Anthony G. Doufas, M.D., Ph.D.

All Publications

• Non-steady State Modeling of the Ventilatory Depressant Effect of Remifentanil in Awake Patients Experiencing Moderate-to-severe Obstructive Sleep Apnea. Anesthesiology Doufas, A. G., Shafer, S. L., Rashid, N. H., Kushida, C. A., Capasso, R. 2018

  Abstract

  WHAT WE ALREADY KNOW ABOUT THIS TOPIC: WHAT THIS ARTICLE TELLS US THAT IS NEW: BACKGROUND:: Evidence suggests that obstructive sleep apnea promotes postoperative pulmonary complications by enhancing vulnerability to opioid-induced ventilatory depression. We hypothesized that patients with moderate-to-severe obstructive sleep apnea are more sensitive to remifentanil-induced ventilatory depression than controls.METHODS: After institutional approval and written informed consent, patients received a brief remifentanil infusion during continuous monitoring of ventilation. We compared minute ventilation in 30 patients with moderate-to-severe obstructive sleep apnea diagnosed by polysomnography and 20 controls with no to mild obstructive sleep apnea per polysomnography. Effect site concentrations were estimated by a published pharmacologic model. We modeled minute ventilation as a function of effect site concentration and the estimated carbon dioxide. Obstructive sleep apnea status, body mass index, sex, age, use of continuous positive airway pressure, apnea/hypopnea events per hour of sleep, and minimum nocturnal oxygen saturation measured by pulse oximetry in polysomnography were tested as covariates for remifentanil effect site concentration at half-maximal depression of minute ventilation (Ce50) and included in the model if a threshold of 6.63 (P < 0.01) in the reduction of objective function was reached and improved model fit.RESULTS: Our model described the observed minute ventilation with reasonable accuracy (22% median absolute error). We estimated a remifentanil Ce50 of 2.20 ng · ml (95% CI, 2.09 to 2.33). The estimated value for Ce50 was 2.1 ng · ml (95% CI, 1.9 to 2.3) in patients without obstructive sleep apnea and 2.3 ng · ml (95% CI, 2.2 to 2.5) in patients with obstructive sleep apnea, a statistically nonsignificant difference (P = 0.081). None of the tested covariates demonstrated a significant effect on Ce50. Likelihood profiling with the model including obstructive sleep apnea suggested that the effect of obstructive sleep apnea on remifentanil Ce50 was less than 5%.CONCLUSIONS: Obstructive sleep apnea status, apnea/hypopnea events per hour of sleep, or minimum nocturnal oxygen saturation measured by pulse oximetry did not influence the sensitivity to remifentanil-induced ventilatory depression in awake patients receiving a remifentanil infusion of 0.2 mug · kg of ideal body weight per minute.

  View details for PubMedID 30247202

• Insomnia From Drug Treatments: Evidence From Meta-analyses of Randomized Trials and Concordance With Prescribing Information. Mayo Clinic proceedings Doufas, A. G., Panagiotou, O. A., Panousis, P., Wong, S. S., Ioannidis, J. P. 2017; 92 (1): 72-87

  Abstract

  To determine whether drugs used to treat diverse conditions cause insomnia symptoms and whether their prescription information is concordant with this evidence.We conducted a survey of meta-analyses (Cochrane Database of Systematic Reviews) and comparisons with package inserts compiled in the Physicians' Desk Reference (PDR). We identified randomized controlled trials (RCTs) in which any drug had been evaluated vs placebo and sleep had been assessed. We collectively referred to insomnia-related outcomes as sleep disturbance. We also searched the PDR to identify any insomnia symptoms listed for drugs with RCT evidence available.Seventy-four Cochrane systematic reviews corresponding to 274 RCTs assessed 88 drugs in 27 different conditions, providing evidence on 109 drug-condition pairs. Of these 88 drugs, 5 decreased sleep problems and 19 increased sleep problems; 64 drugs had no nominally statistically significant effect on sleep. Acetylcholinesterase inhibitors, dopamine agonists, and selective serotonin reuptake inhibitors were the drug classes most importantly associated with sleep disturbance. Of 35 drugs that included disturbed sleep as an adverse effect in the PDR, only 14 had RCT evidence supporting such effect, and 2 had evidence of increasing and decreasing sleep problems in RCTs, although this was not shown in the PDR. We identified weak concordance between the PDR and RCTs (weighted κ=0.31; P<.001).The RCTs offer substantial evidence about the common effects of drugs on the risk of sleep disturbance; currently, prescription information only partially agrees with the available randomized evidence.

  View details for DOI 10.1016/j.mayocp.2016.09.005

  View details for PubMedID 27842706

• Chronic Intermittent Hypoxia Is Independently Associated with Reduced Postoperative Opioid Consumption in Bariatric Patients Suffering from Sleep-Disordered Breathing PLOS ONE Turan, A., You, J., Egan, C., Fu, A., Khanna, A., Eshraghi, Y., Ghosh, R., Bose, S., Qavi, S., Arora, L., Sessler, D. I., Doufas, A. G. 2015; 10 (5)

  View details for DOI 10.1371/journal.pone.0127809

  View details for Web of Science ID 000355183900148

  View details for PubMedID 26010491

• Chronic intermittent hypoxia is independently associated with reduced postoperative opioid consumption in bariatric patients suffering from sleep-disordered breathing. PloS one Turan, A., You, J., Egan, C., Fu, A., Khanna, A., Eshraghi, Y., Ghosh, R., Bose, S., Qavi, S., Arora, L., Sessler, D. I., Doufas, A. G. 2015; 10 (5)

  Abstract

  Evidence suggests that recurrent nocturnal hypoxemia may affect pain response and/or the sensitivity to opioid analgesia. We tested the hypothesis that nocturnal hypoxemia, quantified by sleep time spent at an arterial saturation (SaO2) < 90% and minimum nocturnal SaO2 on polysomnography, are associated with decreased pain and reduced opioid consumption during the initial 72 postoperative hours in patients having laparoscopic bariatric surgery.With Institutional Review Board approval, we examined the records of all patients who underwent laparoscopic bariatric surgery between 2004 and 2010 and had an available nocturnal polysomnography study. We assessed the relationships between the time-weighted average of pain score and total opioid consumption during the initial 72 postoperative hours, and: (a) the percentage of total sleep time spent at SaO2 < 90%, (b) the minimum nocturnal SaO2, and (c) the number of apnea/hypopnea episodes per hour of sleep. We used multivariable regression models to adjust for both clinical and sleep-related confounders.Two hundred eighteen patients were included in the analysis. Percentage of total sleep time spent at SaO2 < 90% was inversely associated with total postoperative opioid consumption; a 5-%- absolute increase in the former would relatively decrease median opioid consumption by 16% (98.75% CI: 2% to 28%, P = 0.006). However, the percentage of total sleep time spent at SaO2 < 90% was not associated with pain. The minimum nocturnal SaO2 was associated neither with total postoperative opioid consumption nor with pain. In addition, neither pain nor total opioid consumption was significantly associated with the number of apnea/hypopnea episodes per hour of sleep.Preoperative nocturnal intermittent hypoxia may enhance sensitivity to opioids.

  View details for DOI 10.1371/journal.pone.0127809

  View details for PubMedID 26010491

• Relationship between Chronic Intermittent Hypoxia and Intraoperative Mean Arterial Pressure in Obstructive Sleep Apnea Patients Having Laparoscopic Bariatric Surgery. Anesthesiology Turan, A., You, J., Egan, C., Fu, A., Gazmuri, I., Khanna, A., Eshraghi, Y., Ghosh, R., Bose, S., Qavi, S., Arora, L., Sessler, D. I., Doufas, A. G. 2015; 122 (1): 64-71

  Abstract

  Recurrent nocturnal hypoxemia in obstructive sleep apnea enhances sympathetic function, decreases baroreceptor sensitivity, and weakens peripheral vascular responses to adrenergic signals. The authors hypothesized that the percentage of total sleep time spent at oxyhemoglobin saturation (SaO2) less than 90% and minimum nocturnal SaO2 on preoperative polysomnography are associated with decreased intraoperative mean arterial pressure.The authors examined the records of all patients who had laparoscopic bariatric surgery at Cleveland Clinic between 2005 and 2009 and an available polysomnography study. The authors assessed the relationships between the percentage of total sleep time spent at SaO2 less than 90% and minimum nocturnal SaO2, and the time-weighted average of mean arterial pressure. The authors used multivariable regression models to adjust for prespecified clinical confounders.Two hundred eighty-one patients were included in the analysis. The average change in the time-weighted average of mean arterial pressure was -0.02 (97.5% CI, -0.08, 0.04) mmHg for each 1% absolute increase in the percentage of sleep time spent at SaO2 less than 90% (P = 0.50). The average change was -0.13 (97.5% CI, -0.27, 0.01) mmHg, for each 1% absolute decrease in the minimum SaO2 (P = 0.04 > significance criterion of 0.025, Bonferroni correction). An unplanned analysis estimated 1% absolute decrease in minimum SaO2 was associated with -0.22 (98.75% CI, -0.39, -0.04) mmHg, change in mean arterial pressure (P = 0.002) in the time period between endotracheal intubation and trocar insertion.Recurrent nocturnal hypoxemia in obstructive sleep apnea is not a risk marker for intraoperative hypotension.

  View details for DOI 10.1097/ALN.0000000000000457

  View details for PubMedID 25254905

• Nocturnal Intermittent Hypoxia Is Independently Associated with Pain in Subjects Suffering from Sleep-disordered Breathing. Anesthesiology Doufas, A. G., Tian, L., Davies, M. F., Warby, S. C. 2013; 119 (5): 1149-1162

  Abstract

  On the basis of experimental and clinical evidence, the authors hypothesized that nocturnal hypoxemia would be associated with pain reports in subjects suffering from sleep-disordered breathing, independently of sleep fragmentation and inflammation.After obtaining institutional approval and access to the Cleveland Family Study phenotype and genotype data, the authors used proportional odds regression to examine the association between arterial desaturation and four different types of pain, as well as their composite measure, sequentially adjusted for: (1) clinical characteristics and (2) sleep fragmentation and inflammation. The authors also examined the association of selected candidate single-nucleotide polymorphisms with pain reports.Decreased minimum nocturnal arterial saturation increased the odds for morning headache (adjusted odds ratio per SD=1.36; 95% CI [1.08-1.71]; P=0.009), headache disrupting sleep (1.29 [1.10-1.51]; P=0.002), and chest pain while in bed (1.37 [1.10-1.70]; P=0.004). A decrease in the minimum nocturnal saturation from 92 to 75% approximately doubled the odds for pain. One single-nucleotide polymorphism for the α 1 chain of collagen type XI (COL11A1-rs1676486) gene was significantly associated with headache disrupting sleep (odds ratio=1.72 [1.01-2.94]; P=0.038), pain disrupting sleep (odds ratio=1.85 [1.04-3.28]; P=0.018), and pain composite (odds ratio=1.89 [1.14-3.14]; P=0.001).Nocturnal arterial desaturation may be associated with an increased pain in subjects with sleep-disordered breathing, independently of sleep fragmentation and inflammation.

  View details for DOI 10.1097/ALN.0b013e3182a951fc

  View details for PubMedID 24025612

• Bispectral Index Dynamics During Propofol Hypnosis Is Similar in Red-Haired and Dark-Haired Subjects ANESTHESIA AND ANALGESIA Doufas, A. G., Orhan-Sungur, M., Komatsu, R., Lauber, R., Akca, O., Shafer, S. L., Sessler, D. I. 2013; 116 (2): 319-326

  Abstract

  We have previously shown that red hair is associated with increased desflurane requirement for immobility, compared with dark hair. The effect of red hair on IV anesthetic requirement remains unknown. We tested the hypothesis that the propofol concentration in the effect site associated with half maximal electroencephalogram response, Ce50, is at least 50% higher in subjects with red hair.We modeled the propofol concentration versus electroencephalogram response relationship using a 2-step approach in 29 healthy dark- and red-haired volunteers receiving a propofol infusion to produce loss of consciousness. Bispectral Index (BIS) was the measure of drug effect. The parameters of a 3-compartment pharmacokinetic model were fit to measured arterial propofol concentrations. The relationship between effect-site propofol concentration (Ce) and BIS was characterized using a sigmoid Emax model. Model performance and accuracy of the estimated parameters were evaluated using accepted metrics and bootstrap resampling. The effect of hair color on the Ce50 for BIS response in the final model was assessed using a threshold of 6.63 (P<0.01) in reduction of -2 log likelihood. The influence of body weight on the model was also assessed.The inclusion of hair color as a model covariate did not improve either the pharmacokinetic or the pharmacodynamic model. A separate analysis for the dark- and red-haired subjects estimated a median (95% confidence interval) Ce50 BIS of 2.71 μg/mL (2.28-3.36 μg/mL) and 2.57 μg/mL (1.68-3.60 μg/mL), respectively. Body weight was a significant covariate for the CL1 and V1.Red hair phenotype does not affect the pharmacokinetics or pharmacodynamics of propofol.

  View details for DOI 10.1213/ANE.0b013e31827533b4

  View details for Web of Science ID 000314078300011

  View details for PubMedID 23302977

• Experimental Pain and Opioid Analgesia in Volunteers at High Risk for Obstructive Sleep Apnea PLOS ONE Doufas, A. G., Tian, L., Padrez, K. A., Suwanprathes, P., Cardell, J. A., Maecker, H. T., Panousis, P. 2013; 8 (1)

  Abstract

  Obstructive sleep apnea (OSA) is characterized by recurrent nocturnal hypoxia and sleep disruption. Sleep fragmentation caused hyperalgesia in volunteers, while nocturnal hypoxemia enhanced morphine analgesic potency in children with OSA. This evidence directly relates to surgical OSA patients who are at risk for airway compromise due to postoperative use of opioids. Using accepted experimental pain models, we characterized pain processing and opioid analgesia in male volunteers recruited based on their risk for OSA.After approval from the Intitutional Review Board and informed consent, we assessed heat and cold pain thresholds and tolerances in volunteers after overnight polysomnography (PSG). Three pro-inflammatory and 3 hypoxia markers were determined in the serum. Pain tests were performed at baseline, placebo, and two effect site concentrations of remifentanil (1 and 2 µg/ml), an μ-opioid agonist. Linear mixed effects regression models were employed to evaluate the association of 3 PSG descriptors [wake after sleep onset, number of sleep stage shifts, and lowest oxyhemoglobin saturation (SaO(2)) during sleep] and all serum markers with pain thresholds and tolerances at baseline, as well as their changes under remifentanil.Forty-three volunteers (12 normal and 31 with a PSG-based diagnosis of OSA) were included in the analysis. The lower nadir SaO(2) and higher insulin growth factor binding protein-1 (IGFBP-1) were associated with higher analgesic sensitivity to remifentanil (SaO(2), P = 0.0440; IGFBP-1, P = 0.0013). Other pro-inflammatory mediators like interleukin-1β and tumor necrosis factor-α (TNF-α) were associated with an enhanced sensitivity to the opioid analgesic effect (IL-1β, P = 0.0218; TNF-α, P = 0.0276).Nocturnal hypoxemia in subjects at high risk for OSA was associated with an increased potency of opioid analgesia. A serum hypoxia marker (IGFBP-1) was associated with hypoalgesia and increased potency to opioid analgesia; other pro-inflammatory mediators also predicted an enhanced opioid potency.Clinicaltrials.gov NCT00672737.

  View details for DOI 10.1371/journal.pone.0054807

  View details for Web of Science ID 000315483200027

  View details for PubMedID 23382975

  View details for PubMedCentralID PMC3558510

• Concordance of Sleep and Pain Outcomes of Diverse Interventions: An Umbrella Review PLOS ONE Doufas, A. G., Panagiotou, O. A., Ioannidis, J. P. 2012; 7 (7)

  Abstract

  Pain influences sleep and vice versa. We performed an umbrella review of meta-analyses on treatments for diverse conditions in order to examine whether diverse medical treatments for different conditions have similar or divergent effects on pain and sleep.We searched published systematic reviews with meta-analyses in the Cochrane Database of Systematic Reviews until October 20, 2011. We identified randomized trials (or meta-analyses thereof, when >1 trial was available) where both pain and sleep outcomes were examined. Pain outcomes were categorized as headache, musculoskeletal, abdominal, pelvic, generic or other pain. Sleep outcomes included insomnia, sleep disruption, and sleep disturbance. We estimated odds ratios for all outcomes and evaluated the concordance in the direction of effects between sleep and various types of pain and the correlation of treatment effects between sleep and pain outcomes.151 comparisons with 385 different trials met our eligibility criteria. 96 comparisons had concordant direction of effects between each pain outcome and sleep, while in 55 the effect estimates were in opposite directions (P<0.0001). In the 20 comparisons with largest amount of evidence, the experimental drug always had worse sleep outcomes and tended to have worse pain outcomes in 17/20 cases. For headache and musculoskeletal pain, 69 comparisons showed concordant direction of effects with sleep outcomes and 36 showed discordant direction (P<0.0001). For the other 4 pain types there were overall 27 vs. 19 pairs with concordant vs. discordant direction of effects (P = 0.095). There was a weak correlation of the treatment effect sizes for sleep vs. headache/musculoskeletal pain (r = 0.17, P = 0.092).Medical interventions tend to have effects in the same direction for pain and sleep outcomes, but exceptions occur. Concordance is primarily seen for sleep and headache or musculoskeletal pain where many drugs may both disturb sleep and cause pain.

  View details for DOI 10.1371/journal.pone.0040891

  View details for PubMedID 22815856

• Reinforcement Learning Versus Proportional-Integral-Derivative Control of Hypnosis in a Simulated Intraoperative Patient ANESTHESIA AND ANALGESIA Moore, B. L., Quasny, T. M., Doufas, A. G. 2011; 112 (2): 350-359

  Abstract

  Research has demonstrated the efficacy of closed-loop control of anesthesia using bispectral index (BIS) as the controlled variable. Model-based and proportional-integral-derivative (PID) controllers outperform manual control. We investigated the application of reinforcement learning (RL), an intelligent systems control method, to closed-loop BIS-guided, propofol-induced hypnosis in simulated intraoperative patients. We also compared the performance of the RL agent against that of a conventional PID controller.The RL and PID controllers were evaluated during propofol induction and maintenance of hypnosis. The patient-hypnotic episodes were designed to challenge both controllers with varying degrees of interindividual variation and noxious surgical stimulation. Each controller was tested in 1000 simulated patients, and control performance was assessed by calculating the median performance error (MDPE), median absolute performance error (MDAPE), Wobble, and Divergence for each controller group. A separate analysis was performed for the induction and maintenance phases of hypnosis.During maintenance, RL control demonstrated an MDPE of -1% and an MDAPE of 3.75%, with 80% of the time at BIS(target) ± 5. The PID controller yielded a MDPE of -8.5% and an MDAPE of 8.6%, with 57% of the time at BIS(target) ± 5. In comparison, the MDAPE in the worst-controlled patient of the RL group was observed to be almost half that of the worst-controlled patient in the PID group.When compared with the PID controller, RL control resulted in slower induction but less overshoot and faster attainment of steady state. No difference in interindividual patient variation and noxious destabilizing challenge on control performance was observed between the 2 patient groups.

  View details for DOI 10.1213/ANE.0b013e318202cb7c

  View details for Web of Science ID 000286576000012

  View details for PubMedID 21156973

• The Performance of Compartmental and Physiologically Based Recirculatory Pharmacokinetic Models for Propofol: A Comparison Using Bolus, Continuous, and Target-Controlled Infusion Data ANESTHESIA AND ANALGESIA Masui, K., Upton, R. N., Doufas, A. G., Coetzee, J. F., Kazama, T., Mortier, E. P., Struys, M. M. 2010; 111 (2): 368-379

  Abstract

  With the growing use of pharmacokinetic (PK)-driven drug delivery and/or drug advisory displays, identifying the PK model that best characterizes propofol plasma concentration (Cp) across a variety of dosing conditions would be useful. We tested the accuracy of 3 compartmental models and 1 physiologically based recirculatory PK model for propofol to predict the time course of propofol Cp using concentration-time data originated from studies that used different infusion schemes.Three compartmental PK models for propofol, called the "Marsh," the "Schnider," and the "Schüttler" models, and 1 physiologically based recirculatory model called the "Upton" model, were used to simulate the time course of propofol Cp. To test the accuracy of the models, we used published measured plasma concentration data that originated from studies of manual (bolus and short infusion) and computer-controlled (target-controlled infusion [TCI] and long infusion) propofol dosing schemes. Measured/predicted (M/P) propofol Cp plots were constructed for each dataset. Bias and inaccuracy of each model were assessed by median prediction error (MDPE) and median absolute prediction error (MDAPE), respectively.The M/P propofol Cp in the 4 PK models revealed bias in all 3 compartmental models during the bolus and short infusion regimens. In the long infusion, a worse M/P propofol Cp at higher concentration was seen for the Marsh and the Schüttler models than for the 2 other models. Less biased M/P propofol Cp was found for all models during TCI. In the bolus group, after 1 min, a clear overprediction was seen for all 3 compartmental models for the entire 5 min; however, this initial error resolved after 4 min in the Schnider model. The Upton model did not predict propofol Cp accurately (major overprediction) during the first minute. During the bolus and short infusion, the Marsh model demonstrated worse MDPE and MDAPE compared with the 3 other models. During short infusion, MDAPE for the Schnider and Schüttler models was better than the Upton and the Marsh models. All models showed similar MDPE and MDAPE during TCI simulations. During long infusion, the Marsh and the Schüttler models underestimated the higher plasma concentrations.When combining the performance during various infusion regimens, it seems that the Schnider model, although still not perfect, is the recommended model to be used for TCI and advisory displays.

  View details for DOI 10.1213/ANE.0b013e3181bdcf5b

  View details for Web of Science ID 000280478400020

  View details for PubMedID 19861357

• Neuromuscular Block Differentially Affects Immobility and Cortical Activation at Near-Minimum Alveolar Concentration Anesthesia ANESTHESIA AND ANALGESIA Doufas, A. G., Komatsu, R., Orhan-Sungur, M., Sengupta, P., Wadhwa, A., Mascha, E., Shafer, S. L., Sessler, D. I. 2009; 109 (4): 1097-1104

  Abstract

  Anesthesia-induced immobility and cortical suppression are governed by anatomically separate, but interacting, areas of the central nervous system. Consequently, larger volatile anesthetic concentrations are required to suppress cortical activation than to abolish movement in response to noxious stimulation. We examined the effect of decreased afferent input, as produced by neuromuscular block (NMB), on immobility and cortical activation, as measured by bispectral index (BIS) of the electrocardiogram, in the presence of noxious stimulation during approximately minimum alveolar concentrations (MACs) of desflurane anesthesia.The effect of NMB on the median effective end-tidal concentration of desflurane (EtDes(50), or MAC(tetanus)) for immobility was estimated using the up-and-down method and isolated forearm technique in 24 healthy volunteers. Each volunteer sequentially received saline, mivacurium, and succinylcholine in a randomized order, while EtDes concentration during each of the treatments was determined based on the movement response of the previous volunteer on the same treatment. Nonlinear mixed-effects modeling was used to evaluate the effect of NMB on BIS versus EtDes concentration relationship at baseline and after noxious stimulation, while the frontal electromyogram (EMG(BIS)) effect on BIS was also modeled as a covariate. Cardiovascular responses to noxious stimulation were compared across treatments.Succinylcholine and mivacurium significantly reduced MAC(tetanus) (95% confidence interval) from 5.00% (4.85%-5.13%), during saline, to 4.05% (3.81%-4.29%) and 3.84% (3.60%-4.08%), respectively. Noxious stimulation significantly, although minimally, increased BIS response during all treatments. Succinylcholine increased BIS independently of an effect on EMG(BIS). Succinylcholine administration increased cardiovascular activity. Interestingly, although cardiovascular reaction to the noxious event was ablated by mivacurium, cortical response, as determined by BIS, was retained.Both succinylcholine and mivacurium enhanced immobility during near-MAC anesthesia. All treatments were associated with a small, although significant, BIS increase in response to noxious stimulation, whereas succinylcholine increased BIS independently of noxious stimulation or EMG(BIS). Mivacurium suppressed autonomic response to a noxious event.

  View details for DOI 10.1213/ANE.0b013e3181af631a

  View details for Web of Science ID 000270209100019

  View details for PubMedID 19762737

• Automated Responsiveness Monitor to Titrate Propofol Sedation ANESTHESIA AND ANALGESIA Doufas, A. G., Morioka, N., Mahgoub, A. N., Bjorksten, A. R., Shafer, S. L., Sessler, D. I. 2009; 109 (3): 778-786

  Abstract

  In previous studies, we showed that failure to respond to automated responsiveness monitor (ARM) precedes potentially serious sedation-related adversities associated with loss of responsiveness, and that the ARM was not susceptible to false-positive responses. It remains unknown, however, whether loss and return of response to the ARM occur at similar sedation levels. We hypothesized that loss and return of response to the ARM occur at similar sedation levels in individual subjects, independent of the propofol effect titration scheme.Twenty-one healthy volunteers aged 20-45 yr underwent propofol sedation using an effect-site target-controlled infusion system and two different dosing protocol schemes. In all, we increased propofol effect-site concentration (Ce) until loss of response to the ARM occurred. Subsequently, the propofol Ce was decreased either by a fixed percentage (20%, 30%, 40%, 50%, 60%, and 70%; fixed percentage protocol, n = 10) or by a linear deramping (0.1, 0.2, and 0.3 microg x mL(-1) x min(-1); deramping protocol, n = 11) until the ARM response returned. Consequently, the propofol Ce was maintained at the new target for a 6-min interval (Ce plateau) during which arterial samples for propofol determination were obtained, and a clinical assessment of sedation (Observer's Assessment of Alertness/Sedation [OAA/S] score) performed. Each participant in the two protocols experienced each percentage or deramping rate of Ce decrease in random order. The assumption of steady state was tested by plotting the limits of agreement between the starting and ending plasma concentration (Cp) at each Ce plateau. The probability of response to the ARM as a function of propofol Ce, Bispectral Index (BIS) of the electroencephalogram, and OAA/S score was estimated, whereas the effect of the protocol type on these estimates was evaluated using the nested model approach (NONMEM). The combined effect of propofol Ce and BIS on the probability for ARM response was also evaluated using a fractional probability model (P(BIS/Ce)).The measured propofol Cp at the beginning and the end of the Ce plateau was almost identical. The Ce50 of propofol for responding to the ARM was 1.73 (95% confidence interval: 1.55-2.10) microg/mL, whereas the corresponding BIS50 was 75 (71.3-77). The OAA/S50 probability for ARM response was 12.5/20 (12-13.4). A fractional probability (P(BIS/Ce)) model for the combined effect of BIS and Ce fitted the data best, with an estimated contribution for BIS of 63%. Loss and return of ARM response occurred at similar sedation levels in individual subjects.Reproducible ARM dynamics in individual subjects compares favorably with clinical and electroencephalogram sedation end points and suggests that the ARM could be used as an independent instrumental guide of drug effect during propofol-only sedation.

  View details for DOI 10.1213/ane.0b013e3181b0fd0f

  View details for Web of Science ID 000269330800015

  View details for PubMedID 19690246

• Fuzzy Control for Closed-Loop, Patient-Specific Hypnosis in Intraoperative Patients: A Simulation Study Annual International Conference of the IEEE-Engineering-in-Medicine-and-Biology-Society Moore, B. L., Pyeatt, L. D., Doufas, A. G. IEEE. 2009: 3083–3086

  Abstract

  Research has demonstrated the efficacy of closed-loop control of anesthesia using bispectral index (BIS) as the controlled variable, and the recent development of model-based, patient-adaptive systems has considerably improved anesthetic control. To further explore the use of model-based control in anesthesia, we investigated the application of fuzzy control in the delivery of patient-specific propofol-induced hypnosis. In simulated intraoperative patients, the fuzzy controller demonstrated clinically acceptable performance, suggesting that further study is warranted.

  View details for Web of Science ID 000280543602136

  View details for PubMedID 19963562

• Lower-body warming mimics the normal epidural-induced reduction in the shivering threshold ANESTHESIA AND ANALGESIA Doufas, A. G., Morioka, N., Maghoub, A. N., Mascha, E., Sessler, D. I. 2008; 106 (1): 252-256

  Abstract

  Neuraxial anesthesia reduces the shivering threshold approximately 0.6 degrees C. This effect might be mediated by an apparent (as opposed to actual) increase in lower body temperature. Accordingly, sufficient lower body warming should result in thermoregulatory inhibition comparable to that exerted by epidural anesthesia. We tested the hypothesis that increasing leg skin temperature to 38 degrees C mimics the normal approximately 0.6 degrees C reduction in the shivering threshold during epidural anesthesia.Shivering threshold during internal body cooling was determined in nine female volunteers on two separate days: one unanesthetized control day, and one day with a T10-11 epidural block. On each study day, lower body skin temperature was maintained near 38 degrees C and upper body skin temperature near 33 degrees C. We assessed equivalency of the shivering thresholds on the control and epidural days using the two one-sided tests method.The thresholds on the control (35.8 degrees C +/- 0.5 degrees C; mean +/- sd) and epidural (35.8 degrees C +/- 0.5 degrees C) days were shown to be equivalent because the 95% CI for the difference in means, 0.0 (-0.4, 0.4), was within our prespecified limits of -0.6 degrees C to +0.6 degrees C (P < 0.025 for both one-sided equivalency tests).Lower body warming mimics the normal epidural-induced reduction in the shivering threshold. Our results support a mechanism based on increased apparent lower body skin temperature during neuraxial anesthesia.

  View details for DOI 10.1213/01.ane.0000287814.78990.4e

  View details for Web of Science ID 000251824300044

  View details for PubMedID 18165586

• Influence of administration rate on propofol plasma - Effect site equilibration 13th Annual Meeting of the International-Society-of-Anesthetic-Pharmacology Struys, M. M., Coppens, M. J., De Neve, N., Mortier, E. P., Doufas, A. G., Van Bocxlaer, J. F., Shafer, S. L. LIPPINCOTT WILLIAMS & WILKINS. 2007: 386–96

  Abstract

  The authors hypothesized a difference in plasma-effect site equilibration, depicted by a first-order constant k(e0), depending on the injection rate of propofol.Sixty-one patients received 2.5 mg/kg propofol given as a bolus or as a 1-, 2-, or 3-min infusion. The Bispectral Index was used to monitor drug effect. Propofol predicted plasma concentration was calculated using a three-compartment model and the effect site concentration over time as the convolution between the predicted plasma concentration and the disposition function of the effect site concentration. The authors evaluated the influence of the infusion rate on the k(e0) by comparing the model with one k(e0) for all groups with models estimating different k(e0) values for each group. The authors also assessed the accuracy of two pharmacokinetic models after bolus injection.The best model based was a fixed (Bispectral Index > or = 90) plus sigmoidal model (Bispectral Index < 90) with two values of k(e0), one for the bolus (t(1/2) k(e0) = 1.2 min) and one for the infusions (t(1/2) k(e0) = 2.2 min). However, the tested pharmacokinetic models poorly predicted the arterial concentrations in the first minutes after bolus injection. Simulations showed the requirement for two k(e0) values for bolus and infusion was mostly a compensation for the inaccurate prediction of arterial concentrations after a bolus.Propofol plasma-effect site equilibration occurs more rapidly after a bolus than after rapid infusion, based on the electroencephalogram as a drug effect measure, mostly because of misspecification of the pharmacokinetic model in the first minutes after bolus.

  View details for Web of Science ID 000249297200006

  View details for PubMedID 17721240

• Sitting position does not alter minimum alveolar concentration for desflurane CANADIAN JOURNAL OF ANAESTHESIA-JOURNAL CANADIEN D ANESTHESIE Lin, C., Wu, C., Lee, S., Lui, T., Huang, C., Li, A. H., Doufas, A. G. 2007; 54 (7): 523-530

  Abstract

  Hypotension is a common complication of the sitting position during anesthesia, and is often counteracted by decreasing anesthetic depth, thereby exposing patients to the risk of being inadequately anesthetized. Baroreceptor unloading and the consequent sympathoexcitation, as during head up tilt, decreases pain threshold and arouses the central nervous system (CNS), whereas hypotension exerts a direct CNS depressant effect. We estimated the minimal alveolar concentration (MAC) of desflurane for immobility in patients undergoing surgery in the sitting position, in comparison to MAC desflurane for patients having a similar type of surgery in the supine position.The Dixon up-and-down method was used to evaluate the MAC for desflurane in patients undergoing cervical spine laminoplasty (n = 24) or discectomy (n = 24) in the sitting and supine positions, respectively. Logistic regression with co-variate adjustment was employed to examine if the two positions (sitting and supine) have different or share the same concentration vs response relationship for immobility. Monte Carlo simulation was used to calculate 95% confidence intervals (CI) for the MAC in each position, and to estimate the difference in MAC (delta MAC) between the sitting and supine positions.Modeling both sitting [6.54% (6.50-6.66, 95% CI)] and supine [6.70 (6.55-6.81)] patients as having different MAC concentrations did not significantly improve our simplified model, which treats the two patient groups as one [6.61 (6.52-6.70), delta -2 log likelihood = 2.735, P = 0.098]. Mean delta MAC (95% CI) was -0.14 (-0.30, 0.03).The sitting position does not change desflurane anesthetic requirements for immobility.

  View details for Web of Science ID 000247844800004

  View details for PubMedID 17602037

• Magnesium sulphate only slightly reduces the shivering threshold in humans 16th Annual Meeting of the American-Society-of-Critical-Care-Anesthesiologists Wadhwa, A., Sengupta, P., Durrani, J., Akca, O., Lenhardt, R., Sessler, D. I., Doufas, A. G. OXFORD UNIV PRESS. 2005: 756–62

  Abstract

  Hypothermia may be an effective treatment for stroke or acute myocardial infarction; however, it provokes vigorous shivering, which causes potentially dangerous haemodynamic responses and prevents further hypothermia. Magnesium is an attractive anti-shivering agent because it is used for treatment of postoperative shivering and provides protection against ischaemic injury in animal models. We tested the hypothesis that magnesium reduces the threshold (triggering core temperature) and gain of shivering without substantial sedation or muscle weakness.We studied nine healthy male volunteers (18-40 yr) on two randomly assigned treatment days: (1) control and (2) magnesium (80 mg kg(-1) followed by infusion at 2 g h(-1)). Lactated Ringer's solution (4 degrees C) was infused via a central venous catheter over a period of approximately 2 h to decrease tympanic membrane temperature by approximately 1.5 degrees C h(-1). A significant and persistent increase in oxygen consumption identified the threshold. The gain of shivering was determined by the slope of oxygen consumption vs core temperature regression. Sedation was evaluated using a verbal rating score (VRS) from 0 to 10 and bispectral index (BIS) of the EEG. Peripheral muscle strength was evaluated using dynamometry and spirometry. Data were analysed using repeated measures anova; P<0.05 was statistically significant.Magnesium reduced the shivering threshold (36.3 [SD 0.4] degrees C vs 36.6 [0.3] degrees C, P = 0.040). It did not affect the gain of shivering (control, 437 [289] ml min(-1) degrees C(-1); magnesium, 573 [370] ml min(-1) degrees C(-1); P=0.344). The magnesium bolus did not produce significant sedation or appreciably reduce muscle strength.Magnesium significantly reduced the shivering threshold. However, in view of the modest absolute reduction, this finding is considered to be clinically unimportant for induction of therapeutic hypothermia.

  View details for DOI 10.1093/bja/aei105

  View details for Web of Science ID 000228930700011

  View details for PubMedID 15749735

• Induction speed is not a determinant of propofol pharmacodynamics ANESTHESIOLOGY Doufas, A. G., Bakhshandeh, M., Bjorksten, A. R., Shafer, S. L., Sessler, D. I. 2004; 101 (5): 1112-1121

  Abstract

  Evidence suggests that the rate at which intravenous anesthetics are infused may influence their plasma-effect site equilibration. The authors used five different rates of propofol administration to test the hypothesis that different sedation endpoints occur at the same effect site propofol concentration, independent of the infusion rate. The authors concurrently evaluated the automated responsiveness monitor (ARM) against other sedation measures and the propofol effect site concentration.With Human Studies Committee approval, 18 healthy volunteers received five consecutive target-controlled propofol infusions. During each infusion, the effect site concentration was increased by a rate of 0.1, 0.3, 0.5, 0.7, or 0.9 microg . ml . min. The Bispectral Index and ARM were recorded at frequent intervals. The times of syringe drop and loss and recovery of responsiveness were noted. Pharmacokinetic and pharmacodynamic modeling was performed using NONMEM.When the correct rate of plasma-effect site equilibration was determined for each individual (plasma-effect site equilibration = 0.17 min, time to peak effect = 2.7 min), the effect site concentrations associated with each clinical measure were not affected by the rate of increase of effect site propofol concentration. ARM correlated with all clinical measures of drug effect. Subjects invariably stopped responding to ARM at lower effect site propofol concentrations than those associated with loss of responsiveness.: Population-based pharmacokinetics, combined with real-time electroencephalographic measures of drug effect, may provide a means to individualize pharmacodynamic modeling during target-controlled drug delivery. ARM seems useful as an automated measure of sedation and may provide the basis for automated monitoring and titration of sedation for a propofol delivery system.

  View details for Web of Science ID 000224738600009

  View details for PubMedID 15505446

• Block-dependent sedation during epidural anaesthesia is associated with delayed brainstem conduction BRITISH JOURNAL OF ANAESTHESIA Doufas, A. G., Wadhwa, A., Shah, Y. M., Lin, C. M., Haugh, G. S., Sessler, D. I. 2004; 93 (2): 228-234

  Abstract

  Neuraxial anaesthesia produces a sedative and anaesthetic-sparing effect. Recent evidence suggests that spinal cord anaesthesia modifies reticulo-thalamo-cortical arousal by decreasing afferent sensory transmission. We hypothesized that epidural anaesthesia produces sensory deafferentation-dependent sedation that is associated with impairment of brainstem transmission. We used brainstem auditory evoked potentials (BAEP) to evaluate reticular function in 11 volunteers.Epidural anaesthesia was induced with 2-chloroprocaine 2%. Haemodynamic and respiratory responses, sensory block level, sedation depth and BAEP were assessed throughout induction and resolution of epidural anaesthesia. Sedation was evaluated using verbal rating score (VRS), observer's assessment alertness/sedation (OAA/S) score, and bispectral index score (BIS). Prediction probability (PK) was used to associate sensory block with sedation, as well as BIS with other sedation measures. Spearman's rank order correlation was used to associate block level and sedation with the absolute and interpeak BAEP latencies.Sensory block level significantly predicted VRS (PK=0.747), OAA/S score (PK=0.748) and BIS. BIS predicted VRS and OAA/S score (PK=0.728). The latency of wave III of BAEP significantly correlated with sedation level (rho=0.335, P<0.01) and sensory block (rho=0.394, P<0.01). The other BAEP parameters did not change during epidural anaesthesia. Haemodynamic and respiratory responses remained stable throughout the study.Sedation during epidural anaesthesia depends on sensory block level and is associated with detectable block-dependent alterations in the brainstem auditory evoked responses. Sensory deafferentation may reduce CNS alertness through mechanisms related to brainstem neural activity.

  View details for DOI 10.1093/bja/aeh192

  View details for Web of Science ID 000222731400011

  View details for PubMedID 15220178

• Anesthetic requirement is increased in redheads ANESTHESIOLOGY Liem, E. B., Lin, C. M., Suleman, M. I., Doufas, A. G., Gregg, R. G., Veauthier, J. M., Loyd, G., Sessler, D. I. 2004; 101 (2): 279-283

  Abstract

  Age and body temperature alter inhalational anesthetic requirement; however, no human genotype is associated with inhalational anesthetic requirement. There is an anecdotal impression that anesthetic requirement is increased in redheads. Furthermore, red hair results from distinct mutations of the melanocortin-1 receptor. Therefore, the authors tested the hypothesis that the requirement for the volatile anesthetic desflurane is greater in natural redheaded than in dark-haired women.The authors studied healthy women with bright red (n = 10) or dark (n = 10) hair. Blood was sampled for subsequent analyses of melanocortin-1 receptor alleles. Anesthesia was induced with sevoflurane and maintained with desflurane randomly set at an end-tidal concentration between 5.5 and 7.5%. After an equilibration period, a noxious electrical stimulation (100 Hz, 70 mA) was transmitted through bilateral intradermal needles. If the volunteer moved in response to stimulation, desflurane was increased by 0.5%; otherwise, it was decreased by 0.5%. This was continued until volunteers "crossed over" from movement to nonmovement (or vice versa) four times. Individual logistic regression curves were used to determine desflurane requirement (P50). Desflurane requirements in the two groups were compared using Mann-Whitney nonparametric two-sample test; P < 0.05 was considered statistically significant.The desflurane requirement in redheads (6.2 vol% [95% CI, 5.9-6.5]) was significantly greater than in dark-haired women (5.2 vol% [4.9-5.5]; P = 0.0004). Nine of 10 redheads were either homozygous or compound heterozygotes for mutations on the melanocortin-1 receptor gene.Red hair seems to be a distinct phenotype linked to anesthetic requirement in humans that can also be traced to a specific genotype.

  View details for Web of Science ID 000222940100005

  View details for PubMedID 15277908

• Dantrolene reduces the threshold and gain for shivering Annual Meeting of the American-Society-of-Anesthesiologists Lin, C. M., Neeru, S., Doufas, A. G., Liem, E., Shah, Y. M., Wadhwa, A., Lenhardt, R., Bjorksten, A., Taguchi, A., Kabon, B., Sessler, D. I., Kurz, A. LIPPINCOTT WILLIAMS & WILKINS. 2004: 1318–24

  Abstract

  Dantrolene is used for treatment of life-threatening hyperthermia, yet its thermoregulatory effects are unknown. We tested the hypothesis that dantrolene reduces the threshold (triggering core temperature) and gain (incremental increase) of shivering. Healthy volunteers were evaluated on 2 random days: control and dantrolene (approximately 2.5 mg/kg plus a continuous infusion). In Study 1, 9 men were warmed until sweating was provoked and then cooled until arteriovenous shunt constriction and shivering occurred. Sweating was quantified on the chest using a ventilated capsule. Absolute right middle fingertip blood flow was quantified using venous-occlusion volume plethysmography. A sustained increase in oxygen consumption identified the shivering threshold. In Study 2, 9 men were given cold lactated Ringer's solution i.v. to reduce core temperature approximately 2 degrees C/h. Cooling was stopped when shivering intensity no longer increased with further core cooling. The gain of shivering was the slope of oxygen consumption versus core temperature regression. In Study 1, sweating and vasoconstriction thresholds were similar on both days. In contrast, shivering threshold decreased 0.3 +/- 0.3 degrees C, P = 0.004, on the dantrolene day. In Study 2, dantrolene decreased the shivering threshold from 36.7 +/- 0.2 to 36.3 +/- 0.3 degrees C, P = 0.01 and systemic gain from 353 +/- 144 to 211 +/- 93 mL.min(-1).degrees C(-1), P = 0.02. Thus, dantrolene substantially decreased the gain of shivering, but produced little central thermoregulatory inhibition.Dantrolene substantially decreases the gain of shivering but produces relatively little central thermoregulatory inhibition. It thus seems unlikely to prove more effective than conventional muscle relaxants for treatment of life-threatening hyperthermia.

  View details for DOI 10.1213/01.ANE.0000108968.21212.D7

  View details for Web of Science ID 000221041800023

  View details for PubMedID 15105208

• Physiology and clinical relevance of induced hypothermia NEUROCRITICAL CARE Doufas, A. G., Sessler, D. I. 2004; 1 (4): 489-498

  Abstract

  Experimental evidence and clinical experience suggest that mild hypothermia protects numerous tissues from damage during ischemic insult. However, the extent to which hypothermia becomes a valued therapeutic option will depend on the clinician's ability to rapidly reduce core body temperature and safely maintain hypothermia. To date, general anesthesia is the best way to block autonomic defenses during induction of mild-to-moderate hypothermia; unfortunately, general anesthesia is not an option in most patients likely to benefit from therapeutic hypothermia. Induction of hypothermia in awake humans is complicated by both the technical difficulties related to thermal manipulation and the remarkable efficacy of thermoregulatory defenses, especially vasoconstriction and shivering. The most effective thermal manipulation devices are generally invasive and, therefore, more prone to complications than surface methods. In an effort to inhibit thermoregulation in awake humans, several agents have been tested either alone or in combination with each other. For example, the combination of meperidine and buspirone has already been applied to facilitate induction of hypothermia in human trials. However, pharmacological induction of thermoregulatory tolerance to cold without excessive sedation, respiratory depression, or other serious toxicity remains a major focus of current therapeutic hypothermia research.

  View details for Web of Science ID 000230489000014

  View details for PubMedID 16174955

• Midazolam causes less sedation in volunteers with red hair CANADIAN JOURNAL OF ANAESTHESIA-JOURNAL CANADIEN D ANESTHESIE Chua, M. V., Tsueda, K., Doufas, A. G. 2004; 51 (1): 25-30

  Abstract

  We studied sedation, cognition, and mood during midazolam infusion in volunteers with red and non-red (blond or brown) hair, to test the hypothesis that patients with red hair may require more drugs to attain desired levels of sedation.Twenty red and 19 non-red hair subjects were studied in a randomized, placebo-controlled cross-over design. Subjects were studied during placebo and midazolam at 30 ng.mL(-1) target effect site concentration. Sedation was assessed using the observer's assessment of alertness/sedation (OAA/S) scale, the drowsiness visual analogue scale (VAS), and the bispectral index; cognition was assessed using the Repeatable Battery for Assessment of Neuropsychological Status; and mood was assessed using the bipolar form of the Profile of Mood States (POMS).Red hair volunteers showed significantly higher OAA/S (P < 0.01) and lower drowsiness VAS (P < 0.05) scores compared to non-red hair subjects during midazolam infusion. Visuospatial score was significantly higher in subjects with red compared to non-red hair during placebo and midazolam trials. Delayed memory score was significantly higher during midazolam infusion in subjects with red compared to non-red hair. There were no group differences in POMS during either trials.Midazolam appears to cause significantly less sedation and cognitive impairment in red haired subjects.

  View details for Web of Science ID 000188713000007

  View details for PubMedID 14709456

• Consequences of inadvertent perioperative hypothermia. Best practice & research. Clinical anaesthesiology Doufas, A. G. 2003; 17 (4): 535-549

  Abstract

  Perioperative hypothermia triples the incidence of adverse myocardial outcomes in high-risk patients. Mild hypothermia significantly increases blood loss and augments allogeneic transfusion requirement, but the molecular pathophysiology of this effect remains to be elucidated. Only 1.9 degrees C core hypothermia triples the incidence of surgical wound infection following colon resection and increases the duration of hospitalization by 20%. Hypothermia adversely affects antibody- and cell-mediated immune defences, as well as the oxygen availability in the peripheral wound tissues. Mild perioperative hypothermia changes the kinetics and action of various anaesthetic and paralysing agents, increases thermal discomfort, and is associated with delayed post-anaesthetic recovery. Finally, mild core hypothermia influences pulse oximetry monitoring and various electrophysiological indices of the nervous system, with questionable clinical significance, as yet.

  View details for PubMedID 14661656

• Women have the same desflurane minimum alveolar concentration as men - A prospective study ANESTHESIOLOGY Wadhwa, A., Durrani, J., Sengupta, P., Doufas, A. G., Sessler, D. I. 2003; 99 (5): 1062-1065

  Abstract

  Women generally report greater sensitivity to pain than do men, and healthy young women require 20% more anesthetic than healthy age-matched men to prevent movement in response to noxious electrical stimulation. In contrast, minimum alveolar concentration (MAC) for xenon is 26% less in elderly Japanese women than in elderly Japanese men. Whether anesthetic requirement is similar in men and women thus remains in dispute. The authors therefore tested the hypothesis that the desflurane concentration required to prevent movement in response to skin incision (MAC) differs between men and women.Using the Dixon "up and down" method, the authors determined MAC for desflurane in 15 female and 15 male patients (18-40 yr old) undergoing surgery.MAC was 6.2 +/- 0.4% desflurane for women versus 6.0 +/- 0.3% for men (P = 0.31), a difference of only 3%. These data provide 90% power to detect a 9% difference between the groups.The MAC of desflurane did not differ between young men and women undergoing surgery with a true surgical incision. Although pain sensitivity may differ in women versus men, MAC of desflurane does not.

  View details for Web of Science ID 000186239800009

  View details for PubMedID 14576540

• A new system to target the effect-site during propofol sedation ACTA ANAESTHESIOLOGICA SCANDINAVICA Doufas, A. G., Bakhshandeh, M., Bjorksten, A. R., Greif, R., Sessler, D. I. 2003; 47 (8): 944-950

  Abstract

  We evaluated a new, integrated, covariate-adjusted, target-controlled infusion system during sedation with propofol combined with 50% nitrous oxide (N2O) and with propofol only (Air).The protocol consisted of sequential 15-minute cycles in 20 volunteers. After a 15-minute control period, propofol was infused to an initial target effect-site concentration of 0.25 microg x ml-1 (N2O) or 1.5 microg x ml-1 (Air). Subsequently, the target effect-site concentration was increased by 0.25 (N2O) or 0.5 microg x ml-1 (Air) for 15 min This sequence was continued until the volunteers lost consciousness as defined by an Observer's Assessment Alertness/Sedation (OAA/S) score = 2.Venous plasma propofol concentrations at the beginning(9 elapsed minutes) and end(15 elapsed minutes) of the pseudo-steady state period differed by only 0.00 +/- 0.16 microg x ml-1 (P = 0.78) during the N2O and 0.00 +/- 0.25 microg x ml-1 (P = 0.91) during the Air trial. OAA/S scores and bispectral index values, as surrogate measures of pharmacodynamic effect, were not different during this time in either trial. The median(25th, 75th percentiles) of the median performance error (%) was -13 (-24, -1) during the N2O and -18 (-26, -9) during the Air trial. The median absolute performance error (%) was 17 (10, 24) in the N2O and 22 (12, 28) in Air trial. The divergence (%/h) was -10 (-26, 4) in the N2O and 14 (-21, 26) in Air trial. The wobble was 7 (5, 10) in the N2O and 6 (4, 8) in the Air trial.When tested with venous blood samples, our TCI system for propofol, using a covariate-adjusted, integrated pharmacokinetic model to target effect-site concentrations, demonstrated a clinically acceptable accuracy and stability during mild to moderate sedation.

  View details for Web of Science ID 000184660100004

  View details for PubMedID 12904185

• Automated responsiveness test and bispectral index monitoring during propofol and propofol/N2O sedation ACTA ANAESTHESIOLOGICA SCANDINAVICA Doufas, A. G., Bakhshandeh, M., Haugh, G. S., Bjorksten, A. R., Greif, R., Sessler, D. I. 2003; 47 (8): 951-957

  Abstract

  Sedation practice, especially when non-anaesthesia personnel are involved, requires efficient anaesthetic depth monitoring. Therefore, we used prediction probability (PK) to evaluate the performance of the bispectral index (BIS) of the EEG and automated responsiveness test (ART) to predict sedation depth and loss of subject's responsiveness during propofol sedation, with and without N2O.Twenty volunteers were studied during propofol administration with (N2O) and without (Air) N2O. The protocol consisted of sequential 15-min cycles. After a control period, propofol was infused to a target effect-site concentration of 0.25 microg/ml (N2O) or 1.5 microg/ml (Air), which was subsequently increased by 0.25 or 0.5 microg/ml, respectively, until loss of responsiveness was detected by loss of response to command [observer's assessment of alertness/sedation (OAA/S) score

  View details for Web of Science ID 000184660100005

  View details for PubMedID 12904186

• Neither arm nor face warming reduces the shivering threshold in unanesthetized humans STROKE Doufas, A. G., Wadhwa, A., Lin, C. M., Shah, Y. M., Hanni, K., Sessler, D. I. 2003; 34 (7): 1736-1740

  Abstract

  Hand warming and face warming, combined with inhalation of heated air, are reported to suppress shivering. However, hand or face temperature contributes only a few percent to control of shivering. Thus, it seems unlikely that manipulating hand or facial skin temperature alone would be sufficient to permit induction of therapeutic hypothermia. We tested the hypothesis that focal arm (forearm and hand) warming or lower facial warming, combined with inhalation of heated and humidified gas, only minimally reduces the shivering threshold (triggering core temperature).We studied 8 healthy male volunteers (18 to 40 years of age) on 3 days: (1) control (no warming), (2) arm warming with forced air at approximately 43 degrees C, and (3) face warming with 21 L/min of air at approximately 42 degrees C at a relative humidity of 100%. Fluid at approximately 4 degrees C was infused via a central venous catheter to decrease tympanic membrane temperature 1 degrees C/h to 2 degrees C/h; mean skin temperature was maintained at 31 degrees C. A sustained increase in oxygen consumption quantified the shivering threshold.Shivering thresholds did not differ significantly between the control (36.7+/-0.1 degrees C), arm-warming (36.5+/-0.3 degrees C), or face-warming (36.5+/-0.3 degrees C; analysis of variance, P=0.34) day. The study was powered to have a 95% probability of detecting a difference of 0.5+/-0.5 degrees C (mean+/-SD) between control and either of the 2 treatments at alpha=0.05.Focal arm or face warming did not substantially reduce the shivering threshold in unanesthetized volunteers. It thus seems unlikely that these nonpharmacological modalities will substantially facilitate induction of therapeutic hypothermia.

  View details for DOI 10.1161/01.STR.0000077014.47422.DB

  View details for Web of Science ID 000183949200046

  View details for PubMedID 12775889

• Dexmedetomidine and meperidine additively reduce the shivering threshold in humans STROKE Doufas, A. G., Lin, C. M., Suleman, M. I., Liem, E. B., Lenhardt, R., Morioka, N., Akca, O., Shah, Y. M., Bjorksten, A. R., Sessler, D. I. 2003; 34 (5): 1218-1223

  Abstract

  Hypothermia might prove to be therapeutically beneficial in stroke victims; however, even mild hypothermia provokes vigorous shivering. Meperidine and dexmedetomidine each linearly reduce the shivering threshold (triggering core temperature) with minimal sedation. We tested the hypothesis that meperidine and dexmedetomidine synergistically reduce the shivering threshold without producing substantial sedation or respiratory depression.We studied 10 healthy male volunteers (18 to 40 years) on 4 days: (1) control (no drug); (2) meperidine (target plasma level 0.3 microg/mL); (3) dexmedetomidine (target plasma level 0.4 ng/mL); and (4) meperidine plus dexmedetomidine (target plasma levels of 0.3 microg/mL and 0.4 ng/mL, respectively). Lactated Ringer's solution (approximately 4 degrees C) was infused through a central venous catheter to decrease tympanic membrane temperature by approximately 2.5 degrees C/h; mean skin temperature was maintained at 31 degrees C. An increase in oxygen consumption >25% of baseline identified the shivering threshold. Sedation was evaluated by using the Observer's Assessment of Sedation/Alertness scale. Two-way repeated-measures ANOVA was used to identify interactions between drugs. Data are presented as mean+/-SD; P<0.05 was statistically significant.The shivering thresholds on the study days were as follows: control, 36.7+/-0.3 degrees C; dexmedetomidine, 36.0+/-0.5 degrees C (P<0.001 from control); meperidine, 35.5+/-0.6 degrees C (P<0.001); and meperidine plus dexmedetomidine, 34.7+/-0.6 degrees C (P<0.001). Although meperidine and dexmedetomidine each reduced the shivering threshold, their interaction was not synergistic but additive (P=0.19). There was trivial sedation with either drug alone or in combination. Respiratory rate and end-tidal Pco2 were well preserved on all days.Dexmedetomidine and meperidine additively reduce the shivering threshold; in the small doses tested, the combination produced only mild sedation and no respiratory toxicity.

  View details for DOI 10.1161/01.STR.0000068787.76670.A4

  View details for Web of Science ID 000182586100023

  View details for PubMedID 12690216

• Initial experience with a novel heat-exchanging catheter in neurosurgical patients Annual Meeting of the American-Society-of-Anesthesiologists Doufas, A. G., Akca, O., Barry, A., Petrusca, D. A., Suleman, M. I., Morioka, N., Guarnaschelli, J. J., Sessler, D. I. LIPPINCOTT WILLIAMS & WILKINS. 2002: 1752–56

  Abstract

  Even mild hypothermia provides marked protection against cerebral ischemia in animal models. Hypothermia may be of therapeutic value during neurosurgical procedures. However, current cooling systems often fail to induce sufficient hypothermia before the dura is opened. Furthermore, they usually fail to restore normothermia by the end of surgery, thus delaying extubation. We evaluated a new internal heat-exchanging catheter. Eight ASA physical status II-IV patients (29-72 yr) undergoing craniotomy were enrolled. After the induction of general anesthesia, we introduced the SetPoint catheter into the inferior vena cava via a femoral vein. The target core body temperature was 34 degrees C-34.5 degrees C. After reaching the target, core temperature was maintained until the dura was closed. Target core temperature was then set to 37.0 degrees C, and the patient was rewarmed as quickly as possible. Seven patients had a tumor resection, and one had an aneurysm clipped. The core-cooling rate was 3.9 degrees C +/- 1.6 degrees C/h, and the rewarming rate was 2.0 degrees C +/- 0.5 degrees C/h; core temperature was 35.9 degrees C +/- 0.2 degrees C by the end of surgery. Patients were subsequently kept normothermic for 3 h before the catheter was removed. No thrombus or other particulate material was identified on the extracted catheters. None of the patients suffered any complications that could be attributed to the SetPoint system or thermal management.Because current systems for inducing therapeutic hypothermia are too slow, we tested an internal counter-current thermal management system during hypothermic neurosurgery. The SetPoint catheter cooled at 3.9 degrees C +/- 1.6 degrees C/h and rewarmed at 2.0 degrees C +/- 0.5 degrees C/h. Catheter-based internal thermal management thus seems to be rapid and effective.

  View details for DOI 10.1213/01.ANE.0000037149.48152.9E

  View details for Web of Science ID 000179646100052

  View details for PubMedID 12456452

• Electro-acupuncture at the Zusanli, Yanglingquan, and Kunlun points does not reduce anesthetic requirement Annual Meeting of the American-Society-of-Anesthesiologists Morioka, N., Akca, O., Doufas, A. G., Chernyak, G., Sessler, D. I. LIPPINCOTT WILLIAMS & WILKINS. 2002: 98–102

  Abstract

  We tested the hypothesis that electro-acupuncture at the Zusanli, Yanglingquan, and Kunlun acupuncture points on the legs decreases anesthetic requirement. Fourteen young, healthy volunteers were anesthetized with desflurane on two separate days. Needle electrodes were positioned at the three acupuncture points thought to produce a generalized sedative and analgesic effect. Needles were percutaneously placed on treatment days; on control days, they were insulated and taped near the insertion points. The electrodes were stimulated on the treatment day. Stimulation consisted of 2-Hz and 100-Hz currents alternated at 2-s intervals. When the end-tidal desflurane concentration of 5.5% was stable for 15 min, noxious electrical stimuli were administered via 25-gauge needles on both thighs (70 mA at 100 Hz for 10 s). Desflurane concentration was increased 0.5% when movement occurred and decreased 0.5% when it did not. An investigator, blinded to treatment, determined movement. These up-and-down sequences were continued until volunteers crossed from movement to no movement four times. A logistic regression determined the partial pressure of desflurane that produced a 50% likelihood of movement in response to noxious stimulation and consequently identified the minimum alveolar anesthetic concentration equivalent for desflurane. There was no significant difference in minimum alveolar anesthetic concentration equivalents between the electro-acupuncture (4.6% +/- 0.6%, mean +/- SD) and control (4.6% +/- 0.8%) days (P = 0.8). These data provided an 80% power for detecting a difference of 0.35 volume-percent between the groups.Electro-stimulation of three general acupuncture points on the leg did not reduce desflurane requirements. This type of acupuncture is thus unlikely to facilitate general anesthesia or decrease the need for anesthetic drugs.

  View details for DOI 10.1213/01.ANE.0000020695.65934.30

  View details for Web of Science ID 000176634100017

  View details for PubMedID 12088950

• Automated responsiveness test (ART) predicts loss of consciousness and adverse physiologic responses during propofol conscious sedation ANESTHESIOLOGY Doufas, A. G., Bakhshandeh, M., Bjorksten, A. R., Greif, R., Sessler, D. I. 2001; 94 (4): 585-592

  Abstract

  The authors evaluated a device designed to provide conscious sedation with propofol (propofol-air), or propofol combined with 50% nitrous oxide (N2O; propofol-N2O). An element of this device is the automated responsiveness test (ART), a method for confirming that patients remain conscious. The authors tested the hypotheses that the ART predicts loss of consciousness and that failure to respond to the ART precedes sedation-induced respiratory or hemodynamic toxicity.The protocol consisted of sequential 15-min cycles in 20 volunteers. After a 15-min control period, propofol was infused to an initial target effect-site concentration of 0.0 microg/ml with N2O or 1.5 microg/ml with air. Subsequently, the propofol target effect-site concentration was increased by a designated increment (0.25 and 0.5 microg/ml) and the process repeated. This sequence was continued until loss of consciousness, as defined by an Observer's Assessment of Alertness/Sedation (OAA/S) score of 10/20 or less, or until an adverse physiologic event was detected.The OAA/S score at which only 50% of the volunteers were able to respond to the ART (P50) during propofol-N2O was 11.1 of 20 (95% confidence interval [CI]: 10.6-11.8); the analogous P50 was 11.8 of 20 (95% CI: 11.4-12.3) with propofol-air. Failure to respond to the ART occurred at a plasma propofol concentration of 0.7 +/- 0.6 microg/ml with propofol-N2O and 1.6 +/- 0.6 microg/ml with propofol-air, whereas loss of consciousness occurred at 1.2 +/- 0.8 microg/ml and 1.9 +/- 0.7 microg/ml, respectively. There were no false-normal ART responses.The ART can guide individual titration of propofol because failure to respond to responsiveness testing precedes loss of consciousness and is not susceptible to false-normal responses. The use of N2O with propofol for conscious sedation decreases the predictive accuracy of the ART.

  View details for Web of Science ID 000167811100007

  View details for PubMedID 11379677

• Opioids for Acute Pain Management in Patients With Obstructive Sleep Apnea: A Systematic Review ANESTHESIA AND ANALGESIA Cozowicz, C., Chung, F., Doufas, A. G., Nagappa, M., Memtsoudis, S. G. 2018; 127 (4): 988–1001

  Abstract

  The intrinsic nature of opioids to suppress respiratory function is of particular concern among patients with obstructive sleep apnea (OSA). The association of OSA with increased perioperative risk has raised the question of whether patients with OSA are at higher risk for opioid-induced respiratory depression (OIRD) compared to the general population. The aims of this systematic review were to summarize current evidence with respect to perioperative OIRD, changes in sleep-disordered breathing, and alterations in pain and opioid sensitivity in patients with OSA. A systematic literature search of studies published between 1946 and October 2017 was performed utilizing the following databases: Medline, ePub Ahead of Print/Medline In-process, Embase, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, PubMed-NOT-Medline and ClinicalTrials.Gov. Of 4321 initial studies, 40 met the inclusion criteria. The Oxford level of evidence was assessed. Overall, high-quality evidence on the comparative impact of acute opioid analgesia in OSA versus non-OSA patients is lacking. The current body of evidence is burdened by significant limitations including risk of bias and large heterogeneity among studies with regard to OSA severity, perioperative settings, outcome definitions, and the presence or absence of various perioperative drivers. These factors complicate an accurate interpretation and robust analysis of the true complication risk. Nevertheless, there is some consistency among studies with regard to a detrimental effect of opioids in the presence of OSA. Notably, the initial 24 hours after opioid administration appear to be most critical with regard to life-threatening OIRD. Further, OSA-related increased pain perception and enhanced opioid sensitivity could predispose patients with OSA to a higher risk for OIRD without overdosing. While high-quality evidence is needed, retrospective analyses indicate that critical, life-threatening OIRD may be preventable with a more cautious approach to opioid use, including adequate monitoring.

  View details for DOI 10.1213/ANE.0000000000003549

  View details for Web of Science ID 000452081700033

  View details for PubMedID 29958218

• Society of Anesthesia and Sleep Medicine Guideline on Intraoperative Management of Adult Patients With Obstructive Sleep Apnea ANESTHESIA AND ANALGESIA Memtsoudis, S. G., Cozowicz, C., Nagappa, M., Wong, J., Joshi, G. P., Wong, D. T., Doufas, A. G., Yilmaz, M., Stein, M. H., Krajewski, M. L., Singh, M., Pichler, L., Ramachandran, S., Chung, F. 2018; 127 (4): 967–87

  Abstract

  The purpose of the Society of Anesthesia and Sleep Medicine Guideline on Intraoperative Management of Adult Patients With Obstructive Sleep Apnea (OSA) is to present recommendations based on current scientific evidence. This guideline seeks to address questions regarding the intraoperative care of patients with OSA, including airway management, anesthetic drug and agent effects, and choice of anesthesia type. Given the paucity of high-quality studies with regard to study design and execution in this perioperative field, recommendations were to a large part developed by subject-matter experts through consensus processes, taking into account the current scientific knowledge base and quality of evidence. This guideline may not be suitable for all clinical settings and patients and is not intended to define standards of care or absolute requirements for patient care; thus, assessment of appropriateness should be made on an individualized basis. Adherence to this guideline cannot guarantee successful outcomes, but recommendations should rather aid health care professionals and institutions to formulate plans and develop protocols for the improvement of the perioperative care of patients with OSA, considering patient-related factors, interventions, and resource availability. Given the groundwork of a comprehensive systematic literature review, these recommendations reflect the current state of knowledge and its interpretation by a group of experts at the time of publication. While periodic reevaluations of literature are needed, novel scientific evidence between updates should be taken into account. Deviations in practice from the guideline may be justifiable and should not be interpreted as a basis for claims of negligence.

  View details for PubMedID 29944522

• Intraoperative Tonic-Clonic Seizure Under General Anesthesia Captured by Electroencephalography: A Case Report A and A Case Reports Burbridge, M. A., Jaffe, R. A., Doufas, A. G., Lopez, J. R. 2017: 9–12

  Abstract

  We present the case of a 34-year-old man undergoing craniotomy for arteriovenous malformation resection under general anesthesia who suffered a tonic-clonic seizure captured by intraoperative electroencephalograph. The seizure was extinguished with a propofol bolus. This patient had no previous history of seizures, and no precipitating cause was identified. Intraoperative electroencephalographic seizures under general anesthesia have been recorded previously in the literature, but our observation is the first to demonstrate this with overt motor manifestations. We also discuss the differential diagnosis of an intraoperative seizure under general anesthesia and provide guidance to the anesthesiologist who encounters this event.

  View details for DOI 10.1213/XAA.0000000000000509

• Society of Anesthesia and Sleep Medicine Guidelines on Preoperative Screening and Assessment of Adult Patients With Obstructive Sleep Apnea. Anesthesia and analgesia Chung, F., Memtsoudis, S. G., Ramachandran, S. K., Nagappa, M., Opperer, M., Cozowicz, C., Patrawala, S., Lam, D., Kumar, A., Joshi, G. P., Fleetham, J., Ayas, N., Collop, N., Doufas, A. G., Eikermann, M., Englesakis, M., Gali, B., Gay, P., Hernandez, A. V., Kaw, R., Kezirian, E. J., Malhotra, A., Mokhlesi, B., Parthasarathy, S., Stierer, T., Wappler, F., Hillman, D. R., Auckley, D. 2016; 123 (2): 452-473

  Abstract

  The purpose of the Society of Anesthesia and Sleep Medicine guideline on preoperative screening and assessment of adult patients with obstructive sleep apnea (OSA) is to present recommendations based on the available clinical evidence on the topic where possible. As very few well-performed randomized studies in this field of perioperative care are available, most of the recommendations were developed by experts in the field through consensus processes involving utilization of evidence grading to indicate the level of evidence upon which recommendations were based. This guideline may not be appropriate for all clinical situations and all patients. The decision whether to follow these recommendations must be made by a responsible physician on an individual basis. Protocols should be developed by individual institutions taking into account the patients' conditions, extent of interventions and available resources. This practice guideline is not intended to define standards of care or represent absolute requirements for patient care. The adherence to these guidelines cannot in any way guarantee successful outcomes and is rather meant to help individuals and institutions formulate plans to better deal with the challenges posed by perioperative patients with OSA. These recommendations reflect the current state of knowledge and its interpretation by a group of experts in the field at the time of publication. While these guidelines will be periodically updated, new information that becomes available between updates should be taken into account. Deviations in practice from guidelines may be justifiable and such deviations should not be interpreted as a basis for claims of negligence.

  View details for DOI 10.1213/ANE.0000000000001416

  View details for PubMedID 27442772

• Ventilator-associated pneumonia in critically ill stroke patients: Frequency, risk factors, and outcomes JOURNAL OF CRITICAL CARE Kasuya, Y., Hargett, J. L., Lenhardt, R., Heine, M. F., Doufas, A. G., Remmel, K. S., Ramirez, J. A., Akca, O. 2011; 26 (3): 273-279

  Abstract

  Our main objective was to assess incidence, risk factors, and outcomes of ventilator-associated pneumonia (VAP) in stroke patients.After obtaining approval from the Human Studies Committee, we reviewed the electronic records from our intensive care unit database of 111 stroke patients on mechanical ventilation for more than 48 hours. Thirty-six risk factors related to disease and general health status, and 8 related to care-all assigned a priori-were collected and analyzed. Selected factors with univariate statistical significance (P < .05) were then analyzed with multivariate logistic regression.Thirty-one patients developed pneumonia (28%). Methicillin-resistant Staphylococcus aureus (n = 12) and methicillin-sensitive S aureus (n = 7) were the most common pathogenic bacteria. Chronic lung disease, neurological status at admission as assessed by the National Institutes of Health Stroke Scale, and hemorrhagic transformation were the independent risk factors contributing to VAP. Worsening oxygenation index (arterial partial pressure of oxygen/fraction of inspired oxygen) and proton pump inhibitor use for ulcer prophylaxis were other potentially important factors.Pneumonia appears as a frequent problem in mechanically ventilated stroke patients. Chronic lung disease history, severity of stroke level at admission, and hemorrhagic transformation of stroke set the stage for developing VAP. The duration of both mechanical ventilation and intensive care unit stay gets significantly prolonged by VAP, but it does not affect mortality.

  View details for DOI 10.1016/j.jcrc.2010.09.006

  View details for Web of Science ID 000291390200009

  View details for PubMedID 21106334

• Reinforcement Learning: A Novel Method for Optimal Control of Propofol-Induced Hypnosis ANESTHESIA AND ANALGESIA Moore, B. L., Doufas, A. G., Pyeatt, L. D. 2011; 112 (2): 360-367

  Abstract

  Reinforcement learning (RL) is an intelligent systems technique with a history of success in difficult robotic control problems. Similar machine learning techniques, such as artificial neural networks and fuzzy logic, have been successfully applied to clinical control problems. Although RL presents a mathematically robust method of achieving optimal control in systems challenged with noise, nonlinearity, time delay, and uncertainty, no application of RL in clinical anesthesia has been reported.

  View details for DOI 10.1213/ANE.0b013e31820334a7

  View details for Web of Science ID 000286576000013

  View details for PubMedID 21156984

• An Adaptive Neural Network Filter for Improved Patient State Estimation in Closed-Loop Anesthesia Control 23rd IEEE International Conference on Tools with Artificial Intelligence (ICTAI) Borera, E. C., Moore, B. L., Doufas, A. G., Pyeatt, L. D. IEEE COMPUTER SOC. 2011: 41–46

  View details for DOI 10.1109/ICTAI.2011.15

  View details for Web of Science ID 000299009900006

• The Hippocratic Paradigm in Medicine: Origins of the Clinical Encounter ANESTHESIA AND ANALGESIA Doufas, A. G., Saidman, L. J. 2010; 110 (1): 4-6

  View details for DOI 10.1213/ANE.0b013e3181c0f223

  View details for Web of Science ID 000273193700002

  View details for PubMedID 20023180

• Reinforcement Learning for Closed-Loop Propofol Anesthesia: A Human Volunteer Study Moore, B. L., Panousis, P., Kulkarni, V., Pyeatt, L. D., Doufas, A. G., AAAI ASSOC ADVANCEMENT ARTIFICIAL INTELLIGENCE. 2010: 1807–13

  View details for Web of Science ID 000392059700289

• Tissue oxygenation response to mild hypercapnia during cardiopulmonary bypass with constant pump output BRITISH JOURNAL OF ANAESTHESIA Akca, O., Sessler, D. I., Delong, D., Keijner, R., Ganzel, B., Doufas, A. G. 2006; 96 (6): 708-714

  Abstract

  Tissue oxygenation is the primary determinant of wound infection risk. Mild hypercapnia markedly improves cutaneous, subcutaneous (s.c.), and muscular tissue oxygenation in volunteers and patients. However, relative contributions of increased cardiac output and peripheral vasodilation to this response remains unknown. We thus tested the hypothesis that increased cardiac output is the dominant mechanism.We recruited 10 ASA III patients, aged 40-65 yr, undergoing cardiopulmonary bypass for this crossover trial. After induction of anaesthesia, a Silastic tonometer was inserted s.c. in the upper arm. S.C. tissue oxygen tension was measured with both polarographic electrode and fluorescence-based systems. Oximeter probes were placed bilaterally on the forehead to monitor cerebral oxygenation. After initiation of cardiopulmonary bypass, in random order patients were exposed to two arterial CO(2) partial pressures for 30 min each: 35 (normocapnia) or 50 mm Hg (hypercapnia). Bypass pump flow was kept constant throughout the measurement periods.Hypercapnia during bypass had essentially no effect on Pa(CO(2)) , mean arterial pressure, or tissue temperature. Pa(CO(2)) and pH differed significantly. S.C. tissue oxygenation was virtually identical during the two Pa(CO(2)) periods [139 (50-163) vs 145 (38-158), P=0.335] [median (range)]. In contrast, cerebral oxygen saturation (our positive control measurement) was significantly less during normocapnia [57 (28-67)%] than hypercapnia [64 (37-89)%, P=0.025].Mild hypercapnia, which normally markedly increases tissue oxygenation, did not do so during cardiopulmonary bypass with fixed pump output. This suggests that hypercapnia normally increases tissue oxygenation by increasing cardiac output rather than direct dilation of peripheral vessels.

  View details for DOI 10.1093/bja/ael093

  View details for Web of Science ID 000237696400006

  View details for PubMedID 16675511

• Postoperative coma in a patient with complete basilar syndrome after anterior cervical discectomy CANADIAN JOURNAL OF ANAESTHESIA-JOURNAL CANADIEN D ANESTHESIE Tsai, Y. F., Doufas, A. G., Huang, C. S., Liou, F. C., Lin, C. M. 2006; 53 (2): 202-207

  Abstract

  Ischemic brainstem stroke resulting from occlusion of the basilar artery during cervical spine surgery in a previously asymptomatic patient is a rare event. We report the development of a large ischemic brainstem stroke, resulting from occlusion of the basilar artery during anterior cervical discectomy, in a patient without previous neurological deficit, or signs of vertebrobasilar insufficiency.A 55-yr-old, diabetic and hypertensive male who developed a cervical spine infection, underwent surgery for anterior discectomy at C5-C6. During the 2.5-hr long procedure the patient was lying supine with his neck hyperextended. Except for a temporary reduction in systolic blood pressure, the intraoperative course was uneventful. At the end of surgery the patient remained unconscious with flaccid paralysis in all extremities, fixed pinpoint pupils, low respiratory rate, and no response to painful stimuli. Naloxone administration did not improve the clinical picture, while brain computed tomography showed a large brainstem and cerebellar stroke, implicating basilar artery occlusion. The patient died five days later from stroke complications. Intraoperative surgical manipulation with a severely inflamed vertebral system, as well as prolonged neck hyperextension occluding the blood flow of vertebrobasilar arteries might have contributed to fatal brainstem stroke in this patient.Neck surgery carries a potential risk for posterior circulation stroke, and this report heightens awareness of this rare, but serious complication.

  View details for Web of Science ID 000234952200016

  View details for PubMedID 16434763

• Effects of dopexamine on lipid peroxidation during aortic surgery in pigs: Comparison with dopamine EUROPEAN JOURNAL OF VASCULAR AND ENDOVASCULAR SURGERY Kostopanagiotou, G., Pandazi, A., Andreadou, I., Doufas, A., Chondroudaki, I., Kotsis, T., Rizos, D., Costopanagiotou, C., Smyrniotis, V. 2005; 30 (6): 648-653

  Abstract

  We investigated the dose-related effect of dopexamine and dopamine on free radical production and lipid peroxidation estimated by MDA measurements in an ischaemia-reperfusion model of supraceliac aortic repair.Prospective, randomized, blinded experimental study.Twenty-five healthy pigs.All experiments were performed under general endotracheal anaesthesia. Supraceliac aortic cross clamping was performed in all pigs. The pigs were randomly assigned into five groups (n=5 in each group) and received a continuous intravenous infusion of normal saline (CTL), dopamine 2 microg kg(-1)min(-1) (dopa 2), dopamine 8 microg kg(-1)min(-1) (dopa 8), dopexamine 2 microg kg(-1)min(-1) (dopex 2), dopexamine 8 microg kg(-1)min(-1) (dopex 8). Cardiac output, mean arterial pressure, arterial blood gas analysis and blood sampling for plasma MDA measurements (to reveal lipid peroxidation) were recorded after induction of anaesthesia (baseline), 60 and 120 min after cross-clamping of aorta (ischaemia phase), and 60 and 120 min after restoration of flow (reperfusion phase).Dopexamine and dopamine at 8 microgkg(-1)min(-1) reduced MDA at 60 and 120 min after reperfusion.Dopexamine seems superior to dopamine in reducing oxygen free radicals and subsequent lipid peroxidation during reperfusion after supraceliac aortic cross clamping in pigs.

  View details for DOI 10.1016/j.ejvs.2005.06.029

  View details for Web of Science ID 000234162400015

  View details for PubMedID 16102983

• Recurrent seizure activity after epidural morphine in a post-partum woman CANADIAN JOURNAL OF ANAESTHESIA-JOURNAL CANADIEN D ANESTHESIE SHIH, C. J., Doufas, A. G., Chang, H. C., Lin, C. M. 2005; 52 (7): 727-729

  Abstract

  We report on a primiparous woman who suffered recurrent seizure activity after repeated small doses of epidural morphine to highlight the neuroexcitation potential of neuraxial opioids in the epileptic patient.Seizure activities as a complication of opioid administration have been reported in laboratory animals and humans. We report the case of a 30-yr-old primiparous woman with a history of epilepsy under carbamazepine treatment, who had epidural anesthesia for elective Cesarean section at 38 weeks gestation. Postoperatively, 1.5 mg of morphine were administered epidurally for pain control. Three hours later the patient suffered from clonic movements of the right arm without loss of consciousness. One day later, she again received 1 mg of epidural morphine twice at a 12-hr interval and similar seizure episodes recurred eight hours after each dose. A relation between the administration of morphine and seizure activity was suspected and the use of opioids for pain control was stopped. The patient was discharged on the fifth postoperative day and, more than one year after the last episode, she remains free of any seizure activity.Our report indicates that even a remote history of epilepsy carries a pro-convulsant potential in the peripartum period, even following the administration of small doses of epidural morphine.

  View details for Web of Science ID 000231743500012

  View details for PubMedID 16103386

• The timing of acupuncture stimulation does not influence anesthetic requirement ANESTHESIA AND ANALGESIA Chernyak, G., Sengupta, P., Lenhardt, R., Liem, E., Doufas, A. G., Sessler, D. I., Akca, O. 2005; 100 (2): 387-392

  Abstract

  Studies suggest that acupuncture is more effective when induced before the induction of general anesthesia than afterwards. We tested the hypothesis that electro-acupuncture initiated 30 min before the induction reduces anesthetic requirement more than acupuncture initiated after the induction. Seven volunteers were each anesthetized with desflurane on 3 study days. Needles were inserted percutaneously at four acupuncture points thought to produce analgesia in the upper abdominal area and provide generalized sedative and analgesic effects: Zusanli (St36), Sanyinjiao (Sp6), Liangqiu (Sp34), and Hegu (LI4). Needles were stimulated at 2 Hz and 10 Hz, with frequencies alternating at 2-s intervals. On Preinduction day, electro-acupuncture was started 30 min before the induction of anesthesia and maintained throughout the study. On At-induction day, needles were positioned before the induction of anesthesia, but electro-acupuncture stimulation was not initiated until after the induction. On Control day, electrodes were positioned near the acupoints, but needles were not inserted. Noxious electrical stimulation was administered via 25-gauge needles on the upper abdomen (70 mA; 100 Hz; 10 s). The desflurane concentration was increased 0.5% when movement occurred and decreased 0.5% when it did not. These up-and-down sequences continued until volunteers crossed from movement to no movement four times. The P(50) of logistic regression identified desflurane requirement. Desflurane requirement was similar on the Control (mean +/- sd; 5.2% +/- 0.6%), Preinduction (5.0% +/- 0.8%), and At-induction (4.7% +/- 0.3%; P = 0.125) days. This type of acupuncture is thus unlikely to facilitate general anesthesia or decrease the requirement for anesthetic drugs.

  View details for DOI 10.1213/01.ANE.0000142114.72117.E0

  View details for Web of Science ID 000226567000016

  View details for PubMedID 15673863

• Effects of transient myocardial ischemia on the ventricular defibrillation threshold PACE-PACING AND CLINICAL ELECTROPHYSIOLOGY Anastasiou-Nana, M. I., Tsagalou, E. P., Charitos, C., Siafakas, K. X., Drakos, S., Terrovitis, J. V., Ntalianis, A., Doufas, A., Mavrikakis, J., Nanas, J. N. 2005; 28 (2): 97-101

  Abstract

  Acute myocardial ischemia and the mode of ventricular fibrillation (VF) induction influence the ventricular defibrillation threshold (DFT).The purpose of this study was to determine the effects of transient regional left ventricular (LV) ischemia on the DFT.Ventricular effective refractory period (ERP), ventricular fibrillation threshold (VFT), and DFT were measured under nonischemic conditions (control) in 26 pigs weighing 25-35 kg. Myocardial ischemia was then induced by occlusion of the mid left anterior descending coronary artery, and measurements of ERP and VFT were repeated after 2 minutes of occlusion. The coronary artery ligation was released immediately after the onset of VF and DFT was measured.LV ERP was unchanged by ischemia (199 +/- 19 ms at control vs. 200 +/- 22 ms under ischemic conditions, P = 0.799), whereas VFT was significantly lower during coronary occlusion (10.7 +/- 5.4 mA vs. 37.7 +/- 13 mA, P = 0.000). Brief myocardial ischemia caused a significant increase in DFT (13.5 +/- 12.6 J after coronary occlusion vs. 6.8 +/- 6.8 J at control, P = 0.023). The duration of coronary occlusion was not correlated with the amounts of energy required to defibrillate (P = 0.526).This experimental study shows that transient myocardial ischemia markedly increases the DFT, suggesting that specific defibrillation algorithms should be designed for recipients of implantable defibrillators at risk of myocardial ischemia.

  View details for Web of Science ID 000227309600003

  View details for PubMedID 15679638

• The new perilaryngeal airway (CobraPLA (TM)) is as efficient as the laryngeal mask airway (LMA (TM)) but provides better airway sealing pressures Annual Meeting of the American-Society-of-Anesthesiologists Akca, O., Wadhwa, A., Sengupta, P., Durrani, J., Hanni, K., Wenke, M., Yucel, Y., Lenhardt, R., Doufas, A. G., Sessler, D. I. LIPPINCOTT WILLIAMS & WILKINS. 2004: 272–78

  Abstract

  The Laryngeal Mask Airway (LMA) is a frequently used efficient airway device, yet it sometimes seals poorly, thus reducing the efficacy of positive-pressure ventilation. The Perilaryngeal Airway (CobraPLA) is a novel airway device with a larger pharyngeal cuff (when inflated). We tested the hypothesis that the CobraPLA was superior to the LMA with regard to insertion time and airway sealing pressure and comparable to the LMA in airway adequacy and recovery characteristics. After midazolam and fentanyl administration, 81 ASA physical status I-II outpatients having elective surgery were randomized to receive an LMA or CobraPLA. Anesthesia was induced with propofol (2.5 mg/kg IV), and the airway was inserted. We measured 1) insertion time; 2) adequacy of the airway (no leak at 15-cm-H2O peak pressure or tidal volume of 5 mL/kg); 3) airway sealing pressure; 4) number of repositioning attempts; and 5) sealing quality (no leak at tidal volume of 8 mL/kg). At the end of surgery, gastric insufflation, postoperative sore throat, dysphonia, and dysphagia were evaluated. Data were compared with unpaired Student's t-tests, chi2 tests, or Fisher's exact tests; P < 0.05 was significant. Patient characteristics, insertion times, airway adequacy, number of repositioning attempts, and recovery were similar in each group. Airway sealing pressure was significantly greater with CobraPLA (23 +/- 6 cm H2O) than LMA (18 +/- 5 cm H2O, P < 0.001). The CobraPLA has insertion characteristics similar to the LMA but better airway sealing capabilities.

  View details for DOI 10.1213/01.ane.0000117003.60213.e9

  View details for Web of Science ID 000222256400052

  View details for PubMedID 15281543

• Time course of fibrillation and defibrillation thresholds after an intravenous bolus of amiodarone - an experimental study RESUSCITATION Tsagalou, E. P., Anastasiou-Nana, M. I., Charitos, C. E., Siafakas, C. X., Drakos, S. G., Ntalianis, A., Terrovitis, J. V., Mavrikakis, E. M., Doufas, A., Nanas, J. N. 2004; 61 (1): 83-89

  Abstract

  Experimental studies have described an increase in ventricular fibrillation threshold (VFT) by intravenous amiodarone. The aim of this study was to examine the early time course of changes in VFT and defibrillation thresholds (DFT) after an intravenous bolus of amiodarone in an experimental pig model of transient myocardial ischemia.VFT and relative effective ventricular refractory period (ERP) were measured in 15 anaesthetized open-chest pigs after 3 min of regional coronary ischaemia before (time 0) and 2, 15, 30, 60, and 90 min after the intravenous injection of normal saline (group A, n = 5) or amiodarone, 5 mg/kg over 15 s (group B, n = 10). DFT was measured by increasing the strength of DC shocks until defibrillation was accomplished. Amiodarone caused an increase in VFT, starting at 2 min after the infusion (11.4 +/- 8.4 mA versus 9.2 +/- 4.6 mA, P = 0.03), became significant at 15 min (13.7 +/- 6.5 mA, P = 0.009), continued to rise at 30 min (34.2 +/- 28.7 mA, P = 0.03) and reached a plateau at 60 min (50.3 +/- 37.8 mA, P = 0.008). An increase was also observed in the ERP (204 +/- 25 ms at 2 min versus 197 +/- 26 ms at baseline, P = 0.074, 211 +/- 38 ms at 15 min, P = 0.084, 212 +/- 40 ms at 30 min, P = 0.037, 220 +/- 34 ms at 60 min, P = 0.002, and 227 +/- 32 ms at 90 min, P = 0.008). No change was observed in DFT after amiodarone administration. No significant change in VFT, ERP, or DFT occurred in the control group.In this porcine model, the intravenous administration of amiodarone increased VFT and ERP over 60 min after the injection, without effect on DFT.

  View details for DOI 10.1016/j.resuscitation.2003.12.003

  View details for Web of Science ID 000221252200012

  View details for PubMedID 15081186

• T-4 but not T-3 administration is associated with increased recurrence of Graves' disease after successful medical therapy JOURNAL OF ENDOCRINOLOGICAL INVESTIGATION Mastorakos, G., Doufas, A. G., Mantzos, E., Mantzos, J., Koutras, D. A. 2003; 26 (10): 979-984

  Abstract

  TSH has been incriminated in Graves' disease for increasing the production of antibodies against TSH receptor (TRAb). It has been, therefore, suggested that T4 administration after successful antithyroid drug (ATD) treatment may indirectly decrease the production of TRAb and, therefore, the frequency of recurrence of hyperthyroidism. To study the role of T4 and T3 on the recurrence rate of Graves' disease 108 patients with Graves' disease (22 males, age: 49.8 +/- 14.3 yr, mean +/- SD, and 86 females, age: 41.7 +/- 12 yr) were followed-up for 24 months after successful treatment with ATD (carbimazole). During the follow-up period, patients daily received either 100 microg T4 or 25 microg T3 or placebo after random and double-blinded assignment into three groups. They were evaluated trimonthly up to 12 months and at 24 months. Plasma TRAb levels were measured at the beginning and at 12 months. At 12 months of the follow-up period, 14 out of 33 (42.4%), 6 out of 38 (15.8%), and 9 out of 37 (24.3%) patients receiving T4, T3 and placebo, respectively, recurred. Recurrence rate of T4-treated patients was statistically higher than that of the T3-treated patients or controls (p < 0.05). At the beginning of the follow-up period patients who were going to recur had significantly higher TRAb levels and goiter weight than patients who were not (p < 0.05). At 24 months of the follow-up period, from the patients who did not drop out of the study, none out of 11 (0%), 2 out of 19 (10.5%) and 1 out of 12 (8.3%) receiving T4, T3 and placebo, respectively, recurred. We conclude that T4 administration after successful ATD treatment of Graves' disease is associated with increased recurrence of hyperthyroidism as compared to the T3 or placebo administration. High TRAb levels and goiter weight at the end of ATD treatment may hint at recurrence.

  View details for Web of Science ID 000187513800008

  View details for PubMedID 14759070

• Blood pressure response to thermoregulatory vasoconstriction during isoflurane and desflurane anesthesia ACTA ANAESTHESIOLOGICA SCANDINAVICA Greif, R., Laciny, S., Rajek, A., Doufas, A. G., Sessler, D. I. 2003; 47 (7): 847-852

  Abstract

  Mild perioperative hypothermia produces morbid cardiac outcomes that may result from sympathetically induced hypertension. However, volatile anesthetics produce vasodilatation that may reduce the hemodynamic response to hypothermia. We tested the hypothesis that the volatile anesthetics isoflurane and desflurane blunt the normal cold-induced hypertensive response.We analyzed prospective data from three analogous studies: 1) 10 volunteers given desflurane (2.6 volume percentage) maintained in left-lateral position; 2) nine volunteers without anesthesia or anesthetized with various doses of desflurane; and 3) eight volunteers given various concentrations of isoflurane. Mean skin temperature was reduced to 31 C, which decreased core body temperature and triggered thermoregulatory vasoconstriction. Mean arterial pressures were determined before and after hypothermia provoked intense thermoregulatory vasoconstriction.The hemodynamic responses to thermoregulatory vasoconstriction were similar without anesthesia and at all concentrations of desflurane and isoflurane. On average, mean arterial pressure increased 14 (SD = 5) mmHg with and without anesthesia.We conclude that thermoregulatory vasoconstriction significantly increases arterial pressure with or without isoflurane or desflurane anesthesia.

  View details for Web of Science ID 000184111700011

  View details for PubMedID 12859306

• Experimental surgery in infrarenal aorta and sigmoid ischemia 11th Congress of the Mediterranean-League-of-Angiology-and-Vascular-Surgery Katsenis, K., Kotsis, T., Pafiti, A., Doufas, A., Dimakakos, P. EDIZIONI MINERVA MEDICA. 2003: 159–63

  Abstract

  Colon ischemia is a rare but serious complication in surgery of the infrarenal aorta, due to ligation of the inferior mesenteric artery and the ischemia-reperfusion syndrome. In order to investigate the degree of intestinal damage, we employed experimental surgery in pigs, applying the usual protocol for elective repair of the infrarenal aorta (AAA or Y graft).Three groups of pigs were operated on. In Group A (n=4, 21-25 kg, mean 22.6) a sham operation was performed. In Group B (n=6, 21-26 kg, mean 24) the infrarenal aorta was cross-clamped along with the internal and external iliac arteries and a longitudinal incision was performed in the aorta, while in Group C (n=5, 20-27 kg, mean 23.8) a Pruitt-Inahara shunt was used to allow flow from the infrarenal aorta towards the iliac arteries and the inferior mesenteric artery during cross-clamping. The duration of cross-clamping was two hours (Group B and C). In all groups we evaluated sigmoid histology after reperfusion under light microscopy.The pathologic examination of the sigmoid revealed increased postischemic injuries in Group B, while the protective effect of the shunt was obvious in Group C. The tissue samples of Group B presented hyperemia, submucosal edema, dilatation of the lymph vessels and severe inflammatory infiltration of the mucosa, muscularis propria and serosa, with cells showing acute and chronic inflammatory responses. In Group C all specimens presented hyperemic vessels and a slight inflammatory reaction of mucosa. In conclusion, Group B, presented the most severe inflammatory changes, involving all layers, while in Group C congestion and slight inflammatory reactions of the mucosa were observed. In Group A, no significant changes in normal histology were observed.The importance of these findings is evident, because in the clinical situation patients have variable degrees of arteriopathy, thus even short periods of ischemia might prove disastrous and this could occur in repair of the infarenal aorta as well as in other cases of inevitable risk, such as in surgery of the thoraco-abdominal aorta.

  View details for Web of Science ID 000184273300007

  View details for PubMedID 12865881

• Effect of intra-operative end-tidal carbon dioxide partial pressure on tissue oxygenation ANAESTHESIA Akca, O., Liem, E., Suleman, M. I., Doufas, A. G., Galandiuk, S., Sessler, D. I. 2003; 58 (6): 536-542

  Abstract

  Postsurgical infection risk is correlated with subcutaneous tissue oxygenation. Mild hypercapnia augments cutaneous perfusion. We tested the hypothesis that peripheral tissue oxygenation increases as a function of arterial PCO2 in surgical patients. Twenty patients were randomly assigned to intra-operative end tidal PCO2 of 3.99 (control) or 5.99 kPa (hypercapnia). All other anaesthetic management was per protocol. Tissue oxygen partial pressure, transcutaneous oxygen tension, cerebral oxygen saturation, and cardiac output were measured. Mean (SD) subcutaneous tissue oxygen tension was 8.39 (1.86) kPa in control and 11.84 (2.53) kPa hypercapnia patients (p = 0.014). Cerebral oxygen saturation was 55 (4)% for control vs. 68 (9)% for hypercapnia (p = 0.004). Neither cardiac index nor transcutaneous tissue oxygen tension differed significantly between the groups. Mild intra-operative hypercapnia increased subcutaneous and cerebral oxygenation. Increases in subcutaneous tissue oxygen partial pressure similar to those observed in patients assigned to hypercapnia are associated with substantial reductions in wound infection risk.

  View details for Web of Science ID 000183025400006

  View details for PubMedID 12846617

• Hypercapnia improves tissue oxygenation ANESTHESIOLOGY Akca, O., Doufas, A. G., Morioka, N., Iscoe, S., Fisher, J., Sessler, D. I. 2002; 97 (4): 801-806

  Abstract

  Wound infections are common, serious, surgical complications. Oxidative killing by neutrophils is the primary defense against surgical pathogens and increasing intraoperative tissue oxygen tension markedly reduces the risk of such infections. Since hypercapnia improves cardiac output and peripheral tissue perfusion, we tested the hypothesis that peripheral tissue oxygenation increases as a function of arterial carbon dioxide tension (PaCO(2)) in anesthetized humans.General anesthesia was induced with propofol and maintained with sevoflurane in 30% oxygen in 10 healthy volunteers. Subcutaneous tissue oxygen tension (PsqO(2)) was recorded from a subcutaneous tonometer. An oximeter probe on the upper arm measured muscle oxygen saturation. Cardiac output was monitored noninvasively. PaCO(2) was adjusted to 20, 30, 40, 50, or 60 mmHg in random order with each concentration being maintained for 45 min.(2) (2)Increasing PaCO(2) linearly increased cardiac index and PsqO(2) : PsqO(2) = 35.42 + 0.77 (PaCO(2)), < 0.001.The observed difference in PsqO(2) is clinically important because previous work suggests that comparable increases in tissue oxygenation reduced the risk of surgical infection from -8% to 2 to 3%. We conclude that mild intraoperative hypercapnia increased peripheral tissue oxygenation in healthy human subjects, which may improve resistance to surgical wound infections.

  View details for Web of Science ID 000178409800008

  View details for PubMedID 12357143

• Insufficiency in a new temporal-artery thermometer for adult and pediatric patients Annual Meeting of the American-Society-of-Anesthesiologists Suleman, M. I., Doufas, A. G., Akca, O., Ducharme, M., Sessler, D. I. LIPPINCOTT WILLIAMS & WILKINS. 2002: 67–71

  Abstract

  SensorTouch is a new noninvasive temperature monitor and consists of an infrared scanner that detects the highest temperature on the skin of the forehead, presumably over the temporal artery. The device estimates core temperature (T(core)). We tested the hypothesis that the SensorTouch is sufficiently precise and accurate for routine clinical use. We studied adults (n = 15) and children (n = 16) who developed mild fever, a core temperature of at least 37.8 degrees C, after cardiopulmonary bypass. Temperature was recorded at 15-min intervals throughout recovery with the SensorTouch thermometer and from the pulmonary artery (adults) or bladder (children). Pulmonary artery (T(core)) and SensorTouch (T(st)) temperatures correlated poorly in adults: T(core) = 0.7. T(st) + 13, r(2) = 0.3. Infrared and pulmonary artery temperatures differed by 1.3 +/- 0.6 degrees C; 89% of the adult temperatures thus differed by more than 0.5 degrees C. Bladder and infrared temperatures correlated somewhat better in pediatric patients: T(core) = 0.9. T(st) + 12, r(2) = 0.6. Infrared and bladder temperatures in children differed by only 0.3 degrees C, but the SD of the difference was 0.5 degrees C. Thus, 31% of the values in the infants and children differed by more than 0.5 degrees C.We evaluated a noninvasive infrared forehead thermometer (SensorTouch) in adult and pediatric cardiac patients. Accuracy was poor in the adults and suboptimal in infants and children.

  View details for DOI 10.1213/01.ANE.0000023344.01246.09

  View details for Web of Science ID 000176634100012

  View details for PubMedID 12088945

• Use of selective opiate receptor inhibitors to prevent postoperative ileus. Minerva anestesiologica Akça, O., Doufas, A. G., Sessler, D. I. 2002; 68 (4): 162-165

  Abstract

  Ileus is a common postoperative complication after major abdominal surgery. Surgical manipulation of the bowel and stimulation of opiod receptor are the main causes of ileus. An investigational drug (ADL 8-2698, Alvinopam) a selective opioid antagonist with a very low oral absorption was recently introduced to clinical medicine. Unlike other opioid antagonist its activity is restricted to GI tract, it is potent, has a long duration of action, is orally effective, does not readily cross the blood-brain barrier even after intravenous administration in animals. Two randomized controlled clinical studies tested its effects in humans. Liu et al.'s study confirmed peripheral restriction of ADL 8-2698 by its lack of central effect on morphine analgesia and pupil miosis. They also showed that ADL 8-2698 prevents increases in gastrointestinal transit time. Taguchi et al. concluded that high dose (6 mg) of ADL 8-2698 archived fast recovery of gastrointestinal function, without antagonising analgesic efficacy of systemic opioid. In summary, selective inhibition of gastrointestinal opioid receptor by a peripherally restricted oral antagonist speeds recovery of bowel function, shortens times of hospitalization and preserves the analgesic effects of opiods.

  View details for PubMedID 12024075

• The threshold and gain of thermoregulatory vasoconstriction differs during anesthesia in the dependent and upper arms in the lateral position ANESTHESIA AND ANALGESIA Greif, R., Laciny, S., Rajek, A., Doufas, A. G., Sessler, D. I. 2002; 94 (4): 1019-1022

  Abstract

  Increased intraluminal pressure may help maintain vasodilation in a dependent arm even after hypothermia triggers centrally mediated thermoregulatory vasoconstriction. We therefore tested the hypotheses that the threshold (triggering core temperature) and gain (increase in vasoconstriction per degree centigrade) of cold-induced vasoconstriction is reduced in the dependent arm during anesthesia. Anesthesia was maintained with 0.4 minimum alveolar anesthetic concentration of desflurane in 10 volunteers in the left-lateral position. Mean skin temperature was reduced to 31 degrees C to decrease core body temperature. Fingertip blood flow in both arms was measured, as was core body temperature. The vasoconstriction threshold was slightly, but significantly, less in the dependent arm (36.2 degrees C +/- 0.3 degrees C, mean +/- SD) than in the upper arm (36.5 degrees C +/- 0.3 degrees C). However, the gain of vasoconstriction in the dependent arm was 2.3-fold greater than in the upper arm. Consequently, intense vasoconstriction (i.e., a fingertip blood flow of 0.15 mL/min) occurred at similar core temperatures. In the lateral position, the vasoconstriction threshold was reduced in the dependent arm; however, gain was also increased in the dependent arm. The thermoregulatory system may thus recognize that hydrostatic forces reduce the vasoconstriction threshold and may compensate by sufficiently augmenting gain.The threshold for cold-induced vasoconstriction is reduced in the dependent arm, but the gain of vasoconstriction is increased. Consequently, the core temperature triggering intense vasoconstriction was similar in each arm, suggesting that the thermoregulatory system compensates for the hydrostatic effects of the lateral position.

  View details for Web of Science ID 000174528600046

  View details for PubMedID 11916816

• Oxygen free radicals in abdominal aortic surgery - An experimental study JOURNAL OF CARDIOVASCULAR SURGERY Dimakakos, P. B., Kotsis, T., Kondi-Pafiti, A., Katsenis, K., Doufas, A., Chondros, K., Kouskouni, E. 2002; 43 (1): 77-82

  Abstract

  In aortic reconstruction, intestinal and muscular ischaemia in the lower limbs occurs during cross-clamping of the aorta. After restoration of blood flow, reactive oxygen intermediates may lead to systemic injury to local or remote organs. In this study we investigated the usefulness of a shunt and vitamin E administration against the oxidant load generated in ischaemia-reperfusion phases.In three groups of pigs (n=16) aortic reconstruction was simulated. In Group A (n=5) clamping of the infrarenal aorta was performed for 2 hours. In Group B (n=6), during aortic cross-clamping, a shunt was used to give flow to the inferior mesenteric and internal iliac arteries. In Group C (n=5) vitamin E was administered before aortic cross-clamping. In all groups we evaluated sigmoid histology after reperfusion, while the oxidant load was estimated by measuring superoxide dismutase (SOD) activity in blood samples from portal and jugular vein.Histology of the sigmoid revealed increased postischaemic injuries in Group A, while the protective effect of shunt and vitamin E was apparent in Group B and C, respectively. SOD activity was minimized in Group C.Vitamin E protected the sigmoid from postischaemic injury and is responsible for the decreased levels of SOD activity.

  View details for Web of Science ID 000174651800016

  View details for PubMedID 11803334

• Transcutaneous electrical stimulation of an auricular acupuncture point decreases anesthetic requirement 8th Annual Meeting of the European-Society-of-Anaesthesiologists Greif, R., Laciny, S., Mokhtarani, M., Doufas, A. G., Bakhshandeh, M., Dorfer, L., Sessler, D. I. LIPPINCOTT WILLIAMS & WILKINS. 2002: 306–12

  Abstract

  German anesthesiologists have long used transcutaneous electrical stimulation of an acupuncture point near the tragus to reduce anesthetic requirement in unblinded and uncontrolled trials. This is known as auricular electrically stimulated analgesia. The authors therefore tested the hypothesis that auricular electrically stimulated analgesia reduces anesthetic requirement.In a randomized, double-blind, crossover trial, volunteers were anesthetized twice with desflurane. Electrical stimulation of an auricular acupuncture point in the vicinity of the tragus was used on 1 randomly assigned day, and no electrical stimulation of the same point was used on the other study day. Treatment consisted of bilateral electrical stimulation of the lateralization control point, 3 cm anterior to the tragus. The 10-mA current was set to 299 Hz on the dominant side of the face and to 149 Hz on the contralateral side. Anesthetic requirement was determined by the Dixon up-and-down method and was defined by the average desflurane concentration required to prevent purposeful movement of the extremities in response to noxious electrical stimulation.Ten men and 10 women completed the protocol. Electrical stimulation of the lateralization control point reduced anesthetic requirement by 11 +/- 7% (P < 0.001), with the reduction being similar in women and men. Women required more desflurane to prevent movement on the control day than the men (5.5 +/- 1.0 vs. 4.6 +/- 0.6 vol%; P = 0.028).This double-blinded trial with an objective outcome demonstrates that electrical stimulation of the lateralization control point significantly reduces anesthetic requirement.

  View details for Web of Science ID 000173606400010

  View details for PubMedID 11818761

• Buspirone and meperidine synergistically reduce the shivering threshold ANESTHESIA AND ANALGESIA Mokhtarani, M., Mahgoub, A. N., Morioka, N., Doufas, A. G., Dae, M., Shaughnessy, T. E., Bjorksten, A. R., Sessler, D. L. 2001; 93 (5): 1233-1239

  Abstract

  Mild hypothermia (i.e., 34 degrees C) may prove therapeutic for patients with stroke, but it usually provokes shivering. We tested the hypothesis that the combination of buspirone (a serotonin 1A partial agonist) and meperidine synergistically reduces the shivering threshold (triggering tympanic membrane temperature) to at least 34 degrees C while producing little sedation or respiratory depression. Eight volunteers each participated on four randomly-assigned days: 1) large-dose oral buspirone (60 mg); 2) large-dose IV meperidine (target plasma concentration of 0.8 microg/mL); 3) the combination of buspirone (30 mg) and meperidine (0.4 microg/mL); and 4) a control day without drugs. Core hypothermia was induced by infusion of lactated Ringer's solution at 4 degrees C. The control shivering threshold was 35.7 degrees C +/- 0.2 degrees C. The threshold was 35.0 degrees C +/- 0.8 degrees C during large-dose buspirone and 33.4 degrees C +/- 0.3 degrees C during large-dose meperidine. The threshold during the combination of the two drugs was 33.4 degrees C +/- 0.7 degrees C. There was minimal sedation on the buspirone and combination days and mild sedation on the large-dose meperidine day. End-tidal PCO2 increased approximately 10 mm Hg with meperidine alone. Buspirone alone slightly reduced the shivering threshold. The combination of small-dose buspirone and small-dose meperidine acted synergistically to reduce the shivering threshold while causing little sedation or respiratory toxicity.Mild hypothermia may be an effective treatment for acute stroke, but it usually triggers shivering, which could be harmful. Our results indicate that the combination of small-dose buspirone and small-dose meperidine acts synergistically to reduce the shivering threshold while causing little sedation or respiratory toxicity. This combination may facilitate the induction of therapeutic hypothermia in stroke victims.

  View details for Web of Science ID 000171820500034

  View details for PubMedID 11682404

• Neither nalbuphine nor atropine posses special antishivering activity ANESTHESIA AND ANALGESIA Greif, R., Laciny, S., Rajek, A. M., Larson, M. D., Bjorksten, A. R., Doufas, A. G., Bakhshandeh, M., Mokhtarani, M., Sessler, D. I. 2001; 93 (3): 620-627

  Abstract

  The special antishivering action of meperidine may be mediated by its kappa or anticholinergic actions. We therefore tested the hypotheses that nalbuphine or atropine decreases the shivering threshold more than the vasoconstriction threshold. Eight volunteers were each evaluated on four separate study days: 1) control (no drug), 2) small-dose nalbuphine (0.2 microg/mL), 3) large-dose nalbuphine (0.4 microg/mL), and 4) atropine (1-mg bolus and 0.5 mg/h). Body temperature was increased until the patient sweated and then decreased until the patient shivered. Nalbuphine produced concentration-dependent decreases (mean +/- SD) in the sweating (-2.5 +/- 1.7 degrees C. microg(-1). mL; r(2) = 0.75 +/- 0.25), vasoconstriction (-2.6 +/- 1.7 degrees C. microg(-1). mL; r(2) = 0.75 +/- 0.25), and shivering (-2.8 +/- 1.7 degrees C. microg(-1). mL; r(2) = 0.79 +/- 0.23) thresholds. Atropine significantly increased the thresholds for sweating (1.0 degrees C +/- 0.4 degrees C), vasoconstriction (0.9 degrees C +/- 0.3 degrees C), and shivering (0.7 degrees C +/- 0.3 degrees C). Nalbuphine reduced the vasoconstriction and shivering thresholds comparably. This differs markedly from meperidine, which impairs shivering twice as much as vasoconstriction. Atropine increased all thresholds and would thus be expected to facilitate shivering. Our results thus fail to support the theory that activation of kappa-opioid or central anticholinergic receptors contribute to meperidine's special antishivering action.

  View details for Web of Science ID 000170672100018

  View details for PubMedID 11524329

• Use of an isolated pancreatic graft (ex vivo) of swine as model for drug studies 4th International Conference on New Trends in Clinical and Experimental Immunosuppression Papalois, A., Smyrniotis, V., Papadimitriou, L., Syriou, V., Konstantellou, E., Tsaroucha, A., Doufas, A. G., Lykoudis, E., Karampela, E., Grigoriou, T., Manoli, E., Papadimitriou, J., Tolis, G. ELSEVIER SCIENCE INC. 2001: 2298–99

  View details for Web of Science ID 000168781300078

  View details for PubMedID 11377535

• Effect of balloon angioplasty and stenting following clips vs suture arterial stenosis: an experimental study VASA-JOURNAL OF VASCULAR DISEASES Dimakakos, P. B., Kotsis, T., Doufas, A., Pafiti-Condi, A., Tsiligiris, B., Antoniou, A., Mourikis, D. 2000; 29 (1): 35-39

  Abstract

  Comparative evaluation of balloon angioplasty following intravascular stenting after experimental stenoses caused by arterial reconstruction with vascular clips and conventional sutures.A total of 24 arteriotomies were carried out at the carotid and common iliac arteries of pigs following a 10 mm longitudinal arteriotomy and provocation of stenosis. Twelve of the arteries were reconstructed with vascular clips and 12 with conventional suture. Ultrasonography revealed stenosis fluctuating from 60-95% (PSV: 1.8-3.5 m/sec EDV: 1.3-1.47 m/sec PSV ratio > 3.5). After 8 weeks, following digital subtraction angiography, which revealed > 50% stenosis in all of the cases, balloon angioplasty followed by placement of intravascular stent was carried out.All the angioplasties remained angiographically and macroscopically patent two months after without thrombus formation. Rupture during dilatation occurred in one of the sutured cases. Histologically no degenerative changes, necrosis or remarkable intimal thickness were observed in either method. Focal inflammatory reaction was seen in 2 sutured and in 1 clipped cases while intimal ulceration was observed in 2 sutured cases. All cases with clips presented an intact endothelial surface.Early experimental results suggested that arterial stenosis provoked by clipped reconstruction could be managed successfully by balloon angioplasty followed by placement of intravascular stent.

  View details for Web of Science ID 000085798300006

  View details for PubMedID 10731886

• The hypothalamic-pituitary-thyroid axis and the female reproductive system Conference on the Young Woman at the Rise of the 21st Century - Gynecological and Reproductive Issues in Health and Disease Doufas, A. G., Mastorakos, G. NEW YORK ACAD SCIENCES. 2000: 65–76

  Abstract

  Increasing evidence derived from experimental and clinical studies suggests that the hypothalamic-pituitary-thyroid axis (HPT) and the hypothalamic-pituitary-ovarian axis (HPO) are physiologically related and act together as a unified system in a number of pathological conditions. The suggestion that specific thyroid hormone receptors at the ovarian level might regulate reproductive function, as well as the suggested influence of estrogens at the higher levels of the HPT axis, seems to integrate the reciprocal relationship of these two major endocrine axes. Both hyper- and hypothyroidism may result in menstrual disturbances. In hyperthyroidism the most common manifestation is simple oligomenorrhea. Anovulatory cycles are very common. Increased bleeding may also occur, but it is rare. Hypothyroidism in girls can cause alterations in the pubertal process; this is usually a delay, but occasionally it can result in pseudo-precocious puberty. In mature women hypothyroidism usually is associated with abnormal menstrual cycles characterized mainly by polymenorrhea, especially anovulatory cycles, and an increase in fetal wastage.

  View details for Web of Science ID 000087754500009

  View details for PubMedID 10818393

• Predominant form of non-toxic goiter in Greece is now autoimmune thyroiditis EUROPEAN JOURNAL OF ENDOCRINOLOGY Doufas, A. G., Mastorakos, G., Chatziioannou, S., Tseleni-Balafouta, S., Piperingos, G., Boukis, M. A., Mantzos, E., Caraiskos, C. S., Mantzos, J., Alevizaki, M., Koutras, D. A. 1999; 140 (6): 505-511

  Abstract

  Endemic non-toxic goiter (NTG) in Greece has been attributed primarily to iodine deficiency. Thirty years ago about 60% of the prepubertal boys and girls examined in endemic goiter regions presented with NTG and among them thyroid autoimmunity was rarely detected. Although iodine supplementation has corrected this deficiency during the past 30 years, new cases of NTG still appear. To evaluate the prevalence and type of NTG and the effect of iodine supplementation on them in Greece at present, we performed two cross-sectional clinical studies and a retrospective pathology one: (i) thyroid gland volume and urinary iodine excretion (UIE) were assessed in a representative sample of 1213 schoolchildren from previously endemic and non-endemic regions; (ii) serum thyroxine, tri-iodothyronine, TSH, thyroid autoantibodies (AAB) (anti-thyroid peroxidase and anti-thyroglobulin antibodies) and UIE (in 60 patients) were measured in 300 consecutive patients with NTG from Athens and Heraklion; and (iii) we compared the prevalence of autoimmunity among fine needle aspiration smears of benign thyroid pathologies performed by the same pathologist between 1985 and 1986 (975 cases) and between 1994 and 1995 (2702 cases). We found that 12. 5% of the schoolchildren examined in regions with a previous history of endemic goiter had NTG, whereas this percentage was only 1.7% in areas without such a history. In Athens (61.6%) and Heraklion (58. 5%) a substantial number of NTG patients were AAB positive and biochemically hypothyroid. UIE in Athens did not differ between patients with autoimmune goiter (ATG) and simple goiter. The prevalence of autoimmune stigmata in pathology smears has increased from 5.94% (years 1985-1986) to 13.91% (years 1994-1995) (P<0.05). We conclude that: (i) the persistence of endemic goiter in regional foci despite iodine deficiency correction suggests a possible role for a naturally occurring goitrogen; (ii) ATG is the predominant form of NTG in Greece nowadays; and (iii) the five-fold decrease in the prevalence of NTG during the past 30 years followed by the increase of ATG may support the relative character of the latter.

  View details for Web of Science ID 000081293800005

  View details for PubMedID 10366406

• Venous repair with vascular clips and conventional suture: A comparative experimental study PHLEBOLOGY Dimakakos, P. B., Pafiti-Kondi, A., Doufas, A., Kotsis, T., Mourikis, D., Rizos, D. 1999; 14 (2): 65-70

  View details for Web of Science ID 000083649300006

• The cerebral effects of carbon dioxide during digital subtraction angiography in the aortic arch and its branches in rabbits AMERICAN JOURNAL OF NEURORADIOLOGY Dimakakos, P. B., Stefanopoulos, T., Doufas, A. G., Papasava, M., Gouliamos, A., Mourikis, D., Deligiorgi, H. 1998; 19 (2): 261-266

  Abstract

  We studied the neurotoxicity of carbon dioxide as a contrast agent in the central nervous system by performing CO2 digital subtraction angiography (DSA) in the aortic arch and its branches in experimental animals.Twenty-five rabbits underwent intraarterial CO2 DSA while under general anesthesia, during which 50 angiograms were obtained after administration of 3 mL/kg CO2. MR imaging was performed before and after the angiographic procedure. The animals were killed 12 hours later and their brains examined macroscopically and microscopically.Three animals died of a cause irrelevant to CO2. No animal had clinical symptoms of hemiplegia or stroke. Neither MR imaging nor macroscopic and microscopic examination of the brain revealed any ischemic infarct hemorrhage, thrombosis, or foci of necrosis.The absence of neurologic symptoms, the lack of pathologic findings at MR imaging, and the negative pathologic findings in the brain encourage further research on CO2 neurotoxicity of the central nervous system and support its application in the imaging of intracranial vessels.

  View details for Web of Science ID 000072015500011

  View details for PubMedID 9504475

• Hyperthyroidism in McCune-Albright syndrome with a review of thyroid abnormalities sixty years after the first report THYROID Mastorakos, G., Mitsiades, N. S., Doufas, A. G., Koutras, D. A. 1997; 7 (3): 433-439

  Abstract

  We present a patient with hyperthyroidism associated with McCune-Albright syndrome (MAS). MAS is a sporadic genetic disease characterized by polyostotic fibrous dysplasia, cafe au lait cutaneous spots and endocrinopathies (peripheral precocious puberty, thyroidopathies, acromegaly, etc.). It is caused by an activating mutation of the gene for the Gs alpha membrane-associated protein, which mediates the thyrotropin (TSH)-induced and other hormone-induced activation of adenylyl cyclase. A 13-month-old girl was diagnosed with MAS. Precocious puberty was treated initially with testolactone and later with oophorectomy. Subclinical hyperthyroidism was detected biochemically at birth, and 10 months later, it became clinically evident, albeit mild, with absence of goiter. A concomitant liver dysfunction precluded treatment with thionamides and she was sporadically treated with beta-blockers. The combination of increased free thyroxine (T4) and triiodothyronine (T3) with low plasma thyrotropin (TSH) levels in the absence of thyroid-stimulating autoantibodies persisted until the age of 6 years, when she was referred to our unit. Hyperthyroidism was then clinically evident with cardiac hyperactivity, and it was cured with administration of radioiodine (131I). Thyroid disease is the second most common endocrinopathy associated with MAS, and since 1936, 63 cases of thyroidopathies have been described, including 19 nodular (14 with and 5 without hyperthyroidism) and 23 diffuse (20 with and 3 without hyperthyroidism) goiters, and 18 cases of hyperthyroidism without goiter. The previously described somatic activating mutation of the gs alpha gene in the ovaries, the liver and the peripheral blood of our patient, in the absence of stigmata, autoimmunity might be incriminated for the secretory and mitotic activation of the thyroid gland. We suggest the treatment of choice of hyperthyroidism in MAS patients should be 131I administration because: (a) hyperthyroidism is very likely to recur after withdrawal of antithyroid medication; (b) the morbidity of these patients is elevated; (c) oophorectomized patients do not need to be advised to avoid procreation during the months after 131I administration; and (d) finally, even in the usual cases of hyperthyroidism in childhood, 131I treatment is becoming more popular worldwide.

  View details for Web of Science ID A1997XL01600019

  View details for PubMedID 9226216

• First experimental study of carbon dioxide digital subtraction lymphangiography EUROPEAN JOURNAL OF PLASTIC SURGERY Dimakakos, P. B., Papasavva, M., Stefanopoulos, T., Mourikis, D., Kostopanagiotou, G., Doufas, A. 1997; 20 (3): 132-135

  View details for Web of Science ID A1997WX34700005