Semimechanistic models to relate noxious stimulation, movement, and pupillary dilation responses in the presence of opioids.

Intraoperative targeting of the analgesic effect still lacks an optimal solution. Opioids are currently the main drug used to achieve antinociception, and although underdosing can lead to an increased stress response, overdose can also lead to undesirable adverse effects. To better understand how to achieve the optimal analgesic effect of opioids, we studied the influence of remifentanil on the pupillary reflex dilation (PRD) and its relationship with the reflex movement response to a standardized noxious stimulus. The main objective was to generate population pharmacodynamic models relating remifentanil predicted concentrations to movement and to pupillary dilation during general anesthesia. A total of 78 patients undergoing gynecological surgery under general anesthesia were recruited for the study. PRD and movement response to a tetanic stimulus were measured multiple times before and after surgery. We used nonlinear mixed effects modeling to generate a population pharmacodynamic model to describe both the time profiles of PRD and movement responses to noxious stimulation. Our model demonstrated that movement and PRD are equally depressed by remifentanil. Using the developed model, we changed the intensity of stimulation and simulated remifentanil predicted concentrations maximizing the probability of absence of movement response. An estimated effect site concentration of 2 ng/ml of remifentanil was found to inhibit movement to a tetanic stimulation with a probability of 81%.

Influence of an "Electroencephalogram-Based" Monitor Choice on the Delay Between the Predicted Propofol Effect-Site Concentration and the Measured Drug Effect.

BACKGROUND: Clinicians can optimize propofol titration by using 2 sources of pharmacodynamic (PD) information: the predicted effect-site concentration for propofol (Ceprop) and the electroencephalographically (EEG) measured drug effect. Relation between these sources should be time independent, that is, perfectly synchronized. In reality, various issues corrupt time independency, leading to asynchrony or, in other words, hysteresis. This asynchrony can lead to conflicting information, making effective drug dosing challenging. In this study, we tried to quantify and minimize the hysteresis between the Ceprop (calculated using the Schnider model for propofol) and EEG measured drug effect, using nonlinear mixed-effects modeling (NONMEM). Further, we measured the influence of EEG-based monitor choice, namely Bispectral index (BIS) versus qCON index (qCON) monitor, on propofol PD hysteresis. METHODS: We analyzed the PD data from 165 patients undergoing propofol-remifentanil anesthesia for outpatient surgery. Drugs were administered using target-controlled infusion (TCI) pumps. Pumps were programmed with Schnider model for propofol and Minto model for remifentanil. We constructed 2 PD models (direct models) relating the Schnider Ceprop to the measured BIS and qCON monitor values. We quantified the models' misspecification due to hysteresis, on an individual level, using the root mean squared errors (RMSEs). Subsequently, we optimized the PD models' predictions by adding a lag term to both models (lag-time PD models) and quantified the optimization using the RMSE. RESULTS: There is a counterclockwise hysteresis between Ceprop and BIS/qCON values. Not accounting for this hysteresis results in a direct PD model with an effect-site concentration which produces 50% of the maximal drug effect (Ce50) of 6.24 and 8.62 µg/mL and RMSE (median and interquartile range [IQR]) of 9.38 (7.92-11.23) and 8.41(7.04-10.2) for BIS and qCON, respectively. Adding a modeled lag factor of 49 seconds to the BIS model and 53 seconds to the qCON model improved both models' prediction, resulting in similar Ce50 (3.66 and 3.62 µg/mL for BIS and qCON) and lower RMSE (median (IQR) of 7.87 (6.49-9.90) and 6.56 (5.28-8.57) for BIS and qCON. CONCLUSIONS: There is a significant "Ceprop versus EEG measured drug effect" hysteresis. Not accounting for it leads to conflicting PD information and false high Ce50 for propofol in both monitors. Adding a lag term improved the PD model performance, improved the "pump-monitor" synchrony, and made the estimates of Ce50 for propofol more realistic and less monitor dependent.

A randomized comparison of the Ambu AuraGain versus the LMA supreme in patients undergoing gynaecologic laparoscopic surgery.

Second generation supraglottic airway devices providing high seal airway pressures are suitable for patients undergoing gynecologic laparoscopy. We compared the seal pressure achieved by the new Ambu AuraGain™ versus LMA Supreme™ following pneumoperitoneum in the Trendelenburg position. Sixty female patients were randomly allocated to ventilation with either the AuraGain or the Supreme. A target-controlled system was used to administer total intravenous anesthesia. Intracuff pressure was maintained below 60 cm H2O. The following parameters were registered: Time, number of attempts and manoeuvres required for insertion; seal pressure and peak inspiratory pressure at four time points; ease of gastric tube insertion, flexible scope view, complications and postoperative morbidity. Both devices were quick and easily inserted, although the Supreme required less rotation manoeuvres (16 in AuraGain vs. 6 in LMA Supreme; p = 0.01). The AuraGain achieved higher seal pressures (34 ± 5 in AuraGain vs. 29 ± 5 in LMA Supreme; p = 0.0002). Following pneumoperitoneum in head-down position, peak airway pressure increased 9 ± 3 cm H2O in both groups, exceeding seal pressure in 3 patients in the Supreme group (p = 0.06). The vocal cords were seen through all AuraGain and 90% of the Supreme devices; epiglottis was often visible inside the tube (68%). No differences were found in the incidence of traces of blood on the mask or postoperative symptoms. Both devices allowed effective ventilation in patients undergoing gynaecologic laparoscopic surgery with a low rate of complications. The Ambu AuraGain provided higher seal pressures and a clear view of glottic inlet in all patients offering the possibility to guide direct tracheal intubation if required.

Comparison of the qCON and qNOX indices for the assessment of unconsciousness level and noxious stimulation response during surgery.

The objective of this work is to compare the performances of two electroencephalogram based indices for detecting loss of consciousness and loss of response to nociceptive stimulation. Specifically, their behaviour after drug induction and during recovery of consciousness was pointed out. Data was recorded from 140 patients scheduled for general anaesthesia with a combination of propofol and remifentanil. The qCON 2000 monitor (Quantium Medical, Barcelona, Spain) was used to calculate the qCON and qNOX. Loss of response to verbal command and loss of eye-lash reflex were assessed during the transition from awake to anesthetized, defining the state of loss of consciousness. Movement as a response to laryngeal mask (LMA) insertion was interpreted as the response to the nociceptive stimuli. The patients were classified as movers or non-movers. The values of qCON and qNOX were statistically compared. Their fall times and rise times defined at the start and at the end of the surgery were calculated and compared. The results showed that the qCON was able to predict loss of consciousness such as loss of verbal command and eyelash reflex better than qNOX, while the qNOX has a better predictive value for response to noxious stimulation such as LMA insertion. From the analysis of the fall and rise times, it was found that the qNOX fall time (median: 217 s) was significantly longer (p value <0.05) than the qCON fall time (median: 150 s). At the end of the surgery, the qNOX started to increase in median at 45 s before the first annotation related to response to stimuli or recovery of consciousness, while the qCON at 88 s after the first annotation related to response to stimuli or recovery of consciousness (p value <0.05). The indices qCON and qNOX showed different performances in the detection of loss of consciousness and loss of response to stimuli during induction and recovery of consciousness. Furthermore, the qCON showed faster decrease during induction. This behaviour is associated with the hypothesis that the loss of response to stimuli (analgesic effect) might be reached after the loss of consciousness (hypnotic effect). On the contrary, the qNOX showed a faster increase at the end of the surgery, associated with the hypothesis that a higher probability of response to stimuli might be reached before the recovery of consciousness.

Passive smoking at home is a risk factor for community-acquired pneumonia in older adults: a population-based case-control study.

OBJECTIVE: To assess whether passive smoking exposure at home is a risk factor for community-acquired pneumonia (CAP) in adults. SETTING: A population-based case-control study was designed in a Mediterranean area with 860 000 inhabitants >14 years of age. PARTICIPANTS: 1003 participants who had never smoked were recruited. PRIMARY AND SECONDARY OUTCOME MEASURES: Risk factors for CAP, including home exposure to passive smoking, were registered. All new cases of CAP in a well-defined population were consecutively recruited during a 12-month period. METHODS: A population-based case-control study was designed to assess risk factors for CAP, including home exposure to passive smoking. All new cases of CAP in a well-defined population were consecutively recruited during a 12-month period. The subgroup of never smokers was selected for the present analysis. RESULTS: The study sample included 471 patients with CAP and 532 controls who had never smoked. The annual incidence of CAP was estimated to be 1.14 cases×10(-3) inhabitants in passive smokers and 0.90×10(-3) in non-passive smokers (risk ratio (RR) 1.26; 95% CI 1.02 to 1.55) in the whole sample. In participants ≥65 years of age, this incidence was 2.50×10(-3) in passive smokers and 1.69×10(-3) in non-passive smokers (RR 1.48, 95% CI 1.08 to 2.03). In this last age group, the percentage of passive smokers in cases and controls was 26% and 18.1%, respectively (p=0.039), with a crude OR of 1.59 (95% CI 1.02 to 2.38) and an adjusted (by age and sex) OR of 1.56 (95% CI 1.00 to 2.45). CONCLUSIONS: Passive smoking at home is a risk factor for CAP in older adults (65 years or more).

Hepatic preconditioning after prolonged warm ischemia by means of S-adenosyl-L-methionine administration in pig liver transplantation from non-heart-beating donors.

BACKGROUND: This study ascertained the effect of S-adenosyl-L-methionine (SAMe) administration on the ischemia-reperfusion injury associated with pig liver transplantation from non-heart-beating donors (NHBDs) after prolonged warm ischemia. METHOD: Twenty-five animals underwent transplantation with an allograft from an NHBD. After donor cardiac arrest, cardiopulmonary bypass and normothermic recirculation (NR) were performed for 30 min. Ten animals were given SAMe during NR. Donors were cooled to 15 degrees C, and liver procurement was performed. RESULTS: SAMe reduced histologic liver damage 5 days after transplantation. The necrotic area affected 15.9%+/-14.5% of the liver biopsies in controls and 7.4%+/-9% in SAMe livers. Six of eight controls and only one of eight survivors in the SAMe group developed ischemic cholangitis. SAMe reduced apoptosis of hepatocytes 5 days after transplantation and apoptosis of sinusoidal endothelial cells at reperfusion and at 5 days. SAMe increased energy charge at the end of NR and favored the balance between adenosine and xanthine. It was also associated with higher portal blood flow (740+/-59.2 vs. 475.2+/-65.0 mL/min-1/m-2), hepatic hyaluronic acid extraction (132+/-72.2 vs. -205.8+/-64.6 microg/L), and lower levels of alpha-glutathione-S-transferase after reperfusion (2,601%+/-581% with respect to baseline vs. 6,488%+/-5,612%). CONCLUSION: SAMe administration during liver procurement from NHBDs prevents liver endothelial, parenchymal, and biliary tract damage. The protective role of SAMe may be partially mediated by the effect of adenosine during liver procurement.