Control of Drug Administration During Monitored Anesthesia Care
ABSTRACT Monitored anesthesia care (MAC) is increasingly used to provide patient comfort for diagnostic and minor surgical procedures. The drugs used in this setting can cause profound respiratory depression even in the therapeutic concentration range. Titration to effect suffers from the difficulty to predict adequate analgesia prior to application of a stimulus, making titration to a continuously measurable side effect an attractive alternative. Exploiting the fact that respiratory depression and analgesia occur at similar drug concentrations, we suggest to administer opioids and propofol during MAC using a feedback control system with transcutaneously measured partial pressures of CO2(PtcCO2) as the controlled variable. To investigate this dosing paradigm, we developed a comprehensive model of human metabolism and cardiorespiratory regulation, including a compartmental pharmacokinetic and a pharmacodynamic model for the fast acting opioid remifentanil. Model simulations are in good agreement with ventilatory experimental data, both in presence and absence of drug. Closed-loop simulations show that the controller maintains a predefined CO2 target in the face of surgical stimulation and variable patient sensitivity. It prevents dangerous hypoventilation and delivers concentrations associated with analgosedation. The proposed control system for MAC could improve clinical practice titrating drug administration to a surrogate endpoint and actively limiting the occurrence of hypercapnia/hypoxia.
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ABSTRACT: Adding a small dose of ketamine to opioids may increase the analgesic effect and prevent opioid-induced hyperalgesia and acute tolerance to opioids. In this randomized, double-blinded, placebo-controlled crossover study, we investigated the effect of remifentanil combined with small concentrations of ketamine on different experimental pain models. Pain detection thresholds to single and repeated IM electrical stimulation and to repeated transcutaneous electrical stimulation, pressure pain tolerance threshold, and sedative, respiratory, and cardiovascular side effects were assessed in 14 healthy volunteers. Saline, remifentanil alone, and remifentanil combined with ketamine at target plasma concentrations of 50 or 100 ng/mL were administered in four study sessions. The ketamine infusion was started after baseline testing at a constant target concentration. Remifentanil was started after testing with ketamine alone at an initial target concentration of 1 ng/mL and then increased to 2 ng/mL and decreased to 1 ng/mL. The last test series were started 10 min after discontinuation of remifentanil. Acute remifentanil-induced hyperalgesia and tolerance were detected only by the pressure pain test and were not suppressed by ketamine. Remifentanil alone induced significant analgesia with all pain tests. Ketamine further increased the remifentanil effect only on IM electrical pain. Remifentanil at a 2 ng/mL target concentration induced a slight respiratory depression that was antagonized by ketamine. We conclude that ketamine effects on opioid analgesia are pain-modality specific. IMPLICATIONS: Coadministration of ketamine and morphine for pain relief is still controversial. Our experimental pain study with volunteers showed that ketamine enhances opioid analgesia without increasing sedation and reduces respiratory depression. Opioid-induced hyperalgesia and tolerance were not affected by ketamine and depended on the type of nociceptive stimulus. This may explain the conflicting results on opioid tolerance in previous studies.Anesthesia & Analgesia 04/2003; 96(3):726-32, table of contents. · 3.30 Impact Factor
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ABSTRACT: Bispectral (BIS) monitoring provides an objective, non-invasive measure of the level of consciousness in sedated patients. BIS has been shown to lag behind the level of sedation during induction and emergence of sedation with propofol. In this study, we sought to determine whether BIS is a useful adjunctive maneuver to registered nurse-administered propofol sedation (NAPS) as measured by reductions in recovery time and doses of propofol administered. A randomized controlled trial of 102 outpatients presenting for colonoscopy was performed. BIS values were recorded continuously in all subjects. Patients were randomized to receive NAPS with BIS visible to nurse and endoscopist versus BIS invisible to nurse and endoscopist. In phase 1 (47 patients), the nurse and endoscopist team were instructed to consider BIS (when visible) as only adjunctive information with regard to titrating sedation. In phase 2 (55 patients), the nurse endoscopist team was instructed to use BIS as the primary endpoint for titration of sedation, and to target BIS to greater than 60 (60-70 is deep sedation). In phase 1, the mean (SD) BIS value from scope-in (SI) to scope-out (SO) for BIS was 59.3 (9.9) and was not different from controls at 59.9 (10.1; p= 0.82). The mean (SD) propofol dose (mg/min) was 15.8 (5.6) and 17.2 (6.2) for BIS and controls, respectively (p= 0.45). The mean (SD) recovery time with BIS visible in phase 1 was 20.6 min (5.5) versus 19.2 min (4.5) in controls (p= 0.34). In phase 2, the mean (SD) BIS from SI to SO in those randomized to have BIS visible was 64.1 (5.4) versus 63.1 (8.5) in controls (p= 0.58). The mean (SD) dose of propofol (mg/min) was 16.1 (11.2) and 16.4 (12.3) for BIS and control groups, respectively (p= 0.92). The mean (SD) recovery time in phase 2 with BIS visible was 18.7 (3.5) versus 20.1 (5.6) in controls (p= 0.27). BIS did not lead to reductions in mean propofol dose or recovery time when used as an adjunct to NAPS for colonoscopy, or when used as the primary target for sedation. No clinically important role for BIS monitoring as an adjunct to NAPS has yet been established.The American Journal of Gastroenterology 10/2006; 101(9):2003-7. · 7.55 Impact Factor
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ABSTRACT: The C50 of remifentanil for ventilatory depression has been previously determined using inspired carbon dioxide and stimulated ventilation, which may not describe the clinically relevant situation in which ventilatory depression occurs in the absence of inspired carbon dioxide. The authors applied indirect effect modeling to non-steady state Paco2 data in the absence of inspired carbon dioxide during and after administration of remifentanil. Ten volunteers underwent determination of carbon dioxide responsiveness using a rebreathing design, and a model was fit to the end-expiratory carbon dioxide and minute ventilation. Afterwards, the volunteers received remifentanil in a stepwise ascending pattern using a computer-controlled infusion pump until significant ventilatory depression occurred (end-tidal carbon dioxide [Peco2] > 65 mmHg and/or imminent apnea). Thereafter, the concentration was reduced to 1 ng/ml. Remifentanil pharmacokinetics and Paco2 were determined from frequent arterial blood samples. An indirect response model was used to describe the Paco2 time course as a function of remifentanil concentration. The time course of hypercarbia after administration of remifentanil was well described by the following pharmacodynamic parameters: F (gain of the carbon dioxide response), 4.30; ke0 carbon dioxide, 0.92 min-1; baseline Paco2, 42.4 mmHg; baseline minute ventilation, 7.06 l/min; kel,CO2, 0.08 min-1; C50 for ventilatory depression, 0.92 ng/ml; Hill coefficient, 1.25. Remifentanil is a potent ventilatory depressant. Simulations demonstrated that remifentanil concentrations well tolerated in the steady state will cause a clinically significant hypoventilation following bolus administration, confirming the acute risk of bolus administration of fast-acting opioids in spontaneously breathing patients.Anesthesiology 11/2003; 99(4):779-87. · 5.16 Impact Factor