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ABSTRACT: BACKGROUND:: Undetected apnea can lead to severe hypoxia, bradycardia, and cardiac arrest. Tracheal sounds entropy has been proved to be a robust method for estimating respiratory flow, thus maybe a more reliable way to detect obstructive and central apnea during sedation. METHODS:: A secondary analysis of a previous pharmacodynamics study was conducted. Twenty volunteers received propofol and remifentinal until they became unresponsive to the insertion of a bougie into the esophagus. Respiratory flow rate and tracheal sounds were recorded using a pneumotachometer and a microphone. The logarithm of the tracheal sound Shannon entropy (Log-E) was calculated to estimate flow rate. An adaptive Log-E threshold was used to distinguish between the presence of normal breath and apnea. Apnea detected from tracheal sounds was compared to the apnea detected from respiratory flow rate. RESULTS:: The volunteers stopped breathing for 15 s or longer (apnea) 322 times during the 12.9-h study. Apnea was correctly detected 310 times from both the tracheal sounds and the respiratory flow. Periods of apnea were not detected by the tracheal sounds 12 times. The absence of tracheal sounds was falsely detected as apnea 89 times. Normal breathing was detected correctly 1196 times. The acoustic method detected obstructive and central apnea in sedated volunteers with 95% sensitivity and 92% specificity. CONCLUSIONS:: We found that the entropy of the acoustic signal from a microphone placed over the trachea may reliably provide an early warning of the onset of obstructive and central apnea in volunteers under sedation.
Anesthesiology 02/2013; · 5.36 Impact Factor
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ABSTRACT: Drug administration errors are frequent and are often associated with the misuse of IV infusion pumps. One source of these errors may be the infusion pump's user interface.
We used failure modes-and-effects analyses to identify programming errors and to guide the design of a new syringe pump user interface. We designed the new user interface to clearly show the pump's operating state simultaneously in more than 1 monitoring location. We evaluated anesthesia residents in laboratory and simulated environments on programming accuracy and error detection between the new user interface and the user interface of a commercially available infusion pump.
With the new user interface, we observed the number of programming errors reduced by 81%, the number of keystrokes per task reduced from 9.2 ± 5.0 to 7.5 ± 5.5 (mean ± SD), the time required per task reduced from 18.1 ± 14.1 seconds to 10.9 ± 9.5 seconds and significantly less perceived workload. Residents detected 38 of 70 (54%) of the events with the new user interface and 37 of 70 (53%) with the existing user interface, despite no experience with the new user interface and extensive experience with the existing interface.
The number of programming errors and workload were reduced partly because it took less time and fewer keystrokes to program the pump when using the new user interface. Despite minimal training, residents quickly identified preexisting infusion pump problems with the new user interface. Intuitive and easy-to-program infusion pump interfaces may reduce drug administration errors and infusion pump-related adverse events.
Anesthesia and analgesia 09/2012; 115(5):1087-97. · 3.08 Impact Factor
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ASA Refresher Courses in Anesthesiology. 08/2012; 36(1):45-59.
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ABSTRACT: Using models of respiratory compromise, loss of response to esophageal instrumentation, and loss of responsiveness, the authors explored through simulation published dosing schemes for endoscopy using propofol alone and in combination with selected opioids. They hypothesized that models would predict adequate conditions for esophageal instrumentation and once drug administration is terminated, rapid return of responsiveness and minimal respiratory compromise.
Four published dosing regimens of propofol alone or in combination with opioids were used to predict the probability of loss of response to esophageal instrumentation for a 10-min procedure and the probability of respiratory compromise and return of responsiveness once the procedure had ended.
Propofol alone provided a low probability (9-20%) and propofol-opioid techniques provided a moderate probability (15-58%) of loss of response to esophageal instrumentation. Once the procedure ended, all techniques provided a high likelihood of rapid return of responsiveness (less than 3 min). Propofol-opioid techniques required more time than propofol alone to achieve a high probability of no respiratory compromise (7 vs. 4 min).
Propofol alone would likely lead to inadequate conditions for esophageal instrumentation but would provide a rapid return to responsiveness and low probability of respiratory compromise once the procedure ended. The addition of remifentanil or fentanyl improved conditions for esophageal instrumentation and had an equally rapid return to responsiveness. The time required to achieve a low probability of respiratory compromise was briefly prolonged; this is likely inconsequential given that patients are responsive and can be prompted to breathe.
Anesthesiology 06/2012; 117(2):252-62. · 5.36 Impact Factor
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ABSTRACT: A new lipid-free preparation of propofol has been developed containing the drug, sulfobutylether ß-cyclodextrin and water. The primary objective of this study was to compare the effects of propofol in the lipid formulation with those of the new cyclodextrin formulation, particularly with regard to pain on injection. We hypothesized that the propofol in cyclodextrin would be associated with less pain on injection than propofol in lipid.
The study was a single-center, double-blind, 2-period, randomized, dose-escalating study using a completely balanced cross-over design in healthy volunteers. Pain on injection was compared between propofol in cyclodextrin and propofol in lipid using subject and observer assessments of pain rated at several different time points. Five response variables to pain were analyzed.
Propofol in cyclodextrin had significantly higher pain scores for all 5 variables. Other endpoints, including sedation, showed no difference.
The propofol in cyclodextrin formulation failed to reduce the pain on injection associated with propofol.
Anesthesia and analgesia 09/2011; 113(4):738-41. · 3.08 Impact Factor
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ABSTRACT: Remifentanil and propofol are increasingly used for short-duration procedures in spontaneously breathing patients. In this setting, it is preferable to block the response to moderate stimuli while avoiding loss of responsiveness (LOR) and intolerable ventilatory depression (IVD). In this study, we explored selected effects of combinations of remifentanil-propofol effect-site concentrations (Ces) that lead to a loss of response to esophageal instrumentation (EI), LOR, and/or onset of IVD. A secondary aim was to use these observations to create response surface models for each effect measure. We hypothesized that (1) in a large percentage of volunteers, selected remifentanil and propofol Ces would allow EI but avoid LOR and IVD, and (2) the drug interaction for these effects would be synergistic.
Twenty-four volunteers received escalating target-controlled remifentanil and propofol infusions over ranges of 0 to 6.4 ng · mL(-1) and 0 to 4.3 μg · mL(-1), respectively. At each set of target concentrations, responses to insertion of a blunt end bougie into the midesophagus (40 cm), level of responsiveness, and respiratory rate were recorded. From these data, response surface models of loss of response to EI and IVD were built and characterized as synergistic, additive, or antagonistic. A previously published model of LOR was used.
Of the possible 384 assessments, volunteers were unresponsive to EI at 105 predicted remifentanil-propofol Ces; in 30 of these, volunteers had no IVD; in 30, volunteers had no LOR; and in 9, volunteers had no IVD or LOR. Many other assessments over the same concentration ranges, however, did have LOR and/or IVD. The combinations that allowed EI and avoided IVD and/or LOR primarily clustered around remifentanil-propofol Ces ranging from 0.8 to 1.6 ng · mL(-1) and 1.5 to 2.7 μg · mL(-1), respectively, and to a lesser extent approximately 3.0 to 4.0 ng · mL(-1) and 0.0 to 1.1 μg · mL(-1), respectively. Models of loss of response to EI and IVD both demonstrated a synergistic interaction between remifentanil and propofol.
Selected remifentanil-propofol concentration pairs, especially higher propofol-lower remifentanil concentration pairs, can block the response to EI while avoiding IVD in spontaneously breathing volunteers. It is, however, difficult to block the response to EI and avoid both LOR and IVD. It may be necessary to accept some discomfort and blunt rather than block the response to EI to consistently avoid LOR and IVD.
Anesthesia and analgesia 03/2011; 113(3):490-9. · 3.08 Impact Factor
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ABSTRACT: We previously reported models that characterized the synergistic interaction between remifentanil and sevoflurane in blunting responses to verbal and painful stimuli. This preliminary study evaluated the ability of these models to predict a return of responsiveness during emergence from anesthesia and a response to tibial pressure when patients required analgesics in the recovery room. We hypothesized that model predictions would be consistent with observed responses. We also hypothesized that under non-steady-state conditions, accounting for the lag time between sevoflurane effect-site concentration (Ce) and end-tidal (ET) concentration would improve predictions.
Twenty patients received a sevoflurane, remifentanil, and fentanyl anesthetic. Two model predictions of responsiveness were recorded at emergence: an ET-based and a Ce-based prediction. Similarly, 2 predictions of a response to noxious stimuli were recorded when patients first required analgesics in the recovery room. Model predictions were compared with observations with graphical and temporal analyses.
While patients were anesthetized, model predictions indicated a high likelihood that patients would be unresponsive (> or = 99%). However, after termination of the anesthetic, models exhibited a wide range of predictions at emergence (1%-97%). Although wide, the Ce-based predictions of responsiveness were better distributed over a percentage ranking of observations than the ET-based predictions. For the ET-based model, 45% of the patients awoke within 2 min of the 50% model predicted probability of unresponsiveness and 65% awoke within 4 min. For the Ce-based model, 45% of the patients awoke within 1 min of the 50% model predicted probability of unresponsiveness and 85% awoke within 3.2 min. Predictions of a response to a painful stimulus in the recovery room were similar for the Ce- and ET-based models.
Results confirmed, in part, our study hypothesis; accounting for the lag time between Ce and ET sevoflurane concentrations improved model predictions of responsiveness but had no effect on predicting a response to a noxious stimulus in the recovery room. These models may be useful in predicting events of clinical interest but large-scale evaluations with numerous patients are needed to better characterize model performance.
Anesthesia and analgesia 10/2009; 111(2):387-94. · 3.08 Impact Factor
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ABSTRACT: Sevoflurane-remifentanil interaction models that predict responsiveness and response to painful stimuli have been evaluated in patients undergoing elective surgery. Preliminary evaluations of model predictions were found to be consistent with observations in patients anesthetized with sevoflurane, remifentanil, and fentanyl. This study explored the feasibility of adapting the predictions of sevoflurane-remifentanil interaction models to an isoflurane-fentanyl anesthetic. We hypothesized that model predictions adapted for isoflurane and fentanyl are consistent with observed patient responses and are similar to the predictions observed in our previous work with sevoflurane-remifentanil/fentanyl anesthetics.
Twenty-five patients scheduled for elective surgery received a fentanyl-isoflurane anesthetic. Model predictions of unresponsiveness were recorded at emergence, and predictions of a response to noxious stimulus were recorded when patients first required analgesics in the recovery room. Model predictions were compared with observations with graphical and temporal analyses. Results were also compared with our previous predictions after the administration of a sevoflurane-remifentanil/fentanyl anesthetic.
Although patients were anesthetized, model predictions indicated a high likelihood that patients would be unresponsive (> or = 99%). After the termination of the anesthetic, model predictions of responsiveness well described the actual fraction of patients observed to be responsive during emergence. Half of the patients woke within 2 min of the 50% model-predicted probability of unresponsiveness; 70% woke within 4 min. Similarly, predictions of a response to a noxious stimulus were consistent with the number of patients who required fentanyl in the recovery room. Model predictions after the administration of an isoflurane-fentanyl anesthetic were similar to model predictions after a sevoflurane-remifentanil/fentanyl anesthetic.
The results confirmed our study hypothesis; model predictions for unresponsiveness and no response to painful stimuli, adapted to isoflurane-fentanyl were consistent with observations. These results were similar to our previous study comparing model predictions and patient observations after a sevoflurane-remifentanil/fentanyl anesthetic.
Anesthesia and analgesia 10/2009; 111(2):380-6. · 3.08 Impact Factor
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ABSTRACT: End tidal carbon dioxide (ETCO(2)) in non-intubated patients can be monitored using either sidestream or flow-through capnometry [Yamamori et al., J Clin Monit Comput 22(3):209-220, 2008]. The hypothesis of this validation study is that, flow-through capnometry will yield a more accurate estimate of ETCO(2) than sidestream capnometry when evaluated in a bench study during low tidal volumes and high oxygen administration via nasal cannula. Secondarily, when ETCO(2) from each is compared to arterial CO(2) (PaCO(2)) during a study in which healthy, non-intubated volunteers are tested under normocapnic, hypocapnic and hypercapnic conditions, the flow-through capnometer will resemble PaCO(2) more closely than the sidestream capnometer. This will be especially true during periods of lower minute ventilation and high oxygen flow rates via mask in non-intubated, remifentanil sedated, healthy volunteers whose physiologic deadspace is small.
The performance of a flow-through (cap-ONE, Nihon Kohden, Tokyo, Japan) and a sidestream (Microcap Smart CapnoLine Plus, Oridion Inc., Needham, MA) capnometer were compared in a bench study and a volunteer trial. A bench study evaluated ETCO(2) accuracy using waveforms generated via mechanical lungs during low tidal volumes and high oxygen flow rates. A volunteer study compared the ETCO(2) for each capnometer against PaCO(2) during sedation in which 8 l O(2) was delivered via mask rather than the nasal cannula.
In the bench study, the flow-through capnometer gave slightly higher values of ETCO(2) during high-flow oxygen and no discernable differences during variable tidal volumes. Bland and Altman plots comparing ETCO(2) to PaCO(2) showed essentially equal performance between the two capnometers in the volunteers.
Within a wide limit of agreement between the volunteer and bench study, flow-through and sidestream capnometry performed equally well during bench testing and in non-intubated, sedated patients.
International Journal of Clinical Monitoring and Computing 05/2009; 23(2):115-22.
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ABSTRACT: Dr. Paul Janssen was the founder of Janssen Pharmaceutica and the developer of over 80 pharmaceutical compounds that proved useful in human, botanical, and veterinary medicine. He and his coworkers synthesized the fentanyl family of drugs, many other potent analgesics, droperidol, etomidate, and numerous other important medicines that were extremely useful in psychiatry, parasitology, gastroenterology, cardiology, virology, and immunology. Anesthesiology and medicine as a whole have benefited a great deal from his resourcefulness, creativity, and entrepreneurial spirit.
Anesthesia and analgesia 03/2008; 106(2):451-62, table of contents. · 3.08 Impact Factor
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ABSTRACT: In this study, we explored how a set of remifentanil-propofol response surface interaction models developed from data collected in volunteers would predict responses to events in patients undergoing elective surgery. Our hypotheses were that these models would predict a patient population's loss and return of responsiveness and the presence or absence of a response to laryngoscopy and the response to pain after surgery.
Twenty-one patients were enrolled. Anesthesia consisted of remifentanil and propofol infusions and fentanyl boluses. Loss and return of responsiveness, responses to laryngoscopy, and responses to postoperative pain were assessed in each patient. Model predictions were compared with observed responses.
The loss of responsiveness model predicted that patients would become unresponsive 2.4 +/- 2.6 min earlier than observed. At the time of laryngoscopy, the laryngoscopy model predicted an 89% probability of no response to laryngoscopy and 81% did not respond. During emergence, the loss of responsiveness model predicted return of responsiveness 0.6 +/- 5.1 min before responsiveness was observed. The mean probability of no response to pressure algometry was 23% +/- 35% when patients required fentanyl for pain control.
This preliminary assessment of a series of remifentanil-propofol interaction models demonstrated that these models predicted responses to selected pertinent events during elective surgery. However, significant model error was evident during rapid changes in predicted effect-site propofol-remifentanil concentration pairs.
Anesthesia and analgesia 03/2008; 106(2):471-9, table of contents. · 3.08 Impact Factor
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Anesthesiology 11/2007; 107(6):1031. · 5.36 Impact Factor
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ABSTRACT: Opioids are commonly used in conjunction with sedative drugs to provide anesthesia. Previous studies have shown that opioids reduce the clinical requirements of sedatives needed to provide adequate anesthesia. Processed electroencephalographic parameters, such as the Bispectral Index (BIS; Aspect Medical Systems, Newton, MA) and Auditory Evoked Potential Index (AAI; Alaris Medical Systems, San Diego, CA), can be used intraoperatively to assess the depth of sedation. The aim of this study was to characterize how the addition of opioids sufficient to change the clinical level of sedation influenced the BIS and AAI.
Twenty-four adult volunteers received a target-controlled infusion of remifentanil (0-15 ng/ml) and inhaled sevoflurane (0-6 vol%) at various target concentration pairs. After reaching pseudo-steady state drug levels, the modified Observer's Assessment of Alertness/Sedation score, BIS, and AAI were measured at each target concentration pair. Response surface pharmacodynamic interaction models were built using the pooled data for each pharmacodynamic endpoint.
Response surface models adequately characterized all pharmacodynamic endpoints. Despite the fact that sevoflurane-remifentanil interactions were strongly synergistic for clinical sedation, BIS and AAI were minimally affected by the addition of remifentanil to sevoflurane anesthetics.
Although clinical sedation increases significantly even with the addition of a small to moderate dose of remifentanil to a sevoflurane anesthetic, the BIS and AAI are insensitive to this change in clinical state. Therefore, during "opioid-heavy" sevoflurane-remifentanil anesthetics, targeting a BIS less than 60 or an AAI less than 30 may result in an unnecessarily deep anesthetic state.
Anesthesiology 04/2007; 106(3):472-83. · 5.36 Impact Factor
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ABSTRACT: A young, healthy adult man exhibited naloxone-reversible, prolonged apnea after a 4-hour infusion of remifentanil, which was used as the opioid component of a general endotracheal anesthetic. Clinical experience and pharmacokinetic simulations indicate that the apnea was clearly atypical.
Journal of Clinical Anesthesia 03/2007; 19(1):60-3. · 1.21 Impact Factor
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ABSTRACT: Combining a hypnotic and an analgesic to produce sedation, analgesia, and surgical immobility required for clinical anesthesia is more common than administration of a volatile anesthetic alone. The aim of this study was to apply response surface methods to characterize the interactions between remifentanil and sevoflurane.
Sixteen adult volunteers received a target-controlled infusion of remifentanil (0-15 ng/ml) and inhaled sevoflurane (0-6 vol%) at various target concentration pairs. After reaching pseudo-steady state drug levels, the Observer's Assessment of Alertness/Sedation score and response to a series of randomly applied experimental pain stimuli (pressure algometry, electrical tetany, and thermal stimulation) were observed for each target concentration pair. Response surface pharmacodynamic interaction models were built using the pooled data for sedation and analgesic endpoints. Using computer simulation, the pharmacodynamic interaction models were combined with previously reported pharmacokinetic models to identify the combination of remifentanil and sevoflurane that yielded the fastest recovery (Observer's Assessment of Alertness/Sedation score > or = 4) for anesthetics lasting 30-900 min.
Remifentanil synergistically decreased the amount of sevoflurane necessary to produce sedation and analgesia. Simulations revealed that as the duration of the procedure increased, faster recovery was produced by concentration target pairs containing higher amounts of remifentanil. This trend plateaued at a combination of 0.75 vol% sevoflurane and 6.2 ng/ml remifentanil.
Response surface analyses demonstrate a synergistic interaction between remifentanil and sevoflurane for sedation and all analgesic endpoints.
Anesthesiology 08/2006; 105(2):267-78. · 5.36 Impact Factor
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ABSTRACT: Background: Combining a hypnotic and an analgesic to produce sedation, analgesia, and surgical immobility required for clinical anesthesia is more common than administration of a volatile anesthetic alone. The aim of this study was to apply response surface methods to characterize the interactions between remifentanil and sevoflurane.
Anesthesiology 07/2006; 105(2):267-278. · 5.36 Impact Factor
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ABSTRACT: This review is focused on recent advances in the application of cyclodextrins to new drug formulations, with emphasis on the field of anesthesia.
Cyclodextrins are well-known excipients in the pharmaceutical industry. Their recent application to the anesthetic induction agent propofol as a means of creating a non-lipid formulation may lead to their introduction into anesthesia pharmacology. The development of a novel cyclodextrin as specific reversal agent for the neuromuscular blocker rocuronium (that acts as an in-vivo scavenging system to bind free rocuronium in the circulation) will also increase the likelihood that cyclodextrins will have a greater clinical presence in anesthesiology in the future. Cyclodextrin-containing polymers are also finding a role in the delivery of nucleic acids and protein therapeutic agents.
Recent developments in cyclodextrins as excipients for anesthetics may soon culminate in their introduction into anesthesiology, although more research is necessary to better define their potential.
Current Opinion in Anaesthesiology 09/2005; 18(4):392-5. · 2.21 Impact Factor
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ABSTRACT: When opioids are used for postoperative pain control, it is useful to define the dose-response relationship for analgesia and respiratory depression. We studied 20 chronically opioid-consuming patients having elective multilevel spine fusion. Preoperatively, each patient received a fentanyl infusion of 2 microg x kg(-1) x min(-1) until the respiratory rate was <5 breaths/min. Pharmacokinetic simulations were used to estimate the effect site concentration at the time of respiratory depression and to predict the patient-controlled analgesia settings that would provide an effect-site fentanyl concentration that was 30% of the concentration associated with respiratory depression. Postoperatively, patient-controlled analgesia settings were adjusted to achieve 2-3 demand doses per hour. At steady-state patient-controlled analgesia settings, arterial blood gases and plasma fentanyl levels were measured. Sixteen patients required no adjustment or one patient-controlled analgesia adjustment. The median arterial Pco(2) level was 41 mm Hg and the interquartile range was 39-46 mm Hg. Plasma fentanyl levels demonstrated a significant correlation to the estimated effect-site concentration associated with respiratory depression determined during the preoperative fentanyl challenge. A preoperative fentanyl challenge used with pharmacokinetic simulations may be a useful tool to individualize the administration of analgesics to chronically opioid-consuming patients. IMPLICATIONS: In chronically opioid-consuming patients, doses causing respiratory depression and analgesia may differ from those in opioid-naive individuals. A preoperative infusion of fentanyl, used in conjunction with pharmacokinetic simulation, may be a valuable tool for identifying clinical end-points, such as respiratory depression and analgesia, and individualizing postoperative treatment of pain in patients who chronically consume opioids.
Anesthesia & Analgesia 08/2005; 101(2):389-95, table of contents. · 3.29 Impact Factor
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ABSTRACT: Remifentanil is the newest of the fentanyl family of short-acting phenylpiperidine derivatives to be released into clinical practice. Remifentanil is a pure agonist at the mu opioid receptor with relatively little binding at the kappa, sigma or delta receptors. This is precisely the same profile as the other opioids currently popular in anaesthetic practice (fentanyl, alfentanil, sufentanil) and it offers the same advantages (profound analgesia, sedation, attenuation of the stress response). This has led to widespread use of remifentanil as an adjunct to general anaesthesia in a variety of clinical settings. The unique pharmacology of remifentanil, in particular its rapid offset, has more recently attracted clinicians and investigators to the use of remifentanil by bolus injection, especially for procedures requiring a brief, intense, opioid effect. The clinical effects of remifentanil, both therapeutic and adverse, are consistent with that of the other fentanyl congeners. However, the pharmacokinetic profile of remifentanil, that is, its rapid effect site equilibration, has also revealed a significant potential for therapeutic misadventure. The untoward effects of remifentanil, given by continuous infusion, are well-described in the literature. They are predictable and easily managed by experienced clinicians. This review will concentrate on the adverse effects of remifentanil given by bolus injection, either alone or in the context of a background infusion.
Expert Opinion on Drug Safety 08/2005; 4(4):643-51. · 3.02 Impact Factor
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Anesthesiology 04/2005; 102(5):1069-1070. · 5.36 Impact Factor
