Anesthesia-induced Changes Research Articles

Transforming Growth Factor β1 Ameliorates Microglial Activation in Perioperative Neurocognitive Disorders.

Perioperative neurocognitive disorder (PND) is a common complication of surgery and anesthesia, especially among older patients. Microglial activation plays a crucial role in the occurrence and development of PND and transforming growth factor beta 1 (TGF-β1) can regulate microglial homeostasis. In the present study, abdominal surgery was performed on 12-14 months-old C57BL/6 mice to establish a PND model. The expression of TGF-β1, TGF-β receptor 1, TGF-β receptor 2, and phosphor-smad2/smad3 (psmad2/smad3) was assessed after anesthesia and surgery. Additionally, we examined changes in microglial activation, morphology, and polarization, as well as neuroinflammation and dendritic spine density in the hippocampus. Behavioral tests, including the Morris water maze and open field tests, were used to examine cognitive function, exploratory locomotion, and emotions. We observed decreased TGF-β1 expression after surgery and anesthesia. Intranasally administered exogenous TGF-β1 increased psmad2/smad3 colocalization with microglia positive for ionized calcium-binding adaptor molecule 1. TGF-β1 treatment attenuated microglial activation, reduced microglial phagocytosis, and reduced surgery- and anesthesia-induced changes in microglial morphology. Compared with the surgery group, TGF-β1 treatment decreased M1 microglial polarization and increased M2 microglial polarization. Additionally, surgery- and anesthesia-induced increase in interleukin 1 beta and tumor necrosis factor-alpha levels was ameliorated by TGF-β1 treatment at postoperative day 3. TGF-β1 also ameliorated cognitive function after surgery and anesthesia as well as rescue dendritic spine loss. In conclusion, surgery and anesthesia induced decrease in TGF-β1 levels in older mice, which may contribute to PND development; however, TGF-β1 ameliorated microglial activation and cognitive dysfunction in PND mice.

Ketone supplementation abolished isoflurane anesthesia-induced elevation in blood glucose level and increased recovery time from anesthesia in Wistar Albino Glaxo Rijswijk rats

BackgroundIt has been suggested that administration of exogenous ketone supplements (EKSs) not only increases blood ketone body levels but also decreases blood glucose level and modulates isoflurane-induced anesthesia in different rodents, such as Wistar Albino Glaxo Rijswijk (WAG/Rij) rats. Thus, we investigated whether administration of EKSs can modulate the isoflurane anesthesia-generated increase in blood glucose level and the time required to recover from isoflurane-induced anesthesia.MethodsTo investigate the effect of EKSs on isoflurane anesthesia-induced changes in blood glucose and R-β-hydroxybutyrate (R-βHB) level as well as recovery time from anesthesia, we used KEMCT (mix of ketone ester/KE and medium chain triglyceride/MCT oil in a 1:1 ratio) in WAG/Rij rats. First, to accustom the animals to the method, water gavage was carried out for 5 days (adaptation period). After adaptation period, rats of first group (group 1) were gavaged by water (3 g/kg), whereas, in the case of second group (group 2), the diet of animals was supplemented by KEMCT (3 g/kg, gavage) once per day for 7 days. One hour after the last gavage, isoflurane (3%) anesthesia was induced for 20 min (group 1 and group 2) and the time required for recovery from anesthesia was measured by using righting reflex. Subsequently, blood levels of both R-βHB and glucose were also evaluated. Changes in blood glucose and R-βHB levels were compared to control, which control glucose and R-βHB levels were measured on the last day of the adaptation period (group 1 and group 2). Time required for recovery from isoflurane anesthesia, which was detected after 7th KEMCT gavage (group 2), was compared to recovery time measured after 7th water gavage (group 1).ResultsThe KEMCT maintained the normal glucose level under isoflurane anesthesia-evoked circumstances preventing the glucose level elevating effect of isoflurane. Thus, we demonstrated that administration of KEMCT not only increased blood level of R-βHB but also abolished the isoflurane anesthesia-generated increase in blood glucose level. Moreover, the time required for recovery from isoflurane-evoked anesthesia increased significantly in KEMCT treated animals.ConclusionsPutative influence of elevated blood ketone body level on isoflurane-evoked effects, such as modulation of blood glucose level and recovery time from anesthesia, should be considered by anesthesiologists.

Identification of Brain Regions Activated by Sevoflurane and Propofol and Regional Changes in Gene Expression.

General anesthetics have different efficacies and side effect incidences based on their mechanism of action. However, detailed comparative studies of anesthetics are incomplete. In this study, target brain regions and gene expression changes in these brain regions were determined for sevoflurane and propofol to understand the mechanisms that cause differences among anesthetics. Rats were anesthetized with sevoflurane or propofol for 1 hr, and brain regions with anesthesia-induced changes in neuronal activity were examined by immunohistochemistry and in situ hybridization for c-Fos. Among the identified target brain regions, gene expression analysis was performed in the habenula, the solitary nucleus and the medial vestibular nucleus from laser microdissected samples. Genes altered by sevoflurane and propofol were different and included genes involved in the incidence of postoperative nausea and vomiting and emergence agitation, such as Egr1 and Gad2. GO enrichment analysis showed that the altered genes tended to be evenly distributed in all functional category. The detailed profiles of target brain regions and induced gene expression changes of sevoflurane and propofol in this study will provide a basis for analyzing the effects of each anesthetic agent and the risk of adverse events.

The mTOR Inhibitor Rapamycin Prevents General Anesthesia-Induced Changes in Synaptic Transmission and Mitochondrial Respiration in Late Postnatal Mice

Preclinical animal studies have continuously reported the possibility of long-lasting neurotoxic effects after general anesthesia in young animals. Such studies also show that the neurological changes induced by anesthesia in young animals differ by their neurodevelopmental stage. Exposure to anesthetic agents increase dendritic spines and induce sex-dependent changes of excitatory/inhibitory synaptic transmission in late postnatal mice, a critical synaptogenic period. However, the mechanisms underlying these changes remain unclear. Abnormal activation of the mammalian target of rapamycin (mTOR) signaling pathway, an important regulator of neurodevelopment, has also been shown to induce similar changes during neurodevelopment. Interestingly, previous studies show that exposure to general anesthetics during neurodevelopment can activate the mTOR signaling pathway. This study, therefore, evaluated the role of mTOR signaling after exposing postnatal day (PND) 16/17 mice to sevoflurane, a widely used inhalation agent in pediatric patients. We first confirmed that a 2-h exposure of 2.5% sevoflurane could induce widespread mTOR phosphorylation in both male and female mice. Pretreatment with the mTOR inhibitor rapamycin not only prevented anesthesia-induced mTOR phosphorylation, but also the increase in mitochondrial respiration and male-dependent enhancement of excitatory synaptic transmission. However, the changes in inhibitory synaptic transmission that appear after anesthesia in female mice were not affected by rapamycin pretreatment. Our results suggest that mTOR inhibitors may act as potential therapeutic agents for anesthesia-induced changes in the developing brain.

Intraoperative Transesophageal Echocardiography in Tricuspid Valve Surgery

Imaging the tricuspid valve (TV) using transesophageal echocardiography (TEE) seems more difficult than imaging other cardiac valves due to not only the complex valvular structure but also the anterior, far-field distance from the probe. The focus of the TEE during the surgery would not be much different from that of preoperative TEE. However, the anesthesia-induced changes of ventricular contractility, filling status, and vascular resistance should be considered when interpreting the images. Here, we thoroughly reviewed the major issues in the preand post-cardiopulmonary bypass intraoperative TEE in the TV surgery. Ultimately, a real-time intraoperative TEE monitoring should involve a simple or less time-consuming analysis which gives quick on-site information regarding the cardiac or hemodynamic status, communicating with the surgeon to lead to an optimal process. Keywords: Intraoperative; Echocardiography, Transesophageal; Tricuspid valve

Intranasal Insulin Increases Synaptic Protein Expression and Prevents Anesthesia-Induced Cognitive Deficits Through mTOR-eEF2 Pathway.

General anesthesia increases the risk for cognitive impairment and Alzheimer's disease (AD) in vulnerable individuals such as the elderly. We previously reported that prior administration of insulin through intranasal delivery can prevent the anesthesia-induced cognitive impairment and biochemical changes in the brain. However, little is known about the underlying molecular mechanisms. Here, we report that general anesthesia resulted in downregulation of mammalian/mechanistic target of rapamycin (mTOR) and eukaryotic elongation factor 2 (eEF2) in the brain along with reduction of presynaptic proteins and brain-derived neurotrophic factor and cognitive impairment in aged mice. Prior administration of intranasal insulin prevented these anesthesia-induced changes. These results suggest the involvement of the mTOR-eEF2 signaling pathway in the anesthesia-induced brain changes and cognitive impairment and in the prevention of these changes with insulin. Correlation analyses and the use of eEF2 kinase inhibitor further support our conclusions. These studies shed light on the molecular mechanism by which anesthesia and insulin could act on synaptic proteins and cognitive function.

Auditory Predictive Coding across Awareness States under Anesthesia: An Intracranial Electrophysiology Study.

The systems-level mechanisms underlying loss of consciousness (LOC) under anesthesia remain unclear. General anesthetics suppress sensory responses within higher-order cortex and feedback connections, both critical elements of predictive coding hypotheses of conscious perception. Responses to auditory novelty may offer promise as biomarkers for consciousness. This study examined anesthesia-induced changes in auditory novelty responses over short (local deviant [LD]) and long (global deviant [GD]) time scales, envisioned to engage preattentive and conscious levels of processing, respectively. Electrocorticographic recordings were obtained in human neurosurgical patients (3 male, 3 female) from four hierarchical processing levels: core auditory cortex, non-core auditory cortex, auditory-related, and PFC. Stimuli were vowel patterns incorporating deviants within and across stimuli (LD and GD). Subjects were presented with stimuli while awake, and during sedation (responsive) and following LOC (unresponsive) under propofol anesthesia. LD and GD effects were assayed as the averaged evoked potential and high gamma (70-150 Hz) activity. In the awake state, LD and GD effects were present in all recorded regions, with averaged evoked potential effects more broadly distributed than high gamma activity. Under sedation, LD effects were preserved in all regions, except PFC. LOC was accompanied by loss of LD effects outside of auditory cortex. By contrast, GD effects were markedly suppressed under sedation in all regions and were absent following LOC. Thus, although the presence of GD effects is indicative of being awake, its absence is not indicative of LOC. Loss of LD effects in higher-order cortical areas may constitute an alternative biomarker of LOC.SIGNIFICANCE STATEMENT Development of a biomarker that indexes changes in the brain upon loss of consciousness (LOC) under general anesthesia has broad implications for elucidating the neural basis of awareness and clinical relevance to mechanisms of sleep, coma, and disorders of consciousness. Using intracranial recordings from neurosurgery patients, we investigated changes in the activation of cortical networks involved in auditory novelty detection over short (local deviance) and long (global deviance) time scales associated with sedation and LOC under propofol anesthesia. Our results indicate that, whereas the presence of global deviance effects can index awareness, their loss cannot serve as a biomarker for LOC. The dramatic reduction of local deviance effects in areas beyond auditory cortex may constitute an alternative biomarker of LOC.

Multi-modal analysis of functional connectivity and cerebral blood flow reveals shared and unique effects of propofol in large-scale brain networks

Anesthesia-induced changes in functional connectivity and cerebral blow flow (CBF) in large-scale brain networks have emerged as key markers of reduced consciousness. However, studies of functional connectivity disagree on which large-scale networks are altered or preserved during anesthesia, making it difficult to find a consensus amount studies. Additionally, pharmacological alterations in CBF could amplify or occlude changes in connectivity due to the shared variance between CBF and connectivity. Here, we used data-driven connectivity methods and multi-modal imaging to investigate shared and unique neural correlates of reduced consciousness for connectivity in large-scale brain networks. Rs-fMRI and CBF data were collected from the same subjects during an awake and deep sedation condition induced by propofol. We measured whole-brain connectivity using the intrinsic connectivity distribution (ICD), a method not reliant on pre-defined seed regions, networks of interest, or connectivity thresholds. The shared and unique variance between connectivity and CBF were investigated. Finally, to account for shared variance, we present a novel extension to ICD that incorporates cerebral blood flow (CBF) as a scaling factor in the calculation of global connectivity, labeled CBF-adjusted ICD). We observed altered connectivity in multiple large-scale brain networks including the default mode (DMN), salience, visual, and motor networks and reduced CBF in the DMN, frontoparietal network, and thalamus. Regional connectivity and CBF were significantly correlated during both the awake and propofol condition. Nevertheless changes in connectivity and CBF between the awake and deep sedation condition were only significantly correlated in a subsystem of the DMN, suggesting that, while there is significant shared variance between the modalities, changes due to propofol are relatively unique. Similar, but less significant, results were observed in the CBF-adjusted ICD analysis, providing additional evidence that connectivity differences were not fully explained by CBF. In conclusion, these results provide further evidence of alterations in large-scale brain networks are associated with reduced consciousness and suggest that different modalities capture unique aspects of these large scale changes.

Effect of propofol anesthesia on resting state brain functional connectivity in Indian population with chronic back pain.

Functional magnetic resonance imaging (fMRI) studies in healthy volunteers have shown alterations in brain connectivity following anesthesia as compared to the awake state. It is not known if the anesthesia-induced changes in brain connectivity are different in a pathological state. This study aims to evaluate changes in the resting state functional connectivity in the brain, after propofol anesthesia, in patients with chronic back pain (CBP). Fourteen adults with CBP were included in this prospective study over 6 months. After excluding structural brain pathology, a resting state fMRI was performed in the awake state, and the sequences were repeated after propofol anesthesia. The primary outcome measure was change in resting state connectivity after propofol. Student's t-test was performed between the pre and post-propofol sedation data of all patients with total brain volume as covariates of interest. A repeated measures analysis of variance was used to compare pre- and post-propofol changes in cardiorespiratory parameters. There were 8 male and 6 female patients in the study, and the mean age of the study population was 46.9 ± 11.3 years. Propofol sedation resulted in an increased strength of functional connectivity between the posterior cingulate cortex (PCC) and thalamus in patients with CBP, whereas there was a generalized decrease in functional integration within the large scale brain networks. The changes in cardiorespiratory parameters before and after propofol administration were not statistically significant. Strengthening of functional connectivity was seen between PCC and thalamus with decrease in large scale brain networks following propofol anesthesia in patients with CBP. These changes are similar to those previously described in normal volunteers.

Alterations in Tear Biochemistry Associated with Postanesthetic Chronic Dry Eye Syndrome.

Perioperative dry eye syndrome (DES) is a common ocular complication of long-term general anesthesia. Chronic DES can lead to permanent damage to the cornea and disturbance of visual function, up to total loss of vision. Here, a relationship between the duration of general anesthesia and the risk of chronic DES in patients was demonstrated. Using an experimental model of perioperative corneal abrasions in rabbits, it was found that introduction of animals to 3-h general anesthesia resulted in clinically significant chronic damage to the cornea in 50% of cases. The development of the complication was not associated with irreversible or long-term impairment of tear secretion, but it was accompanied by a decrease in tear film stability and growth of the total protein content as well as decrease in total antioxidant activity of the tear induced by low molecular weight antioxidants. In addition, anesthesia-induced changes in activity of tear antioxidant enzymes including superoxide dismutase and enzymes providing homeostasis of reduced glutathione (glutathione peroxidase, glutathione-S-transferase, glutathione reductase) were observed. All these alterations were protracted (up to 1-2 weeks) and therefore might account for transition of the perioperative DES into the chronic form. These findings can be useful in the development of novel approaches for the prevention and treatment of chronic forms of DES in the postanesthetic period.

Eyeblink classical conditioning and BOLD fMRI of anesthesia-induced changes in the developing brain

Millions of children undergo general anesthesia each year in the USA alone, and a growing body of literature from animals and humans suggests that exposure to anesthesia at an early age can impact neuronal development, leading to learning and memory impairments later in childhood. Although a number of studies have reported behavioral and structural effects of anesthesia exposure during infancy, the functional manifestation of these changes has not been previous examined. In this study we used BOLD fMRI to measure the functional response to stimulation in the whisker barrel cortex of awake rabbits before and after learning a trace eyeblink classical conditioning paradigm. The functional changes, in terms of activated volume and time course, in rabbits exposed to isoflurane anesthesia during infancy was compared to unanesthetized controls when both groups reached young adulthood. Our findings show that whereas both groups exhibited decreased BOLD response duration after learning, the anesthesia-exposed group also showed a decrease in BOLD response volume in the whisker barrel cortex, particularly in the deeper infragranular layer. These results suggest that anesthesia exposure during infancy may affect the intracortical processes that mediate learning-related plasticity.

Anesthesia in children and adolescents with congenital heart defects

The incidence of congenital heart defects (CHD) has remained constant over many years; however, due to improved therapeutic options an increasing number of children and adolescents even with complex heart defects now reach adulthood. The increasing prevalence of adults with persisting or surgically corrected CHD as well as age-dependent non-cardiac comorbidities will increase the need for medical and non-cardiac surgical treatment in this population. Although elective medical care for these patients should be reserved for highly specialized centers, emergency treatment might become necessary in a non-specialized hospital setting as well. Due to the variety and complexity of CHD it is difficult to provide standardized guidelines for the anesthetic management. The treatment of patients with complex CHD requires a profound understanding of the underlying CHD and the current state of the hemodynamics by the anesthesiologist. Furthermore, typical comorbidities, such as chronic heart failure, altered coagulation and arrhythmia also have to be taken into account to ensure successful perioperative treatment. Especially in patients with shunt lesions or passive pulmonary blood flow the anesthetic management often substantially affects the hemodynamics and may be the starting point of severe decompensation. Awareness of anesthesia-induced changes of pulmonary and/or systemic vascular resistance as well as of preload alterations are the basis for successful anesthetic management. Finally, a multidisciplinary approach including cardiologists and radiologists in the planning is absolutely essential to achieve an optimal postoperative result for the patient.

Heartworm-positive dogs recover without complications from surgical sterilization using cardiovascular sparing anesthesia protocol

Expedited home placement of heartworm-positive shelter dogs is desirable and may outweigh the perceived increase in anesthetic risk for pre-adoption sterilization; however, this issue has not been addressed in the literature. Our goal was to determine whether heartworm-positive dogs suffered clinically evident perioperative complications after sterilization under general anesthesia. Anticipated complications could result from anesthesia-induced changes in pulmonary vascular resistance and cardiac output leading to signs of thromboembolic disease and even death from dislodged parasites. The medical records of 15 hemodynamically stable, intact, heartworm-positive, mixed-breed shelter dogs with no or mild clinical signs were examined. Pre-operative evaluation of patients included a complete blood count, clinical chemistry profile, heartworm antigen and microfilariae screen, electrocardiogram, and thoracic radiographs. The anesthetic protocol for heartworm-positive dogs included acepromazine (0.01–0.05mg/kg), butorphanol (0.1mg/kg IM) and meloxicam (0.2mg/kg IM), or carprofen (2mg/kg SQ) in the preanesthetic period; tiletamine/zolazepam (3–6mg/kg IV) or ketamine/diazepam (3–6mg/kg/0.25–5mg/kg IV) to effect for induction; maintenance on isoflurane or sevoflurane and oxygen. A lidocaine testicular block was performed on 11 males. All dogs were monitored postoperatively for a minimum of 24h and then daily until discharge. There were no clinically evident perioperative complications in heartworm-positive dogs. Purposeful pre-operative evaluation of heartworm-positive dogs while utilizing cardiovascular-sparing anesthetic protocols may allow clinicians to proceed with sterilization of hemodynamically stable heartworm-positive shelter dogs prior to heartworm treatment.

Evolution of Changes in Upper Airway Collapsibility during Slow Induction of Anesthesia with Propofol

Upper airway collapsibility is known to increase under anesthesia. This study assessed how this increase in collapsibility evolves during slow Propofol induction and how it relates to anesthesia-induced changes in upper airway muscle activity and conscious state. Nine healthy volunteers were studied. Anesthesia was induced with Propofol in a step-wise manner (effect-site concentration steps of 0.5 microg x ml(-1) from 0 to 3 microg x ml(-1) and thereafter to 4 microg x ml(-1) and 6 microg x ml(-1) [target-controlled infusion]). Airway patency was maintained with continuous positive airway pressure. Pharyngeal collapsibility was assessed at each concentration by measuring critical pressure. Intramuscular genioglossus electromyogram and anesthetic depth (bispectral index score) were monitored throughout. Loss of consciousness was defined as failure to respond to loud verbal command. Loss of consciousness occurred at varying Propofol effect-site concentrations between 1.5 and 4.0 microg x ml(-1). Initially genioglossus electromyographic activity was sustained with increases in Propofol concentration, increasing in some individuals. At or approaching loss of consciousness, it decreased, often abruptly, to minimal values with an accompanying increase in critical pressure. In most subjects, bispectral index score decreased alinearly with increasing Propofol concentration with greatest rate of change coinciding with loss of consciousness. Slow stepwise induction of Propofol anesthesia is associated with an alinear increase in upper airway collapsibility. Disproportionate decreases in genioglossus electromyogram activity and increases in pharyngeal critical closing pressure were observed proximate to loss of consciousness, suggesting that particular vulnerability exists after transition from conscious to unconscious sedation. Such changes may have parallels with upper airway behavior at sleep onset.

Isoflurane anesthesia inhibits clozapine- and risperidone-induced dopamine release and anesthesia-induced changes in dopamine metabolism was modified by fluoxetine in the rat striatum: An in vivo microdialysis study

Previously, we have reported that halothane anesthesia increases the extracellular concentrations of dopamine (DA) metabolites in the rat striatum using in vivo microdialysis techniques, and we have suggested that volatile anesthetics affect DA release and metabolism in various ways. The present investigation assesses the effect of isoflurane, widely used in clinical anesthesia, on DA release and metabolism. A microdialysis probe was implanted in the striatum of male Sprague–Dawley rats ( n = 5–7 per group). After recovery, the probe was perfused with modified Ringer's solution and 40 μl of dialysate were injected into a high performance liquid chromatograph every 20 min. The rats were given saline or the same volume of 10 mg kg −1 clozapine, risperidone, fluoxetine or citalopram. After the pharmacological treatment, the rats were anesthetized with 1.0% or 2.5% isoflurane for 1 h. The data were analyzed using two-way analysis of variance (ANOVA). For each drug with significant ( p < 0.05) drug–time interactions, the statistical analysis included one-way ANOVA and Newman–Keuls post hoc comparisons. A high concentration of isoflurane (2.5%) anesthesia increased the extracellular concentration of DA metabolites during emergence from anesthesia. The levels of DA metabolites increased in an isoflurane concentration-dependent manner. Isoflurane attenuated DA release induced by clozapine and risperidone. Fluoxetine, but not citalopram, antagonized the isoflurane-induced increase in metabolites. The results of current investigation suggest that isoflurane enhances presynaptic DA metabolism, and that the oxidation of DA might be partially modulated by the activities of the dopaminergic–serotonergic pathway at a presynaptic site in the rat striatum.

Dynamic changes of touch- and laser heat-evoked field potentials of primary somatosensory cortex in awake and pentobarbital-anesthetized rats

In this investigation, changes of mechanical- (MEP) and laser-evoked potentials (LEP) in rat primary somatosensory cortex during the course of pentobarbital (PB) anesthesia were examined. Temporal analysis of changes in the magnitude and latency of MEP and LEP, EEG activity, gross motor behaviors, and the tail flick response following laser stimulation before, during, and after PB administration (50 mg/kg, i.p.) was performed and correlated in chronically implanted rats. During the wakeful condition, there were two major cortical components each following mechanical stimulation (MEP1 and MEP2, n=17) and laser stimulation (LEP1 and LEP2, n=10), respectively. After PB administration, the positive peak in MEP1 was enhanced, and all other components disappeared. These components returned with different time courses. Two hours after PB administration, when the rat had spontaneous movements and flexor reflexes, LEP2 showed reversed polarity. MEP2 returned gradually 3 h after PB administration when the rat regained its ability to execute coordinated movements. After 4 h, LEP1 began to reappear and LEP2 returned to its negative polarity. We found that PB facilitated Aβ fiber-related cortical evoked potential (MEP1), while differentially inhibited Aδ and C fiber-related components (MEP2, LEP1 and LEP2). Characterization of these anesthesia-induced changes in cortical output may be useful in studying the neural basis of tactile and pain sensations.

Atelectasis and Chest Wall Shape during Halothane Anesthesia

Anesthesia produces atelectasis in the dependent areas of the lungs by mechanisms that remain unknown. It has been proposed that anesthesia produces a cephalad shift in the end-expiratory position of the diaphragm, which compresses the lungs and produces atelectasis. This study tested the hypothesis that the extent of atelectasis is correlated with the cephalad displacement of the dependent portion of the diaphragm produced by halothane anesthesia in healthy young human subjects. Twelve volunteers (mean age 34 yr) were studied while awake and during approximately 1.2 minimum alveolar concentration halothane anesthesia. Chest wall configuration was determined using images of the thorax obtained by three-dimensional fast computed tomography. Functional residual capacity was measured by a nitrogen dilution technique. Measurements were performed during quiet breathing in all subjects and after paralysis with 0.1 mg/kg vecuronium and mechanical ventilation in six subjects. Atelectasis was assumed to be present in regions of the lung that showed radiographic attenuation values similar to solid organs such as the liver. Atelectasis in dependent lung regions was not apparent in scans performed while the subjects were awake. Anesthesia with spontaneous breathing increased the volume of atelectasis measured at end-expiration by more than 1 ml in 9 of 12 subjects. For all subjects, the volume of atelectasis was 29 +/- 10 ml (M +/- SE), representing 0.67 +/- 0.23% of the total thoracic volume. The distribution of atelectasis varied along the cephalocaudal axis, with less atelectasis in more cephalad transverse sections. Paralysis and mechanical ventilation significantly decreased the volume of atelectasis present at end-expiration. There was no correlation between the average amount of cephalad displacement of the most dependent region of the diaphragm and the amount of atelectasis, nor was there any correlation between the amount of atelectasis and anesthesia-induced changes in the end-expiratory position of any chest wall structure. The dependent lung atelectasis produced by halothane anesthesia does not appear to be related to changes in the position of any single chest wall structure in these healthy young subjects, but rather to an interaction of several factors that remain to be identified.

Anesthesia-induced Changes in Regional Blood Flow: Implications for Drug Disposition

Anesthesia and anesthetics have the potential to influence drug pharmacokinetics through changes in body perfusion, hepatic and metabolic function, protein binding, and renal function. A chronically catheterized sheep preparation has been developed whereby blood flow through, and drug and oxygen extraction by, the heart and lungs, kidneys, gut, and liver can be measured. Thiopentone/halothane general anesthesia consistently decreased regional blood flow and extraction of test drugs by each of the organ groups. High subarachnoid anesthesia with tetracaine scarcely perturbed flow or function. Test drugs chosen were cefoxitin for kidney extraction, mepiridine for liver and kidney extraction, and chlormethiazole for liver, lung, and kidney extraction. It is suggested that the lack of effects of subarachnoid block on regional blood flow drug pharmacokinetics commend its use over general anesthesia for patients with limited cardiovascular or organ reserve. Further investigation of drug pharmacokinetics in surgical patients is still required so that deleterious effects are not experienced from drugs in use during the peroperative period.