David Drover

All Publications

• Antimicrobial Disposition During Pediatric Continuous Renal Replacement Therapy Using an Ex Vivo Model. Critical care medicine Purohit, P. J., Elkomy, M. H., Frymoyer, A., Sutherland, S. M., Drover, D. R., Hammer, G. B., Su, F. 2019

  Abstract

  OBJECTIVES: Little is known on the impact of continuous renal replacement therapy on antimicrobial dose requirements in children. In this study, we evaluated the pharmacokinetics of commonly administered antimicrobials in an ex vivo continuous renal replacement therapy model.DESIGN: An ex vivo continuous renal replacement therapy circuit was used to evaluate drug-circuit interactions and determine the disposition of five commonly used antimicrobials (meropenem, piperacillin, liposomal amphotericin B, caspofungin, and voriconazole).SETTING: University research laboratory.PATIENTS: None.INTERVENTIONS: Antimicrobials were administered into a reservoir containing whole human blood. The reservoir was connected to a pediatric continuous renal replacement therapy circuit programmed for a 10 kg child. Continuous renal replacement therapy was performed in the hemodiafiltration mode and in three phases correlating with three different continuous renal replacement therapy clearance rates: 1) no clearance (0 mL/kg/hr, to measure adsorption), 2) low clearance (20 mL/kg/hr), and 3) high clearance (40 mL/kg/hr). Blood samples were drawn directly from the reservoir at baseline and at 5, 20, 60, and 180 minutes during each phase. Five independent continuous renal replacement therapy runs were performed to assess inter-run variability. Antimicrobial concentrations were measured using validated liquid chromatography-mass spectrometry assays. A closed-loop, flow-through pharmacokinetic model was developed to analyze concentration-time profiles for each drug.MEASUREMENTS AND MAIN RESULTS: Circuit adsorption of antimicrobials ranged between 13% and 27%. Meropenem, piperacillin, and voriconazole were cleared by the continuous renal replacement therapy circuit and clearance increased with increasing continuous renal replacement therapy clearance rates (7.66 mL/min, 4.97 mL/min, and 2.67 mL/min, respectively, for high continuous renal replacement therapy clearance). Amphotericin B and caspofungin had minimal circuit clearance and did not change with increasing continuous renal replacement therapy clearance rates.CONCLUSIONS: Careful consideration of drug-circuit interactions during continuous renal replacement therapy is essential for appropriate drug dosing in critically ill children. Antimicrobials have unique adsorption and clearance profiles during continuous renal replacement therapy, and this knowledge is important to optimize antimicrobial therapy.

  View details for DOI 10.1097/CCM.0000000000003895

  View details for PubMedID 31306179

• Assessment of Ketamine Adult Anesthetic Doses in Pediatrics Using Pharmacokinetic Modeling and Simulations PHARMACOTHERAPY Elkomy, M. H., Alruwaili, N., Elmowafy, M., Shalaby, K., Drover, D. R., Ramamoorthy, C. 2019; 39 (4): 454–62

  View details for DOI 10.1002/phar.2243

  View details for Web of Science ID 000466401200004

• Assessment of Ketamine Adult Anesthetic Doses in Pediatrics using Pharmacokinetic Modeling and Simulations. Pharmacotherapy Elkomy, M. H., Alruwaili, N., Elmowafy, M., Shalaby, K., Drover, D. R., Ramamoorthy, C. 2019

  Abstract

  Although few studies have used ketamine for induction and maintenance of pediatric anesthesia, official dosage recommendations are lacking. This study evaluates the outcomes of adult anesthetic doses in a pediatric population through pharmacokinetic modeling and computer simulations in an attempt to recommend an adequate ketamine dosing regimen. Ketamine plasma concentration-time data in 19 children (age 8 months to 16 years; weight 5.5 to 67 kg) were analyzed according to a non-compartmental pharmacokinetic approach. The relationship between pharmacokinetic parameters and demographic covariates was mathematically characterized. A one-compartment open model was implemented to simulate the plasma profile following administration of 1-4.5 mg/kg IV bolus dose and 0.1-0.5 mg/kg/min continuous infusion of ketamine and to predict anesthesia onset and offset. Pharmacokinetic parameters determined were clearance 0.025±0.008 L/kg/min; distribution volume 3.3±1.3 L/kg; half-life 2.6±1 h; and mean residence time 2.3±0.64 h. Body weight was the best predictor of clearance and distribution volume according to a 0.75-power model. Using weight to scale doses was associated with limited variability in simulated concentrations. Ketamine administered as 2.25 mg/kg IV bolus dose, followed by 0.1 mg/kg/min continuous IV infusion enables anesthesia initiation within 3 minutes and maintains it for 3 hours. In conclusion, weight-based dosing minimizes age-dependent variation in the plasma concentration of ketamine. Low-to-intermediate adult doses are suitable for induction and maintenance of safe anesthesia in children undergoing short-term surgical operations. However, this finding requires validation in controlled clinical trials before it is adopted into surgical standard practices. This article is protected by copyright. All rights reserved.

  View details for PubMedID 30825333

• Speeding the Detection of Vessel Cannulation: An In-Vitro Stimulation Study. Anesthesia and analgesia Muffly, M. K., Ku, A., Drover, D. R., Rodriguez, S., Caruso, T. J., Ku, A., Tsui, B. C. 2019

  Abstract

  BACKGROUND: Some practitioners "prime" small IV angiocatheter needles with 0.9% sodium chloride-claiming this modification speeds visual detection of blood in the angiocatheter flash chamber on vessel cannulation.METHODS: We compared the time required for human blood to travel the length of saline-primed and saline-unprimed 24- and 22-gauge angiocatheter needles (Introcan Safety IV Catheter; B. Braun, Bethlehem, PA). A syringe pump (Medfusion 4000, Cary, NC) advanced each angiocatheter needle through the silicone membrane of an IV tubing "t-piece" (Microbore Extension Set, 5 Inch; Hospira, Lake Forest, IL) filled with freshly donated human blood. When the angiocatheter needle contacted the blood, an electrical circuit was completed, illuminating a light-emitting diode. We determined the time from light-emitting diode illumination to visual detection of blood in the flash chamber by video review. We tested 105 saline-primed angiocatheters and 105 unprimed angiocatheters in the 24- and 22-gauge angiocatheter sizes (420 catheters total). We analyzed the median time to visualize the flash using the nonparametric Wilcoxon rank sum test in R (http://www.R-project.org/). The Stanford University Administrative Panel on Human Subjects in Medical Research determined that this project did not meet the definition of human subjects research and did not require institutional review board oversight.RESULTS: In the 24-gauge angiocatheter group, the median (and interquartile range) time for blood to travel the length of the unprimed angiocatheter needle was 1.14 (0.61-1.47) seconds compared with 0.76 (0.41-1.20) seconds in the saline-primed group (P = 0.006). In the 22-gauge catheter group, the median (interquartile range) time for blood to travel the length of the unprimed angiocatheter needle was 1.80 (1.23-2.95) seconds compared with 1.46 (1.03-2.54) seconds in the saline-primed group (P = .046).CONCLUSIONS: These results support the notion that priming small angiocatheter needles, in particular 24-gauge catheters, with 0.9% sodium chloride may provide earlier detection of vessel cannulation than with the unprimed angiocatheter.

  View details for PubMedID 30633054

• Pharmacokinetics of Dexmedetomidine in Infants and Children After Orthotopic Liver Transplantation. Anesthesia and analgesia Damian, M. A., Hammer, G. B., Elkomy, M. H., Frymoyer, A., Drover, D. R., Su, F. 2018

  Abstract

  BACKGROUND: Dexmedetomidine (DEX) is a sedative and analgesic medication that is frequently used postoperatively in children after liver transplantation. Hepatic dysfunction, including alterations in drug clearance, is common immediately after liver transplantation. However, the pharmacokinetics (PK) of DEX in this population is unknown. The objective of this study was to determine the PK profile of DEX in children after liver transplantation.METHODS: This was a single-center, open-label PK study of DEX administered as an intravenous loading dose of 0.5 mug/kg followed by a continuous infusion of 0.5 mug/kg/h. Twenty subjects, 1 month to 18 years of age, who were admitted to the pediatric intensive care unit after liver transplantation were enrolled. Whole blood was collected and analyzed for DEX concentration using a dried blood spot method. Nonlinear mixed-effects modeling was used to characterize the population PK of DEX.RESULTS: DEX PK was best described by a 2-compartment model with first-order elimination. A typical child after liver transplantation with an international normalized ratio (INR) of 1.8 was found to have a whole blood DEX clearance of 52 L/h (95% confidence interval [CI], 31-73 L/h). In addition, intercompartmental clearance was 246 L/h (95% CI, 139-391 L/h), central volume of distribution was 186 L/70 kg (95% CI, 140-301 L/70 kg), and peripheral volume of distribution was 203 L (95% CI, 123-338 L). Interindividual variability ranged from 11% to 111% for all parameters. Clearance was not found to be associated with weight but was found to be inversely proportional to INR. An increase in INR to 3.2 resulted in a 50% decrease in DEX clearance. Weight was linearly correlated with central volume of distribution. All other covariates, including age, ischemic time, total bilirubin, and alanine aminotransferase, were not found to be significant predictors of DEX disposition.CONCLUSIONS: Children who received DEX after liver transplantation have large variability in clearance, which was not found to be associated with weight but is influenced by underlying liver function, as reflected by INR. In this population, titration of DEX dosing to clinical effect may be important because weight-based dosing is poorly associated with blood concentrations. More attention to quality of DEX sedation may be warranted when INR values are changing.

  View details for PubMedID 30198929

• Remifentanil and Nitrous Oxide Anesthesia Produces a Unique Pattern of EEG Activity During Loss and Recovery of Response FRONTIERS IN HUMAN NEUROSCIENCE Eagleman, S. L., Drover, C. M., Drover, D. R., Ouellette, N. T., MacIver, M. 2018; 12: 173

  Abstract

  Nitrous oxide (N2O) and remifentanil (remi) are used along with other anesthetic and adjuvant agents for routine surgical anesthesia, yet the electroencephalogram (EEG) changes produced by this combination are poorly described. N2O administered alone produces EEG spectral characteristics that are distinct from most hypnotics. Furthermore, EEG frequency-derived trends before and after clinically relevant time points vary depending on N2O concentration. Remifentanil typically increases low frequency and decreases high frequency activity in the EEG, but how it influences N2O's EEG effect is not known. Previous attempts to characterize EEG signals of patients anesthetized with N2O using frequency-derived measures have shown conflicts and inconsistencies. Thus, in addition to determining the spectral characteristics of this unique combination, we also test whether a newly proposed characterization of time-delayed embeddings of the EEG signal tracks loss and recovery of consciousness significantly at clinically relevant time points. We retrospectively investigated the effects of remi and N2O on EEG signals recorded from 32 surgical patients receiving anesthesia for elective abdominal surgeries. Remifentanil and N2O (66%) were co-administered during the procedures. Patients were tested for loss and recovery of response (ROR) to verbal stimuli after induction and upon cessation of anesthesia, respectively. We found that the addition of remifentanil to N2O anesthesia improves the ability of traditional frequency-derived measures, including the Bispectral Index (BIS), to discriminate between loss and ROR. Finally, we found that a novel analysis of EEG using nonlinear dynamics showed more significant differences between states than most spectral measures.

  View details for PubMedID 29867405

• Improved operative efficiency using a real-time MRI-guided stereotactic platform for laser amygdalohippocampotomy JOURNAL OF NEUROSURGERY Ho, A. L., Sussman, E. S., Pendharkar, A. V., Le, S., Mantovani, A., Keebaugh, A. C., Drover, D. R., Grant, G. A., Wintermark, M., Halpern, C. H. 2018; 128 (4): 1165–72

  Abstract

  OBJECTIVE MR-guided laser interstitial thermal therapy (MRgLITT) is a minimally invasive method for thermal destruction of benign or malignant tissue that has been used for selective amygdalohippocampal ablation for the treatment of temporal lobe epilepsy. The authors report their initial experience adopting a real-time MRI-guided stereotactic platform that allows for completion of the entire procedure in the MRI suite. METHODS Between October 2014 and May 2016, 17 patients with mesial temporal sclerosis were selected by a multidisciplinary epilepsy board to undergo a selective amygdalohippocampal ablation for temporal lobe epilepsy using MRgLITT. The first 9 patients underwent standard laser ablation in 2 phases (operating room [OR] and MRI suite), whereas the next 8 patients underwent laser ablation entirely in the MRI suite with the ClearPoint platform. A checklist specific to the real-time MRI-guided laser amydalohippocampal ablation was developed and used for each case. For both cohorts, clinical and operative information, including average case times and accuracy data, was collected and analyzed. RESULTS There was a learning curve associated with using this real-time MRI-guided system. However, operative times decreased in a linear fashion, as did total anesthesia time. In fact, the total mean patient procedure time was less in the MRI cohort (362.8 ± 86.6 minutes) than in the OR cohort (456.9 ± 80.7 minutes). The mean anesthesia time was significantly shorter in the MRI cohort (327.2 ± 79.9 minutes) than in the OR cohort (435.8 ± 78.4 minutes, p = 0.02). CONCLUSIONS The real-time MRI platform for MRgLITT can be adopted in an expedient manner. Completion of MRgLITT entirely in the MRI suite may lead to significant advantages in procedural times.

  View details for PubMedID 28665249

• Do complexity measures of frontal EEG distinguish loss of consciousness in geriatric patients under anesthesia? Frontiers in Neuroscience Eagleman*, S. L., Vaughn*, D. A., Drover, D. R., Drover, C. M., Cohen, M. S., Ouellette, N. T., MacIver, B. 2018

  View details for DOI 10.3389/fnins.2018.00645

• Calculations of consciousness: electroencephalography analyses to determine anesthetic depth. Current opinion in anaesthesiology Eagleman, S. L., Drover, D. R. 2018; 31 (4): 431–38

  Abstract

  Electroencephalography (EEG) was introduced into anesthesia practice in the 1990s as a tool to titrate anesthetic depth. However, limitations in current analysis techniques have called into question whether these techniques improve standard of care, or instead call for improved, more ubiquitously applicable measures to assess anesthetic transitions and depth. This review highlights emerging analytical approaches and techniques from neuroscience research that have the potential to better capture anesthetic transitions to provide better measurements of anesthetic depth.Since the introduction of electroencephalography, neuroscientists, engineers, mathematicians, and clinicians have all been developing new ways of analyzing continuous electrical signals. Collaborations between these fields have proliferated several analytical techniques that demonstrate how anesthetics affect brain dynamics and conscious transitions. Here, we review techniques in the following categories: network science, integration and information, nonlinear dynamics, and artificial intelligence.Up-and-coming techniques have the potential to better clinically define and characterize altered consciousness time points. Such new techniques used alongside traditional measures have the potential to improve depth of anesthesia measurements and enhance an understanding of how the brain is affected by anesthetic agents. However, new measures will be needed to be tested for robustness in real-world environments and on diverse experimental protocols.

  View details for PubMedID 29847364

• Do Complexity Measures of Frontal EEG Distinguish Loss of Consciousness in Geriatric Patients Under Anesthesia? Frontiers in neuroscience Eagleman, S. L., Vaughn, D. A., Drover, D. R., Drover, C. M., Cohen, M. S., Ouellette, N. T., MacIver, M. B. 2018; 12: 645

  Abstract

  While geriatric patients have a high likelihood of requiring anesthesia, they carry an increased risk for adverse cognitive outcomes from its use. Previous work suggests this could be mitigated by better intraoperative monitoring using indexes defined by several processed electroencephalogram (EEG) measures. Unfortunately, inconsistencies between patients and anesthetic agents in current analysis techniques have limited the adoption of EEG as standard of care. In attempts to identify new analyses that discriminate clinically-relevant anesthesia timepoints, we tested 1/f frequency scaling as well as measures of complexity from nonlinear dynamics. Specifically, we tested whether analyses that characterize time-delayed embeddings, correlation dimension (CD), phase-space geometric analysis, and multiscale entropy (MSE) capture loss-of-consciousness changes in EEG activity. We performed these analyses on EEG activity collected from a traditionally hard-to-monitor patient population: geriatric patients on beta-adrenergic blockade who were anesthetized using a combination of fentanyl and propofol. We compared these analyses to traditional frequency-derived measures to test how well they discriminated EEG states before and after loss of response to verbal stimuli. We found spectral changes similar to those reported previously during loss of response. We also found significant changes in 1/f frequency scaling. Additionally, we found that our phase-space geometric characterization of time-delayed embeddings showed significant differences before and after loss of response, as did measures of MSE. Our results suggest that our new spectral and complexity measures are capable of capturing subtle differences in EEG activity with anesthesia administration-differences which future work may reveal to improve geriatric patient monitoring.

  View details for PubMedID 30294254

• Calculations of Consciousness: EEG analyses to determine anesthetic depth. Current Opinion in Anesthesiology Eagleman, S., Drover, D. 2018

  View details for DOI 10.1097/ACO.0000000000000618

• Optimization of Maternal Magnesium Sulfate Administration for Fetal Neuroprotection: Application of a Prospectively Constructed Pharmacokinetic Model to the BEAM Cohort. Journal of clinical pharmacology Brookfield, K. F., Elkomy, M., Su, F., Drover, D. R., Carvalho, B. 2017

  Abstract

  The aim of the study was to identify the optimal therapeutic maternal magnesium drug exposure and maternal serum concentration to prevent cerebral palsy in the extremely preterm fetus. We applied a previously constructed pharmacokinetic model adjusted for indication to a large cohort of pregnant women receiving magnesium sulfate to prevent cerebral palsy in their preterm offspring at 20 different US academic centers between December 1997 and May 2004. We simulated the population-based individual maternal serum magnesium concentration at the time of delivery and the total magnesium dose for each woman who received magnesium sulfate to determine the relationship between maternal serum magnesium level at the time of delivery and the development of cerebral palsy. Among 1905 women who met inclusion criteria, the incidence of cerebral palsy in the cohort was 3.6% for women who had received magnesium sulfate and 6.4% for controls. The simulated maternal serum concentration at delivery associated with the lowest probability of delivering an infant with cerebral palsy was 4.1 mg/dL (95%CI 3.7 to 4.4). Our population-based estimates of magnesium disposition suggest that to optimize fetal neuroprotection and prevent cerebral palsy, magnesium sulfate administration should target a maternal serum magnesium level between 3.7 and 4.4 mg/dL at delivery.

  View details for DOI 10.1002/jcph.941

  View details for PubMedID 28589614

• Small-Volume Injections: Evaluation of Volume Administration Deviation From Intended Injection Volumes. Anesthesia and analgesia Muffly, M. K., Chen, M. I., Claure, R. E., Drover, D. R., Efron, B., Fitch, W. L., Hammer, G. B. 2017

  Abstract

  In the perioperative period, anesthesiologists and postanesthesia care unit (PACU) nurses routinely prepare and administer small-volume IV injections, yet the accuracy of delivered medication volumes in this setting has not been described. In this ex vivo study, we sought to characterize the degree to which small-volume injections (≤0.5 mL) deviated from the intended injection volumes among a group of pediatric anesthesiologists and pediatric postanesthesia care unit (PACU) nurses. We hypothesized that as the intended injection volumes decreased, the deviation from those intended injection volumes would increase.Ten attending pediatric anesthesiologists and 10 pediatric PACU nurses each performed a series of 10 injections into a simulated patient IV setup. Practitioners used separate 1-mL tuberculin syringes with removable 18-gauge needles (Becton-Dickinson & Company, Franklin Lakes, NJ) to aspirate 5 different volumes (0.025 mL, 0.05 mL, 0.1 mL, 0.25 mL, and 0.5 mL) of 0.25 mM Lucifer Yellow (LY) fluorescent dye constituted in saline (Sigma Aldrich, St. Louis, MO) from a rubber-stoppered vial. Each participant then injected the specified volume of LY fluorescent dye via a 3-way stopcock into IV tubing with free-flowing 0.9% sodium chloride (10 mL/min). The injected volume of LY fluorescent dye and 0.9% sodium chloride then drained into a collection vial for laboratory analysis. Microplate fluorescence wavelength detection (Infinite M1000; Tecan, Mannedorf, Switzerland) was used to measure the fluorescence of the collected fluid. Administered injection volumes were calculated based on the fluorescence of the collected fluid using a calibration curve of known LY volumes and associated fluorescence. To determine whether deviation of the administered volumes from the intended injection volumes increased at lower injection volumes, we compared the proportional injection volume error (loge [administered volume/intended volume]) for each of the 5 injection volumes using a linear regression model. Analysis of variance was used to determine whether the absolute log proportional error differed by the intended injection volume. Interindividual and intraindividual deviation from the intended injection volume was also characterized.As the intended injection volumes decreased, the absolute log proportional injection volume error increased (analysis of variance, P < .0018). The exploratory analysis revealed no significant difference in the standard deviations of the log proportional errors for injection volumes between physicians and pediatric PACU nurses; however, the difference in absolute bias was significantly higher for nurses with a 2-sided significance of P = .03.Clinically significant dose variation occurs when injecting volumes ≤0.5 mL. Administering small volumes of medications may result in unintended medication administration errors.

  View details for DOI 10.1213/ANE.0000000000001976

  View details for PubMedID 28338490

• Small-Volume Injections: Evaluation of Volume Administration Deviation From Intended Injection Volumes. Anesthesia and analgesia Muffly, M. K., Chen, M. I., Claure, R. E., Drover, D. R., Efron, B., Fitch, W. L., Hammer, G. B. 2017

  Abstract

  In the perioperative period, anesthesiologists and postanesthesia care unit (PACU) nurses routinely prepare and administer small-volume IV injections, yet the accuracy of delivered medication volumes in this setting has not been described. In this ex vivo study, we sought to characterize the degree to which small-volume injections (≤0.5 mL) deviated from the intended injection volumes among a group of pediatric anesthesiologists and pediatric postanesthesia care unit (PACU) nurses. We hypothesized that as the intended injection volumes decreased, the deviation from those intended injection volumes would increase.Ten attending pediatric anesthesiologists and 10 pediatric PACU nurses each performed a series of 10 injections into a simulated patient IV setup. Practitioners used separate 1-mL tuberculin syringes with removable 18-gauge needles (Becton-Dickinson & Company, Franklin Lakes, NJ) to aspirate 5 different volumes (0.025 mL, 0.05 mL, 0.1 mL, 0.25 mL, and 0.5 mL) of 0.25 mM Lucifer Yellow (LY) fluorescent dye constituted in saline (Sigma Aldrich, St. Louis, MO) from a rubber-stoppered vial. Each participant then injected the specified volume of LY fluorescent dye via a 3-way stopcock into IV tubing with free-flowing 0.9% sodium chloride (10 mL/min). The injected volume of LY fluorescent dye and 0.9% sodium chloride then drained into a collection vial for laboratory analysis. Microplate fluorescence wavelength detection (Infinite M1000; Tecan, Mannedorf, Switzerland) was used to measure the fluorescence of the collected fluid. Administered injection volumes were calculated based on the fluorescence of the collected fluid using a calibration curve of known LY volumes and associated fluorescence. To determine whether deviation of the administered volumes from the intended injection volumes increased at lower injection volumes, we compared the proportional injection volume error (loge [administered volume/intended volume]) for each of the 5 injection volumes using a linear regression model. Analysis of variance was used to determine whether the absolute log proportional error differed by the intended injection volume. Interindividual and intraindividual deviation from the intended injection volume was also characterized.As the intended injection volumes decreased, the absolute log proportional injection volume error increased (analysis of variance, P < .0018). The exploratory analysis revealed no significant difference in the standard deviations of the log proportional errors for injection volumes between physicians and pediatric PACU nurses; however, the difference in absolute bias was significantly higher for nurses with a 2-sided significance of P = .03.Clinically significant dose variation occurs when injecting volumes ≤0.5 mL. Administering small volumes of medications may result in unintended medication administration errors.

  View details for DOI 10.1213/ANE.0000000000001976

  View details for PubMedID 28338490

• Decreased Morphine Clearance in Neonates With Hypoxic Ischemic Encephalopathy Receiving Hypothermia JOURNAL OF CLINICAL PHARMACOLOGY Frymoyer, A., Bonifacio, S. L., Drover, D. R., Su, F., Wustoff, C. J., Van Meurs, K. P. 2017; 57 (1): 64-76

  Abstract

  Morphine is commonly used in neonates with hypothermic ischemic encephalopathy (HIE) during therapeutic hypothermia to provide comfort and analgesia. However, pharmacokinetic data to support morphine dosing in this vulnerable population are lacking. A prospective, two-center, clinical pharmacokinetic study of morphine was conducted in 20 neonates (birthweight 1.82-5.3 kg) with HIE receiving hypothermia. Morphine dosing was per standard of care at each center. Morphine and glucuronide metabolites (morphine-3-glucuronide and morphine-6-gluronide) were measured via a validated dried blood spot LC-MS/MS assay. From the available concentration data (n = 106 for morphine; n = 106 for each metabolite), a population pharmacokinetic model was developed using nonlinear mixed-effects modeling (NONMEM). The clearance of morphine and glucuronide metabolites were best predicted by birthweight allometrically scaled using an exponent of 1.23. In addition, the clearance of each glucuronide metabolite was influenced by serum creatinine. No other significant predictors of clearance or volume of distribution were found. For a 3.5 kg neonate, morphine clearance was 0.77 L/h (CV 48%) and the steady-state volume of distribution was 8.0 L (CV 49%). Compared to previous studies in full-term newborns without HIE, morphine clearance was markedly lower. Dosing strategies customized for this vulnerable population will be needed. Applying the final population pharmacokinetic model, repeated Monte Carlo simulations (n = 1000 per simulation) were performed to evaluate various morphine dosing strategies that optimized achievement of morphine concentrations between 10-40 ng/ml. An optimized morphine loading dose of 50 μg/kg followed by a continuous infusion of 5 μg/kg/h was predicted across birthweight. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1002/jcph.775

  View details for PubMedID 27225747

• Pharmacodynamic Analysis of Morphine Time-to-Remedication Events in Infants and Young Children After Congenital Heart Surgery. Clinical pharmacokinetics Elkomy, M. H., Drover, D. R., Galinkin, J. L., Hammer, G. B., Glotzbach, K. L. 2016; 55 (10): 1217-1226

  Abstract

  The aim of this study was to characterize the relationship between morphine plasma concentration and repeated time to postoperative remedication events in children undergoing cardiac surgery.Data from our previously published study of morphine pharmacokinetics were utilized in this pharmacodynamic study. A population survival analysis based on hazard functions was undertaken in NONMEM(®).Hazard was best described by a Gompertz function changing in steps over time. Concentration and age were the only predictors of the hazard function. Concentration producing 50 % reduction in hazard was 19.6 (bootstrap 95 % confidence interval 5.90-49.5 ng/ml). The hazard ratio for a 1-year-old child to a 1-month-old child was 1.91 (1.35-2.86). Sensitivity to morphine decreased with age and leveled off after 1-year of life. Morphine sulfate doses >0.1 mg/kg did not noticeably increase tolerable pain durations.Time to remedication is a clinically useful endpoint for assessing opioid-induced analgesia. Sensitivity to morphine treatment is age-dependent. Morphine sulfate doses of 0.1-0.2 mg/kg are adequate for the management of postoperative pain in children. Our findings may help avoid unnecessary large morphine doses in children.

  View details for DOI 10.1007/s40262-016-0398-z

  View details for PubMedID 27098060

• Pharmacokinetics and placental transfer of magnesium sulfate in pregnant women AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY Brookfield, K. F., Su, F., Elkomy, M. H., Drover, D. R., Lyell, D. J., Carvalho, B. 2016; 214 (6)

  Abstract

  Magnesium sulfate is one of the most commonly prescribed intravenous medications in obstetrics. Despite its widespread use, there are limited data about magnesium pharmacokinetics, and magnesium is prescribed empirically without dose adjustment for different indications.The aim of this study was to characterize the pharmacokinetics and placental transfer of magnesium sulfate in pregnant women and to determine key covariates that impact the pharmacokinetics.This is a prospective pharmacokinetic cohort study of pregnant women who were prescribed magnesium sulfate for preeclampsia, preterm labor, or extreme prematurity. Women received a 4-g loading dose and 2 g/h maintenance dose as clinically indicated. Maternal blood samples were obtained before and at multiple time points during and after magnesium administration. Cord blood also was sampled at delivery. A population pharmacokinetic approach that used a nonlinear mixed-effects modeling was used to characterize magnesium disposition.Pharmacokinetic profiles of 111 pregnant women were analyzed. Magnesium clearance was 3.98 L/h in preeclamptic women and 5.88 L/h non-preeclamptic women. Steady-state concentration of magnesium was 7.2 mg/dL in preeclamptic women compared with 5.1 mg/dL in non-preeclamptic women. Maternal weight significantly impacted time to steady state. The ratio of the mean umbilical vein magnesium level to the mean maternal serum magnesium level at the time of delivery was 0.94 ± 0.15.The study accurately characterizes the pharmacokinetics of magnesium administered to pregnant women. Preeclamptic status and maternal weight significantly impact serum magnesium levels. This pharmacokinetic model could be applied to larger cohorts to help tailor magnesium treatment and account for these covariates.

  View details for DOI 10.1016/j.ajog.2015.12.060

  View details for PubMedID 26767791

• Variable Findings for Drug-Induced Sleep Endoscopy in Obstructive Sleep Apnea with Propofol versus Dexmedetomidine. Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery Capasso, R., Rosa, T., Tsou, D. Y., Nekhendzy, V., Drover, D., Collins, J., Zaghi, S., Camacho, M. 2016; 154 (4): 765-770

  Abstract

  To compare VOTE classification findings (velum, oropharyngeal-lateral walls, tongue base, and epiglottis) for drug-induced sleep endoscopy (DISE) among patients with obstructive sleep apnea (OSA) using 2 sedation protocols.Case series with chart review.Single tertiary institution.Patients with OSA who underwent DISE.A total of 216 patients underwent DISE between November 23, 2011, and May 1, 2015. DISE findings based on VOTE classification were compared between patients receiving the propofol- and dexmedetomidine-based sedation protocols.Patients with OSA (N = 216; age, 44.3 ± 11.7 years; body mass index, 27.9 ± 4.8 kg/m(2)) underwent DISE with intravenous administration of propofol (n = 52) or dexmedetomidine (n = 164). There were no statistically significant differences between the 2 groups in baseline apnea-hypopnea index, oxygen desaturation index, Mallampati score, tonsil size, Epworth Sleepiness Scale score, peripheral oxygen saturation nadir, age, sex, or body mass index. Patients in the propofol group had a significantly increased likelihood of demonstrating complete tongue base obstruction (75%, 39 of 52) versus partial or no obstruction (25%, 13 of 52) in the anterior-posterior dimension, as compared with the dexmedetomidine group (complete obstruction: 42.7%, 70 of 164; partial or no obstruction: 57.3%, 94 of 164; odds ratio: 4.0; 95% confidence interval: 2.0-8.1; P = .0001). Obstruction of other airway subsites was not significantly different.Use of propofol versus dexmedetomidine to induce sedation may have a significant effect on the pattern of upper airway obstruction observed during DISE. Randomized prospective studies are indicated to confirm these initial findings.

  View details for DOI 10.1177/0194599815625972

  View details for PubMedID 26814208

• Pharmacokinetics of Morphine and Its Metabolites in Infants and Young Children After Congenital Heart Surgery AAPS JOURNAL Elkomy, M. H., Drover, D. R., Glotzbach, K. L., Galinkin, J. L., Frymoyer, A., Su, F., Hammer, G. B. 2016; 18 (1): 124-133

  Abstract

  The objective of this study was to characterize morphine glucuronidation in infants and children following cardiac surgery for possible treatment individualization in this population. Twenty children aged 3 days to 6 years, admitted to the cardiovascular intensive care unit after congenital heart surgery, received an intravenous (IV) loading dose of morphine (0.15 mg/kg) followed by subsequent intermittent IV bolus doses based on a validated pain scale. Plasma samples were collected over 6 h after the loading dose and randomly after follow-up doses to measure morphine and its major metabolite concentrations. A population pharmacokinetic model was developed with the non-linear mixed effects software NONMEM. Parent disposition was adequately described by a linear two-compartment model. Effect of growth (size and maturation) on morphine parameters was accounted for by allometric body weight-based models. An intermediate compartment with Emax model best characterized glucuronide concentrations. Glomerular filtration rate was identified as a significant predictor of glucuronide formation time delay and maximum concentrations. Clearance of morphine in children with congenital heart disease is comparable to that reported in children without cardiac abnormalities of similar age. Children 1-6 months of age need higher morphine doses per kilogram to achieve an area under concentration-time curve comparable to that in older children. Pediatric patients with renal failure receiving morphine therapy are at increased risk of developing opioid toxicity due to accumulation of morphine metabolites.

  View details for DOI 10.1208/s12248-015-9826-5

  View details for Web of Science ID 000367529900010

  View details for PubMedCentralID PMC4706285

• Optimization of maternal magnesium sulfate administration for fetal neuroprotection and cerebral palsy prevention Brookfield, K., Su, F., El-Komy, M., Ho, P., Drover, D., Carvalho, B. MOSBY-ELSEVIER. 2016: S370

  View details for DOI 10.1016/j.ajog.2015.10.749

  View details for Web of Science ID 000367092800695

• Pharmacokinetics of Morphine and Its Metabolites in Infants and Young Children After Congenital Heart Surgery. The AAPS journal Elkomy, M. H., Drover, D. R., Glotzbach, K. L., Galinkin, J. L., Frymoyer, A., Su, F., Hammer, G. B. 2016; 18 (1): 124–33

  Abstract

  The objective of this study was to characterize morphine glucuronidation in infants and children following cardiac surgery for possible treatment individualization in this population. Twenty children aged 3 days to 6 years, admitted to the cardiovascular intensive care unit after congenital heart surgery, received an intravenous (IV) loading dose of morphine (0.15 mg/kg) followed by subsequent intermittent IV bolus doses based on a validated pain scale. Plasma samples were collected over 6 h after the loading dose and randomly after follow-up doses to measure morphine and its major metabolite concentrations. A population pharmacokinetic model was developed with the non-linear mixed effects software NONMEM. Parent disposition was adequately described by a linear two-compartment model. Effect of growth (size and maturation) on morphine parameters was accounted for by allometric body weight-based models. An intermediate compartment with Emax model best characterized glucuronide concentrations. Glomerular filtration rate was identified as a significant predictor of glucuronide formation time delay and maximum concentrations. Clearance of morphine in children with congenital heart disease is comparable to that reported in children without cardiac abnormalities of similar age. Children 1-6 months of age need higher morphine doses per kilogram to achieve an area under concentration-time curve comparable to that in older children. Pediatric patients with renal failure receiving morphine therapy are at increased risk of developing opioid toxicity due to accumulation of morphine metabolites.

  View details for PubMedID 26349564

• Safety and Efficacy of Sodium Nitroprusside During Prolonged Infusion in Pediatric Patients PEDIATRIC CRITICAL CARE MEDICINE Hammer, G. B., Lewandowski, A., Drover, D. R., Rosen, D. A., Cohane, C., Anand, R., Mitchell, J., Reece, T., Schulman, S. R. 2015; 16 (5): 397-403

  Abstract

  Sodium nitroprusside is a direct-acting vasodilator used to lower blood pressure in the operating room and ICU. The efficacy of sodium nitroprusside has been analyzed in few pediatric randomized trials. This study assesses the efficacy and safety of sodium nitroprusside following at least 12 hours of IV infusion in children.Randomized, double-blind withdrawal to placebo study.ICUs.Pediatric patients younger than 17 years.Following 12-24 hours of open-label sodium nitroprusside titration, a blinded infusion of sodium nitroprusside or placebo was administered (at the stable rate used at the end of the open-label phase) for up to 30 minutes.The primary efficacy measure was whether control of mean arterial blood pressure was lost, that is, increased above ambient baseline for two consecutive minutes during the blinded phase. The proportion of patients who lost mean arterial blood pressure control in the placebo group (15/19; 79%) was significantly different than those in the sodium nitroprusside group (9/20; 45%) (p = 0.048). Three patients experienced rebound hypertension during the blinded phase, and all were in the placebo group. Serious adverse event rates were low (7/52; 13%), and in only one patient was the serious adverse event determined to be related to sodium nitroprusside by the site investigator. Fourteen patients (27%) had whole blood cyanide levels above 0.5 μg/mL, with high correlation (0.7) between infusion rate and cyanide levels, but there were few clinical signs of cyanide toxicity.Sodium nitroprusside is efficacious in maintaining mean arterial blood pressure control in children following a 12-hour infusion. Although a high proportion of patients were found to have elevated cyanide levels, toxicity was not observed.

  View details for DOI 10.1097/PCC.0000000000000383

  View details for Web of Science ID 000358289300001

• Pharmacokinetics of Prophylactic Cefazolin in Parturients Undergoing Cesarean Delivery (vol 58, pg 3504, 2014) ANTIMICROBIAL AGENTS AND CHEMOTHERAPY Elkomy, M. H., Sultan, P., Drover, D. R., Epshtein, E., Galinkin, J. L., Carvalho, B. 2015; 59 (6): 3694

  View details for PubMedID 25977453

• Population pharmacokinetics of etomidate in neonates and infants with congenital heart disease BIOPHARMACEUTICS & DRUG DISPOSITION Su, F., El-Komy, M. H., Hammer, G. B., Frymoyer, A., Cohane, C. A., Drover, D. R. 2015; 36 (2): 104-114

  Abstract

  Etomidate is a rapid-onset, short-acting hypnotic medication administered for induction of anesthesia. It is currently approved by the Food and Drug Administration for use in older children and adults. Pharmacokinetic data to help guide dosing in neonates and infants is lacking.The aim of this study was to determine the pharmacokinetics of etomidate in neonates and infants with congenital heart disease undergoing cardiac surgery.Four neonates and sixteen infants, postnatal age 0.3 - 11.7 months, requiring open-heart surgery received 0.3 mg/kg of etomidate administered as a single intravenous dose prior to surgery. Blood sampling for plasma etomidate concentration occurred immediately following etomidate administration until the initiation of cardiopulmonary bypass. A population pharmacokinetic approach using nonlinear mixed-effects modeling was applied to characterize etomidate pharmacokinetics.The pharmacokinetics of etomidate was described by a two-compartment model with first-order elimination. An allometric weight-based model was applied to scale results to a 70 kg adult. Covariates including age and cardiac physiology were not found to significantly impact etomidate pharmacokinetics. The study population was found to have a central and intercompartmental clearance of 0.624 L/min/70-kg and 0.44 L/min/70-kg, respectively; central and peripheral distribution volume of 9.47 and 22.8 L/70-kg, respectively. Inter-individual variability was between 94-142% for all parameters and residual variability was 29%.The clearance of etomidate is lower in neonates and infants with congenital heart disease compared to published values for older children without congenital heart disease. In addition, etomidate pharmacokinetics is highly variable in this pediatric cardiac population. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1002/bdd.1924

  View details for PubMedID 25377074

• Risk factors for respiratory depression in patients undergoing retrobulbar block for vitreoretinal surgery. Ophthalmic surgery, lasers & imaging retina Silva, R. A., Leng, J. C., He, L., Brock-Utne, J. G., Drover, D. R., Leng, T. 2015; 46 (2): 243-247

  Abstract

  To determine the risk factors for respiratory depression during retrobulbar block administration before vitreoretinal surgery.Prospective, observational case series of 113 patients undergoing monitored anesthesia care and retrobulbar block before vitreoretinal surgery at a tertiary medical center.Chin lift, jaw thrust, and bag mask ventilation were performed in eight (7.1%), nine (8%), and six (5.3%) patients, respectively. No patients required intubation. Age, sex, body mass index, history of obstructive sleep apnea, American Society of Anesthesiologists physical status level, and baseline oxygen saturation were not predictive of airway intervention. Of the four anesthetic agents utilized (midazolam, fentanyl, alfentanil, and propofol), only propofol and fentanyl were associated with an increased risk for clinically significant apnea. Use of three medications for sedation was associated with a 5.4-fold increase in the relative risk of requiring a respiratory rescue intervention.During preoperative sedation for retrobulbar block administration, the use of propofol, fentanyl, or a combination of three anesthetics is associated with a statistically significant increase in the risk for respiratory depression requiring resuscitation. [Ophthalmic Surg Lasers Imaging Retina. 2015;46:243-247.].

  View details for DOI 10.3928/23258160-20150213-22

  View details for PubMedID 25707051

• Ondansetron pharmacokinetics in pregnant women and neonates: towards a new treatment for neonatal abstinence syndrome. Clinical pharmacology & therapeutics Elkomy, M., Sultan, P., Carvalho, B., Peltz, G., Wu, M., Clavijo, C., Galinkin, J., Drover, D. 2015; 97 (2): 167-176

  Abstract

  Ondansetron is the drug of choice to prevent nausea in women undergoing cesarean surgery and can be used to prevent neonatal abstinence syndrome (NAS). The pharmacokinetics of ondansetron have not been characterized in pregnant women or in newborns. A nonlinear mixed-effects modeling approach was used to analyze plasma samples obtained from 20 nonpregnant and 40 pregnant women following a single administration of 4 or 8 mg ondansetron, from umbilical cord blood at delivery, and from neonates after birth. The analysis indicates that: ondansetron disposition is not affected by pregnancy (P > 0.05), but influenced by dose (P < 0.05), and is characterized by rapid transplacental transfer and longer elimination half-life in neonates compared to their mother. A dosing regimen for prevention of NAS was designed based on the model. The regimen involves IV administration of 4 mg to the mothers shortly before cord clamping, or oral administration of 0.07 mg/kg (or equivalently 0.04 mg/kg IV) to neonates.

  View details for DOI 10.1002/cpt.5

  View details for PubMedID 25670522

  View details for PubMedCentralID PMC4325425

• Risk Factors for Respiratory Depression in Patients Undergoing Retrobulbar Block for Vitreoretinal Surgery OPHTHALMIC SURGERY LASERS & IMAGING RETINA Silva, R. A., Leng, J. C., He, L., Brock-Utne, J. G., Drover, D. R., Leng, T. 2015; 46 (2): 243-247

  Abstract

  To determine the risk factors for respiratory depression during retrobulbar block administration before vitreoretinal surgery.Prospective, observational case series of 113 patients undergoing monitored anesthesia care and retrobulbar block before vitreoretinal surgery at a tertiary medical center.Chin lift, jaw thrust, and bag mask ventilation were performed in eight (7.1%), nine (8%), and six (5.3%) patients, respectively. No patients required intubation. Age, sex, body mass index, history of obstructive sleep apnea, American Society of Anesthesiologists physical status level, and baseline oxygen saturation were not predictive of airway intervention. Of the four anesthetic agents utilized (midazolam, fentanyl, alfentanil, and propofol), only propofol and fentanyl were associated with an increased risk for clinically significant apnea. Use of three medications for sedation was associated with a 5.4-fold increase in the relative risk of requiring a respiratory rescue intervention.During preoperative sedation for retrobulbar block administration, the use of propofol, fentanyl, or a combination of three anesthetics is associated with a statistically significant increase in the risk for respiratory depression requiring resuscitation. [Ophthalmic Surg Lasers Imaging Retina. 2015;46:243-247.].

  View details for DOI 10.3928/23258160-20150213-22

  View details for Web of Science ID 000353360100013

  View details for PubMedID 25707051

• Population pharmacokinetics of ketamine in children with heart disease INTERNATIONAL JOURNAL OF PHARMACEUTICS Elkomy, M. H., Drover, D. R., Hammer, G. B., Galinkin, J. L., Ramamoorthy, C. 2015; 478 (1): 223-231

  Abstract

  This study aims at developing a population pharmacokinetic model for ketamine in children with cardiac diseases in order to rationalize an effective 2-h anesthetic medication, personalized based on cardiac function and age. Twenty-one children (6 months to 18 years old) were enrolled in this prospective, open label study. Ketamine 2mg/kg IV was administered and blood samples were then collected over 8h for ketamine assay. Pharmacokinetic data analysis using NONMEM, was undertaken. Ketamine pharmacokinetics was adequately described by a two-compartment linear disposition model. Typical population parameters were: total clearance: 60.6×(weight/70)(0.75)L/h, intercompartmental clearance: 73.2×(weight/70)(0.75)L/h, central distribution volume: 57.3×(weight/70)L, and peripheral distribution volume: 152×(weight/70)L. Ketamine clearance in children with pre-existing congenital heart disease was comparable to values reported in healthy subjects. Computer simulations indicated that an initial loading dose of ketamine 2mg/kg IV over 1min followed by a constant rate infusion of 6.3mg/kg/h for 29min, 4.5mg/kg/h from 30 to 80min, and 3.9mg/kg/h from 80 to 120min achieves and maintains anesthetic plasma level for 2h in children 1 year or older (weight ≥10kg).

  View details for DOI 10.1016/j.ijpharm.2014.11.026

  View details for Web of Science ID 000348621100026

• Population pharmacokinetics of ketamine in children with heart disease. International journal of pharmaceutics Elkomy, M. H., Drover, D. R., Hammer, G. B., Galinkin, J. L., Ramamoorthy, C. 2015; 478 (1): 223-231

  Abstract

  This study aims at developing a population pharmacokinetic model for ketamine in children with cardiac diseases in order to rationalize an effective 2-h anesthetic medication, personalized based on cardiac function and age. Twenty-one children (6 months to 18 years old) were enrolled in this prospective, open label study. Ketamine 2mg/kg IV was administered and blood samples were then collected over 8h for ketamine assay. Pharmacokinetic data analysis using NONMEM, was undertaken. Ketamine pharmacokinetics was adequately described by a two-compartment linear disposition model. Typical population parameters were: total clearance: 60.6×(weight/70)(0.75)L/h, intercompartmental clearance: 73.2×(weight/70)(0.75)L/h, central distribution volume: 57.3×(weight/70)L, and peripheral distribution volume: 152×(weight/70)L. Ketamine clearance in children with pre-existing congenital heart disease was comparable to values reported in healthy subjects. Computer simulations indicated that an initial loading dose of ketamine 2mg/kg IV over 1min followed by a constant rate infusion of 6.3mg/kg/h for 29min, 4.5mg/kg/h from 30 to 80min, and 3.9mg/kg/h from 80 to 120min achieves and maintains anesthetic plasma level for 2h in children 1 year or older (weight ≥10kg).

  View details for DOI 10.1016/j.ijpharm.2014.11.026

  View details for PubMedID 25448584

• Evaluation of sodium nitroprusside for controlled hypotension in children during surgery. Frontiers in pharmacology Drover, D. R., Hammer, G. B., Barrett, J. S., Cohane, C. A., Reece, T., Zajicek, A., Schulman, S. R. 2015; 6: 136-?

  Abstract

  (1) To define the onset and offset of the blood-pressure-lowering effects of sodium nitroprusside (SNP) for use in developing instructions for dose titration in children undergoing a surgical or medical procedure, and (2) to assess the safety of SNP administration in pediatric patients requiring controlled reduction of blood pressure.We conducted a randomized, double-blind, parallel-group, dose-ranging, effect-controlled, multicenter study of intravenous (IV) infusions of SNP in pediatric patients <17 years, who required controlled hypotension for at least 2 h while undergoing a surgical or medical procedure. A blinded SNP dose of 0.3, 1, 2, or 3 μg/kg/min was infused for 30 min, followed by open-label administration for at least 90 min. Both infusions were titrated to effect.The final intent-to-treat group comprised 203 patients. Significant reductions in mean arterial pressure (MAP) from baseline were observed for all four doses at 20 and 25 min after the start of infusion (p ≤ 0.009 and p ≤ 0.010 for each time, respectively). Overall, 98.5% of the patients achieved the target MAP; 72.9% first achieved the target MAP during the blinded infusion. The mean infusion rate at target MAP was 1.07 μg/kg/min.We determined that 0.3 μg/kg/m is a reasonable starting dose for SNP in pediatric patients requiring controlled hypotension. The infusion rate can then be increased to achieve the desired reduction in blood pressure. On the basis of our results, we found an average infusion rate of 1 μg/kg/min might be appropriate. Of note, no cyanide toxicity was reported, and no measureable cyanide levels were detected in any blood samples obtained during the study. http://clinicaltrials.gov/show/NCT00135668.

  View details for DOI 10.3389/fphar.2015.00136

  View details for PubMedID 26217225

• Pharmacokinetics of magnesium sulfate in pregnant women Brookfield, K., Su, F., Drover, D., Adelus, M., Lyell, D., Carvalho, B. MOSBY-ELSEVIER. 2015: S102

  View details for DOI 10.1016/j.ajog.2014.10.221

  View details for Web of Science ID 000361140900177

• Umbilical cord magnesium levels and neonatal resuscitation in infants exposed to magnesium sulfate Brookfield, K., Su, F., Drover, D., Adelus, M., Lyell, D., Carvalho, B. MOSBY-ELSEVIER. 2015: S395–S396

  View details for DOI 10.1016/j.ajog.2014.10.1029

  View details for Web of Science ID 000361140900815

• Safety and efficacy of sodium nitroprusside during prolonged infusion in pediatric patients. Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies Hammer, G. B., Lewandowski, A., Drover, D. R., Rosen, D. A., Cohane, C., Anand, R., Mitchell, J., Reece, T., Schulman, S. R. 2015; 16 (5): 397–403

  Abstract

  Sodium nitroprusside is a direct-acting vasodilator used to lower blood pressure in the operating room and ICU. The efficacy of sodium nitroprusside has been analyzed in few pediatric randomized trials. This study assesses the efficacy and safety of sodium nitroprusside following at least 12 hours of IV infusion in children.Randomized, double-blind withdrawal to placebo study.ICUs.Pediatric patients younger than 17 years.Following 12-24 hours of open-label sodium nitroprusside titration, a blinded infusion of sodium nitroprusside or placebo was administered (at the stable rate used at the end of the open-label phase) for up to 30 minutes.The primary efficacy measure was whether control of mean arterial blood pressure was lost, that is, increased above ambient baseline for two consecutive minutes during the blinded phase. The proportion of patients who lost mean arterial blood pressure control in the placebo group (15/19; 79%) was significantly different than those in the sodium nitroprusside group (9/20; 45%) (p = 0.048). Three patients experienced rebound hypertension during the blinded phase, and all were in the placebo group. Serious adverse event rates were low (7/52; 13%), and in only one patient was the serious adverse event determined to be related to sodium nitroprusside by the site investigator. Fourteen patients (27%) had whole blood cyanide levels above 0.5 μg/mL, with high correlation (0.7) between infusion rate and cyanide levels, but there were few clinical signs of cyanide toxicity.Sodium nitroprusside is efficacious in maintaining mean arterial blood pressure control in children following a 12-hour infusion. Although a high proportion of patients were found to have elevated cyanide levels, toxicity was not observed.

  View details for PubMedID 25715047

• Evaluation of sodium nitroprusside for controlled hypotension in children during surgery. Frontiers in pharmacology Drover, D. R., Hammer, G. B., Barrett, J. S., Cohane, C. A., Reece, T., Zajicek, A., Schulman, S. R. 2015; 6: 136-?

  View details for DOI 10.3389/fphar.2015.00136

  View details for PubMedID 26217225

• A hemodynamic model to guide blood pressure control during deliberate hypotension with sodium nitroprusside in children. Frontiers in pharmacology Barrett, J. S., Hirankarn, S., Holford, N., Hammer, G. B., Drover, D. R., Cohane, C. A., Anderson, B., Dombrowski, E., Reece, T., Zajicek, A., Schulman, S. R. 2015; 6: 151-?

  View details for DOI 10.3389/fphar.2015.00151

  View details for PubMedID 26283961

• A hemodynamic model to guide blood pressure control during deliberate hypotension with sodium nitroprusside in children. Frontiers in pharmacology Barrett, J. S., Hirankarn, S., Holford, N., Hammer, G. B., Drover, D. R., Cohane, C. A., Anderson, B., Dombrowski, E., Reece, T., Zajicek, A., Schulman, S. R. 2015; 6: 151-?

  Abstract

  Sodium nitroprusside (SNP) has been widely used to control blood pressure in infants and children. The goals of this analysis were to develop models that describe the hemodynamic response to SNP dosing in pediatric patients; examine sources of variation in dose-response, defining age, and size dependencies; and determine vulnerable populations or patient subtypes that may elicit dosing modifications. A multi-center, randomized, double-blinded, parallel-group, dose-ranging, effect-controlled study, followed by an open-label dose titration of an intravenous infusion of SNP was undertaken in 203 pediatric subjects, who required deliberate hypotension or controlled normotension during anesthesia. A total of 3464 MAP measurements collected from 202 patients during the study's blinded phase, including baseline measurements up to 6 min prior to the blinded were available for analysis. A population K-PD model was developed with a one-compartment model assumed for SNP. Size differences in CL and V of the effect compartment were described using theory-based allometry. An inhibitory sigmoidal Emax model was used to describe the effect of SNP. A power function of age was used to describe age-related differences in baseline MAP. A mixture model of two groups with low and high EC50 was used to explain variability in MAP response. Change in MAP was characterized by a linear disease progression slope during the blinded phase. In the final population model, CL and V increased with weight, and baseline MAP increased with age. The effect compartment half-life of SNP was 13.4 min. The infusion rate producing 50% of Emax (ER50) at steady state for high EC50, was 0.34 μg/kg/min and for low EC50 0.103 μg/kg/min. The K-PD model well-describes initial dosing of SNP under controlled circumstances; model-based dosing guidance agrees with current practice. An initial titration strategy supported via algorithm-based feedback should improve maintenance of target MAP.

  View details for DOI 10.3389/fphar.2015.00151

  View details for PubMedID 26283961

• THE PHARMACOKINETICS OF ETOMIDATE IN NEONATES AND INFANTS WITH CONGENITAL HEART DISEASE Su, F., Cohane, C., Drover, D., El-Komy, M., Frymoyer, A., Hammer, G. LIPPINCOTT WILLIAMS & WILKINS. 2014

  View details for Web of Science ID 000346211800623

• Detection of respiratory compromise by acoustic monitoring, capnography, and brain function monitoring during monitored anesthesia care JOURNAL OF CLINICAL MONITORING AND COMPUTING Tanaka, P. P., Tanaka, M., Drover, D. R. 2014; 28 (6): 561-566

  Abstract

  Episodes of apnea in sedated patients represent a risk of respiratory compromise. We hypothesized that acoustic monitoring would be equivalent to capnography for detection of respiratory pauses, with fewer false alarms. In addition, we hypothesized that the patient state index (PSI) would be correlated with the frequency of respiratory pauses and therefore could provide information about the risk of apnea during sedation. Patients undergoing sedation for surgical procedures were monitored for respiration rate using acoustic monitoring and capnography and for depth of sedation using the PSI. A clinician blinded to the acoustic and sedation monitor observed the capnograph and patient to assess sedation and episodes of apnea. Another clinician retrospectively reviewed the capnography and acoustic waveform and sound files to identify true positive and false positive respiratory pauses by each method (reference method). Sensitivity, specificity, and likelihood ratio for detection of respiratory pause was calculated for acoustic monitoring and capnography. The correlation of PSI with respiratory pause events was determined. For the 51 respiratory pauses validated by retrospective analysis, the sensitivity, specificity, and likelihood ratio positive for detection were 16, 96 %, and 3.5 for clinician observation; 88, 7 %, and 1.0 for capnography; and 55, 87 %, and 4.1 for acoustic monitoring. There was no correlation between PSI and respiratory pause events. Acoustic monitoring had the highest likelihood ratio positive for detection of respiratory pause events compared with capnography and clinician observation and, therefore, may provide the best method for respiration rate monitoring during these procedures.

  View details for DOI 10.1007/s10877-014-9556-8

  View details for PubMedID 24420342

• Association between vancomycin trough concentration and area under the concentration-time curve in neonates. Antimicrobial agents and chemotherapy Frymoyer, A., Hersh, A. L., El-Komy, M. H., Gaskari, S., Su, F., Drover, D. R., Van Meurs, K. 2014; 58 (11): 6454-6461

  Abstract

  National treatment guidelines for invasive methicillin-resistant Staphylococcus aureus (MRSA) infections recommend targeting a vancomycin 24-hour area under the curve (AUC24)/MIC >400. The range of vancomycin trough concentrations that best predicts AUC24 >400 in neonates is not known. This understanding would help clarify target trough concentrations for neonates when treating MRSA. A retrospective chart review from a level III neonatal intensive care unit was performed to identify neonates treated with vancomycin over a 5-year period. Vancomycin concentrations and clinical covariates were utilized to develop a one-compartment population pharmacokinetic model and examine relationships between trough and AUC24 in study neonates. Monte Carlo simulations were performed to examine the effect of dose, post-menstrual age (PMA), and serum creatinine on trough and AUC24 achievement. A total of 1702 vancomycin concentrations from 249 neonates were available for analysis. The median [interquartile range] PMA was 39 wks [32-42 wks] and weight was 2.9 kg [1.6-3.7kg]. Vancomycin clearance was predicted by weight, PMA, and creatinine. At a trough of 10 mg/L, 89% of study neonates had an AUC24 >400. Monte Carlo simulations demonstrated that troughs ranging from 7-11 mg/L were highly predictive of an AUC24 >400 across a range of PMA, serum creatinine, and vancomycin doses. However, a trough ≥10 mg/L was not readily achieved in most simulated subgroups using routine starting doses. Higher starting doses frequently resulted in troughs >20 mg/L. A vancomycin trough of ∼10 mg/L is likely adequate for most neonates with invasive MRSA infections based on AUC24 considerations. Due to pharmacokinetic and clinical heterogeneity in neonates, consistently achieving this target vancomycin exposure with routine starting doses will be difficult. More robust clinical dosing support tools are needed to help clinicians with dose individualization.

  View details for DOI 10.1128/AAC.03620-14

  View details for PubMedID 25136027

• Association between Vancomycin Trough Concentration and Area under the Concentration-Time Curve in Neonates ANTIMICROBIAL AGENTS AND CHEMOTHERAPY Frymoyer, A., Hersh, A. L., El-Komy, M. H., Gaskari, S., Su, F., Drover, D. R., Van Meurs, K. 2014; 58 (11): 6454-6461

  View details for DOI 10.1128/AAC.03620-14

  View details for Web of Science ID 000344158600014

• Predictors of Arterial Blood Pressure Control During Deliberate Hypotension with Sodium Nitroprusside in Children ANESTHESIA AND ANALGESIA Spielberg, D. R., Barrett, J. S., Hammer, G. B., Drover, D. R., Reece, T., Cohane, C. A., Schulman, S. R. 2014; 119 (4): 867-874

  Abstract

  Sodium nitroprusside (SNP) is used to decrease arterial blood pressure (BP) during certain surgical procedures. There are limited data regarding efficacy of BP control with SNP. There are no data on patient and clinician factors that affect BP control. We evaluated the dose-response relationship of SNP in infants and children undergoing major surgery and performed a quantitative assessment of BP control.One hundred fifty-three subjects at 7 sites received a blinded infusion followed by open-label SNP during operative procedures requiring controlled hypotension. SNP was administered by continuous infusion and titrated to maintain BP control (mean arterial BP [MAP] within ±10% of clinician-defined target). BP was recorded using an arterial catheter. Statistical process control methodology was used to quantify BP control. A multivariable model assessed the effects of patient and procedural factors.BP was controlled an average 45.4% (SD 23.9%; 95% CI, 41.5%-49.18%) of the time. Larger changes in infusion rate were associated with worse BP control (7.99% less control for 1 μg·kg·min increase in average titration size, P = 0.0009). A larger difference between a patient's baseline and target MAP predicted worse BP control (0.93% worse control per 1-mm Hg increase in MAP difference, P = 0.0013). Both effects persisted in multivariable models.SNP was effective in reducing BP. However, BP was within the target range less than half of the time. No clinician or patient factors were predictive of BP control, although 2 inverse relationships were identified. These relationships require additional study and may be best coupled with exposure-response modeling to propose improved dosing strategies when using SNP for controlled hypotension in the pediatric population.

  View details for DOI 10.1213/ANE.0000000000000376

  View details for Web of Science ID 000341828200014

  View details for PubMedCentralID PMC4169308

• The pharmacokinetics of methadone and its metabolites in neonates, infants, and children PEDIATRIC ANESTHESIA Ward, R. M., Drover, D. R., Hammer, G. B., Stemland, C. J., Kern, S., Tristani-Firouzi, M., Lugo, R. A., Satterfield, K., Anderson, B. J. 2014; 24 (6): 591-601

  Abstract

  The lack of methadone pharmacokinetic data in children and neonates restrains dosing to achieve the target concentration in these populations. A minimum effective analgesic concentration of methadone in opioid naïve adults is 0.058 mg·l(-1) , while no withdrawal symptoms were observed in neonates suffering opioid withdrawal if plasma concentrations of methadone were above 0.06 mg·l(-1) . The racemate of methadone which is commonly used in pediatric and anesthetic care is metabolized to 2-ethylidine-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) and 2-ethyl-5-methyl-3,3-diphenylpyrroline (EMDP).Data from four studies (age 33-week PMA-15 years) were pooled (n = 56) for compartment analysis using nonlinear mixed effects modeling. Parameter estimates were standardized to a 70-kg person using an allometric model approach. Investigation was made of the racemate and metabolite (EDDP and EMDP) dispositions. In addition, neonatal data (n = 7) allowed further study of R- and S-enantiomer pharmacokinetics.A three-compartment linear disposition model best described the observed time-concentration profiles with additional compartments for metabolites. Population parameter estimates (between-subject variability) were central volume (V1) 21.5 (29%) l.70 kg(-1) , peripheral volumes of distribution V2 75.1 (23%) l.70 kg(-1) and V3 484 (8%) l.70 kg(-1) , clearance (CL) 9.45 (11%) l·h(-1) .70 kg(-1) , and intercompartment clearances Q2 325 (21%) l·h(-1) .70 kg(-1) and Q3 136 (14%) l·h(-1) .70 kg(-1) . EDDP formation clearance was 9.1 (11%) l·h(-1) .70 kg(-1) , formation clearance of EMDP from EDDP 7.4 (63%) l·h(-1) .70 kg(-1) , elimination clearance of EDDP was 40.9 (26%) l·h(-1) .70 kg(-1) and the rate constant for intermediate compartments 2.17 (43%) h(-1) .Current pharmacokinetic parameter estimates in children and neonates are similar to those reported in adults. There was no clearance maturation with age. Neonatal enantiomer clearances were similar to those described in adults. A regimen of 0.2 mg·kg(-1) per 8 h in neonates achieves a target concentration of 0.06 mg·l(-1) within 36 h. Infusion, rather than intermittent dosing, should be considered if this target is to be achieved in older children after cardiac surgery.

  View details for DOI 10.1111/pan.12385

  View details for Web of Science ID 000335753700007

  View details for PubMedID 24666686

  View details for PubMedCentralID PMC4016164

• Pharmacokinetics of prophylactic cefazolin in parturients undergoing cesarean delivery. Antimicrobial agents and chemotherapy Elkomy, M. H., Sultan, P., Drover, D. R., Epshtein, E., Galinkin, J. L., Carvalho, B. 2014; 58 (6): 3504-3513

  Abstract

  The objectives of this work were (i) to characterize the pharmacokinetics of cefazolin in pregnant women undergoing elective cesarean delivery and in their neonates; (ii) to assess cefazolin transplacental transmission; (iii) to evaluate the dosing and timing of preoperative, prophylactic administration of cefazolin to pregnant women; and (iv) to investigate the impact of maternal dosing on therapeutic duration and exposure in newborns. Twenty women received 1 g of cefazolin preoperatively. Plasma concentrations of total cefazolin were analyzed from maternal blood samples taken before, during, and after delivery; umbilical cord blood samples obtained at delivery; and neonatal blood samples collected 24 h after birth. The distribution volume of cefazolin was 9.44 liters/h. The values for pre- and postdelivery clearance were 7.18 and 4.12 liters/h, respectively. Computer simulations revealed that the probability of maintaining free cefazolin concentrations in plasma above 8 mg/liter during scheduled caesarean surgery was <50% in the cord blood when cefazolin was administered in doses of <2 g or when it was administered <1 h before delivery. Therapeutic concentrations of cefazolin persisted in neonates >5 h after birth. Cefazolin clearance increases during pregnancy, and larger doses are recommended for surgical prophylaxis in pregnant women to obtain the same antibacterial effect as in nonpregnant patients. Cefazolin has a longer half-life in neonates than in adults. Maternal administration of up to 2 g of cefazolin is effective and produces exposure within clinically approved limits in neonates.

  View details for DOI 10.1128/AAC.02613-13

  View details for PubMedID 24733461

• The effects of ketamine on dexmedetomidine-induced electrophysiologic changes in children. Paediatric anaesthesia Char, D., Drover, D. R., Motonaga, K. S., Gupta, S., Miyake, C. Y., Dubin, A. M., Hammer, G. B. 2013; 23 (10): 898-905

  Abstract

  BACKGROUND: Dexmedetomidine is an alpha2-adrenergic agonist used for sedation and analgesia in children. We previously showed that dexmedetomidine depresses sinus and AV nodal function resulting in adverse hemodynamic effects such as bradycardia and increased blood pressure. We hypothesized that these effects of dexmedetomidine might be antagonized by co-administration of ketamine, which has sympathomimetic properties. METHODS: Twenty-two children (ages 5-17 years) undergoing electrophysiologic (EP) study and ablation for supraventricular tachycardia were enrolled. Patients were kept sedated with continuous infusion of propofol at a fixed rate. Hemodynamic and EP parameters were measured before and after a loading dose of dexmedetomidine (1 μg·kg(-1) ). A continuous infusion of dexmedetomidine (0.7 μg·kg(-1) ·h(-1) ) was initiated and a ketamine loading dose (1 mg·kg(-1) ), followed by continuous infusion (1 mg·kg(-1) ·h(-1) ), was given. A repeat set of hemodynamic and EP parameters were then measured at the time of projected peak tissue concentration for both drugs. RESULTS: A significant increase in mean arterial pressure (MAP) was seen compared with baseline after loading of dexmedetomidine. This returned to baseline after co-administration of ketamine (mean difference between baseline and after ketamine 1.8 mmHg; 95%CI, -7.8 to 4.3; P = <0.001). A decrease in heart rate was seen after dexmedetomidine followed by a return to baseline after co-administration of ketamine (mean difference between baseline and after ketamine -6.5 bpm; 95%CI, -11.2 to -1.8; P = 0.005). Sinus node recovery time was lengthened after dexmedetomidine but returned to baseline after ketamine (mean difference between baseline and after ketamine -16.2 ms; 95%CI, -63 to 30; P = 0.014). QT was prolonged after dexmedetomidine and returned to baseline after ketamine (mean difference between baseline and after ketamine -34.2 ms; 95%CI, -48.4 to -20.2; P = 0.004). AV nodal effective refractory period was also impaired after dexmedetomidine and showed weak evidence for return to baseline function after ketamine (mean difference between baseline and after ketamine -22.8 ms; 95%CI, -40.2 to -5.2; P = 0.069). CONCLUSION: The concurrent use of ketamine may mitigate the negative chronotropic effects of dexmedetomidine.

  View details for DOI 10.1111/pan.12143

  View details for PubMedID 23506472

• Comparison of a New Cobinamide-Based Method to a Standard Laboratory Method for Measuring Cyanide in Human Blood JOURNAL OF ANALYTICAL TOXICOLOGY Swezey, R., Shinn, W., Green, C., Drover, D. R., Hammer, G. B., Schulman, S. R., Zajicek, A., Jett, D. A., Boss, G. R. 2013; 37 (6): 382-385

  Abstract

  Most hospital laboratories do not measure blood cyanide concentrations, and samples must be sent to reference laboratories. A simple method is needed for measuring cyanide in hospitals. The authors previously developed a method to quantify cyanide based on the high binding affinity of the vitamin B12 analog, cobinamide, for cyanide and a major spectral change observed for cyanide-bound cobinamide. This method is now validated in human blood, and the findings include a mean inter-assay accuracy of 99.1%, precision of 8.75% and a lower limit of quantification of 3.27 µM cyanide. The method was applied to blood samples from children treated with sodium nitroprusside and it yielded measurable results in 88 of 172 samples (51%), whereas the reference laboratory yielded results in only 19 samples (11%). In all 19 samples, the cobinamide-based method also yielded measurable results. The two methods showed reasonable agreement when analyzed by linear regression, but not when analyzed by a standard error of the estimate or paired t-test. Differences in results between the two methods may be because samples were assayed at different times on different sample types. The cobinamide-based method is applicable to human blood, and can be used in hospital laboratories and emergency rooms.

  View details for DOI 10.1093/jat/bkt037

  View details for Web of Science ID 000321456900010

  View details for PubMedID 23653045

  View details for PubMedCentralID PMC3708715

• Sodium nitroprusside is not associated with metabolic acidosis during intraoperative infusion in children BMC ANESTHESIOLOGY Hammer, G. B., Connolly, S. G., Schulman, S. R., Lewandowski, A., Cohane, C., Reece, T. L., Anand, R., Mitchell, J., Drover, D. R. 2013; 13

  Abstract

  Sodium nitroprusside (SNP) is a potent vasodilator that has been used to induce deliberate hypotension in children during surgery involving significant blood loss, including craniofacial and spinal fusion procedures. SNP metabolism liberates cyanide, which may cause interference with cellular energy metabolism, leading to metabolic acidosis and central nervous system injury. We performed a retrospective, case-control study to determine whether the short-term intra-operative use of SNP for deliberate hypotension is associated with metabolic acidosis in children undergoing surgical procedures for craniofacial or spinal anomalies. Cyanide and thiocyanate concentrations were also recorded in patients who received SNP.Data from 166 children undergoing craniofacial and spinal fusion surgery between 2005 and 2010 at Lucile Packard Children's Hospital (LPCH) at Stanford were analyzed. Records from 60 patients who received SNP (SNP group) as part of a multicenter, randomized, double-blind study were compared with records from 106 eligible patients who had blood pressure reduction using anesthetic agents and did not receive SNP (control group). Metabolic acidosis was defined as serum bicarbonate (HCO3) < 18.5 mEq/L. Whole blood CN, plasma thiocyanate and urinary thiocyanate concentrations were measured in patients in the SNP group. Differences in metabolic acidosis rates between the SNP and control groups were assessed through a test of noninferiority in the rate for the SNP group with a noninferiority threshold of 0.2. A z-test was used to test the null hypothesis. The alternative hypothesis was that the difference in these rates was less than 0.2. The same noninferiority threshold of 0.2 was also used to perform separate, secondary tests for noninferiority in the proportion of patients with HCO3 levels below 18.5 mEq/L and the proportion of patients who required HCO3 administration.Fewer patients in the SNP group experienced metabolic acidosis compared to the control group (31.7% vs. 36.8%, respectively; p < .001). No whole blood CN levels above the lower limit of quantification were detected in any of the 51 patients with validated CN data. Plasma and urinary thiocyanate levels were also low.Our findings suggest that SNP, when used for short-term deliberate hypotension, does not cause an increased incidence of metabolic acidosis compared with the use of anesthetic agents alone.Trial registration number: NCT00135668.

  View details for DOI 10.1186/1471-2253-13-9

  View details for Web of Science ID 000318602200001

  View details for PubMedID 23631460

  View details for PubMedCentralID PMC3648371

• Aversive and Reinforcing Opioid Effects A Pharmacogenomic Twin Study ANESTHESIOLOGY Angst, M. S., Lazzeroni, L. C., Phillips, N. G., Drover, D. R., Tingle, M., Ray, A., Swan, G. E., Clark, J. D. 2012; 117 (1): 22-37

  Abstract

  The clinical utility of opioids is limited by adverse drug effects including respiratory depression, sedation, nausea, and pruritus. In addition, abuse of prescription opioids is problematic. Gaining a better understanding of the genetic and environmental mechanisms contributing to an individual's susceptibility to adverse opioid effects is essential to identify patients at risk.A classic twin study paradigm provided estimates for the genetic and familial (genetic and/or shared environment) contribution to acute adverse and affective opioid responses, all secondary outcomes of a larger dataset. One hundred twenty-one twin pairs were recruited in a single occasion, randomized, double-blind, and placebo-controlled study. The μ-opioid receptor agonist alfentanil and saline placebo were administered as target-controlled infusions under carefully monitored laboratory conditions. Measured outcomes included respiratory depression, sedation, nausea, pruritus, drug liking, and drug disliking. Demographic information was collected, and aspects of mood and sleep were evaluated.Significant heritability was detected for respiratory depression (30%), nausea (59%), and drug disliking (36%). Significant familial effects were detected for sedation (29%), pruritus (38%), dizziness (32%), and drug liking (26%). Significant covariates included age, sex, race, ethnicity, education, mood, and depression. Covariates affected sedation, pruritus, drug liking and disliking, and dizziness.This study demonstrates that large-scale efforts to collect quantitative and well-defined opioid response data are not only feasible but also produce data that are suitable for genetic analysis. Genetic, environmental, and demographic factors work together to control adverse and reinforcing opioid responses, but contribute differently to specific responses.

  View details for PubMedID 22713632

• Pain sensitivity and opioid analgesia: A pharmacogenomic twin study PAIN Angst, M. S., Phillips, N. G., Drover, D. R., Tingle, M., Ray, A., Swan, G. E., Lazzeroni, L. C., Clark, J. D. 2012; 153 (7): 1397-1409

  Abstract

  Opioids are the cornerstone medication for the management of moderate to severe pain. Unfortunately, vast inter-individual differences in dose requirements complicate their effective and safe clinical use. Mechanisms underlying such differences are incompletely understood, are likely multifactorial, and include genetic and environmental contributions. While accumulating evidence suggests that variants of several genes account for some of the observed response variance, the relative contribution of these factors remains unknown. This study used a twin paradigm to provide a global estimate of the genetic and environmental contributions to inter-individual differences in pain sensitivity and analgesic opioid effects. Eighty one monozygotic and 31 dizygotic twin pairs successfully underwent a computer-controlled infusion with the μ-opioid agonist alfentanil in a single occasion, randomized, double-blind and placebo-controlled study design. Pain sensitivity and analgesic effects were assessed with experimental heat and cold pressor pain models along with important covariates including demographic factors, depression, anxiety, and sleep quality. Significant heritability was detected for cold pressor pain tolerance and opioid-mediated elevations in heat and cold pressor pain thresholds. Genetic effects accounted for 12-60% of the observed response variance. Significant familial effects accounting for 24-32% of observed variance were detected for heat and cold pressor pain thresholds and opioid-mediated elevation in cold pressor pain tolerance. Significant covariates included age, gender, race, education, and anxiety. Results provide a strong rationale for more detailed molecular genetic studies to elucidate mechanisms underlying inter-individual differences in pain sensitivity and analgesic opioid responses. Such studies will require careful consideration of the studied pain phenotype.

  View details for DOI 10.1016/j.pain.2012.02.022

  View details for PubMedID 22444188

• The Pharmacokinetics of Ketorolac After Single Postoperative Intranasal Administration in Adolescent Patients ANESTHESIA AND ANALGESIA Drover, D. R., Hammer, G. B., Anderson, B. J. 2012; 114 (6): 1270-1276

  Abstract

  Ketorolac tromethamine (ketorolac) administration reduces postoperative opioid requirements. The pharmacokinetic characteristics of intranasal ketorolac tromethamine in children have not been characterized. Our objective of this study was to determine the pharmacokinetics of a single intranasal dose of ketorolac in adolescent patients.Twenty surgical patients, ages 12 to 17 years, were enrolled. After surgery, subjects received intranasal ketorolac 15 mg (weight ≤50 kg) or 30 mg (weight >50 kg) using a proprietary administration system. Blood samples were obtained for ketorolac assay at baseline (within 15 minutes before the dose) and at 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 hours after the dose. A population analysis was undertaken using nonlinear mixed-effects models. Parameter estimates were standardized to a 70-kg person.The intranasal dosing in adolescents was well tolerated with minimal adverse effects. A 1-compartment model with first-order absorption and elimination was satisfactory to describe time-concentration profiles. Population parameter estimates (between subject variability) were clearance (CL/F) 2.05 L/h (60.5%), volume of distribution (V/F) 15.2 L (32.4%), absorption half-life (t(1/2)abs) 0.173 hour (25.0%). Time to peak concentration (Tmax) was 52 minutes (SD 6 minutes).Administration of ketorolac by the intranasal route resulted in a rapid increase in plasma concentration and may be a useful therapeutic alternative to IV injection in adolescents because plasma concentrations attained with the device are likely to be analgesic (investigational new drug no. 62,829).

  View details for DOI 10.1213/ANE.06013e31824f92c2

  View details for PubMedID 22467894

• Sodium Nitroprusside Is Not Associated with Metabolic Acidosis During Intraoperative Infusion in Children Hammer, G., Drover, D., Connolly, S., Cohane, C., Schulman, S. OXFORD UNIV PRESS. 2012: 293

  View details for Web of Science ID 000302299100491

• Intrathecal fentanyl added to bupivacaine and morphine for cesarean delivery may induce a subtle acute opioid tolerance INTERNATIONAL JOURNAL OF OBSTETRIC ANESTHESIA Carvalho, B., Drover, D. R., Ginosar, Y., Cohen, S. E., Riley, E. T. 2012; 21 (1): 29-34

  Abstract

  Previous studies have demonstrated that the addition of intrathecal fentanyl to a spinal anesthetic for cesarean delivery improves intraoperative analgesia. However, intrathecal fentanyl may induce acute tolerance to opioids. The objective of this study was to investigate whether the addition of intrathecal fentanyl to spinal anesthesia with intrathecal morphine increases postoperative analgesic requirements and pain scores.In this randomized, double-blinded study, 40 women having elective cesarean delivery were enrolled. Patients received spinal anesthesia with hyperbaric bupivacaine 12 mg, morphine 200 μg, and fentanyl 0, 5, 10 or 25 μg. Each patient received intravenous patient-controlled analgesia morphine for 24h postoperatively. Outcome measures included postoperative morphine usage and pain scores, as well as intraoperative pain, nausea, hypotension and vasopressor use.Total morphine use over the 24-h post-spinal study period was similar among the study groups (P=0.129). Postoperative pain scores were higher in patients receiving fentanyl 5, 10 and 25 μg compared to fentanyl 0 μg control group (P=0.003).The study results suggest that intrathecal fentanyl may induce acute tolerance to intrathecal morphine. However, because there was no difference in postoperative analgesia requirement and the difference in pain scores was small, the clinical significance of this finding is uncertain.

  View details for DOI 10.1016/j.ijoa.2011.09.002

  View details for Web of Science ID 000301325800006

  View details for PubMedID 22100823

• Intrathecal Dosing for Cesarean Delivery in Obese and Nonobese Patients Reply ANESTHESIOLOGY Carvalho, B., Drover, D. R., Collins, J. 2011; 115 (4): 900-900

  View details for DOI 10.1097/ALN.0b013e31822c656b

  View details for Web of Science ID 000295079500033

• Comparative clinical effects of hydromorphone and morphine: a meta-analysis BRITISH JOURNAL OF ANAESTHESIA Felden, L., Walter, C., Harder, S., Treede, R., Kayser, H., Drover, D., Geisslinger, G., Loetsch, J. 2011; 107 (3): 319-328

  Abstract

  We have conducted a meta-analysis of the clinical effects of morphine and hydromorphone to compare their benefit in analgesia. Embase and Medline were searched with an end-date of June 2009 for randomized, controlled trials or observational studies that addressed comparative analgesic and side-effects or particular side-effects. Two researchers independently identified included studies and extracted the data. Estimates of opioid effects were combined by using a random-effects model. Meta-analysis of eight studies suggested that hydromorphone (494 patients) provides slightly better (P=0.012) clinical analgesia than morphine (510 patients). The effect-size was small (Cohen's d=0.266) and disappeared when one study was removed, although the advantage of hydromorphone was more evident in studies of better quality (Jadad's rating). Side-effects were similar, for example, nausea (P=0.383, nine studies, 456 patients receiving hydromorphone and 460 morphine); vomiting (P=0.306, six studies, 246 patients receiving hydromorphone and 239 morphine); or itching (P=0.249, eight studies, 405 patients receiving hydromorphone, 410 morphine). This suggests some advantage of hydromorphone over morphine for analgesia. Additional potential clinical pharmacological advantages with regard to side-effects, such as safety in renal failure or during acute analgesia titration, are based on limited evidence and require substantiation by further studies.

  View details for DOI 10.1093/bja/aer232

  View details for Web of Science ID 000293910400005

  View details for PubMedID 21841049

• Prior epidural lidocaine alters the pharmacokinetics and drug effects of extended-release epidural morphine (DepoDur®) after cesarean delivery. Anesthesia and analgesia Atkinson Ralls, L., Drover, D. R., Clavijo, C. F., Carvalho, B. 2011; 113 (2): 251-258

  Abstract

  A potential physicochemical interaction between epidural local anesthetics and extended-release epidural morphine (EREM) could negate the sustained release. In this study, we sought to determine the pharmacokinetic and drug effects of prior epidural lidocaine administration on EREM.Thirty healthy women undergoing cesarean delivery were enrolled in this randomized study. Patients received 8 mg EREM 1 hour after either a combined spinal-epidural (intrathecal bupivacaine and fentanyl 20 μg with no epidural medication; group SE) or an epidural anesthetic (epidural 2% lidocaine with fentanyl 100 μg; group E). Maximal concentration (Cmax), time to Cmax (Tmax), and AUC(0-last) (area under the concentration-time curve until the last plasma concentration that was below the limit of quantitation) for morphine levels were determined from a plasma sample at 0, 5, 10, 15, and 30 minutes, and 1, 4, 8, 12, 24, 36, 48, and 72 hours. Drug effects including pain, analgesic use, and side effects were measured for 72 hours after cesarean delivery.Epidural lidocaine administration (20-35 mL) 1 hour before epidural EREM administration increased the Cmax in group E (11.1 ± 4.9) compared with group SE (8.3 ± 7.1 ng/mL) (P = 0.038). There were no significant effects on Tmax and AUC(0-last) of venous morphine between the groups (P > 0.05). There was an increased incidence in vomiting, oxygen use, and hypotension in group E (patients who received lidocaine before EREM).A large dose of epidural lidocaine 1 hour before EREM administration alters the pharmacokinetics and drug effects of EREM. Clinicians must apply caution when EREM is administered even 1 hour after an epidural lidocaine "top-up" for cesarean delivery.

  View details for DOI 10.1213/ANE.0b013e318222f59c

  View details for PubMedID 21642610

• Prior Epidural Lidocaine Alters the Pharmacokinetics and Drug Effects of Extended-Release Epidural Morphine (DepoDur (R)) After Cesarean Delivery ANESTHESIA AND ANALGESIA Ralls, L. A., Drover, D. R., Clavijo, C. F., Carvalho, B. 2011; 113 (2): 251-258

  Abstract

  A potential physicochemical interaction between epidural local anesthetics and extended-release epidural morphine (EREM) could negate the sustained release. In this study, we sought to determine the pharmacokinetic and drug effects of prior epidural lidocaine administration on EREM.Thirty healthy women undergoing cesarean delivery were enrolled in this randomized study. Patients received 8 mg EREM 1 hour after either a combined spinal-epidural (intrathecal bupivacaine and fentanyl 20 μg with no epidural medication; group SE) or an epidural anesthetic (epidural 2% lidocaine with fentanyl 100 μg; group E). Maximal concentration (Cmax), time to Cmax (Tmax), and AUC(0-last) (area under the concentration-time curve until the last plasma concentration that was below the limit of quantitation) for morphine levels were determined from a plasma sample at 0, 5, 10, 15, and 30 minutes, and 1, 4, 8, 12, 24, 36, 48, and 72 hours. Drug effects including pain, analgesic use, and side effects were measured for 72 hours after cesarean delivery.Epidural lidocaine administration (20-35 mL) 1 hour before epidural EREM administration increased the Cmax in group E (11.1 ± 4.9) compared with group SE (8.3 ± 7.1 ng/mL) (P = 0.038). There were no significant effects on Tmax and AUC(0-last) of venous morphine between the groups (P > 0.05). There was an increased incidence in vomiting, oxygen use, and hypotension in group E (patients who received lidocaine before EREM).A large dose of epidural lidocaine 1 hour before EREM administration alters the pharmacokinetics and drug effects of EREM. Clinicians must apply caution when EREM is administered even 1 hour after an epidural lidocaine "top-up" for cesarean delivery.

  View details for DOI 10.1213/ANE.0b013e318222f59c

  View details for Web of Science ID 000293064500009

• TITRATION OF SEVOFLURANE IN ELDERLY PATIENTS: BLINDED, RANDOMIZED CLINICAL TRIAL, IN NON-CARDIAC SURGERY AFTER BETA-ADRENERGIC BLOCKADE JOURNAL OF CLINICAL MONITORING AND COMPUTING Drover, D. R., Schmiesing, C., Buchin, A. F., Ortega, H. R., Tanner, J. W., Atkins, J. H., Macario, A. 2011; 25 (3): 175-181

  Abstract

  Monitoring depth of anesthesia via the processed electroencephalogram (EEG) has been found useful in reducing the amount of anesthetic drugs, optimizing wake-up times, and, in some studies, reducing awareness. Our goal was to determine if titrating sevoflurane as the maintenance anesthetic to a depth of anesthesia monitor (SEDLine™, Masimo, CA) would shorten time to extubation in elderly patients undergoing non-cardiac surgery while on beta-adrenergic blockade. This patient population was selected because the usual cardiovascular signs of inadequate general anesthesia may be masked by beta-blocker therapy.Surgical patients older than 65 years of age receiving beta-adrenergic blockers for a minimum of 24 h preoperatively were randomized to two groups: a group whose titration of sevoflurane was based on SEDLine™ data (SEDLine™ group) and a group whose titration was based on usual clinical criteria (control group) where SEDLine™ data were concealed. The primary endpoint was time from skin closure to time to extubation. Aldrete score, White Fast Track score and QoR-40 were also assessed.There was no significant difference in time to extubation [12.5 (SD 7.4) min in the control group versus 13.0 (SD 5.9) min for the treatment group]. The control group used more fentanyl [339 mcg (SD 205)] than did the treatment group [238 mcg (SD 123)] (P<0.02). There was no difference in sevoflurane utilization, Aldrete, White Fast Track scores, time to PACU discharge, or QoR-40 assessments between the groups.Use of the SEDLine™ monitor's data to titrate sevoflurane did not improve the time to extubation or change short-term outcome of geriatric surgical patients receiving beta-adrenergic blockers. (ClinicalTrials.gov number, NCT00938782).

  View details for DOI 10.1007/s10877-011-9293-1

  View details for PubMedID 21830049

• A sensitive assay for the quantification of morphine and its active metabolites in human plasma and dried blood spots using high-performance liquid chromatography-tandem mass spectrometry ANALYTICAL AND BIOANALYTICAL CHEMISTRY Clavijo, C. F., Hoffman, K. L., Thomas, J. J., Carvalho, B., Chu, L. F., Drover, D. R., Hammer, G. B., Christians, U., Galinkin, J. L. 2011; 400 (3): 715-728

  Abstract

  Opioids such as morphine are the cornerstone of pain treatment. The challenge of measuring the concentrations of morphine and its active metabolites in order to assess human pharmacokinetics and monitor therapeutic drugs in children requires assays with high sensitivity in small blood volumes. We developed and validated a semi-automated LC-MS/MS assay for the simultaneous quantification of morphine and its active metabolites morphine 3β-glucuronide (M3G) and morphine 6β-glucuronide (M6G) in human plasma and in dried blood spots (DBS). Reconstitution in water (DBS only) and addition of a protein precipitation solution containing the internal standards were the only manual steps. Morphine and its metabolites were separated on a Kinetex 2.6-μm PFP analytical column using an acetonitrile/0.1% formic acid gradient. The analytes were detected in the positive multiple reaction mode. In plasma, the assay had the following performance characteristics: range of reliable response of 0.25-1000 ng/mL (r(2) > 0.99) for morphine, 1-1,000 ng/mL (r(2) > 0.99) for M3G, and 2.5-1,000 ng/mL for M6G. In DBS, the assay had a range of reliable response of 1-1,000 ng/mL (r(2) > 0.99) for morphine and M3G, and of 2.5-1,000 ng/mL for M6G. For inter-day accuracy and precision for morphine, M3G and M6G were within 15% of the nominal values in both plasma and DBS. There was no carryover, ion suppression, or matrix interferences. The assay fulfilled all predefined acceptance criteria, and its sensitivity using DBS samples was adequate for the measurement of pediatric pharmacokinetic samples using a small blood of only 20-50 μL.

  View details for DOI 10.1007/s00216-011-4775-z

  View details for Web of Science ID 000289297000015

  View details for PubMedID 21400080

• The effectiveness of preemptive sphenopalatine ganglion block on postoperative pain and functional outcomes after functional endoscopic sinus surgery 56th Annual Fall Scientific Meeting of the American-Rhinologic-Society (ARS) Cho, D., Drover, D. R., Nekhendzy, V., Butwick, A. J., Collins, J., Hwang, P. H. WILEY-BLACKWELL. 2011: 212–18

  Abstract

  The sphenopalatine ganglion block (SPGB) with local anesthetic is used to treat facial pain and headache of various etiologies; it has been widely used during functional endoscopic sinus surgery (FESS). The purpose of this study was to investigate whether preemptive SPGB may positively impact postoperative pain and functional outcomes after FESS.A prospective, double-blind, randomized, placebo-controlled study was performed. A total of 60 patients (18-70 years), undergoing general anesthesia for bilateral FESS, were randomly assigned to receive SPGB with either 2 mL 0.25% bupivacaine with epinephrine 1:100,000 (BP, treatment group) or normal saline (NS, control group). SPGB was performed preemptively 10 minutes before the start of surgery. Preoperative and postoperative (day 0, day 7, and day 30) visual analog pain scale, Sino-Nasal Outcome Test (SNOT-20), computed tomography (CT) and endoscopic scores were compared between the 2 groups.A total of 29 patients were enrolled in BP, and 27 were enrolled in NS. Three patients withdrew from the study, and 1 was withdrawn by the investigator due to severe hypertension after induction of anesthesia. There were no differences in patient demographic characteristics between the study groups. On day 7, the mean visual analog pain scales were 1.12 ± 0.3 in NS and 0.48 ± 0.23 in BP (p = 0.053). There were no statistical differences in other outcome measures (SNOT-20, CT and endoscopic scores) between the 2 groups.A limited trend toward reduced postoperative pain after FESS was noted with bupivacaine compared to saline, but statistical significance was not achieved. Preemptive SPGB may offer sinonasal symptomatic benefits for patients undergoing FESS, but larger studies are warranted.

  View details for DOI 10.1002/alr.20040

  View details for PubMedID 22287376

• ED50 and ED95 of Intrathecal Bupivacaine in Morbidly Obese Patients Undergoing Cesarean Delivery ANESTHESIOLOGY Carvalho, B., Collins, J., Drover, D. R., Ralls, L. A., Riley, E. T. 2011; 114 (3): 529-535

  Abstract

  It has been suggested that morbidly obese parturients may require less local anesthetic for spinal anesthesia. The aim of this study was to determine the effective dose (ED(50)/ED(95)) of intrathecal bupivacaine for cesarean delivery in morbidly obese patients.Morbidly obese parturients (body mass index equal to or more than 40) undergoing elective cesarean delivery were enrolled in this double-blinded study. Forty-two patients were randomly assigned to receive intrathecal hyperbaric bupivacaine in doses of 5, 6, 7, 8, 9, 10, or 11 mg (n = 6 per group) coadministered with 200 μg morphine and 10 μg fentanyl. Success (induction) was defined as block height to pinprick equal to or more than T6 and success (operation) as success (induction) plus no requirement for epidural supplementation throughout surgery. The ED(50)/ED(95) values were determined using a logistic regression model.ED(50) and ED(95) (with 95% confidence intervals) for success (operation) were 9.8 (8.6-11.0) and 15.0 (10.0-20.0), respectively, and were similar to corresponding values of a nonobese population determined previously using similar methodology. We were unable to measure ED(50)/ED(95) values for success (induction) because so few blocks failed initially, even at the low-dose range. There were no differences with regard to secondary outcomes (i.e., hypotension, vasopressor use, nausea, and vomiting).Obese and nonobese patients undergoing cesarean delivery do not appear to respond differently to modest doses of intrathecal bupivacaine. This dose-response study suggests that doses of intrathecal bupivacaine less than 10 mg may not adequately ensure successful intraoperative anesthesia. Even when the initial block obtained with a low dose is satisfactory, it will not guarantee adequate anesthesia throughout surgery.

  View details for DOI 10.1097/ALN.0b013e318209a92d

  View details for PubMedID 21307769

• Morphine and its metabolites after patient-controlled analgesia: considerations for respiratory depression JOURNAL OF CLINICAL ANESTHESIA Sam, W. J., Mackey, S. C., Loetsch, J., Drover, D. R. 2011; 23 (2): 102-106

  Abstract

  To assess concentrations of morphine and its metabolites after patient-controlled analgesia (PCA).Pilot pharmacokinetic study of morphine and pharmacokinetic simulation.Post-anesthesia care room and ward of an academic teaching hospital.10 ASA physical status I, II, and III postoperative surgical patients.Patients received morphine via PCA by routine hospital protocols.The population mean plasma and effect-site concentrations of morphine, morphine-6-glucuronide (M6G), and morphine-3-glucuronide (M3G) was simulated in 4 patient group scenarios: morphine PCA used alone, morphine PCA used with continuous background morphine infusion of 0.5 mg/hr, morphine PCA used with continuous background morphine infusion of 1.0 mg/hr, and morphine PCA used with continuous background morphine infusion of 2.0 mg/hr.The 4 groups exhibited simulated peak morphine, M6G, and M3G effect-site concentrations at 8 to 24 hours post-infusion. The highest peak morphine, M6G, and M3G effect-site concentrations decreased in the following order by group: 2.0 mg/hr morphine infusion + PCA group, 1.0 mg/hr morphine infusion + PCA group, and 0.5. mg/hr morphine infusion + PCA group.Patients receiving morphine PCA should be monitored closely from 8 to 24 hours postoperatively. Morphine PCA given with background infusion rates up to 1.0 mg/hr does not offer distinct pharmacokinetic advantages over morphine PCA alone. Morphine PCA with background infusion rate of 2.0 mg/hr is associated with the greatest risk of respiratory depression.

  View details for DOI 10.1016/j.jclinane.2010.08.002

  View details for PubMedID 21377072

• Efficacy, Safety, and Pharmacokinetics of Sugammadex for the Reversal of Rocuronium-induced Neuromuscular Blockade in Elderly Patients ANESTHESIOLOGY McDonagh, D. L., Benedict, P. E., Kovac, A. L., Drover, D. R., Brister, N. W., Morte, J. B., Monk, T. G. 2011; 114 (2): 318-329

  Abstract

  The management of elderly patients can be challenging for anesthesiologists for many reasons, including altered pharmacokinetics and dynamics. This study compared the efficacy, safety, and pharmacokinetics of sugammadex for moderate rocuronium-induced neuromuscular blockade reversal in adult (aged 18-64 yr) versus elderly adult (aged 65 yr or older) patients.This phase 3a, multicenter, parallel-group, comparative, open-label study enrolled 162 patients aged 18 yr and older, American Society of Anesthesiologists class 1-3, scheduled for surgery with general anesthesia and requiring neuromuscular blockade. After anesthesia induction, patients received rocuronium, 0.6 mg/kg, before tracheal intubation, with maintenance doses of 0.15 mg/kg as required. At the end of surgery, patients received sugammadex, 2.0 mg/kg, at reappearance of the second twitch of the train-of-four (TOF) for reversal. The primary efficacy variable was time from sugammadex administration to recovery of the TOF ratio to 0.9 or greater. Pharmacokinetics and safety were also evaluated.Overall, 150 patients were treated and had at least one postbaseline efficacy assessment; 48 were aged 18-64 yr (adult), 62 were aged 65-74 yr (elderly), and 40 were aged 75 yr or older (old-elderly). The geometric mean time (95% confidence interval) from sugammadex administration to recovery of the TOF ratio to 0.9 increased with age, from 2.3 (2.0-2.6) min (adults) to 2.9 (2.7-3.2) min (elderly/old-elderly groups combined). Recovery of the TOF ratio to 0.9 was estimated to be 0.7 min faster in adults compared with patients aged 65 yr or older (P = 0.022). Sugammadex was well tolerated by all patients.Sugammadex facilitates rapid reversal from moderate rocuronium-induced neuromuscular blockade in adults of all ages.

  View details for Web of Science ID 000286586200014

  View details for PubMedID 21239968

• Opioid Pharmacogenomics Using a Twin Study Paradigm: Methods and Procedures for Determining Familial Aggregation and Heritability TWIN RESEARCH AND HUMAN GENETICS Angst, M. S., Phillips, N. G., Drover, D. R., Tingle, M., Galinkin, J. L., Christians, U., Swan, G. E., Lazzeroni, L. C., Clark, J. D. 2010; 13 (5): 412-425

  Abstract

  Opioids are the cornerstone medication for the treatment of moderate to severe pain. However, analgesic opioid requirements and the propensity to suffer from aversive opioid effects, including fatal respiratory depression and addiction, vary widely among patients. The factors underlying the substantial response variance remain largely unknown and need clarification for using opioids more effectively in appropriately selected patients. This ongoing study takes advantage of the twin paradigm to estimate the genetic and environmental contributions to inter-individual differences in opioid responses. Evidence of significant heritability will justify more detailed and extensive genomic studies. The enrollment target is 80 monozygotic and 45 dizygotic twin pairs who undergo a target-controlled infusion of the opioid alfentanil and saline placebo in sequential but randomized order. In a laboratory-type setting, well-defined pharmacodynamic endpoints are measured to quantify pain sensitivity, analgesic opioid effects, and aversive opioid effects including respiratory depression, sedation and reinforcing affective responses. First results obtained in 159 participants provide evidence for the feasibility and utility of this interventional study paradigm to estimate familial aggregation and heritability components of relevant drug effects. Areas highlighted in this report include recruitment strategies, required infrastructure and personnel, selection of relevant outcome measures, drug infusion algorithm minimizing pharmacokinetic variability, and considerations for optimizing data quality and quantity without hampering feasibility. Applying the twin paradigm to complex and potentially harmful studies comprehensively characterizing pharmacological response profiles is without much precedent. Methods and first results including heritability estimates for heat and cold pain sensitivity should be of interest to investigators considering similar studies.

  View details for PubMedID 20874462

• SAS-BASED HEMODYNAMIC CONTROL CHARTS FOR THE MANAGEMENT OF NITROPRUSSIDE IN CHILDREN Dombrowsky, E. L., Jayaraman, B., Schulman, S. R., Hammer, G. B., Drover, D., Barrett, J. S. SAGE PUBLICATIONS INC. 2010: 1076

  View details for Web of Science ID 000281858000080

• Pharmacokinetic-pharmacodynamic modeling of the hypotensive effect of remifentanil in infants undergoing cranioplasty PEDIATRIC ANESTHESIA Standing, J. F., Hammer, G. B., Sam, W. J., Drover, D. R. 2010; 20 (1): 7-18

  Abstract

  Although remifentanil has been used to induce hypotension during surgery in infants, no pharmacokinetic-pharmacodynamic (PKPD) model exists for its quantitative analysis. Our aim was to determine the quantitative relationship between whole blood remifentanil concentration and its hypotensive effect during surgery in infants.We studied seven infants (age 0.3-1 year) who underwent cranioplasty surgery and received remifentanil delivered by a computer-controlled infusion pump during the maintenance of anesthesia. Arterial blood samples to determine remifentanil concentration and mean arterial blood pressure (MAP) measurements were collected. A simultaneous PKPD mixed-effects model was built in NONMEM.A total of 77 remifentanil concentrations and 185 MAP measurements were collected. Remifentanil pharmacokinetics was described with a two-compartment model, parameter estimates were 2.99 l x min(-1) x 70 kg(-1) for clearance and 16.23 l x 70 kg(-1) for steady state volume of distribution. Mean baseline MAP was 69.7 mmHg and was decreased as per clinical requirements. A sigmoidal E(max) model driven by an effect compartment described the decrease in MAP, with an estimated concentration to decrease MAP by half (EC(50)) being 17.1 ng x ml(-1).Remifentanil is effective in causing hypotension. The final model predicts that a steady state remifentanil concentration of 14 ng.ml(-1) would typically achieve a 30% decrease in MAP.

  View details for DOI 10.1111/j.1460-9592.2009.03174.x

  View details for Web of Science ID 000273525800002

  View details for PubMedID 19825011

• A POOR CORRELATION EXISTS BETWEEN OSCILLOMETRIC AND RADIAL ARTERIAL BLOOD PRESSURE AS MEASURED BY THE PHILIPS MP90 MONITOR JOURNAL OF CLINICAL MONITORING AND COMPUTING Mireles, S. A., Jaffe, R. A., Drover, D. R., Brock-Utne, J. G. 2009; 23 (3): 169-174

  Abstract

  In anesthesia and critical care, invasive arterial blood pressure monitoring is the gold standard against which other methods of monitoring are compared. In this assessment of the Philips MP90 monitor, the objective was to determine whether or not oscillometric measurements were within the accuracy standards set by the Association for the Advancement of Medical Instrumentation (AAMI) and the British Hypertension Society (BHS). Three hundred and one invasive and noninvasive paired measurements were obtained from eleven adult patients on the neurosurgical service at Stanford University Medical Center. Bland-Altman plots were created to assess agreement between the two measurement systems. Paired correlation analysis, bias and precision calculations were performed. Oscillometric blood pressure measurements correlated with arterial measurements yielding Pearson r values of 0.68, 0.67 and 0.62 for systolic, diastolic and mean pressures, respectively (P < 0.01.) Mean differences with 95% confidence intervals were -3.8 mmHg +/- 13.6, -2.4 mmHg +/- 10.0, and 4.0 mmHg +/- 13.1 for systolic, diastolic and mean pressures, respectively. The mean difference for these measurements was

  View details for DOI 10.1007/s10877-009-9178-8

  View details for PubMedID 19396553

• No evidence for the development of acute tolerance to analgesic, respiratory depressant and sedative opioid effects in humans PAIN Angst, M. S., Chu, L. F., Tingle, M. S., Shafer, S. L., Clark, J. D., Drover, D. R. 2009; 142 (1-2): 17-26

  Abstract

  It is widely accepted that chronic opioid therapy is associated with the development of pharmacological tolerance. More controversial is the question as to whether acute opioid administration can result in "acute tolerance." The aim of this double-blind, placebo-controlled study in thirty-six healthy human volunteers was to examine whether a 3-h intravenous infusion delivering two different but clinically relevant doses of the mu-opioid receptor agonist remifentanil would result in tolerance to analgesic, respiratory depressant and/or sedative opioid effects. The blood remifentanil concentration versus opioid effect relationship was determined before and after the 3-h infusion. Tolerance was inferred if the potency of remifentanil was significantly lower after the 3-h infusion. Opioid analgesia was assessed with the aid of the cold pressor test and models of electrical and heat pain. Respiratory depression was assessed by measuring arterial pCO2 and minute ventilation. Subjective sedation scores were assessed on a visual analogue scale. Mixed effects modeling was used to relate the steady-state blood remifentanil concentration to each pharmacodynamic assessment. Neither dose of remifentanil produced detectable tolerance to any of the measured opioid effects following a 3-h infusion. The study was adequately powered to detect a decrease in potency of 5-24% for analgesia, 20-48% for respiratory depression, and 32% for sedative effects. These results suggest that short-term administration of clinically useful doses of remifentanil is not associated with the development of significant tolerance to analgesic, respiratory depressant, or sedative opioid effects.

  View details for DOI 10.1016/j.pain.2008.11.001

  View details for PubMedID 19135798

• Determination of the pharmacodynamic interaction of propofol and dexmedetomidine during esophagogastroduodenoscopy in children PEDIATRIC ANESTHESIA Hammer, G. B., Sam, W. J., Chen, M. I., Golianu, B., Drover, D. R. 2009; 19 (2): 138-144

  Abstract

  Propofol is a sedative-hypnotic drug commonly used to anesthetize children undergoing esophagogastroduodenoscopy (EGD). Dexmedetomidine is a highly selective alpha-2 adrenergic receptor agonist that has been utilized in combination with propofol to provide anesthesia. There is currently no information regarding the effect of intravenous dexmedetomidine on the propofol plasma concentration-response relationship during EGD in children. This study aimed to investigate the pharmacodynamic interaction of propofol and dexmedetomidine when used in combination for children undergoing EGD.A total of 24 children undergoing EGD, ages 3-10 years, were enrolled in this study. Twelve children received dexmedetomidine 1 microg x kg(-1) given over 10 min as well as a continuous infusion of propofol delivered by a computer-assisted target-controlled infusion (TCI) system with target plasma concentrations ranging from 2.8 to 4.0 microg x ml(-1) (DEX group). Another group of 12 children undergoing EGD also received propofol administered by TCI targeting comparable plasma concentrations without dexmedetomidine (control group). We used logistic regression to predict plasma propofol concentrations at which 50% of the patients exhibited minimal response to stimuli (EC50 for anesthesia).The EC50 +/- SE values in the control and DEX groups were 3.7 +/- 0.4 microg x ml(-1) and 3.5 +/- 0.2 microg x ml(-1), respectively. There was no significant shift in the propofol concentration-response curve in the presence of dexmedetomidine.The EC50 of propofol required to produce adequate anesthesia for EGD in children was unaffected by a concomitant infusion of dexmedetomidine 1 microg x kg(-1) given over 10 min.

  View details for DOI 10.1111/j.1460-9592.2008.02823.x

  View details for PubMedID 19207899

• Population pharmacokinetics of remifentanil in infants and children undergoing cardiac surgery. BMC anesthesiology Sam, W. J., Hammer, G. B., Drover, D. R. 2009; 9: 5-?

  Abstract

  The aim of this study was to provide a model-based analysis of the pharmacokinetics of remifentanil in infants and children undergoing cardiac surgery with cardiopulmonary bypass (CPB).We studied nine patients aged 0.5 to 4 years who received a continuous remifentanil infusion via a computer-controlled infusion pump during cardiac surgery with mildly hypothermic CPB were studied. Arterial blood samples taken prior to, during and after CPB were analyzed for remifentanil concentrations using a validated gas-chromatographic mass-spectrophotometric assay. We used population mixed-effects modeling to characterize remifentanil pharmacokinetics. The final model was evaluated by its predictive performance.The pharmacokinetics of remifentanil was described by a 1-compartment model with adjustments for CPB. Population mean parameter estimates were 1.41 L for volume of distribution (V) and 0.244 L/min for clearance. V was increased during CPB and post-CPB to 2.41 times the pre-CPB value. The median prediction error and the median of individual median absolute prediction error were 2.44% and 21.6%, respectively.Remifentanil dosage adjustments are required during and after CPB due to marked changes in the V of the drug. Simulations indicate that a targeted blood concentration of 14 ng/mL is achieved and maintained in 50% of typical patients by administration of an initial dose of 18 mug remifentanil followed by an infusion of 3.7 mug/min before, during and post-CPB, supplemented with a bolus dose of 25 mug given at the start of CPB.

  View details for DOI 10.1186/1471-2253-9-5

  View details for PubMedID 19635151

• The effects of dexmedetomidine on cardiac electrophysiology in children ANESTHESIA AND ANALGESIA Hammer, G. B., Drover, D. R., Cao, H., Jackson, E., Williams, G. D., Ramamoorthy, C., Van Hare, G. F., Niksch, A., Dubin, A. M. 2008; 106 (1): 79-83

  Abstract

  Dexmedetomidine (DEX) is an alpha2-adrenergic agonist that is approved by the Food and Drug Administration for short-term (<24 h) sedation in adults. It is not approved for use in children. Nevertheless, the use of DEX for sedation and anesthesia in infants and children appears to be increasing. There are some concerns regarding the hemodynamic effects of the drug, including bradycardia, hypertension, and hypotension. No data regarding the effects of DEX on the cardiac conduction system are available. We therefore aimed to characterize the effects of DEX on cardiac conduction in pediatric patients.Twelve children between the ages of 5 and 17 yr undergoing electrophysiology study and ablation of supraventricular accessory pathways had hemodynamic and cardiac electrophysiologic variables measured before and during administration of DEX (1 microg/kg IV over 10 min followed by a 10-min continuous infusion of 0.7 microg x kg(-1) x h(-1)).Heart rate decreased while arterial blood pressure increased significantly after DEX administration. Sinus node function was significantly affected, as evidenced by an increase in sinus cycle length and sinus node recovery time. Atrioventricular nodal function was also depressed, as evidenced by Wenckeback cycle length prolongation and prolongation of PR interval.DEX significantly depressed sinus and atrioventricular nodal function in pediatric patients. Heart rate decreased and arterial blood pressure increased during administration of DEX. The use of DEX may not be desirable during electrophysiology study and may be associated with adverse effects in patients at risk for bradycardia or atrioventricular nodal block.

  View details for DOI 10.1213/01.ane.0000297421.92857.4e

  View details for PubMedID 18165557

• Pharmacokinetics And Pharmacodynamics Of Fenoldopam Mesylate For Blood Pressure Control In Pediatric Patients. BMC anesthesiology Hammer, G. B., Verghese, S. T., Drover, D. R., Yaster, M., Tobin, J. R. 2008; 8: 6-?

  Abstract

  Fenoldopam mesylate, a selective dopamine1-receptor agonist, is used by intravenous infusion to treat hypertension in adults. Fenoldopam is not approved by the FDA for use in children; reports describing its use in pediatrics are limited. In a multi-institutional, placebo controlled, double-blind, multi-dose trial we determined the pharmacokinetic (PK) and pharmacodynamic (PD) characteristics and side-effect profile of fenoldopam in children.Seventy seven (77) children from 3 weeks to 12 years of age scheduled for surgery in which deliberate hypotension would be induced were enrolled. Patients were randomly assigned to one of five, blinded treatment groups (placebo or fenoldopam 0.05, 0.2, 0.8, or 3.2 mcg/kg/min iv) for a 30-minute interval after stabilization of anesthesia and placement of vascular catheters. Following the 30-minute blinded interval, investigators adjusted the fenoldopam dose to achieve a target mean arterial pressure in the open-label period until deliberate hypotension was no longer indicated (e.g., muscle-layer closure). Mean arterial pressure and heart rate were continuously monitored and were the primary endpoints.Seventy-six children completed the trial. Fenoldopam at doses of 0.8 and 3.2 mcg/kg/min significantly reduced blood pressure (p < 0.05) during the blinded interval, and doses of 1.0-1.2 mcg/kg/min resulted in continued control of blood pressure during the open-label interval. Doses greater than 1.2 mcg/kg/min during the open-label period resulted in increasing heart rate without additional reduction in blood pressure. Fenoldopam was well-tolerated; side effects occurred in a minority of patients. The PK/PD relationship of fenoldopam in children was determined.Fenoldopam is a rapid-acting, effective agent for intravenous control of blood pressure in children. The effective dose range is significantly higher in children undergoing anesthesia and surgery (0.8-1.2 mcg/kg/min) than as labeled for adults (0.05-0.3 mcg/kg/min). The PK and side-effect profiles for children and adults are similar.

  View details for DOI 10.1186/1471-2253-8-6

  View details for PubMedID 18837982

• Randomized, dose-finding, Phase II study of the selective relaxant binding drug, sugammadex, capable of safely reversing profound rocuronium-induced neuromuscular block ANESTHESIA AND ANALGESIA Groudine, S. B., Soto, R., Lien, C., Drover, D., Roberts, K. 2007; 104 (3): 555-562

  Abstract

  The reversal of a deep neuromuscular blockade remains a significant clinical problem. Sugammadex, a modified gamma-cyclodextrin, encapsulates steroidal neuromuscular blocking drugs, promoting their rapid dissociation from nicotinic receptors. Sugammadex is the first drug that acts as a selective relaxant binding agent.We enrolled 50 patients into a Phase II dose-finding study of the efficacy and safety of sugammadex. Subjects, anesthetized with nitrous oxide and propofol, were randomized to one of two doses of rocuronium (0.6 or 1.2 mg/kg) and to one of five doses of sugammadex (0.5, 1.0, 2.0, 4.0, or 8.0 mg/kg). Neuromuscular monitoring was performed using the TOF Watch SX acceleromyograph. Recovery was defined as a train-of-four ratio > or =0.9. Sugammadex was administered during profound block when neuromuscular monitoring demonstrated a posttetanic count of one or two.Reversal of neuromuscular block was obtained after administration of sugammadex in all but the lowest dose groups (0.5-1.0 mg/kg) where several subjects could not be adequately reversed. At the 2 mg/kg dose all patients were reversed with sugammadex, but there was significant variability (1.8-15.2 min). Patient variability decreased and speed of recovery increased in a dose-dependent manner. At the highest dose (8 mg/kg), mean recovery time was 1.2 min (range 0.8-2.1 min). No serious adverse events were reported during this trial.Sugammadex was well tolerated and effective in rapidly reversing profound rocuronium-induced neuromuscular block. The mean time to recovery decreased with increasing doses. Profound rocuronium-induced neuromuscular block can be reversed successfully with sugammadex at doses >/=2 mg/kg.

  View details for DOI 10.1213/01.ane.00002601358.46070.c3

  View details for Web of Science ID 000244431500022

  View details for PubMedID 17312208

• Patient state index. Best practice & research. Clinical anaesthesiology Drover, D., ORTEGA, H. R. 2006; 20 (1): 121-128

  Abstract

  The patient state index (PSI) is a clinically validated measure of the effect of anaesthesia and sedation. The PSI is calculated via a proprietary algorithm by a high-resolution 4-channel electroencephalograph (EEG) monitor after advanced artifact rejection. The PSI has been designed specifically for intra-operative and intensive care use to monitor patient sedation and drug effect. The algorithm relies on EEG power, frequency and phase information from anterior-posterior relationships of the brain as well as coherence between bilateral brain regions. The EEG monitor, initially called the PSA4000, is also the SEDLine monitor, the newest generation of the device. The SEDLine system provides the clinician the option of storing and downloading patient data for future use as well as monitoring bilateral brain function and symmetry with a density spectral array (DSA) display.

  View details for PubMedID 16634419

• Pharmacology of drugs formulated with DepoFoaM (TM) - A sustained release drug delivery system for parenteral administration using multivesicular liposome technology CLINICAL PHARMACOKINETICS Angst, M. S., Drover, D. R. 2006; 45 (12): 1153-1176

  Abstract

  Lamellar liposome technology has been used for several decades to produce sustained-release drug formulations for parenteral administration. Multivesicular liposomes are structurally distinct from lamellar liposomes and consist of an aggregation of hundreds of water-filled polyhedral compartments separated by bi-layered lipid septa. The unique architecture of multivesicular liposomes allows encapsulating drug with greater efficiency, provides robust structural stability and ensures reliable, steady and prolonged drug release. The favourable characteristics of multivesicular liposomes have resulted in many drug formulations exploiting this technology, which is proprietary and referred to as DepoFoam. Currently, two formulations using multivesicular liposome technology are approved by the US FDA for clinical use, and many more formulations are at an experimental developmental stage. The first clinically available formulation contains the antineoplastic agent cytarabine (DepoCyt) for its intrathecal injection in the treatment of malignant lymphomatous meningitis. Intrathecal injection of DepoCyt reliably results in the sustained release of cytarabine and produces cytotoxic concentrations in cerebrospinal fluid (CSF) that are maintained for at least 2 weeks. Early efficacy data suggest that DepoCyt is fairly well tolerated, and its use allows reduced dosing frequency from twice a week to once every other week and may improve the outcome compared with frequent intrathecal injections of unencapsulated cytarabine. The second available formulation contains morphine (DepoDur) for its single epidural injection in the treatment of postoperative pain. While animal studies confirm that epidural injection of DepoDur results in the sustained release of morphine into CSF, the CSF pharmacokinetics have not been determined in humans. Clinical studies suggest that the use of DepoDur decreases the amount of systemically administered analgesics needed for adequate postoperative pain control. It may also provide superior pain control during the first 1-2 postoperative days compared with epidural administration of unencapsulated morphine or intravenous administration of an opioid. However, at this timepoint the overall clinical utility of DepoDur has yet to be defined and some safety concerns remain because of the unknown CSF pharmacokinetics of DepoDur in humans. The versatility of multivesicular liposome technology is reflected by the many agents including small inorganic and organic molecules and macromolecules including proteins that have successfully been encapsulated. Data concerning many experimental formulations containing antineoplastic, antibacterial and antiviral agents underscore the sustained, steady and reliable release of these compounds from multivesicular liposomes after injection by the intrathecal, subcutaneous, intramuscular, intraperitoneal and intraocular routes. Contingent on the specific formulation and manufacturing process, agents were released over a period of hours to weeks as reflected by a 2- to 400-fold increase in elimination half life. Published data further suggest that the encapsulation process preserves bioactivity of agents as delicate as proteins and supports the view that examined multivesicular liposomes were non-toxic at studied doses. The task ahead will be to examine whether the beneficial structural and pharmacokinetic properties of multivesicular liposome formulations will translate into improved clinical outcomes, either because of decreased drug toxicity or increased drug efficacy.

  View details for PubMedID 17112293

• The ED50 and ED95 of intrathecal isobaric bupivacaine with opioids for cesarean delivery ANESTHESIOLOGY Carvalho, B., Durbin, M., Drover, D. R., Cohen, S. E., Ginosar, Y., Riley, E. T. 2005; 103 (3): 606-612

  Abstract

  The ideal intrathecal isobaric bupivacaine dose for cesarean delivery anesthesia is uncertain. While small doses (5-9 mg) of bupivacaine may reduce side effects such as hypotension, they potentially increase spinal anesthetic failures. This study determined the ED50 and ED95 of intrathecal isobaric bupivacaine (with adjuvant opioids) for cesarean delivery.After institutional review board approval and written informed consent were obtained, 48 parturients undergoing elective cesarean delivery under combined spinal-epidural anesthesia were enrolled in this double-blind, randomized, dose-ranging study. Patients received a 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-mg intrathecal isobaric bupivacaine dose with 10 microg fentanyl and 200 microg morphine. Overall anesthetic success was recorded when no intraoperative epidural supplement was required during the cesarean delivery. ED50 and ED95 values for overall anesthetic success were determined using a logistic regression model.ED50 and ED95 values for overall anesthetic success were 7.25 and 13.0 mg, respectively. No advantages for low doses could be demonstrated with regard to hypotension, nausea, vomiting, pruritus, or maternal satisfaction, although this study was underpowered to detect significant differences in secondary outcome variables.The ED50 and ED95 values (7.25 and 13.0 mg, respectively) for intrathecal isobaric bupivacaine in this circumstance are similar to values the authors determined recently for hyperbaric bupivacaine using similar methodology. These ED50 and ED95 values are significantly higher than those advocated in previous reports in which success was claimed using lower intrathecal bupivacaine doses. The current study used stricter criteria to define "successful" anesthesia and support the use of larger bupivacaine doses to ensure adequate patient comfort.

  View details for PubMedID 16129987

• The use of a sum of inverse Gaussian functions to describe the absorption profile of drugs exhibiting complex absorption PHARMACEUTICAL RESEARCH Csajka, C., Drover, D., Verotta, D. 2005; 22 (8): 1227-1235

  Abstract

  The aim of this study was to evaluate the utility of a parametric deconvolution method using a sum of inverse Gaussian functions (IG) to characterize the absorption and concentrations vs. time profile of drugs exhibiting complex absorption.For a linear time-invariant system the response, Y(t), following an arbitrary input function I(t), is the convolution of I(t) with the disposition function, H(t), of the system: [Formula: see text]. The method proposed uses a sum of n inverse Gaussian functions to characterize I(t). The approach was compared with a standard nonparametric method using linear splines. Data were provided from previously published studies on two drugs (hydromorphone and veralipride) showing complex absorption and analyzed with NONMEM.A satisfactory fit for hydromorphone and veralipride data following oral administration was achieved by fitting a sum of two or three IG functions. The predictions of the input functions were very similar to those using linear splines.The use of a sum of IG as opposed to nonparametric functions, such as splines, offers a simpler implementation, a more intuitive interpretation of the results, a built-in extrapolation, and an easier implementation in a population context. Disadvantages are an apparent greater sensitivity to initial value estimates (when used with NONMEM).

  View details for DOI 10.1007/s11095-005-5266-8

  View details for Web of Science ID 000230990900003

  View details for PubMedID 16078132

• Postoperative analgesia after spinal blockade in infants and children undergoing cardiac surgery ANESTHESIA AND ANALGESIA Hammer, G. B., Ramamoorthy, C., Cao, H., Williams, G. D., Boltz, M. G., Kamra, K., Drover, D. R. 2005; 100 (5): 1283-1288

  Abstract

  The aim of this prospective, randomized, controlled clinical trial was to define the opioid analgesic requirement after a remifentanil (REMI)-based anesthetic with spinal anesthetic blockade (SAB+REMI) or without (REMI) spinal blockade for open-heart surgery in children. We enrolled 45 patients who were candidates for tracheal extubation in the operating room after cardiac surgery. Exclusion criteria included age <3 mo and >6 yr, pulmonary hypertension, congestive heart failure, contraindication to SAB, and failure to obtain informed consent. All patients had an inhaled induction with sevoflurane and maintenance of anesthesia with REMI and isoflurane (0.3% end-tidal). In addition, patients assigned to the SAB+REMI group received SAB with tetracaine (0.5-2.0 mg/kg) and morphine (7 mug/kg). After tracheal extubation in the operating room, patients received fentanyl 0.3 mug/kg IV every 10 min by patient-controlled analgesia for pain score = 4. Pain scores and fentanyl doses were recorded every hour for 24 h or until the patient was ready for discharge from the intensive care unit. Patients in the SAB+REMI group had significantly lower pain scores (P = 0.046 for the first 8 h; P =0.05 for 24 h) and received less IV fentanyl (P = 0.003 for the first 8 h; P = 0.004 for 24 h) than those in the REMI group. There were no intergroup differences in adverse effects, including hypotension, bradycardia, highest PaCO(2), lowest pH, episodes of oxygen desaturation, pruritus, and vomiting.

  View details for DOI 10.1213/01.ANE.0000148698.84881.10

  View details for PubMedID 15845670

• Determination of the pharmacodynamic interaction of propofol and remifentanil during esophagogastroduodenoscopy in children ANESTHESIOLOGY Drover, D. R., Litalien, C., Wellis, V., Shafer, S. L., Hammer, G. B. 2004; 100 (6): 1382-1386

  Abstract

  Propofol is commonly used to anesthetize children undergoing esophagogastroduodenoscopy. Opioids are often used in combination with propofol to provide total intravenous anesthesia. Because both propofol and remifentanil are associated with rapid onset and offset, the combination of these two drugs may be particularly useful for procedures of short duration, including esophagogastroduodenoscopy. The authors previously demonstrated that the median effective concentration (C50) of propofol during esophagogastroduodenoscopy in children is 3.55 microg/ml. The purpose of this study was to describe the pharmacodynamic interaction of remifentanil and propofol when used in combination for esophagogastroduodenoscopy in pediatric patients.The authors studied 32 children aged between 3 and 10 yr who were scheduled to undergo esophagogastroduodenoscopy. Propofol was administered via a target-controlled infusion system using the STANPUMP software based on a pediatric pharmacokinetic model. Remifentanil was administered as a constant rate infusion of 25, 50, and 100 ng.kg(-1).min(-1) to each of three study groups, respectively. A sigmoid Emax model was developed to describe the interaction of remifentanil and propofol.There was a positive interaction between remifentanil and propofol when used in combination. The concentration of propofol alone associated with 50% probability of no response was 3.7 microg/ml (SE, 0.4 microg/ml), and this was decreased to 2.8 microg/ml (SE, 0.1 microg/ml) when used in combination with remifentanil.A remifentanil infusion of 25 ng.kg(-1).min(-1) reduces the concentration of propofol required for adequate anesthesia for esophagogastroduodenoscopy from 3.7 to 2.8 microg/ml. Increasing the remifentanil infusion yields minimal additional decrease in propofol concentration and may increase the risk of side effects.

  View details for Web of Science ID 000221551300007

  View details for PubMedID 15166555

• ED50 and ED95 of intrathecal hyperbaric bupivacaine coadministered with opioids for cesarean delivery Annual Meeting of the American-Society-of-Anesthesiologists Ginosar, Y., Mirikatani, E., Drover, D. R., Cohen, S. E., Riley, E. T. LIPPINCOTT WILLIAMS & WILKINS. 2004: 676–82

  Abstract

  Successful cesarean delivery anesthesia has been reported with use of small doses (5-9 mg) of intrathecal bupivacaine coadministered with opioids. This double-blind, randomized, dose-ranging study determined the ED50 and ED95 of intrathecal bupivacaine (with adjuvant opioids) for cesarean delivery anesthesia.Forty-two parturients undergoing elective cesarean delivery with use of combined spinal-epidural anesthesia received intrathecal hyperbaric bupivacaine in doses of 6, 7, 8, 9, 10, 11, or 12 mg in equal volumes with an added 10 microg intrathecal fentanyl and 200 microg intrathecal morphine. Sensory levels (pinprick) were evaluated every 2 min until a T6 level was achieved. The dose was a success(induction) if a bilateral T6 block occurred in 10 min; otherwise, it was a failure(induction). In addition to being a success(induction), the dose was a success(operation) if no intraoperative epidural supplement was required; otherwise, it was a failure(operation). ED50 and ED95 for both success(induction) and success(operation) were determined with use of a logistic regression model.ED50 for success(induction) and success(operation) were 6.7 and 7.6 mg, respectively, whereas the ED95 for success(induction) and success(operation) were 11.0 and 11.2 mg. Speed of onset correlated inversely with dose. Although no clear advantage for low doses could be demonstrated (hypotension, nausea, vomiting, pruritus, or maternal satisfaction), this study was underpowered to detect significance in these variables.The ED95 of intrathecal bupivacaine under the conditions of this study is considerably in excess of the low doses proposed for cesarean delivery in some recent publications. When doses of intrathecal bupivacaine less than the ED95, particularly near the ED50, are used, the doses should be administered as part of a catheter-based technique.

  View details for PubMedID 15108985

• Noncardiogenic pulmonary edema and venous air embolus as complications of operative hysteroscopy JOURNAL OF CLINICAL ANESTHESIA Grove, J. J., Shinaman, R. C., Drover, D. R. 2004; 16 (1): 48-50

  Abstract

  A 37-year-old patient undergoing operative hysteroscopy developed noncardiogenic pulmonary edema after fluid absorption of 6 L of Ringer's lactate distension solution. No electrolyte or neurologic sequelae were associated with this fluid absorption. A subsequent 35-year-old patient having similar surgery in which a device was used to control intrauterine pressure and fluid absorption, developed a venous air embolus. The use of Ringer's lactate solution reduces the consequences associated with fluid absorption but it is not without risks. A device to limit intrauterine pressure and fluid absorption does not eliminate other risks.

  View details for DOI 10.1016/j.jclinane.2003.03.010

  View details for PubMedID 14984860

• Comparative pharmacokinetics and pharmacodynamics of short-acting hypnosedatives - Zaleplon, zolpidem and zopiclone CLINICAL PHARMACOKINETICS Drover, D. R. 2004; 43 (4): 227-238

  Abstract

  Benzodiazepines have historically been the mainstay of treatment for sleeping disorders, yet they have many shortcomings. A new group of sedative hypnotic agents has been developed for this purpose. Similar to the benzodiazepines, zaleplon, zolpidem and zopiclone have activity at the GABA receptor complex, yet they appear to have more selectivity for certain subunits of the GABA receptor. This produces a clinical profile that is more efficacious with fewer side effects. Zaleplon, zolpidem and zopiclone are structurally distinct. Due to variation in binding to the GABA receptor subunits, these three compounds show subtle differences in their effect on sleep stages, and as antiepileptics, anxiolytics and amnestics. The duration of action of zaleplon, zolpidem and zopiclone can be related to their individual pharmacokinetic profile, which subsequently determines the time course of drug effect. Each of these compounds has a unique pharmacokinetic profile with different bioavailability, volume of distribution and elimination half-lives. Zaleplon has a rapid elimination so there are fewer residual side effects after taking a single dose at bedtime. By comparison, zolpidem and zopiclone have a more delayed elimination so there may be a prolonged drug effect. This can result in residual sedation and side effects but may be useful for sustained treatment of insomnia with less waking during the night. There are also differences in potency based on plasma concentrations suggesting that there are differences in binding to the GABA receptor complex. Although zaleplon has a much lower bioavailability (30%), the treatment dose is similar to zolpidem and zopiclone (bioavilaibility of 70%) because of the increased potency of zaleplon. The pharmacokinetics and pharmacodynamics of zaleplon, zolpidem and zopiclone are significantly different from benzodiazepines. The new drugs are sufficiently unique from each other to allow customisation of treatment for various types of insomnia. While zaleplon may be best indicated for the delayed onset of sleep, zolpidem and zopiclone may be better indicated for maintaining a complete night's sleep. Only the patient's symptoms and response to treatment will dictate the best course of treatment.

  View details for PubMedID 15005637

• Input characteristics and bioavailability after administration of immediate and a new extended-release formulation of hydromorphone in healthy volunteers Annual Meeting of the American-Society-of-Anesthesiologists Drover, D. R., Angst, M. S., Valle, M., Ramaswamy, B., Naidu, S., Stanski, D. R., Verotta, D. LIPPINCOTT WILLIAMS & WILKINS. 2002: 827–36

  Abstract

  To compare the pharmacokinetics of intravenous, oral immediate-release (IR), and oral extended-release (OROS ) formulations of hydromorphone.In this randomized, six-session, crossover-design study, 12 subjects received hydromorphone 8-mg intravenous, 8-mg IR oral, and 8-, 16-, and 32-mg OROS formulations or placebo orally followed by plasma sampling for hydromorphone determination. Pharmacokinetic analysis was performed using NONMEM. Using the disposition of hydromorphone from the intravenous administration, deconvolution was used to estimate the input rate function (release rate from the gut to the blood) for the IR and OROS formulations. A linear spline was used to describe the drug input rate function.The deconvolution using linear splines described the release characteristics of both the IR and OROS formulations. The mean absolute bioavailability for the 8-mg OROS formulation was significantly larger ( = 0.025) than for the 8-mg IR formulation: 0.24 (SD 0.059) versus 0.19 (SD 0.054), respectively. The bioavailability was the same for the three doses of the OROS formulation. Predicted degree of fluctuation of plasma concentrations would be expected to be 130% and 39% for the IR and OROS 8-mg doses, respectively.The OROS formulation of hydromorphone produced continued release of medication over 24 h, which should allow for once-daily oral dosing. The extended release of hydromorphone will produce less fluctuation of plasma concentrations compared with IR formulations, which should provide for more constant pain control. The in vivo release of hydromorphone from both IR and OROS formulations were adequately described using a linear spline deconvolution approach. The increased bioavailability from the OROS formulation may be related to decreased metabolism by a first-pass effect or enterohepatic recycling of hydromorphone.

  View details for PubMedID 12357147

• Patient state index - Titration of delivery and recovery from propofol, alfentanil, and nitrous oxide anesthesia ANESTHESIOLOGY Drover, D. R., Lemmens, H. J., Pierce, E. T., Plourde, G., Loyd, G., Ornstein, E., Prichep, L. S., Chabot, R. J., Gugino, L. 2002; 97 (1): 82-89

  Abstract

  The Patient State Index (PSI) uses derived quantitative electroencephalogram features in a multivariate algorithm that varies as a function of hypnotic state. Data are recorded from two anterior, one midline central, and one midline posterior scalp locations. PSI has been demonstrated to have a significant relation to level of hypnosis during intravenous propofol, inhalation, and nitrous oxide-narcotic anesthesia. This multisite study evaluated the utility of PSI monitoring as an adjunct to standard anesthetic practice for guiding the delivery of propofol and alfentanil to accelerate emergence from anesthesia.Three hundred six patients were enrolled in this multicenter prospective randomized clinical study. Using continuous monitoring throughout the period of propofol-alfentanil-nitrous oxide anesthesia delivery, PSI guidance was compared with use of standard practice guidelines (both before [historic controls] and after exposure to the PSA 4000 monitor [Physiometrix, Inc., N. Billerica, MA; standard practice controls]). Anesthesia was always administered with the aim of providing hemodynamic stability, with rapid recovery.No significant differences were found for demographic variables or for site. The PSI group received significantly less propofol than the standard practice control group (11.9 microg x kg(-1) x min(-1); P < 0.01) and historic control group (18.2 microg x kg(-1) x min(-1); P < 0.001). Verbal response time, emergence time, extubation time, and eligibility for operating room discharge time were all significantly shorter for the PSI group compared with the historic control (3.3-3.8 min; P < 0.001) and standard practice control (1.4-1.5 min; P < 0.05 or P < 0.01) groups. No significant differences in the number of unwanted somatic events or hemodynamic instability and no incidences of reported awareness were found.Patient State Index-directed titration of propofol delivery resulted in faster emergence and recovery from propofol-alfentanil-nitrous oxide anesthesia, with modest decrease in the amount of propofol delivered, without increasing the number of unwanted events.

  View details for PubMedID 12131107

• Determination of the median effective concentration (EC50) of propofol during oesophagogastroduodenoscopy in children PAEDIATRIC ANAESTHESIA Hammer, G. B., Litalien, C., Wellis, V., Drover, D. R. 2001; 11 (5): 549-553

  Abstract

  Propofol is commonly used to provide anaesthesia for children undergoing oesophagogastroduodenoscopy (OGD). Despite this, the plasma concentration-response relationships for propofol used in this setting have not been established.In order to determine the EC50 of propofol during OGD, we studied 12 children aged 3-10 years. No premedication was given. Propofol was administered via a target-controlled infusion system using the STANPUMP software based on a paediatric pharmacokinetic model. The 'up-and-down' method described by Dixon was used to determine the EC50. Accordingly, the target plasma propofol concentration for each patient, beginning with the second subject, was determined by the response of the previous patient. A patient was considered a 'responder' if there was minimal movement and the heart rate (HR) and blood pressure (BP) remained < or = 120% of baseline during the procedure. Patients who moved excessively, i.e. requiring more than gentle restraint, or who manifest HR and BP >120% of baseline, were considered 'nonresponders'.The EC50 of propofol during OGD was 3.55 microg.ml(-1) in this study.The plasma propofol concentration associated with adequate anaesthesia for OGD in 50% of unpremedicated children is 3.55 microg.ml(-1). This concentration is higher than that required for OGD in adult patients.

  View details for PubMedID 11696118

• Pharmacodynamics of orally administered sustained-release hydromorphone in humans ANESTHESIOLOGY Angst, M. S., Drover, D. R., Lotsch, J., Ramaswamy, B., Naidu, S., Wada, D. R., Stanski, D. R. 2001; 94 (1): 63-73

  Abstract

  The disposition kinetics of hydromorphone generally necessitates oral administration every 4 h of the conventional immediate-release tablet to provide sustained pain relief. This trial examined time course and magnitude of analgesia to experimental pain after administration of sustained-release hydromorphone as compared with that after immediate-release hydromorphone or placebo.Using a 4 x 4 Latin square double-blind design, 12 subjects were randomized to receive a single dose of 8, 16, and 32 mg sustained-release hydromorphone and placebo. The same subjects had received 8 mg immediate-release hydromorphone before this study. Using an electrical experimental pain paradigm, analgesic effects were assessed for up to 30 h after administration, and venous hydromorphone plasma concentrations were measured at corresponding times.The hydromorphone plasma concentration peaked significantly later (12.0 h [12.0--18.0] vs. 0.8 h [0.8--1.0]; median and interquartile range) but was maintained significantly longer at greater than 50% of peak concentration (22.7 +/- 8.2 h vs. 1.1 +/- 0.7 h; mean +/- SD) after sustained-release than after immediate-release hydromorphone. Similarly, sustained-release hydromorphone produced analgesic effects that peaked significantly later (9.0 h [9.0--12.0] vs. 1.5 h [1.0--2.0]) but were maintained significantly longer at greater than 50% of peak analgesic effect (13.3 +/- 6.3 h vs. 3.6 +/- 1.7 h). A statistically significant linear relation between the hydromorphone plasma concentration and the analgesic effect on painful stimuli existed.A single oral dose of a new sustained-release formulation of hydromorphone provided analgesia to experimental pain beyond 24 h of its administration.

  View details for PubMedID 11135723

• Pharmacokinetics, pharmacodynamics, and relative pharmacokinetic/pharmacodynamic profiles of zaleplon and zolpidem CLINICAL THERAPEUTICS Drover, D., Lemmens, H., Naidu, S., Cevallos, W., Darwish, M., Stanski, D. 2000; 22 (12): 1443-1461

  Abstract

  This study compared the pharmacokinetics, pharmacodynamics, and pharmacokinetic/pharmacodynamic (PK/PD) profile of zaleplon, a new pyrazolopyrimidine hypnotic, with those of zolpidem and placebo.This was a double-blind, 5-period crossover study in which healthy volunteers with no history of sleeping disorder were randomized to 10- or 20-mg oral doses of zaleplon, 10- or 20-mg oral doses of zolpidem, or placebo. The pharmacokinetic characteristics of the active drugs were estimated using a noncompartmental method and NONMEM. Pharmacodynamic characteristics were determined using psychophysical tests, including measures of sedation, mood, mental and motor speed, and recent and remote recall. Results of these tests were used to compare the drugs' relative PK/PD profiles.Ten healthy male and female volunteers, aged 23 to 31 years, took part in the study. The apparent elimination half-life of zaleplon (60.1+/-8.9 min) was significantly shorter than that of zolpidem (124.5+/-37.9 min) (P < 0.001). Zaleplon produced less sedation than zolpidem at the 2 doses studied (P < 0.001). The sedation scores of the zaleplon groups returned to baseline in less time than those of the zolpidem groups (4 vs 8 hours; P < 0.05). Zaleplon had no effect on recent or remote recall, whereas zolpidem had a significant effect on both measures (P < 0.05).In this study in 10 young, healthy volunteers, zaleplon was eliminated more rapidly, produced no memory loss, and caused less sedation than zolpidem at the same doses.

  View details for PubMedID 11192136

• Rapacuronium recovery characteristics and infusion requirements during inhalation versus propofol-based anaesthesia BRITISH JOURNAL OF ANAESTHESIA Fu, W., Klein, K. W., White, P. F., Chiu, J. W., Lemmens, H. J., Whalley, D. G., Drover, D. R., Greenberg, C. P. 2000; 85 (2): 302-305

  Abstract

  We examined the effect of four maintenance anaesthetics on the neuromuscular blocking activity and spontaneous recovery characteristics after a short-term infusion of rapacuronium. Eighty ASA I-III adult patients undergoing elective surgery were studied at four centres. Anaesthesia was induced with propofol 1.5-2.5 mg kg-1 and fentanyl 1-2 micrograms kg-1, followed by a bolus of rapacuronium 1.5 mg kg-1. The patients were randomized to receive either desflurane (2-4% end-tidal, ET), sevoflurane (0.75-1.5% ET), isoflurane (0.4-0.8% ET), or a propofol infusion (75-150 micrograms kg-1 min-1) for maintenance of anaesthesia in combination with nitrous oxide (60-70%) in oxygen. When the first twitch (T1) of a train-of-four stimulus (using the TOF Guard accelerometer) returned to 5%, an infusion of rapacuronium was started at 3 mg kg-1 h-1 and adjusted to maintain T1/T0 at 10%. The duration of infusion lasted between 45 and 60 min, and the average infusion rates of rapacuronium were similar in all groups, ranging from 1.6 to 2.5 mg kg-1 h-1. There were no significant differences among the groups in the times for T1/T0 to return to 25%, 75% or 90%, or for T4/T1 to return to 70% and 80% upon discontinuation of the infusion. When potent inhalation anaesthetics are used in clinically relevant concentrations for maintenance of anaesthesia, the neuromuscular recovery profile of rapacuronium administered as a variable-rate infusion for up to 1 h is similar to that found with a propofol-based anaesthetic technique.

  View details for Web of Science ID 000088594600023

  View details for PubMedID 10992842

• Orthotopic liver transplantation for carcinoid tumour metastatic to the liver: anesthetic management CANADIAN JOURNAL OF ANAESTHESIA-JOURNAL CANADIEN D ANESTHESIE Claure, R. E., Drover, D. D., Haddow, G. R., Esquivel, C. O., Angst, M. S. 2000; 47 (4): 334-337

  Abstract

  To report the anesthetic management of a patient with carcinoid tumour metastatic to the liver who presented for orthotopic liver transplantation. Anesthetic implications of metastatic carcinoid tumour on liver transplantation and the use of octreotide are discussed.A 51-yr-old woman with intestinal carcinoid tumour metastatic to the liver presented for orthotopic liver transplantation, a recent treatment option for patients with extensive hepatic carcinoid metastases and disabling symptoms unresponsive to conventional therapy. Despite continuous administration of the somatostatin analogue octreotide via a hepatic artery infusate pump, the patient suffered from daily break through symptoms, which included flushing, palpitations, paroxysmal hypertension, and dyspnea. The patient presented to the operating room with sinus tachycardia and severe arterial hypertension. Octreotide and phentolamine were used to prevent further mediator release and to control the paroxysmal hypertension. Midazolam, fentanyl, thiopental, succinylcholine, vecuronium, and isoflurane were used to induce and maintain anesthesia safely. An intravenous octreotide infusion was initiated after induction and continued throughout the case. Infrequent and non-threatening peaks in arterial blood pressure were readily treated with small intravenous doses of vasoactive drugs and octreotide. No other manifestations of the carcinoid syndrome occurred. The patient had an uneventful recovery and was discharged on postoperative day #6.The patient safely underwent orthotopic liver transplantation for treatment of symptomatic carcinoid tumour metastatic to the liver. The anesthetic management followed recent recommendations favouring the use of octreotide to prevent patients from becoming symptomatic. Outlined dosing regimen for octreotide provided satisfactory hemodynamic stability.

  View details for PubMedID 10764178

• Population pharmacokinetics of fast release oral diclofenac in healthy volunteers: Relation to pharmacodynamics in an experimental pain model PHARMACEUTICAL RESEARCH Lotsch, J., Kettenmann, B., Renner, B., Drover, D., Brune, K., Geisslinger, G., Kobal, G. 2000; 17 (1): 77-84

  Abstract

  Population pharmacokinetics of a fast release diclofenac were assessed with special focus on pharmacodynamic implications.In a double blind four-way crossover study, 20 healthy volunteers received orally 50 and 100 mg diclofenac-Na effervescent ("fast-release NSAID"), 50 mg diclofenac tablets ("control"), or placebo. Population pharmacokinetics of the fast release diclofenac were assessed using a nonlinear mixed effects modeling approach (NON-MEM). Analgesic effects were investigated by means of an experimental pain model based on both pain-ratings and cortical evoked potentials after specific stimulation of nasal nociceptors with short pulses of gaseous CO2.Pharmacokinetics of fast release diclofenac were best described by a two-compartment population model, with an estimated terminal half-life of 1.2 hours. Pharmacokinetics of diclofenac tablets were highly variable and a population pharmacokinetic model could not be obtained. As an indication of an early onset of analgesic effects, 100 mg fast release diclofenac but not the tablets significantly reduced the amplitudes of pain-related evoked potentials at 30 min after administration.Earlier drug absorption and lower pharmacokinetic variability of the fast-release formulation are likely to be preserved in a population.

  View details for Web of Science ID 000085543800013

  View details for PubMedID 10714612

• Determination of the median effective concentration (EC50) of propofol during esophagogastroduodenoscopy (EGD) in children Hammer, G. B., Litalien, C., Wellis, V., Drover, D., Garcia, M. LIPPINCOTT WILLIAMS & WILKINS. 1999: U493–U493

  View details for Web of Science ID 000082480601268

• An inverse Gaussian density provided an adequate model to describe the absorption characteristics of sustained release hydromorphone Drover, D. R., Angst, M. S., Naidu, S., Lotsch, J. LIPPINCOTT WILLIAMS & WILKINS. 1999: U245–U245

  View details for Web of Science ID 000082480600457

• The population pharmacokinetics of hydromorphone Drover, D. R., Angst, M. S., Naidu, S., Ramaswamy, B. LIPPINCOTT WILLIAMS & WILKINS. 1999: U244–U244

  View details for Web of Science ID 000082480600454

• Single dose SR-hydromorphone provides sustained analgesia for more than 24 hours Angst, M. S., Drover, D. R., Naidu, S., Ramaswamy, B. LIPPINCOTT WILLIAMS & WILKINS. 1999: U402–U402

  View details for Web of Science ID 000082480600950

• Determination of the EC50 of propofol combined with remifentanil during EGD in children Hammer, G. B., Litalien, C., Wellis, V., Drover, D., Garcia, M. LIPPINCOTT WILLIAMS & WILKINS. 1999: U492–U492

  View details for Web of Science ID 000082480601263

• The comparative pharmacokinetics of zaleplon and zolpidem. Drover, D. R., Lemmens, H. J., Naidu, S., Cevallos, W. H., Martin, P., Stanski, D. NATURE PUBLISHING GROUP. 1999: 168–68

  View details for Web of Science ID 000078747600204

• Population pharmacodynamics and pharmacokinetics of remifentanil as a supplement to nitrous oxide anesthesia for elective abdominal surgery 48th Annual Meeting of American-Society-of-Anesthesiologists Drover, D. R., Lemmens, H. J. LIPPINCOTT WILLIAMS & WILKINS. 1998: 869–77

  Abstract

  Remifentanil blood concentrations necessary for adequate intraoperative anesthesia have not been defined. The goal of this study was to determine the blood concentrations of remifentanil needed for anesthesia with 66% nitrous oxide during intraabdominal surgery. In addition, the pharmacokinetics of remifentanil and the effects of covariates on both the pharmacodynamics and the pharmacokinetics were determined.Anesthesia was induced and maintained with 66% nitrous oxide in oxygen and remifentanil. Remifentanil was administered by a computer-controlled infusion pump that rapidly attained, and then maintained, constant remifentanil blood concentrations. If the patient showed signs of inadequate anesthesia (autonomic or somatic response), the target concentration was increased by 1 or 2 ng/ml. If no response occurred during a 15-min period, the concentration was decreased by 1 or 2 ng/ml. Remifentanil pharmacodynamics and pharmacokinetics were estimated using NONMEM.The remifentanil blood concentration for which there is a 50% probability of adequate anesthesia during abdominal surgery (Cb50) with 66% nitrous oxide was 4.1 ng/ml in men and 7.5 ng/ml in women. The Cb50 values for prostatectomy, nephrectomy, and other abdominal procedures were 3.8, 5.6, and 7.5 ng/ml, respectively. Remifentanil pharmacokinetics were best described by a two-compartment model with lean body mass as a significant covariate, where V1 = 0.129(lean body mass-50) + 3.79 l, V2 = 6.87 l, CL1 = 0.0389(lean body mass-50) + 2.34 l/min and CL2 = 1.14 l/min.The Cb50 differed according to patient gender. However, because surgery type was not specified for each man or woman, this may reflect a difference in surgical procedure.

  View details for PubMedID 9778004

• Determination of the distribution volume that can be used to calculate the intravenous loading dose CLINICAL PHARMACOKINETICS Wada, D. R., Drover, D. R., Lemmens, H. J. 1998; 35 (1): 1-7

  Abstract

  An intravenous loading dose is given to rapidly achieve a desired drug concentration in the blood. A loading dose calculated with the volume of distribution (Vd) at steady state will result in high peak concentrations and possibly serious adverse effects. A loading dose based on the central compartment Vd (Vc) followed by a maintenance infusion may also miss the target drug concentration and cause serious adverse effects. The Vd can be viewed as a time-dependent variable that expands from the Vc immediately after injection, to eventually include the steady-state Vd. If the loading dose is calculated from a Vd determined after the time of peak effect (tmax), then the actual concentration will exceed the target concentration at the tmax. If a loading dose is calculated from a Vd before the peak effect occurs, the actual concentration will be insufficient to achieve the target concentration at tmax. A loading dose based on the Vd at the tmax will accurately achieve the concentration at the tmax without unexpected adverse effects. To determine the Vd at peak effect, it is necessary that an effect can be measured, the peak effect can be detected and the plasma concentrations are sampled frequently enough to quantify the plasma concentrations at the tmax. For drugs that attain an ultra-fast effect (1 to 2 minutes), arterial samples need to be measured. If the onset of effect is intermediate or slow, venous blood can be sampled as the arterial and venous concentrations may be similar at the tmax.

  View details for PubMedID 9673831

• Double blind, placebo-controlled, randomized, crossover, pharmacodynamic study of 10 and 20 mg doses of zaleplon and zolpidem. Drover, D. R., Lemmens, H. J., Naidu, S., Cevallos, W. H., Troy, S., Martin, P. T., Stanski, D. R. NATURE PUBLISHING GROUP. 1998: 199–99

  View details for Web of Science ID 000072420300247

• DRUG ALLERGIES IN THE SURGICAL POPULATION CANADIAN JOURNAL OF ANAESTHESIA-JOURNAL CANADIEN D ANESTHESIE Hung, O. R., Bands, C., LANEY, G., Drover, D., Stevens, S., MacSween, M. 1994; 41 (12): 1149-1155

  Abstract

  Many patients claim to have drug allergies. However, the signs and symptoms of "allergic reactions" are seldom documented and the drug allergies are rarely properly assessed. The goal of this study was to determine the incidence of claimed "drug allergies" in a surgical population. After obtaining institutional approval, the study was carried out at five hospitals affiliated with Dalhousie University. Patients were interviewed by the investigators during the preoperative anaesthetic evaluation over six months and all signs and symptoms of drug reactions were recorded. The validity of the claimed allergy was based on the history. The allergies were assigned to one of three groups: (1) High probability of an allergic reaction: one or more of the signs and symptoms typical of an immunological reaction, with or without a family history, or a history of atopy; (ii) Low probability of an allergic reaction: signs and symptoms of the reaction were predictable reactions or side effects of the drug, without the occurrence of reactions mentioned above; or (iii) Unknown status: no information concerning the reaction of history was available. Of 1818 adult and paediatric patients (914 female/904 male) interviewed, 511 (28.1%) claimed to have one or more drug allergies (a total of 671 allergies). More women than men claimed to have drug allergies (60.3% vs 39.7%) and there was a positive correlation between age, number of medications and reported drug allergies. Antibiotics (50%), opioids (27%), non-steroidal anti-inflammatory agents (10%), and sedatives (5%) accounted for 92% of all claimed drug allergies. Overall, 50% of claimed allergies had a high probability of true allergic reactions.(ABSTRACT TRUNCATED AT 250 WORDS)

  View details for Web of Science ID A1994PW26900004

  View details for PubMedID 7867107

• Analysis of trichothecene mycotoxins in human blood by capillary column gas chromatography-ammonia chemical ionization mass spectrometr J Chromatogr D'Agostino, P. A., Provost, L. R., Drover, D. R. 1986; 367 (1): 77-86