The drug titration paradox: more drug does not correlate with more effect in individual clinical data.

BACKGROUND: A fundamental concept in pharmacology is that increasing dose increases drug effect. This is the basis of anaesthetic titration: the dose is increased when increased drug effect is desired and decreased when reduced drug effect is desired. In the setting of titration, the correlation of doses and observed drug effects can be negative, for example increasing dose reduces drug effect. We have termed this the drug titration paradox. We hypothesised that this could be explained, at least in part, by intrasubject variability. If the drug titration paradox is simply an artifact of pooling population data, then a mixed-effects analysis that accounts for interindividual variability in drug sensitivity should 'flip' the observed correlation, such that increasing dose increases drug effect. METHODS: We tested whether a mixed-effects analysis could correctly reveal the underlying pharmacology using previously published data obtained during automatic feedback control of mean arterial pressure (MAP) with alfentanil (effect site concentration, CeAlf) during surgery. The relationship between MAP and CeAlf was explored with linear regression and a linear mixed-effects model. RESULTS: A linear mixed-effects model did not identify the correct underlying pharmacology because of the presence of the titration paradox in the individual data. CONCLUSIONS: The relationship between drug dose and drug effect must be determined under carefully controlled experimental conditions. In routine care, where the effect is profoundly influenced by varying clinical conditions and drugs are titrated to achieve the desired effect, it is nearly impossible to draw meaningful conclusions about the relationship between dose and effect.

Utility of the SmartPilot® View advisory screen to improve anaesthetic drug titration and postoperative outcomes in clinical practice: a two-centre prospective observational trial.

BACKGROUND: The advisory system SmartPilot® View (Drägerwerk AG, Lübeck, Germany) provides real-time, demographically adjusted pharmacodynamic information throughout anaesthesia, including time course of effect-site concentrations of administered drugs and a measure of potency of the combined drug effect termed the "'Noxious Stimulation Response Index' (NSRI). This dual-centre, prospective, observational study assesses whether the availability of SmartPilot® View alters the behaviour of anaesthetic drug titration of anaesthetists and improves the Anaesthesia Quality Score (AQS; percentage of time spent with MAP 60-80 mm Hg and Bispectral Index [BIS] 40-60 [blinded]). METHODS: We recruited 493 patients scheduled for elective surgery in two university centres. A control group (CONTROL; n=170) was enrolled to observe drug titration in current practice. Thereafter, an intervention group was enrolled, for which SmartPilot® View was made available to optimise drug titration (SPV; n=188). The AQS, haemodynamic and hypnotic effects, recovery times, pain scores, and other parameters were compared between groups. RESULTS: There were 358 patients eligible for analysis. Anaesthesia quality score was similar between CONTROL and SPV (median AQS [Q1-Q3]) 25.3% [7.4-41.5%] and 22.2% [8.0-44.4%], respectively; P=0.898). Compared with CONTROL, SPV patients had less severe hypotension and hypertension, less BIS <40, faster tracheal extubation, and lower early postoperative pain scores. CONCLUSIONS: Adding SmartPilot® View information did not affect average drug titration behaviour. However, small improvements in control of MAP and BIS and early recovery suggest improved titration for some patients without increasing the risk of overdosing or underdosing. CLINICAL TRIAL REGISTRATION: NCT01467167.

[Sound Bites in TV News Between Narration and Argumentation]. / O-Töne in Fernsehnachrichten im Spannungsfeld von Narration und Argumentation.

Against the background of the re-constructive character of media reporting (section 1), this article explains the concept of >news narratives< (2). Then the role and previous research of sound bites and their narrative integration are discussed (3). Explanations of the research question, corpus and method (4) are followed by quantitative and then more detailed exemplary qualitative analyses (5). Here, contributions from the Swiss ¼Tagesschau« and the American ¼CBS Evening News« since the 1960s are analyzed. It becomes apparent that the coverage is increasingly narrative in a narrower sense, that this development took place earlier in the USA, and that the argumentative functionalization of original sound clips can be reconstructed but remains implicit.

The aging human recipient of transfusion products.

In this review the different mechanisms of aging and frailty such as DNA defects due to impaired DNA repair, inflammatory processes, disturbances of oxidative phosphorylation are discussed together with mechanisms of cell repair. Components of blood plasma, such as the growth-differentiation protein GDF11, were shown to enhance neurogenesis and to improve the vasculature in the animal cortex and to rejuvenate muscle tissue. Advances in laboratory assays allow to identify plasma proteins that may affect tissue regeneration. This new knowledge from animal research might affect transfusion practice in geriatric patients in the future. Provided it can be translated and confirmed in human research, blood products might no longer be considered only as oxygen carriers or drugs to improve hemostasis. In the present time blood transfusion (RBCs, plasma or platelets) should be directed by differentiated guidelines considering not only cut-off values of hemoglobin, platelet count or coagulation but also old age-specific biologic variation, comorbidities and the clinical context e.g. of bleeding.

A Simple Guideline Reduces the Need for Red Blood Cell Transfusions in Swiss Hospitals: A Prospective, Multicentre, Before-and-After Study in Elective Hip and Knee Replacement.

INTRODUCTION: Optimising the use of blood has become a core task of transfusion medicine. Because no general guidelines are available in Switzerland, we analysed the effects of the introduction of a guideline on red blood cell (RBC) transfusion for elective orthopaedic surgery. METHODS: Prospective, multicentre, before-and-after study comparing the use of RBCs in adult elective hip or knee replacement before and after the implementation of a guideline in 10 Swiss hospitals, developed together with all participants. RESULTS: We included 2,134 patients, 1,238 in 7 months before, 896 in 6 months after intervention. 57 (34 or 2.7% before, 23 or 2.6% after) were lost before follow-up visit. The mean number of transfused RBC units decreased from 0.5 to 0.4 per patient (0.1, 95% CI 0.08-0.2; p = 0.014), the proportion of transfused patients from 20.9% to 16.9% (4%, 95% C.I. 0.7-7.4%; p = 0.02), and the pre-transfusion haemoglobin from 82.6 to 78.2 g/l (4.4 g/l, 95% C. I. 2.15-6.62 g/l, p < 0.001). We did not observe any statistically significant changes in in-hospital mortality (0.4% vs. 0%) and morbidity (4.1% vs. 4.0%), median hospital length of stay (9 vs. 9 days), follow-up mortality (0.4% vs. 0.2%) and follow-up morbidity (6.9% vs. 6.0%). CONCLUSIONS: The introduction of a simple transfusion guideline reduces and standardises the use of RBCs by decreasing the haemoglobin transfusion trigger, without negative effects on the patient outcome. Local support, training, and monitoring of the effects are requirements for programmes optimising the use of blood.

A response surface model approach for continuous measures of hypnotic and analgesic effect during sevoflurane-remifentanil interaction: quantifying the pharmacodynamic shift evoked by stimulation.

BACKGROUND: The authors studied the interaction between sevoflurane and remifentanil on bispectral index (BIS), state entropy (SE), response entropy (RE), Composite Variability Index, and Surgical Pleth Index, by using a response surface methodology. The authors also studied the influence of stimulation on this interaction. METHODS: Forty patients received combined concentrations of remifentanil (0 to 12 ng/ml) and sevoflurane (0.5 to 3.5 vol%) according to a crisscross design (160 concentration pairs). During pseudo-steady-state anesthesia, the pharmacodynamic measures were obtained before and after a series of noxious and nonnoxious stimulations. For the "prestimulation" and "poststimulation" BIS, SE, RE, Composite Variability Index, and Surgical Pleth Index, interaction models were applied to find the best fit, by using NONMEM 7.2.0. (Icon Development Solutions, Hanover, MD). RESULTS: The authors found an additive interaction between sevoflurane and remifentanil on BIS, SE, and RE. For Composite Variability Index, a moderate synergism was found. The comparison of pre- and poststimulation data revealed a shift of C50SEVO for BIS, SE, and RE, with a consistent increase of 0.3 vol%. The Surgical Pleth Index data did not result in plausible parameter estimates, neither before nor after stimulation. CONCLUSIONS: By combining pre- and poststimulation data, interaction models for BIS, SE, and RE demonstrate a consistent influence of "stimulation" on the pharmacodynamic relationship between sevoflurane and remifentanil. Significant population variability exists for Composite Variability Index and Surgical Pleth Index.

Repeated spinal anesthesia in a tetraparetic patient with Guillain-Barré syndrome.

A 78 year old man with tetraparesis, reduced forced vital capacity, and neurogenic bladder dysfunction due to Guillain-Barré syndrome was admitted for elective transurethral prostate resection and percutaneous lithotripsy of a bladder stone. On the sixth postoperative day, he was readmitted for emergency evacuation of a clot in the bladder. Both operations were performed with spinal anesthesia (hyperbaric bupivacaine + fentanyl) without neurologic sequelae.

Transition from nerve stimulator to sonographically guided axillary brachial plexus anesthesia in hand surgery: block quality and patient satisfaction during the transition period.

OBJECTIVES: Sonographic guidance for peripheral nerve anesthesia has proven increasingly successful in clinical practice; however, fears that a change to sonographically guided regional anesthesia may impair the block quality and operating room work flow persist in certain units. In this retrospective cohort study, block quality and patient satisfaction during the transition period from nerve stimulator to sonographic guidance for axillary brachial plexus anesthesia in a tertiary referral center were investigated. METHODS: Anesthesia records of all patients who had elective surgery of the wrist or hand during the transition time (September 1, 2006-August 25, 2007) were reviewed for block success, placement time, anesthesiologist training level, local anesthetic volume, and requirement of additional analgesics. Postoperative records were reviewed, and patient satisfaction was assessed by telephone interviews in matched subgroups. RESULTS: Of 415 blocks, 341 were sonographically guided, and 74 were nerve stimulator guided. Sonographically guided blocks were mostly performed by novices, whereas nerve stimulator-guided blocks were performed by advanced users (72.3% versus 14%; P < .001). Block performance times and success rates were similar in both groups. In sonographically guided blocks, significantly less local anesthetics were applied compared to nerve stimulator-guided blocks (mean ± SD, 36.1 ± 7.1 versus 43.9 ± 6.1 mL; P< .001), and less opioids were required (fentanyl, 66.1 ± 30 versus 90 ± 62 µg; P< .001). Interviewed patients reported significantly less procedure-related discomfort, pain, and prolonged procedure time when block placement was sonographically guided (2% versus 20%; P = .002). CONCLUSIONS: Transition from nerve stimulator to sonographic guidance for axillary brachial plexus blocks did not change block performance times or success rates. Patient satisfaction was improved even during the early institutional transition period.

Interaction between nitrous oxide, sevoflurane, and opioids: a response surface approach.

BACKGROUND: The interaction of sevoflurane and opioids can be described by response surface modeling using the hierarchical model. We expanded this for combined administration of sevoflurane, opioids, and 66 vol.% nitrous oxide (N2O), using historical data on the motor and hemodynamic responsiveness to incision, the minimal alveolar concentration, and minimal alveolar concentration to block autonomic reflexes to nociceptive stimuli, respectively. METHODS: Four potential actions of 66 vol.% N2O were postulated: (1) N2O is equivalent to A ng/ml of fentanyl (additive); (2) N2O reduces C50 of fentanyl by factor B; (3) N2O is equivalent to X vol.% of sevoflurane (additive); (4) N2O reduces C50 of sevoflurane by factor Y. These four actions, and all combinations, were fitted on the data using NONMEM (version VI, Icon Development Solutions, Ellicott City, MD), assuming identical interaction parameters (A, B, X, Y) for movement and sympathetic responses. RESULTS: Sixty-six volume percentage nitrous oxide evokes an additive effect corresponding to 0.27 ng/ml fentanyl (A) with an additive effect corresponding to 0.54 vol.% sevoflurane (X). Parameters B and Y did not improve the fit. CONCLUSION: The effect of nitrous oxide can be incorporated into the hierarchical interaction model with a simple extension. The model can be used to predict the probability of movement and sympathetic responses during sevoflurane anesthesia taking into account interactions with opioids and 66 vol.% N2O.

Sevoflurane remifentanil interaction: comparison of different response surface models.

BACKGROUND: Various pharmacodynamic response surface models have been developed to quantitatively describe the relationship between two or more drug concentrations with their combined clinical effect. We examined the interaction of remifentanil and sevoflurane on the probability of tolerance to shake and shout, tetanic stimulation, laryngeal mask airway insertion, and laryngoscopy in patients to compare the performance of five different response surface models. METHODS: Forty patients preoperatively received different combined concentrations of remifentanil (0-12 ng/ml) and sevoflurane (0.5-3.5 vol.%) according to a criss-cross design (160 concentration pairs, four per patient). After having reached pseudosteady state, the response to shake and shout, tetanic stimulation, laryngeal mask airway insertion, and laryngoscopy was recorded. For the analysis of the probability of tolerance, five different interaction models were tested: Greco, Reduced Greco, Minto, Scaled C50(O) Hierarchical, and Fixed C50(O) Hierarchical model. All calculations were performed with NONMEM VI (Icon Development Solutions, Ellicott City, MD). RESULTS: The pharmacodynamic interaction between sevoflurane and remifentanil was strongly synergistic for both the hypnotic and the analgesic components of anesthesia. The Greco model did not result in plausible parameter estimates. The Fixed C50(O) Hierarchical model performed slightly better than the Scaled C50(O) Hierarchical and Reduced Greco models, whereas the Minto model fitted less well. CONCLUSION: We showed the importance of exploring various surface model approaches when studying drug interactions. The Fixed C50(O) Hierarchical model fits our data on sevoflurane remifentanil interaction best and appears to be an appropriate model for use in hypnotic-opioid drug interaction.

Low-dose recombinant factor VIIa for massive bleeding: a single centre observational cohort study with 73 patients.

QUESTIONS UNDER STUDY: recombinant activated factor VII (rFVIIa) is used off-label for massive bleeding. There is no convincing evidence of the benefits of this practice and the minimal effective dose is unknown. The aim of the study was to evaluate our in-house guideline recommending a low dose of 60 µg/kg for off-label use of rFVIIa. METHODS: observational cohort study at the Inselspital Bern, a tertiary care University Hospital in Switzerland. All patients with massive bleeding treated off-label with rFVIIa between January 2005 and December 2007 were included. Survival, change of bleeding and transfusion rates, coagulation parameters and complications were analysed. RESULTS: seventy-three patients received rFVIIa. Severe haemorrhage was documented by a bleeding rate of 1000 mL/h (median; interquartile range 350-3000) and total volume replacement of 11.9 L (6.6-15.2) before administration of rFVIIa. The median rFVIIa-dose was 64 µg/kg (56-71). rFVIIa was administered once in 79% patients, twice in 18%. The bleeding rate was reduced in 82% of the patients. Transfused packed red blood cells decreased from 14 units (8-22) over 4.9 h (2.5-8.8) before rFVIIa to 2 (0-6) in 24 h thereafter, platelet concentrates from 2 units (1-3) to 1 (0-2) and FFP from 11 units (6-16) to 2 (0-9). In-hospital mortality was 14% within 24 h and 32% at day 30. There were two arterial thromboembolic complications possibly related to rFVIIa. CONCLUSION: a single injection of 60 µg/kg rFVIIa, a lower dose than usually recommended, appears to be efficacious in controlling massive bleeding with a very low complication rate.

Noxious stimulation response index: a novel anesthetic state index based on hypnotic-opioid interaction.

BACKGROUND: The noxious stimulation response index (NSRI) is a novel anesthetic depth index ranging between 100 and 0, computed from hypnotic and opioid effect-site concentrations using a hierarchical interaction model. The authors validated the NSRI on previously published data. METHODS: The data encompassed 44 women, American Society of Anesthesiology class I, randomly allocated to three groups receiving remifentanil infusions targeting 0, 2, and 4 ng/ml. Propofol was given at stepwise increasing effect-site target concentrations. At each concentration, the observer assessment of alertness and sedation score, the response to eyelash and tetanic stimulation of the forearm, the bispectral index (BIS), and the acoustic evoked potential index (AAI) were recorded. The authors computed the NSRI for each stimulation and calculated the prediction probabilities (PKs) using a bootstrap technique. The PKs of the different predictors were compared with multiple pairwise comparisons with Bonferroni correction. RESULTS: The median (95% CI) PK of the NSRI, BIS, and AAI for loss of response to tetanic stimulation was 0.87 (0.75-0.96), 0.73 (0.58-0.85), and 0.70 (0.54-0.84), respectively. The PK of effect-site propofol concentration, BIS, and AAI for observer assessment of alertness and sedation score and loss of eyelash reflex were between 0.86 (0.80-0.92) and 0.92 (0.83-0.99), whereas the PKs of NSRI were 0.77 (0.68-0.85) and 0.82 (0.68-0.92). The PK of the NSRI for BIS and AAI was 0.66 (0.58-0.73) and 0.63 (0.55-0.70), respectively. CONCLUSION: The NSRI conveys information that better predicts the analgesic component of anesthesia than AAI, BIS, or predicted propofol or remifentanil concentrations. Prospective validation studies in the clinical setting are needed.

Anesthesia or sedation for gastroenterologic endoscopies.

PURPOSE OF REVIEW: Because propofol is the sedative preferred by gastroenterologists, we focus this review on gastroenterologist-directed propofol sedation, provide simulations of the respiratory depressant effect of different dosing protocols and give a perspective on future developments in computer-assisted sedation techniques. RECENT FINDINGS: Propofol use by nonanesthesiologists remains a contraindication in the package insert of propofol in most countries. Sedation guidelines produced by the American Society of Gastroenterology partially contradict those produced by the American Society of Anesthesiologists for sedation by nonanesthesiologists, whereas the German guidelines were developed with anesthesiologists involved. The use of fospropofol, recently approved by the US Food and Drug Administration for sedation, is considered an alternative to propofol by some gastroenterologists. Methodological errors in earlier pharmacological studies have to be solved before widespread use of fospropofol is justified, however. Our simulations show that dosing protocols with small boluses administered at reasonable intervals induce less respiratory depression than large boluses. Interindividual variability of propofol-induced respiratory depression is illustrated by different pharmacokinetic and dynamic parameter sets used in the simulation. Two computer-assisted propofol infusion systems are currently being investigated. They not only incorporate the target effect but also the side effects, which may limit respiratory depression. SUMMARY: Propofol use by gastroenterologists may be well tolerated if appropriate patient selection, staff training, monitoring and low-dose sedation protocols are applied.

The accuracy of FAST in relation to grade of solid organ injuries: a retrospective analysis of 226 trauma patients with liver or splenic lesion.

BACKGROUND: This study investigated the role of a negative FAST in the diagnostic and therapeutic algorithm of multiply injured patients with liver or splenic lesions. METHODS: A retrospective analysis of 226 multiply injured patients with liver or splenic lesions treated at Bern University Hospital, Switzerland. RESULTS: FAST failed to detect free fluid or organ lesions in 45 of 226 patients with spleen or liver injuries (sensitivity 80.1%). Overall specificity was 99.5%. The positive and negative predictive values were 99.4% and 83.3%. The overall likelihood ratios for a positive and negative FAST were 160.2 and 0.2. Grade III-V organ lesions were detected more frequently than grade I and II lesions. Without the additional diagnostic accuracy of a CT scan, the mean ISS of the FAST-false-negative patients would be significantly underestimated and 7 previously unsuspected intra-abdominal injuries would have been missed. CONCLUSION: FAST is an expedient tool for the primary assessment of polytraumatized patients to rule out high grade intra-abdominal injuries. However, the low overall diagnostic sensitivity of FAST may lead to underestimated injury patterns and delayed complications may occur. Hence, in hemodynamically stable patients with abdominal trauma, an early CT scan should be considered and one must be aware of the potential shortcomings of a "negative FAST".

Percutaneous vertebroplasty, kyphoplasty and lordoplasty: implications for the anesthesiologist.

PURPOSE OF REVIEW: Vertebroplasty, kyphoplasty and lordoplasty are minimally invasive procedures mainly performed for refractory pain due to osteoporotic vertebral body fractures. This review summarizes recent findings on outcome, complications and their impact on anesthetic management. RECENT FINDINGS: Despite an increasing number of publications on surgical technique, therapeutic efficacy and side effects of these interventions, anesthetic management per se is hardly investigated. All three treatments provide similar pain relief. Adverse effects include local cement leakage and new fractures adjacent to augmented vertebrae. Asymptomatic pulmonary cement embolism occurs in 4.6-6.8% of patients depending on cement viscosity, injection pressure and number of injected vertebrae. Potentially life-threatening embolism of cement or fat may occur. Kyphoplasty and lordoplasty aim at correcting vertebral deformity and are equally effective; lordoplasty is substantially less expensive, however. The incidence of systemic cement or fat embolism is similar to that in vertebroplasty. Whereas vertebroplasty is mostly performed under local anesthesia and sedation, general anesthesia is required for kyphoplasty and lordoplasty. The anesthetic regimen follows the principles of anesthesia in the elderly population. SUMMARY: Vertebroplasty, kyphoplasty and lordoplasty are effective minimally invasive treatments for stable vertebral compression fractures without compression of the spinal canal. The anesthesiologist must be prepared to manage systemic cement or fat embolism.

Drug-induced respiratory depression: an integrated model of drug effects on the hypercapnic and hypoxic drive.

Drug-induced respiratory depression is a common side effect of the agents used in anesthesia practice to provide analgesia and sedation. Depression of the ventilatory drive in the spontaneously breathing patient can lead to severe cardiorespiratory events and it is considered a primary cause of morbidity. Reliable predictions of respiratory inhibition in the clinical setting would therefore provide a valuable means to improve the safety of drug delivery. Although multiple studies investigated the regulation of breathing in man both in the presence and absence of ventilatory depressant drugs, a unified description of respiratory pharmacodynamics is not available. This study proposes a mathematical model of human metabolism and cardiorespiratory regulation integrating several isolated physiological and pharmacological aspects of acute drug-induced ventilatory depression into a single theoretical framework. The description of respiratory regulation has a parsimonious yet comprehensive structure with substantial predictive capability. Simulations relative to the synergistic interaction of the hypercarbic and hypoxic respiratory drive and the global effect of drugs on the control of breathing are in good agreement with published experimental data. Besides providing clinically relevant predictions of respiratory depression, the model can also serve as a test bed to investigate issues of drug tolerability and dose finding/control under non-steady-state conditions.

Closed-loop control of mean arterial blood pressure during surgery with alfentanil: clinical evaluation of a novel model-based predictive controller.

BACKGROUND: In contrast to hypnosis, there is no surrogate parameter for analgesia in anesthetized patients. Opioids are titrated to suppress blood pressure response to noxious stimulation. The authors evaluated a novel model predictive controller for closed-loop administration of alfentanil using mean arterial blood pressure and predicted plasma alfentanil concentration (Cp Alf) as input parameters. METHODS: The authors studied 13 healthy patients scheduled to undergo minor lumbar and cervical spine surgery. After induction with propofol, alfentanil, and mivacurium and tracheal intubation, isoflurane was titrated to maintain the Bispectral Index at 55 (+/- 5), and the alfentanil administration was switched from manual to closed-loop control. The controller adjusted the alfentanil infusion rate to maintain the mean arterial blood pressure near the set-point (70 mmHg) while minimizing the Cp Alf toward the set-point plasma alfentanil concentration (Cp Alfref) (100 ng/ml). RESULTS: Two patients were excluded because of loss of arterial pressure signal and protocol violation. The alfentanil infusion was closed-loop controlled for a mean (SD) of 98.9 (1.5)% of presurgery time and 95.5 (4.3)% of surgery time. The mean (SD) end-tidal isoflurane concentrations were 0.78 (0.1) and 0.86 (0.1) vol%, the Cp Alf values were 122 (35) and 181 (58) ng/ml, and the Bispectral Index values were 51 (9) and 52 (4) before surgery and during surgery, respectively. The mean (SD) absolute deviations of mean arterial blood pressure were 7.6 (2.6) and 10.0 (4.2) mmHg (P = 0.262), and the median performance error, median absolute performance error, and wobble were 4.2 (6.2) and 8.8 (9.4)% (P = 0.002), 7.9 (3.8) and 11.8 (6.3)% (P = 0.129), and 14.5 (8.4) and 5.7 (1.2)% (P = 0.002) before surgery and during surgery, respectively. A post hoc simulation showed that the Cp Alfref decreased the predicted Cp Alf compared with mean arterial blood pressure alone. CONCLUSION: The authors' controller has a similar set-point precision as previous hypnotic controllers and provides adequate alfentanil dosing during surgery. It may help to standardize opioid dosing in research and may be a further step toward a multiple input-multiple output controller.

Pharmacodynamic modelling of drug-induced ventilatory depression and automatic drug dosing in conscious sedation.

In conscious sedation (CS) procedures, the patient is sedated but retains the ability to breathe spontaneously. Drug-induced ventilatory depression represents a dangerous side effect of CS, possibly leading to hypoventilation and subsequent hypoxia. In this work, we propose a new pharmacodynamic model for drug-induced ventilatory depression. The model presents a parsimonious structure and shows good agreement with experimental data for different drugs. In addition, we explore the innovative idea of regulating drug infusion during CS by means of a feedback control system based on measurements of transcutaneous partial pressure of CO(2). In simulations, the controller proves able to maintain a predefined target of CO(2) despite pain, external disturbances and inter-patient variability in the sensibility to the drug. The implementation of the controller during CS procedures would improve clinical practice minimizing the occurrence of drug-induced ventilatory depression by tailoring drug infusion to patient's needs.

Xenon does not reduce opioid requirement for orthopedic surgery.

PURPOSE: Is to test the hypothesis that 70% xenon has a relevant opioid sparing effect compared to a minimum alveolar concentration (MAC)-equivalent combination of N(2)O and desflurane. METHODS: In this randomized, controlled study of 30 patients undergoing major orthopedic surgery, we determined the plasma alfentanil concentration required to suppress response to skin incision in 50% of patients (Cp(50)) anesthetized with xenon (70%) or a combination of N(2)O (70%) and desflurane (2%). A response was defined as movement, pressor response > 15 mmHg, heart rate > 90 beats x min(-1), autonomic reactions or a combination of these. At skin incision, alfentanil was administered at a randomly selected target plasma concentration thereafter the concentration was increased or decreased according to the patient's response. After skin incision, desflurane was adjusted to maintain the bispectral index below 60 and prevent responsiveness in both groups. RESULTS: The Cp(50) (+/- standard error) of alfentanil was 83 +/- 48ng x mL(-1) with xenon and 49 +/- 26 ng x mL(-1) with N(2)O/desflurane (P =0.451). During surgery five xenon and 15 N(2)O/desflurane patients were given desflurane at 1.0 +/- 0.5 volume % and 2.5 +/- 0.7 volume %. The total age adjusted MAC was 0.97 +/- 0.07 and 0.94 +/- 0.07 respectively (P = 0.217). The intraoperative plasma alfentanil concentrations were 95 +/- 80 and 93 +/- 60 ng x mL(-1) respectively (mean +/- SD; P = 0.451). Patients given xenon were slightly more bradycardic, whereas blood pressure was similar. CONCLUSION: Xenon compared to a MAC-equivalent combination of N(2)O and desflurane does not substantially reduce opioid requirement for orthopedic surgery. A small but clinically irrelevant difference cannot be excluded, however.

Measuring depth of sedation with auditory evoked potentials during controlled infusion of propofol and remifentanil in healthy volunteers.

Avoiding excessively deep levels of sedation is a major problem in intensive care patients. We studied whether clinically relevant levels of sedation can be objectively assessed using long latency auditory evoked potentials. We measured the auditory evoked potentials at 100 ms after the stimulus (N100) in 10 healthy volunteers during stepwise increasing, clinically relevant levels of sedation (Ramsay score [RS] 2-4). The volunteers were studied on three separate occasions and received an infusion of either propofol or a combination of propofol and remifentanil. Effects of remifentanil infusion alone were tested during target controlled infusion (target plasma concentrations: 1, 2, and 3 ng/mL). Remifentanil did not affect evoked potential amplitudes and latencies. During both propofol-induced and propofol/remifentanil-induced sedation, the N100 amplitude decreased similarly without an effect on the latencies as the level of sedation increased from Ramsay score 2 to Ramsay score 4 (P < 0.01). At the same clinical level of sedation, propofol plasma concentrations were larger when sedation was achieved by propofol alone (propofol versus propofol/remifentanil, RS 3: 2.12 mug/mL +/- 0.51 versus 1.32 +/- 0.43, P < 0.01; RS 4: 3.37 +/- 0.47 versus 1.86 +/- 0.34, P < 0.01). Our results suggest that long latency auditory evoked potentials provide an objective electrophysiological analog to the clinical assessment of sedation independent of the sedation regime used.