Pharmacodynamic modeling of moderate sedation and rationale for dosing using midazolam, propofol and alfentanil.

PURPOSE: Regulations have broadened to allow moderate sedation administration for gastrointestinal endoscopy by non-anesthesia personnel. The line between moderate and deep sedation is ambiguous. Deep sedation offers patient comfort as well as greater safety concerns. Unintended deep sedation can occur if drug interactions are overlooked. We present a pharmacodynamic model for moderate sedation using midazolam, alfentanil and propofol. The model is suitable for training and devising rationales for appropriate dosing. METHODS: The study consists of two parts: modeling and validation. In modeling, patients scheduled for esophagogastroduodenoscopy (EGD) or colonoscopy sedation are enrolled. The modified observer's assessment of alertness/sedation (MOAA/S) score < 4 is defined as loss of response to represent moderate sedation. Two patient groups receiving bronchoscopy or endoscopic retrograde cholangiopancreatography (ERCP) are used for validation. Model performance is assessed by receiver operating characteristic (ROC) curves and area under the curve (AUC). Simulations are performed to demonstrate how the model is used to rationally determine drug regimen for moderate sedation. RESULTS: Interaction between propofol and alfentanil is stronger than the other pairwise combinations. Additional synergy is observed with three drugs. ROC AUC is 0.83 for the modeling group, and 0.96 and 0.93 for ERCP and bronchoscopy groups respectively. Model simulation suggests that 1 mg midazolam, 250 µg alfentanil and propofol maximally benefits from drug interactions and suitable for moderate sedation. CONCLUSION: We demonstrate the accurate prediction of a three-drug response surface model for moderate sedation and simulation suggests a rational dosing strategy for moderate sedation with midazolam, alfentanil and propofol.

Simulation-Based Gastrointestinal Endoscopy Sedations: A Novel Validation to Multidrug Pharmacodynamic Modeling.

Pharmacodynamic models have described the interactions between anesthetics. Applying the models to clinical practice is still problematic due to inherent limitations: 1. modeling conditions are different from practice. 2. One model can only describe one endpoint. To tackle these, we propose a new method of model validation for recovery and intraprocedural sedation adequacy with a three-drug pharmacodynamic model using six published clinical studies that contain midazolam, opioid, and propofol. Mean drug dose, intraprocedural sedation level, procedure, and recovery time are extracted from each study. Simulated drug regimens are designed to best approximate study conditions. A published deep sedation model is used for simulation. Model-predicted recovery time and intraprocedural sedation scores are compared with the original clinical study outcomes. The model successfully predicted recovery times in eight out of nine regimens. Lower doses of midazolam are associated with faster recovery. Model prediction of intraprocedural sedation level was compatible with the clinical studies in five out of seven regimens. The three-drug pharmacodynamic model describes the course of gastrointestinal endoscopy sedations from clinical studies well. Model predictions are consistent with the results from clinical studies. The approach implies that large scale validation can be performed repeatedly.

Opioid and propofol pharmacodynamics modeling during brain mapping in awake craniotomy.

BACKGROUND: Awake craniotomy (AC) is performed to identify cerebral language center. The challenge of anesthesia is to maintain a calm, comfortable, and cooperative patient during the mapping phase. Response surface models (RSMs) are multidrug modeling algorithms. In this pharmacodynamic study, we investigate the first use of RSM with bispectral index (BIS) to predict patient's response to name calling (RNC) and wakefulness (complete neurological tests) during AC. METHODS: The study is performed in two phases. We prospectively enrolled 40 patients who received video-assisted thoracoscopic surgery (VATS) using propofol and fentanyl as the modeling group. Effect-site concentrations (Ce) and BIS values were recorded and a RSM is built from the data set. We verified the RSM retrospectively in AC patients, designated as the validation group. Corresponding BIS values were analyzed for RNC and wakefulness. RESULTS: A total of 155 data sets of propofol Ce, fentanyl Ce, and BIS pairs were available for modeling. The range of propofol and fentanyl Ce were 0 to 9.95 µg/mL and 0 to 3.69 ng/mL, respectively. Observed BIS ranged from 21 to 98. The model identified an additive interaction between propofol and an opioid. RNC at BIS 64 is predicted by the model and 70 is required for wakefulness. CONCLUSION: RSM built from VATS patients is verified with a separate group of AC patient. The BIS target advised for RSM-predicted wakefulness is 70. The model illustrates the timeline to wakefulness during AC under propofol and an opioid. It has implications in guiding, dosing, and estimation of time to wakefulness with propofol and an opioid.

Time-dependent analysis of dosage delivery information for patient-controlled analgesia services.

Pain relief always plays the essential part of perioperative care and an important role of medical quality improvement. Patient-controlled analgesia (PCA) is a method that allows a patient to self-administer small boluses of analgesic to relieve the subjective pain. PCA logs from the infusion pump consisted of a lot of text messages which record all events during the therapies. The dosage information can be extracted from PCA logs to provide easily understanding features. The analysis of dosage information with time has great help to figure out the variance of a patient's pain relief condition. To explore the trend of pain relief requirement, we developed a PCA dosage information generator (PCA DIG) to extract meaningful messages from PCA logs during the first 48 hours of therapies. PCA dosage information including consumption, delivery, infusion rate, and the ratio between demand and delivery is presented with corresponding values in 4 successive time frames. Time-dependent statistical analysis demonstrated the trends of analgesia requirements decreased gradually along with time. These findings are compatible with clinical observations and further provide valuable information about the strategy to customize postoperative pain management.

Assessing the Impact of Renal Function on Trajectory of Intravenous Patient-controlled Analgesic Demands Over Time After Open and Laparoscopic Colorectal Surgery Using Latent Curve Analysis.

OBJECTIVES: Intravenous patient-controlled analgesia (IVPCA) is often used to relieve pain after colorectal surgery. This study aimed to model the trajectory of analgesic demand over time after colorectal cancer surgery and explore potentially relevant influential factors using latent curve analysis, focusing on laparoscopic-assisted surgery and renal function. MATERIALS AND METHODS: Patients receiving colorectal surgery with postoperative IVPCA were randomly divided into 2 equal parts to enable model construction and cross validation. Archived data were retrieved from the IVPCA pump. Latent curve modeling with 2 latent variables that reflected the baseline and slope of IVPCA demand trajectory over time was used and the effects of potentially influential factors on the 2 latent variables were evaluated. Goodness-of-fit indices were used to assess the model fit to both the model construction and validation data sets. RESULTS: Data were collected from 834 patients, of whom 112 had laparoscopic-assisted surgery. Latent curve analysis revealed that body weight increased the baseline analgesic demand over time, whereas increasing age, female sex, poor renal function, and laparoscopic-assisted surgery decrease it. By contrast, only age and weight exerted significant effects on the slope parameter to modify the trajectory of IVPCA demand. Patients with higher age or less weight tended to have a smoother decreasing trajectory of analgesic demands over time. There was good cross validation, as the parameter estimates derived from the model construction data set fitted well to the validation data set (root mean square error of approximation: 0.05). CONCLUSION: Laparoscopic-assisted surgery and renal function affected the baseline trajectory of IVPCA demand over time, but had no significant effect on its shape.

On-line SERS detection of single bacterium using novel SERS nanoprobes and a microfluidic dielectrophoresis device.

The integration of novel surface-enhanced Raman scattering (SERS) nanoprobes and a microfluidic dielectrophoresis (DEP) device is developed for rapid on-line SERS detection of Salmonella enterica serotype Choleraesuis and Neisseria lactamica. The SERS nanoprobes are prepared by immobilization of specific antibody onto the surface of nanoaggregate-embedded beads (NAEBs), which are silica-coated, dye-induced aggregates of a small number of gold nanoparticles (AuNPs). Each NAEB gives highly enhanced Raman signals owing to the presence of well-defined plasmonic hot spots at junctions between AuNPs. Herein, the on-line SERS detection and accurate identification of suspended bacteria with a detection capability down to a single bacterium has been realized by the NAEB-DEP-Raman spectroscopy biosensing strategy. The practical detection limit with a measurement time of 10 min is estimated to be 70 CFU mL(-1) . In comparison with whole-cell enzyme-linked immunosorbent assay (ELISA), the SERS-nanoprobe-based biosensing method provides advantages of higher sensitivity and requiring lower amount of antibody in the assay (100-fold less). The total assay time including sample pretreatment is less than 2 h. Hence, this sensing strategy is promising for faster and effective on-line multiplex detection of single pathogenic bacterium by using different bioconjugated SERS nanoprobes.

Direct detection of orchid viruses using nanorod-based fiber optic particle plasmon resonance immunosensor.

A fiber optic particle plasmon resonance (FOPPR) immunosensor is developed for label-free detection of orchid viruses that use gold nanorods (AuNRs) as the sensing material. The AuNRs are employed to create a near-infrared sensing window to solve the color interference problem of sample matrix for direct sensing of target analyte. This work cannot be achieved using gold nanospheres (AuNSs) because the signal of sample color absorption largely overlaps the signal of molecular recognition events in the visible spectrum, making the signal interpretation much more difficult. The AuNRs are immobilized on the unclad fiber core surface, and functionalized by antibodies which can specifically recognize the corresponding Cymbidium mosaic virus (CymMV) or Odontoglossum ringspot virus (ORSV) for rapid viral infection diagnosis. The refractive index resolution of the AuNR-FOPPR sensor is estimated to be 8×10(-6) RIU. The limits of detection (LODs) for CymMV and ORSV in leaf saps are 48 and 42 pg/mL, respectively, which are better than the LODs of 1200 pg/mL for both viruses obtained by enzyme-linked immunosorbent assay (ELISA). Exploiting the AuNR-FOPPR sensing strategy not only solves the color interference problem encountered by using AuNSs, but provides faster analysis, better reproducibility, and lower detection limit than ELISA. The sensor can distinguish between healthy and infected orchids in 10 min, and can further provide the quantitative analysis of infection level. It is potentially applicable to the quality control of orchid cultivation industry, but not limited to this, especially for creating special spectral sensing window for particular samples.

Patient-machine interactions of intravenous patient-controlled analgesia in bilateral versus unilateral total knee arthroplasty: a retrospective study.

BACKGROUND: Continuous passive motion after a major knee surgery optimizes functional prognosis, but causes severe pain. In this study, we assessed the effect of intravenous patient-controlled analgesia (IVPCA) on postoperative pain management in unilateral and bilateral total knee arthroplasty (TKA). METHODS: Data were collected retrospectively from a single medical center from March 2003 to October 2007. All patients who had undergone TKA were given general anesthesia, and the type of surgery that each patient received was planned according to individual needs. A total of 223 patients qualified for this study, with 174 patients in the unilateral TKA group. Data on patient demography, pain scores, and side effect scores were collected. Total dose consumption, demand, delivery doses, demand-to-delivery ratio, and infusion rate were collected from PCA machines and analyzed. RESULTS: The patient pain score and patient satisfaction showed no significant difference between the unilateral and bilateral TKA groups. The incidence of sedation (p < 0.001), nausea (p = 0.013), and vomiting (p = 0.044) during the postoperative 24-48-hour period was higher in the bilateral TKA group. Compared with the patients in the unilateral group, those in the bilateral group showed significantly greater dose consumption during the postoperative 6-12-, 12-18-, and 18-24-hour periods. They also showed more demand for medication during the postoperative 12-18- and 18-24-hour periods and received more bolus doses during the postoperative 12-18-, 18-24-, and 30-36-hour periods. In addition, there was also a significantly higher demand-to-delivery ratio for patients in the bilateral group during the postoperative 6-12-, 12-18-hour periods. CONCLUSION: In this study, we successfully demonstrated that our IVPCA protocol can provide adequate analgesia for patients after both bilateral and unilateral TKA. However, sedation, nausea, and vomiting occurred more frequently during the postoperative 24-48-hour period in patients who underwent bilateral than unilateral TKA. This may due of the increased number of bolus doses administered to the patients in the bilateral TKA group during the postoperative 12-18, 18-24, and 30-36-hour periods. Therefore, the initial infusion rates for patients undergoing bilateral TKA could be set at a lower threshold in order to reduce the incidence of these side effects.

Patient controlled epidural analgesia for bilateral versus unilateral total knee arthroplasty: a retrospective study of pain control.

BACKGROUND: Patient controlled epidural analgesia (PCEA) has been used commonly for postoperative pain management following total knee arthroplasty (TKA). The purpose of this study was to compare a single standardized PCEA protocol in patients who received unilateral TKA with patients who received simultaneous bilateral TKA. METHODS: From October 2003 to October 2008, 912 patients were enrolled. Patient-machine interaction data were retrieved from PCA machines and stratified into 12 hour intervals. The data were analyzed according to the side of surgery, gender and methods of anesthesia. Patient demographic data, pain scores and side effect scores were compared to evaluate clinical efficacy. RESULTS: There was no significant difference between the unilateral and bilateral TKA groups for pain scores, severity of side effects, and total drug use. However, there was a paradoxical increase in demand, delivery, and demand/delivery ratio of analgesics for unilateral rather than bilateral TKA. This was only noted in the first 12 hours. Both genders demanded more bolus doses than set by the standard protocol. Women with unilateral TKA received more delivery doses. All of the patients who received general anesthesia had a higher demand/delivery ratio while spinal anesthesia patients had no significant ratio difference. CONCLUSION: PCEA provided equal analgesia for patients with unilateral or bilateral TKA. However, the paradoxical increase in demand suggested that psychological factors may play a role in pain perception. A comprehensive pain management program that addresses gender and anesthesia methods in the first 12 hours will improve clinical efficacy and patient satisfaction of PCEA.

A novel full-length isoform of murine pregnancy-specific glycoprotein 16 (psg16) is expressed in the brain but does not mediate murine coronavirus (MHV) entry.

The mouse pregnancy-specific glycoprotein 16 (PSG16) has been reported to be an alternative receptor for mouse hepatitis virus (MHV), some strains of which cause encephalitis in mice lacking the canonical receptor CEACAM1a. The known isoforms of PSG16 are N-terminally truncated relative to other PSG family proteins and are expressed in neurons as well as in the placenta. We have cloned a novel full-length isoform of psg16 that is also expressed in the brain, placenta, and retina but, like the truncated form, lacks MHV receptor activity when expressed on 293T cells, suggesting that PSG16 does not mediate CEACAM1a-independent spread of MHV.

The relationship between lockout interval and requirement for patient-controlled epidural analgesia.

BACKGROUND: Patient-controlled epidural analgesia (PCEA) with background infusion provides better analgesia than the use of a demand dose alone but might be associated with more consumption of PCEA solution and adverse effects. Therefore, we conducted this retrospective study to evaluate the influence of parameters of the drug delivery system on the PCEA requirements of patients receiving thoracic or upper abdominal surgeries. METHODS: Patients having operations involving the chest or upper abdomen with postoperative PCEA were included in the analyses. A standardized analgesic solution of bupivacaine (0.0625%) and fentanyl (1 microg/mL) was used for all patients. The cumulative doses of PCEA on the first, second and third postoperative days were recorded. Collected data included patient demographics and their quantity of PCEA. A general linear model was used to compare within-subject time effects and between-subject effects. Interactions with time between subjects were also examined. RESULTS: A total of 228 patients (68 females, 160 males) were included in the study. The PCEA requirements decreased gradually over time (p < 0.001). Patients with lower body mass index had a greater difference in their PCEA requirement between the first and second postoperative days (p < 0.001). For variables related to PCEA usage, patients using PCEA with the 30-minute lockout interval used less PCEA infusate per day (p = 0.04 for main effect, p = 0.02 for interaction with time). Moreover, a longer lockout interval was not associated with poorer analgesic effects (p = 0.48). Other parameters had no significant influence on daily PCEA requirements. CONCLUSION: Patients receiving PCEA with a 30-minute lockout and background infusion used the least amount of PCEA infusate and the differences increased over time. Further investigations are recommended to evaluate potential benefits and drawbacks of a longer lockout interval.

Silica nanoparticles for separation of biologically active amines by capillary electrophoresis with laser-induced native fluorescence detection.

This paper describes the analysis of biologically active amines by capillary electrophoresis (CE) in conjunction with laser-induced native fluorescence detection. In order to simultaneously analyze amines and acids as well as to achieve high sensitivity, 10 mM formic acid solutions (pH < 4.0) containing silica nanoparticles (SiNPs) were chosen as the background electrolytes. With increasing SiNP concentration, the migration times for seven analytes decrease as a result of increase in electroosmotic flow (EOF) and decrease in their electrophoretic mobilities against EOF. A small EOF generated at pH 3.0 reveals adsorption of SiNPs on the deactivated capillary wall. The decreases in electrophoretic mobilities with increasing SiNP concentration up to 0.3x indicate the interactions between the analytes and the SiNPs. Having a great sensitivity (the limits of detection at a signal-to-noise ratio (S/N) = 3 of 0.09 nM for tryptamine (TA)), high efficiency, and excellent reproducibility (less than 2.4% of the migration times), this developed method has been applied to the analysis of urinal samples with the concentrations of 0.50 +/- 0.02 microM, 0.49 +/- 0.04 microM, and 74 +/- 2 microM for TA, 5-hydroxytryptamine, and tryptophan, respectively. The successful examples demonstrated in this study open up a possibility of using functional nanoparticles for the separation of different analytes by CE.

Fast and sensitive diagnosis of thalassemia by capillary electrophoresis.

This paper demonstrates the diagnosis of beta-thalassemia by capillary electrophoresis in conjunction with laser-induced fluorescence using poly(ethylene oxide) (PEO) solutions in the presence of electroosmotic flow (EOF). During the electrophoretic separation, PEO solution entered a capillary from the anodic vial by EOF. The separation of a mixture of the polymerase chain reaction (PCR) products (330 and 334 base pairs) from a healthy person and a beta-thalassemia patient was accomplished within 15 min at 15 kV using 1.5% PEO containing 2 M urea at 30 degrees C. The electropherogram patterns instead of migration times were used to diagnose beta-thalassemia, with an accuracy of 100% for the analyses of 11 blood samples from suspected patients. After injecting a large volume of the mixture to the capillary filled with 800 mM Tris-borate buffer (pH 10.0), the DNA fragments stacked due to increases in viscosity and sieving when migrating into 1.5% PEO solution. As a result of improved sensitivity, only 15 PCR cycles were required when using 500 ng of DNA templates. The results shown in this study indicate the potential of this simple, rapid, and cost-effective method for the diagnosis of beta-thalassemia.

On-column concentration and separation of double-stranded DNA by gradient capillary electrophoresis.

We describe the separation of dsDNA by capillary electrophoresis in the presence of electroosmotic flow (EOF) using poly(ethylene oxide) (PEO). Using 1.0% PEO, the separation of DNA fragments with sizes ranging from 51 bp to 23 kbp has been achieved in less than 12 min, which is better than conventional methods (in the absence of EOF) in terms of speed and resolution. In order to concentrate and separate the DNA sample, gradient changes in the concentrations of PEO and ethidium bromide (EtBr) have been conducted. Different concentrations of PEO solutions are injected to the polyethylene tubes by pressure, where they enter the capillary by EOF. Because the large DNA fragments migrate faster towards the cathode end under counterflow conditions, the introduction sequence is from low to high concentrations of PEO solutions after sample injection. Using the gradient CE approach, the separations of the DNA sample injected at 30 cm height for times up to 120 s have been demonstrated. The linearity between injection time and peak height shows that the DNA fragments stacked during migration from the sample zone to PEO. We found that stacking efficiency is greater when the analysis was performed by simultaneously changing the PEO and EtBr concentration, compared to individual changes in PEO concentration.