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1.  Lactate Clearance in the Acutely Traumatized Patient 
Anesthesiology  2012;117(6):1162-1164.
doi:10.1097/ALN.0b013e31827334c2
PMCID: PMC3982586  PMID: 23168423
2.  Transfusion of Stored Autologous Blood Does Not Alter Reactive Hyperemia Index in Healthy Volunteers 
Anesthesiology  2012;117(1):56-63.
Background
Transfusion of human blood stored for over 2 weeks is associated with increased mortality and morbidity. During storage, packed erythrocytes progressively release hemoglobin, which avidly binds nitric oxide. We hypothesized that the nitric oxide mediated hyperemic response following ischemia would be reduced after transfusion of packed erythrocytes stored for 40 days.
Methods and results
We conducted a cross-over randomized interventional study, enrolling 10 healthy adults. Nine volunteers completed the study. Each volunteer received one unit of 40-day and one of 3-day stored autologous leukoreduced packed erythrocytes, on different study days according to a randomization scheme. Blood withdrawal and reactive hyperemia index measurements were performed before and 10 min, 1 h, 2 h, and 4 h after transfusion. The reactive hyperemia index during the first 4 h after transfusion of 40-day as compared to 3-day stored packed erythrocytes was unchanged. Plasma hemoglobin and bilirubin levels were higher after transfusion of 40-day than after 3-day stored packed erythrocytes (p = 0.02, [95% CI difference 10-114mg/l] and 0.001, [95% CI difference 0.6-1.5mg/dl], respectively). Plasma levels of potassium, Lactate dehydrogenase, haptoglobin, cytokines, as well as blood pressure, did not differ between the two transfusions and remained within the normal range. Plasma nitrite concentrations increased after transfusion of 40-day stored packed erythrocytes, but not after transfusion of 3-day stored packed erythrocytes (p = 0.01, [95% CI difference 0.446 - 0.66 μM]).
Conclusions
Transfusion of autologous packed erythrocytes stored for 40 days is associated with increased hemolysis, an unchanged reactive hyperemia index, and increased levels of plasma nitrite.
doi:10.1097/ALN.0b013e31825575e6
PMCID: PMC3980575  PMID: 22531338
3.  Forebrain HCN1 channels contribute to hypnotic actions of ketamine 
Anesthesiology  2013;118(4):785-795.
Background
Ketamine is a commonly used anesthetic but the mechanistic basis for its clinically relevant actions remains to be determined. We previously showed that HCN1 channels are inhibited by ketamine and demonstrated that global HCN1 knockout mice are two-fold less sensitive to hypnotic actions of ketamine. Although that work identified HCN1 channels as a viable molecular target for ketamine, it did not determine the relevant neural substrate.
Methods
To localize the brain region responsible for HCN1-mediated hypnotic actions of ketamine, we employed a conditional knockout strategy to delete HCN1 channels selectively in excitatory cells of the mouse forebrain. A combination of molecular, immunohistochemical and cellular electrophysiological approaches was used to verify conditional HCN1 deletion; a loss-of-righting reflex assay served to ascertain effects of forebrain HCN1 channel ablation on hypnotic actions of ketamine.
Results
In conditional knockout mice, HCN1 channels were selectively deleted in cortex and hippocampus, with expression retained in cerebellum. In cortical pyramidal neurons from forebrain-selective HCN1 knockout mice, effects of ketamine on HCN1-dependent membrane properties were absent; notably, ketamine was unable to evoke membrane hyperpolarization or enhance synaptic inputs. Finally, the half maximal effective concentration (EC50) for ketamine-induced loss-of-righting reflex was shifted to significantly higher concentrations (by ~31%).
Conclusions
These data indicate that forebrain principal cells represent a relevant neural substrate for HCN1-mediated hypnotic actions of ketamine. We suggest that ketamine inhibition of HCN1 shifts cortical neuron electroresponsive properties to contribute to ketamine-induced hypnosis.
doi:10.1097/ALN.0b013e318287b7c8
PMCID: PMC3605219  PMID: 23377220
4.  Anesthetics Interfere with Axon Guidance in Developing Mouse Neocortical Neurons In Vitro via a γ-Aminobutyric Acid Type A Receptor Mechanism 
Anesthesiology  2013;118(4):825-833.
Background
The finding that exposure to general anesthetics (GAs) in childhood may increase rates of learning disabilities has raised a concern that anesthetics may interfere with brain development. The generation of neuronal circuits, a complex process in which axons follow guidance cues to dendritic targets, is an unexplored potential target for this type of toxicity.
Methods
GA exposures were conducted in developing neocortical neurons in culture and in early postnatal neocortical slices overlaid with fluorescently labeled neurons. Axon targeting, growth cone collapse, and axon branching were measured using quantitative fluorescence microscopy.
Results
Isoflurane exposure causes errors in Semaphorin 3A dependent axon targeting (n = 77 axons) and a disruption of the response of axonal growth cones to Semaphorin 3A (n = 2,358 growth cones). This effect occurs at clinically relevant anesthetic doses of numerous GAs with allosteric activity at γ-aminobutyric acid type A receptors, and it was reproduced with a selective agonist. Isoflurane also inhibits growth cone collapse induced by Netrin-1, but does not interfere branch induction by Netrin-1. Insensitivity to guidance cues caused by isoflurane is seen acutely in growth cones in dissociated culture, and errors in axon targeting in brain slice culture occur at the earliest point at which correct targeting is observed in controls.
Conclusion
Our results demonstrate a generalized inhibitory effect of GAs on repulsive growth cone guidance in the developing neocortex that may occur via a γ-aminobutyric acid type A receptor mechanism. The finding that GAs interfere with axon guidance, and thus potentially with circuit formation, represents a novel form of anesthesia neurotoxicity in brain development.
doi:10.1097/ALN.0b013e318287b850
PMCID: PMC3605271  PMID: 23364597
5.  Adult-Child Interactions in the Post Anesthesia Care Unit: Behavior Matters 
Anesthesiology  2013;118(4):834-841.
Background
Many children experience significant distress before and after surgery. Previous studies indicate that healthcare providers’ and parents’ behaviors may influence children’s outcomes. This study examines the influence of adults’ behaviors on children’s distress and coping in the post anesthesia care unit.
Methods
Children aged 2–10 years old were videotaped during their post anesthesia care unit stay (n=146). Adult and child behaviors were coded from video including the onset, duration, and order of behaviors. Correlations were used to examine relations between behaviors, and time-window sequential statistical analyses were used to examine whether adult behaviors cued or followed children’s distress and coping.
Results
Sequential analysis demonstrated that children were significantly less likely to become distressed after an adult used empathy, distraction, or coping/assurance talk than they were at any other time. Conversely, if a child was already distressed, children were significantly more likely to remain distressed if an adult used reassurance or empathy than they were at any other time. Children were more likely to display coping behavior (distraction, nonprocedural talk) after an adult used this behavior.
Conclusions
Adults can influence children’s distress and coping in the post anesthesia care unit. Empathy, distraction and assurance talk may be helpful in keeping a child from becoming distressed and nonprocedural talk and distraction may cue children to cope. Reassurance should be avoided when a child is already distressed.
doi:10.1097/ALN.0b013e31827e501b
PMCID: PMC3789592  PMID: 23254147
6.  ISOFLURANE-INDUCED NEUROAPOPTOSIS IN THE NEONATAL RHESUS MACAQUE BRAIN 
Anesthesiology  2010;112(4):834-841.
Background
Brief isoflurane anesthesia induces neuroapoptosis in the developing rodent brain, but susceptibility of nonhuman primates to the apoptogenic action of isoflurane has not been studied. Therefore, we exposed postnatal day 6 (P6) rhesus macaques to a surgical plane of isoflurane anesthesia for 5 h, and studied the brains 3 h later for histopathological changes.
Method
With the same intensity of physiological monitoring typical for human neonatal anesthesia, five P6 rhesus macaques were exposed for 5 h to isoflurane maintained between 0.7 and 1.5 end tidal Vol% (endotracheally intubated, mechanically ventilated), and five controls were exposed for 5 h to room air without further intervention. Three hours later, the brains were harvested and serially sectioned across the entire forebrain and midbrain, and stained immunohistochemically with antibodies to activated caspase-3 for detection and quantification of apoptotic neurons.
Results
Quantitative evaluation of brain sections revealed a median of 32.5 (range, 18.0 to 48.2) apoptotic cells per mm3 of brain tissue in the isoflurane group and only 2.5 (range, 1.9 to 3.8) in the control group (difference significant at p = 0.008). Apoptotic neuronal profiles were largely confined to the cerebral cortex. In the control brains, they were sparse and randomly distributed, whereas in the isoflurane brains they were abundant and preferentially concentrated in specific cortical layers and regions.
Conclusion
The developing nonhuman primate brain is sensitive to the apoptogenic action of isoflurane, and displays a 13-fold increase in neuroapoptosis after 5 h exposure to a surgical plane of isoflurane anesthesia.
doi:10.1097/ALN.0b013e3181d049cd
PMCID: PMC3962067  PMID: 20234312
7.  Perioperative Comparative Effectiveness of Anesthetic Technique in Orthopedic Patients 
Anesthesiology  2013;118(5):1046-1058.
Background
The impact of anesthetic technique on perioperative outcomes remains controversial. We studied a large national sample of primary joint arthroplasty recipients and hypothesized that neuraxial anesthesia favorably influences perioperative outcomes.
Methods
Data from approximately 400 hospitals between 2006 and 2010 were accessed. Patients who underwent primary hip or knee arthroplasty were identified and subgrouped by anesthesia technique: general, neuraxial, and combined neuraxial–general. Demographics, postoperative complications, 30-day mortality, length of stay, and patient cost were analyzed and compared. Multivariable analyses were conducted to identify the independent impact of choice of anesthetic on outcomes.
Results
Of 528,495 entries of patients undergoing primary hip or knee arthroplasty, information on anesthesia type was available for 382,236 (71.4%) records. Eleven percent were performed under neuraxial, 14.2% under combined neuraxial– general, and 74.8% under general anesthesia. Average age and comorbidity burden differed modestly between groups. When neuraxial anesthesia was used, 30-day mortality was significantly lower (0.10, 0.10, and 0.18%; P < 0.001), as was the incidence of prolonged (>75th percentile) length of stay, increased cost, and in-hospital complications. In the multivariable regression, neuraxial anesthesia was associated with the most favorable complication risk profile. Thirty-day mortality remained significantly higher in the general compared with the neuraxial or neuraxial–general group for total knee arthroplasty (adjusted odds ratio [OR] of 1.83, 95% CI 1.08–3.1, P = 0.02; OR of 1.70, 95% CI 1.06–2.74, P = 0.02, respectively).
Conclusions
The utilization of neuraxial versus general anesthesia for primary joint arthroplasty is associated with superior perioperative outcomes. More research is needed to study potential mechanisms for these findings.
doi:10.1097/ALN.0b013e318286061d
PMCID: PMC3956038  PMID: 23612126
8.  Predicting Acute Pain after Cesarean Delivery Using Three Simple Questions 
Anesthesiology  2013;118(5):1170-1179.
Background
Interindividual variability in postoperative pain presents a clinical challenge. Preoperative quantitative sensory testing is useful but time consuming in predicting postoperative pain intensity. The current study was conducted to develop and validate a predictive model of acute postcesarean pain using a simple three-item preoperative questionnaire.
Methods
A total of 200 women scheduled for elective cesarean delivery under subarachnoid anesthesia were enrolled (192 subjects analyzed). Patients were asked to rate the intensity of loudness of audio tones, their level of anxiety and anticipated pain, and analgesic need from surgery. Postoperatively, patients reported the intensity of evoked pain. Regression analysis was performed to generate a predictive model for pain from these measures. A validation cohort of 151 women was enrolled to test the reliability of the model (131 subjects analyzed).
Results
Responses from each of the three preoperative questions correlated moderately with 24-h evoked pain intensity (r = 0.24-0.33, P < 0.001). Audio tone rating added uniquely, but minimally, to the model and was not included in the predictive model. The multiple regression analysis yielded a statistically significant model (R2 = 0.20, P < 0.001), whereas the validation cohort showed reliably a very similar regression line (R2 = 0.18). In predicting the upper 20th percentile of evoked pain scores, the optimal cut point was 46.9 (z =0.24) such that sensitivity of 0.68 and specificity of 0.67 were as balanced as possible.
Conclusions
This simple three-item questionnaire is useful to help predict postcesarean evoked pain intensity, and could be applied to further research and clinical application to tailor analgesic therapy to those who need it most.
doi:10.1097/ALN.0b013e31828e156f
PMCID: PMC3951732  PMID: 23485992
9.  Bidirectional regulation of intravenous general anesthetic actions by α3-containing γ-aminobutyric acidA receptors 
Anesthesiology  2013;118(3):562-576.
Background
γ-aminobutyric acidA (GABAA) receptors mediate the actions of several intravenous general anesthetics. However, the contribution of α3-containing GABAA receptors to the action of these drugs is unknown.
Methods
We compared anesthetic endpoints (hypnosis, immobility, hypothermia) in response to various intravenous anesthetics in mice lacking the α3 subunit of the GABAA receptor (α3KO) and wild type mice. Furthermore, we generated and analyzed conditional mutant mice expressing the GABAA receptor α3 subunit exclusively in noradrenergic neurons.
Results
α3KO mice displayed decreased hypnotic and hypothermic responses to etomidate and midazolam, but an increased response to pentobarbital. While the hypnotic response to ketamine was unaltered, the hypothermic response was increased. In contrast, the hypnotic but not the hypothermic response to medetomidine was increased. The combination of ketamine/xylazine displayed increased hypnotic, immobilizing, and hypothermic effects in α3KO mice. Mice expressing the α3 subunit exclusively in noradrenergic neurons were generated to assess whether the lack of α3 subunits on noradrenergic neurons may be responsible for this effect. In these mice, the increases of the hypnotic and immobilizing actions induced by ketamine/xylazine were largely absent, while the increase in the hypothermic action was still present.
Conclusion
α3-containing GABAA receptors bidirectionally regulate essential anesthetic actions: they mediate anesthetic actions of etomidate and midazolam, known to selectively act at GABAA receptors, and they negatively constrain anesthetic actions of compounds with targets partly or exclusively distinct from GABAA receptors such as medetomidine, ketamine and pentobarbital. Furthermore, our results indicate that α3-containing GABAA receptors on noradrenergic neurons may contribute to this constraint.
doi:10.1097/ALN.0b013e3182800d76
PMCID: PMC3951843  PMID: 23303487
10.  Local myotoxicity from sustained release of bupivacaine from microparticles 
Anesthesiology  2008;108(5):921-928.
Background
Sustained release of local anesthetics is frequently associated with myotoxicity. We investigate the role of particulate delivery systems and of the pattern of drug release in causing myotoxicity.
Methods
Rats were given sciatic nerve blocks with bupivacaine solutions, two types of bupivacaine-containing microparticles (polymeric microspheres and lipid-protein-sugar particles), or blank particles with or without bupivacaine in the carrier fluid. Myotoxicity was scored in histological sections of the injection sites. Bupivacaine release kinetics from the particles was measured. Myotoxicity of a range of bupivacaine concentrations from exposures up to 3 weeks was assessed in C2C12 myoblasts, with or without microparticles.
Results
Both types of bupivacaine-loaded microparticles, but not blank particles, were associated with myotoxicity. While 0.5% bupivacaine solution caused little myotoxicity, a concentration of bupivacaine that mimicked the amount of bupivacaine released initially from particles caused myotoxicity. Local anesthetics showed both concentration and time-dependent myotoxicity in C2C12s. Importantly, even very low concentrations, that were nontoxic over brief exposures, became highly toxic after days or weeks of exposure. The presence of particles did not increase bupivacaine myotoxicity in vitro, but did in vivo. Findings applied to both particle types.
Conclusions
While the release vehicles themselves were not myotoxic, both burst and extended release of bupivacaine were. A possible implication of the latter finding is that myotoxicity is an inevitable concomitant of sustained release of local anesthetics. Particles, and perhaps other vehicles, may enhance local toxicity through indirect mechanisms.
doi:10.1097/ALN.0b013e31816c8a48
PMCID: PMC3939710  PMID: 18431129
11.  Selective anesthesia-induced neuroinflammation in developing mouse brain and cognitive impairment 
Anesthesiology  2013;118(3):502-515.
Background
Recent population studies have suggested that children with multiple exposures to anesthesia and surgery at an early age are at an increased risk of cognitive impairment. We therefore have established an animal model with multiple versus single exposures of anesthetic(s) in young versus adult mice, aiming to distinguish the role of different anesthesia in cognitive impairment.
Methods
Six day and 60 day-old mice were exposed to various anesthesia regimen. We then determined the effects of the anesthesia on learning and memory function, levels of pro-inflammatory cytokine interleukin-6 and tumor necrosis factor-α in brain tissues, and the amount of ionized calcium binding adaptor molecule 1 positive cells, the marker of microglia activation, in the hippocampus.
Results
Here we show that anesthesia with 3% sevoflurane two hours daily for three days induced cognitive impairment and neuroinflammation [e.g., increased interleukin-6 levels: 151% ± 2.3 (mean ± SD) versus 100% ± 9.0, P = 0.035, n = 6] in young, but not adult, mice. Anesthesia with 3% sevoflurane two hours daily for one day and 9% desflurane two hours daily for three days induced neither cognitive impairment nor neuroinflammation. Finally, an enriched environment and anti-inflammation treatment (ketorolac) ameliorated the sevoflurane anesthesia-induced cognitive impairment.
Conclusions
Anesthesia-induced cognitive impairment may depend on developmental stage, anesthetic agent, and the number of exposures. These findings also suggest the cellular basis and the potential prevention and treatment strategies for the anesthesia-induced cognitive impairment, which may ultimately lead to safer anesthesia care and better postoperative outcomes for children.
doi:10.1097/ALN.0b013e3182834d77
PMCID: PMC3580002  PMID: 23314110
12.  Association between Endothelial Dysfunction and Acute Brain Dysfunction during Critical Illness 
Anesthesiology  2013;118(3):631-639.
Background
Acute brain dysfunction (delirium and coma) during critical illness is prevalent and costly, but the pathophysiology remains unclear. The relationship of acute brain dysfunction with endothelial function, which is impaired in critical illness and may contribute to alterations in cerebral blood flow and blood-brain barrier permeability, has not been studied. We sought to determine whether systemic endothelial dysfunction is associated with acute brain dysfunction during critical illness.
Methods
In this prospective cohort study, we enrolled adult medical/surgical intensive care unit patients in shock and/or respiratory failure. We assessed endothelial function at enrollment using peripheral artery tonometry to calculate the reactive hyperemia index, with lower reactive hyperemia index indicative of worse endothelial function. Patients were assessed for coma and delirium with the Richmond Agitation-Sedation Scale and Confusion Assessment Method for the Intensive Care Unit. We used multivariable linear regression to analyze the association between reactive hyperemia index and 1) delirium/coma-free days among all patients and 2) delirium duration among survivors, both over 14 days.
Results
We enrolled 147 patients with median age of 57 years and median Acute Physiology and Chronic Health Evaluation II score of 26. After adjusting for age, severity of illness, severe sepsis, preexisting cognitive function, medical vs. surgical intensive care unit admission, and prehospital statin use, lower reactive hyperemia index (worse systemic endothelial function) was associated with fewer delirium/coma-free days (p=0.02) and more delirium days (p=0.05).
Conclusions
In this study, critically ill patients with lower vascular reactivity indicative of worse systemic endothelial function had increased duration of acute brain dysfunction.
doi:10.1097/ALN.0b013e31827bd193
PMCID: PMC3580006  PMID: 23263016
13.  Drosophila Ryanodine Receptors Mediate General Anesthesia by Halothane 
Anesthesiology  2013;118(3):587-601.
Background
Although in vitro studies have identified numerous possible targets, the molecules that mediate the in vivo effects of volatile anesthetics remain largely unknown. The mammalian ryanodine receptor (Ryr) is a known halothane target, and we hypothesized that it has a central role in anesthesia.
Methods
Gene function of the Drosophila Ryr (dRyr) was manipulated in the whole body or in specific tissues using a collection of mutants and transgenes, and responses to halothane were measured with a reactive climbing assay. Cellular responses to halothane were studied using Ca2+ imaging and patch clamp electrophysiology.
Results
Halothane potency strongly correlates with dRyr gene copy number, and missense mutations in regions known to be functionally important in mammalian Ryrs gene cause dominant hypersensitivity. Tissue-specific manipulation of dRyr shows that expression in neurons and glia, but not muscle, mediates halothane sensitivity. In cultured cells, halothane-induced Ca2+ efflux is strictly dRyr-dependent, suggesting a close interaction between halothane and dRyr. Ca2+ imaging and electrophysiology of Drosophila central neurons reveal halothane-induced Ca2+ flux that is altered in dRyr mutants and correlates with strong hyperpolarization.
Conclusions
In Drosophila, neurally-expressed dRyr mediates a substantial proportion of halothane's anesthetic effects in vivo, is potently activated by halothane in vitro, and activates an inhibitory conductance. Our results provide support for Ryr as an important mediator of immobilization by volatile anesthetics.
doi:10.1097/ALN.0b013e31827e52c6
PMCID: PMC3580016  PMID: 23254148
14.  Dual effects of isoflurane on proliferation, differentiation and survival in human neuroprogenitor cells 
Anesthesiology  2013;118(3):537-549.
Background
Previous studies have demonstrated that isoflurane can provide both neuroprotection and neurotoxicity in various tissue culture models and in rodent developing brains. The cellular and molecular mechanisms mediating these dual effects are not clear, but the exposure level and duration of isoflurane appear to be determinant factors.
Methods
Using the ReNcell CX human neural progenitor cell line, we investigated the impact of prolonged exposure to varying isoflurane concentrations on cell survival and neurogenesis. In addition, we assessed the impact of short isoflurane preconditioning on elevation of cytosolic Ca2+ concentration and cytotoxic effects mediated by prolonged isoflurane exposures and the contribution of InsP3 or ryanodine receptors activation to these processes.
Results
Short exposures to low isoflurane concentrations promote proliferation and differentiation of ReNcell CX cells, with no cell damage. However, prolonged exposures to high isoflurane concentrations induced significant ReNcell CX cell damage and inhibited cell proliferation. These prolonged exposures suppressed neuronal cell fate, while promoting glial cell fate. Preconditioning of ReNcell CX cultures with short exposures to low concentrations of isoflurane ameliorated the effects of prolonged exposures to isoflurane. Pretreatment of ReNcell cultures with InsP3 or ryanodine receptor antagonists mostly prevented isoflurane-mediated effects on survival, proliferation, and differentiation. Finally, isoflurane preconditioned cultures showed significantly less isoflurane-evoked changes in calcium concentration.
Conclusion
The commonly used general anesthetic isoflurane exerts dual effects on neuronal stem cell survival, proliferation and differentiation, which may be attributed to differential regulation of calcium release through activation of endoplasmic reticulum localized InsP3 and/or ryanodine receptors.
doi:10.1097/ALN.0b013e3182833fae
PMCID: PMC3580019  PMID: 23314167
15.  Sevoflurane anesthesia in pregnant mice induces neurotoxicity in fetal and offspring mice 
Anesthesiology  2013;118(3):516-526.
Background
Each year over 75,000 pregnant women in the United States undergo anesthesia care. We set out to assess the effects of anesthetic sevoflurane in pregnant mice on neurotoxicity and learning and memory in fetal and offspring mice.
Methods
Pregnant mice (gestation stage day 14) and mouse primary neurons were treated with 2.5% sevoflurane for 2 h and 4.1% sevoflurane for 6 h, respectively. Brain tissues of both fetal and offspring mice (postnatal day 31), and the primary neurons were harvested and subjected to Western blot and immunhistochemistry to assess interleukin-6, synaptic markers postsynaptic density-95 and synaptophysin, and caspase-3 levels. Separately, learning and memory function in the offspring mice was determined in the Morris Water Maze.
Results
Sevoflurane anesthesia in pregnant mice induced caspase-3 activation, increased interleukin-6 levels [256% ± 50.98 (mean ± SD) vs. 100% ± 54.12, P = 0.026], and reduced postsynaptic density-95 (61% ± 13.53 vs. 100% ± 10.08, P = 0.036) and synaptophysin levels in fetal and offspring mice. The sevoflurane anesthesia impaired learning and memory in offspring mice at postnatal day 31. Moreover, interleukin-6 antibody mitigated the sevoflurane-induced reduction in postsynaptic density-95 levels in the neurons. Finally, environmental enrichment attenuated the sevoflurane-induced increases in interleukin-6 levels, reductions of synapse markers, and learning and memory impairment.
Conclusion
These results suggest that sevoflurane may induce detrimental effects in fetal and offspring mice, which can be mitigated by environmental enrichment. These findings should promote more studies to determine the neurotoxicity of anesthesia in the developing brain.
doi:10.1097/ALN.0b013e3182834d5d
PMCID: PMC3580035  PMID: 23314109
16.  EFFECT OF SEDATION ON PAIN PERCEPTION 
Anesthesiology  2013;118(3):611-621.
Background
Sedation or anesthesia is used to facilitate many cases of an estimated 45 million diagnostic and therapeutic medical procedures in the United States. Preclinical studies have called attention to the possibility that sedative hypnotic drugs can increase pain perception but it remains unclear whether this observation holds true in humans and whether pain-modulating effects are agent specific or characteristic of intravenous sedation in general.
Methods
To study this important clinical question, we recruited 86 healthy volunteers and randomly assigned them to receive one of three sedative drugs; midazolam, propofol or dexmedetomidine. We asked participants to rate their pain in response to four experimental pain tasks (cold, heat, ischemic or electrical pain) before and during moderate sedation.
Results
Midazolam increased cold, heat and electrical pain perception significantly (10-point pain rating scale change = 0.82 ± 0.29, mean ± SEM). Propofol reduced ischemic pain and dexmedetomidine reduced both cold and ischemic pain significantly (−1.58 ± 0.28, mean ± SEM). We observed a gender-by-race interaction for dexmedetomidine. In addition to these drug specific effects, we observed gender effects on pain perception; females rated identical experimental pain stimuli higher than males. We also noted racedrug interaction effects for dexmedetomidine with higher doses of drug needed to sedate Caucasians when compared to African-Americans.
Conclusions
The results of our study call attention to the fact that intravenous sedatives may increase pain perception. The effect of sedation on pain perception is agent and pain type specific. Knowledge of these effects provides a rational basis for analgesia and sedation to facilitate medical procedures.
doi:10.1097/ALN.0b013e318281592d
PMCID: PMC3744342  PMID: 23314164
17.  Depletion of Bone Marrow-derived Macrophages Perturbs the Innate Immune Response to Surgery and Reduces Postoperative Memory Dysfunction 
Anesthesiology  2013;118(3):527-536.
Background
According to rodent models of postoperative cognitive decline, activation of the innate immune response following aseptic surgical trauma results in the elaboration of hippocampal proinflammatory cytokines, which are capable of disrupting long-term potentiation, the neurobiologic correlate of memory. We hypothesize that hippocampal recruitment of bone marrow-derived (BMD) macrophages plays a causal role in these processes, resulting in memory dysfunction.
Methods
Clodrolip injection (liposomal formulation of clodronate) prior to stabilized tibial fracture under general anesthesia was used to deplete BMD macrophages. Systemic and neuroinflammation were studied on postoperative day 1, and memory in a fear-trace conditioning paradigm was assessed on postoperative day 3. CX3CR1GFP/+ CCR2RFP/+ mice were used to identify BMD macrophages.
Results
Clodrolip effectively depleted splenic CCR2+ BMD macrophages. It also attenuated the surgery-induced increase of interleukin-6 in the serum and the hippocampus, and prevented hippocampal infiltration of CCR2+ cells without affecting the number of CX3CR1+ microglia. It did not alter the surgery-induced increase in hippocampal MCP-1, the recruitment signal for CCR2+ cells. Clodrolip prevented surgery-induced memory dysfunction, as evidenced by a significant increase in freezing time (29%, 95% CI: 21 to 38% vs. 48%, 95% CI: 38 to 58%, n= 20, P = 0.004), but did not affect memory in nonsurgical mice.
Conclusion
Depletion of BMD macrophages prevents hippocampal neuroinflammation and memory dysfunction after experimental tibial fracture. These data suggest that the hippocampal recruitment of BMD macrophages is a necessary mechanism in murine postoperative cognitive dysfunction. Interventions designed to prevent its activation and/or migration into the brain may represent a feasible preemptive strategy.
doi:10.1097/ALN.0b013e3182834d94
PMCID: PMC3779063  PMID: 23426204
18.  ROLE OF MENINGEAL MAST CELLS IN INTRATHECAL MORPHINE EVOKED GRANULOMA FORMATION 
Anesthesiology  2013;118(3):664-678.
Background
Intrathecal morphine forms granulomas that arise from the adjacent arachnoid membrane. We propose that these inflammatory cells exit the meningeal vasculature secondary to meningeal mast cell degranulation.
Methods
Three sets of experiments were accomplished in dogs. 1) Ex vivo Meningeal mast cell degranulation. Histamine release was measured ex vivo from canine dura incubated with opiates. 2) In vivo cutaneous mast cell degranulation. Flare areas on the dog abdomen were measured after subcutaneous opiates. 3) In vivo granuloma pharmacology. Dogs with lumbar intrathecal catheters received infusion of intrathecal saline or intrathecal morphine. Intrathecal morphine dogs received: i) No other treatment (Control); ii) Twice daily subcutaneous naltrexone; iii) Intrathecal co-infusion of cromolyn; or, iv) Twice daily subcutaneous cromolyn for the 24–28 day study course.
Results
1) Morphine but not fentanyl evoked dural histamine release, which was blocked by cromolyn but not naloxone. 2) Wheal/flare was produced by subcutaneous morphine, methadone, hydromorphone, but not fentanyl, and was unaffected by naltrexone but prevented by cromolyn. 3) Granulomas occurred in all dogs receiving intrathecal morphine (15/15); subcutaneous naltrexone had no effect on granulomas (6/6), but was reduced by concurrent intrathecal cromolyn (0/5) or twice daily subcutaneous cromolyn (1 of 5).
Conclusions
The pharmacology of cutaneous/dural MC degranulation and intrathecal granulomas are comparable, not mediated by opioid receptors, and reduced by agents preventing MC degranulation. If an agent produces cutaneous MC degranulation at concentrations produced by intrathecal delivery, the agent may initiate granulomas.
doi:10.1097/ALN.0b013e31828351aa
PMCID: PMC3788115  PMID: 23426209
19.  Effects of Anesthetic Isoflurane and Desflurane on Human Cerebrospinal Fluid Aβ and τ Level 
Anesthesiology  2013;119(1):52-60.
Background
Accumulation of β-amyloid protein (Aβ) and tau protein is the main feature of Alzheimer disease neuropathogenesis. Anesthetic isoflurane, but not desflurane, may increase Aβ levels in vitro and in animals. Therefore, we set out to determine the efects of isoflurane and desflurane on cerebrospinal fuid (CSF) levels of Aβ and tau in humans.
Methods
The participants were assigned into spinal anesthesia (N = 35), spinal plus desflurane anesthesia (N = 33), or spinal plus isoflurane anesthesia (N = 38) group by randomization using computer-generated lists. Pre- and postoperative human CSF samples were obtained through an inserted spinal catheter. The levels of Aβ (Aβ40 and Aβ42) and total tau in the CSF were determined.
Results
Here, we show that isoflurane, but not desflurane, was associated with an increase in human CSF Aβ40 levels (from 10.90 to 12.41 ng/ml) 24 h after the surgery under anesthesia compared to spinal anesthesia (from 11.59 to 11.08 ng/ml), P = 0.022. Desflurane, but not isoflurane, was associated with a decrease in Aβ42 levels 2 h after the surgery under anesthesia (from 0.39 to 0.35 ng/ml) compared to spinal anesthesia (from 0.43 to 0.44 ng/ml), P = 0.006. Isoflurane and desflurane did not significantly affect the tau levels in human CSF.
Conclusions
These studies have established a system to study the effects of anesthetics on human biomarkers associated with Alzheimer disease and cognitive dysfunction. These findings have suggested that isoflurane and desflurane may have different effects on human CSF Aβ levels.
doi:10.1097/ALN.0b013e31828ce55d
PMCID: PMC3938174  PMID: 23438677
20.  A Users’ Guide to Interpreting Observational Studies of Pediatric Anesthetic Neurotoxicity 
Anesthesiology  2012;117(3):459-462.
doi:10.1097/ALN.0b013e31826446a5
PMCID: PMC3929306  PMID: 22797284
21.  Adenosine A1 Receptors in Mouse Pontine Reticular Formation Depress Breathing, Increase Anesthesia Recovery Time, and Decrease Acetylcholine Release 
Anesthesiology  2013;118(2):327-336.
Background
Clinical and preclinical data demonstrate the analgesic actions of adenosine. Central administration of adenosine agonists, however, suppresses arousal and breathing by poorly understood mechanisms. This study tested the two-tailed hypothesis that adenosine A1 receptors in the pontine reticular formation (PRF) of C57BL/6J mice modulate breathing, behavioral arousal, and PRF acetylcholine release.
Methods
Three sets of experiments used 51 mice. First, breathing was measured by plethysmography after PRF microinjection of the adenosine A1 receptor agonist N6-sulfophenyl adenosine (SPA) or saline. Second, mice were anesthetized with isoflurane and time to recovery of righting response (RoRR) was quantified after PRF microinjection of SPA or saline. Third, acetylcholine release in the PRF was measured before and during microdialysis delivery of SPA, the adenosine A1 receptor antagonist 1,3-dipropyl-8-cyclopentylxanthine (DPCPX), or SPA and DPCPX.
Results
First, SPA significantly decreased respiratory rate (−18%), tidal volume (−12%) and minute ventilation (−16%). Second, SPA concentration accounted for 76% of the variance in RoRR. Third, SPA concentration accounted for a significant amount of the variance in acetylcholine release (52%), RoRR (98%), and breathing rate (86%). DPCPX alone caused a concentration-dependent increase in acetylcholine, decrease in RoRR, and decrease in breathing rate. Coadministration of SPA and DPCPX blocked the SPA-induced decrease in acetylcholine and increase in RoRR.
Conclusions
Endogenous adenosine acting at adenosine A1 receptors in the PRF modulates breathing, behavioral arousal, and acetylcholine release. The results support the interpretation that an adenosinergic-cholinergic interaction within the PRF comprises one neurochemical mechanism underlying the wakefulness stimulus for breathing.
doi:10.1097/ALN.0b013e31827d413e
PMCID: PMC3553235  PMID: 23263018
22.  Effects of divided attention and operating room noise on perception of pulse oximeter pitch changes: A laboratory study 
Anesthesiology  2013;118(2):376-381.
Background
Anesthesiology requires performing visually-oriented procedures while monitoring auditory information about a patient’s vital signs. A concern in operating rooms environments is the amount of competing information and the effects that divided attention have on patient monitoring, such as detecting auditory changes in arterial oxygen saturation via pulse oximetry.
Methods
We measured the impact of visual attentional load and auditory background noise on the ability of anesthesia residents to monitor the pulse oximeter auditory display in a laboratory setting. Accuracies and response times were recorded reflecting anesthesiologists’ abilities to detect changes in oxygen saturation across three levels of visual attention in quiet and with noise.
Results
Results show that visual attentional load substantially impacts the ability to detect changes in oxygen saturation levels conveyed by auditory cues signaling 99 and 98% saturation. These effects are compounded by auditory noise, with up to a 17% decline in performance. These deficits are seen in the ability to accurately detect a change in oxygen saturation and in speed of response.
Conclusions
Most anesthesia accidents are initiated by small errors that cascade into serious events. Lack of monitor vigilance and inattention are two of the more commonly cited factors. Reducing such errors is thus a priority for improving patient safety. Specifically, efforts to reduce distractors and lower background noise should be considered during induction and emergence, periods of especially high risk, when anesthesiologists must attend to many tasks and are thus susceptible to error.
doi:10.1097/ALN.0b013e31827d417b
PMCID: PMC3689317  PMID: 23263015
23.  Obesity-Induced Insulin Resistance and Hyperglycemia: Etiological Factors and Molecular Mechanisms 
Anesthesiology  2008;109(1):137-148.
Obesity is a major cause of type 2 diabetes, clinically evidenced as hyperglycemia. The altered glucose homeostasis is caused by faulty signal transduction via the insulin signaling proteins, which results in decreased glucose uptake by the muscle, altered lipogenesis, and increased glucose output by the liver. The etiology of this derangement in insulin signaling is related to a chronic inflammatory state, leading to the induction of inducible nitric oxide synthase and release of high levels of nitric oxide and reactive nitrogen species, which together cause post-translational modifications in the signaling proteins. There are substantial differences in the molecular mechanisms of insulin resistance in muscle versus liver. Hormones and cytokines from adipocytes can enhance or inhibit both glycemic sensing and insulin signaling. The role of the central nervous system in glucose homeostasis has also been established. Multi-pronged therapies aimed at rectifying obesity-induced anomalies in both central nervous system and peripheral tissues may prove to be beneficial.
doi:10.1097/ALN.0b013e3181799d45
PMCID: PMC3896971  PMID: 18580184
24.  Early Exposure to General Anesthesia Disturbs Mitochondrial Fission and Fusion in the Developing Rat Brain 
Anesthesiology  2013;118(5):10.1097/ALN.0b013e318289bc9b.
Background
General anesthetics induce apoptotic neurodegeneration in the developing mammalian brain. General anesthesia (GA) also causes significant disturbances in mitochondrial morphogenesis during intense synaptogenesis. Mitochondria are dynamic organelles that undergo remodeling via fusion and fission. The fine balance between these two opposing processes determines mitochondrial morphometric properties, allowing for their regeneration and enabling normal functioning. As mitochondria are exquisitely sensitive to anesthesia-induced damage, we examined how GA affects mitochondrial fusion/fission.
Methods
Seven-day-old rat pups received anesthesia containing a sedative dose of midazolam followed by a combined nitrous oxide and isoflurane anesthesia for 6 h.
Results
GA causes 30% upregulation of reactive oxygen species (n = 3–5 pups/group), accompanied by a 2-fold downregulation of an important scavenging enzyme, superoxide dismutase (n = 6 pups/group). Reactive oxygen species upregulation is associated with impaired mitochondrial fission/fusion balance, leading to excessive mitochondrial fission. The imbalance between fission and fusion is due to acute sequestration of the main fission protein, dynamin-related protein 1, from the cytoplasm to mitochondria, and its oligomerization on the outer mitochondrial membrane. These are necessary steps in the formation of the ring-like structures that are required for mitochondrial fission. The fission is further promoted by GA-induced 40% downregulation of cytosolic mitofusin-2, a protein necessary for maintaining the opposing process, mitochondrial fusion (n = 6 pups/group).
Conclusions
Early exposure to GA causes acute reactive oxygen species upregulation and disturbs the fine balance between mitochondrial fission and fusion, leading to excessive fission and disturbed mitochondrial morphogenesis. These effects may play a causal role in GA-induced developmental neuroapoptosis.
doi:10.1097/ALN.0b013e318289bc9b
PMCID: PMC3879793  PMID: 23411726
25.  Activation of D1 dopamine receptors induces emergence from isoflurane general anesthesia 
Anesthesiology  2013;118(1):30-39.
BACKGROUND
A recent study showed that methylphenidate induces emergence from isoflurane anesthesia. Methylphenidate inhibits dopamine and norepinephrine reuptake transporters. The objective of this study was to test the hypothesis that selective dopamine receptor activation induces emergence from isoflurane anesthesia.
METHODS
In adult rats, we tested the effects of chloro-APB (D1 agonist) and quinpirole (D2 agonist) on time to emergence from isoflurane general anesthesia. We then performed a dose–response study to test for chloro-APB-induced restoration of righting during continuous isoflurane anesthesia. SCH-23390 (D1 antagonist) was used to confirm that the effects induced by chloro-APB are specifically mediated by D1 receptors. In a separate group of animals, spectral analysis was performed on surface electroencephalogram recordings to assess neurophysiological changes induced by chloro-APB and quinpirole during isoflurane general anesthesia.
RESULTS
Chloro-APB decreased median time to emergence from 330s to 50s. The median difference in time to emergence between the saline control group (n=6) and the chloro-APB group (n = 6) was 222s (95% CI: 77–534s, Mann-Whitney test). This difference was statistically significant (p = 0.0082). During continuous isoflurane anesthesia, chloro-APB dose-dependently restored righting (n = 6) and decreased electroencephalogram delta power (n = 4). These effects were inhibited by pretreatment with SCH-23390. Quinpirole did not restore righting (n = 6) and had no significant effect on the electroencephalogram (n = 4) during continuous isoflurane anesthesia.
CONCLUSIONS
Activation of D1 receptors by chloro-APB decreases time to emergence from isoflurane anesthesia, and produces behavioral and neurophysiological evidence of arousal during continuous isoflurane anesthesia. These findings suggest that selective activation of a D1 receptor-mediated arousal mechanism is sufficient to induce emergence from isoflurane general anesthesia.
doi:10.1097/ALN.0b013e318278c896
PMCID: PMC3527840  PMID: 23221866

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