNA+ cells in the tissue compared to medium alone. AIC had similar cytokine mRNA reactivity as control tissue. AIC and TT increased IFNgamma-mRNA expression. Unlinked Amb-a-1 and ISS showed similar effects to AIC, however this response was weaker. The number of TNF mRNA+ cells, T cells, B cells and neutrophils remained unchanged. CONCLUSIONS AIC is effective in stimulating a local allergen-specific Th1- and abolishing Th2-cytokine mRNA reactivity in the nose and may be considered as a strong candidate for an improved approach to immunotherapy in ragweed-sensitive individuals.

Research on anesthesia, consciousness or both? Understanding our anesthetic drugs and defining the neural substrate

ConclusionIt is fundamental for our specialty to elucidate the mechanisms by which anesthetic drugs exert their action. It now seems that anesthesia is not the result of a generalized and non-specific action of drugs on the CNS, but occurs due to a complex action on cell membranes, specific ion channels and discrete parts of the CNS. The fact that we can induce discrete and dose-specific effects on attention, pain appreciation, memory, complex cognitive functions or consciousness itself suggests that our drugs act on specific parts of the CNS. From a broader perspective, it also means that we can use our clinical expertise to induce controlled modulation of cognitive functions in order to uncover their neural correlates. In the end, research on anesthetic mechanisms and consciousness are not dissociable because understanding our tools also helps to define the substrate.