Evaluation of a novel mouse model of intracisternal strychnine-induced trigeminal allodynia.

PURPOSE: Intractable neuropathic dynamic allodynia remains one of the major symptoms of human trigeminal neuropathy and is commonly accepted to be the most excruciatingly painful condition known to humankind. At present, a validated animal model of this disorder is necessary for efficient and effective development of novel drug treatments. Intracisternal strychnine in rats has been shown to result in localized trigeminal dynamic allodynia, thus representing a possible model of trigeminal neuralgia. The purpose of this study was to validate a mouse model of trigeminal glycinergic inhibitory dysfunction using established positive (carbamazepine epoxide) and negative (morphine) controls. METHODS: The actions of conventional first-line treatment (carbamazepine epoxide [CBZe]) and clinically ineffective morphine were tested for trigeminal dynamic mechanical allodynia produced by intracisternal strychnine. In mice under halothane anesthesia, we injected either strychnine (0.3 µg), strychnine with CBZe (4 ng), or artificial cerebrospinal fluid (aCSF) intracisternally (i.c.). In a separate set of experiments, subcutaneous morphine (3 mg·kg(-1) sc) was injected with intracisternal strychnine. Dynamic mechanical allodynia was induced by stroking the fur with polyethylene (PE-10) tubing. The response of each mouse was rated to determine its allodynia score, and scores of each group were compared. In addition, in a separate dichotomous disequilibrium study, pairs of mice were injected with strychnine/saline, strychnine/strychnine-CBZe, or strychnine/strychnine-morphine. A blinded observer recorded which mouse of each pair had the greater global pain behaviour. RESULTS: Strychnine (i.c.) produced higher quantitative allodynia scores in the trigeminal distribution (mean 81.5%; 95% confidence interval [CI] 76.4 to 86.6) vs the aCSF group (mean 11.3%; 95% CI 8.1 to 14.4) (P < 0.0001). Carbamazepine epoxide (i.c.) completely abolished allodynia when co-injected with strychnine (mean 83.2%; 95% CI 78.1 to 88.4) vs strychnine alone (mean 3.2%; 95% CI -0.9 to 7.2) (P < 0.0001). Morphine co-injected with strychnine did not result in reduced allodynia (mean 65.7%; 95% CI 42.0 to 89.4) compared with strychnine alone (mean 87.6%; 95% CI 77.6 to 97.6) (P = 0.16). In a further global allodynia assessment, strychnine (i.c.) produced greater allodynia than both aCSF and strychnine administered with CBZe (P = 0.03). Morphine (ip) administered with strychnine did not result in reduced global allodynia compared with strychnine administered alone (P = 1.0). CONCLUSION: In this study, we have developed and validated a novel murine model of trigeminal dynamic allodynia induced by intracisternal strychnine. The use of mice to study trigeminal allodynia has many benefits, including access to a vast repository of transgenic mouse variants, ease of handling, low cost, and minimal variance of results. The present model may have utility in screening drug treatments for dynamic mechanical allodynia resulting from trigeminal neuropathies.

Indication for surgery and the risk of postoperative nausea and vomiting after craniotomy: a case-control study.

BACKGROUND: The primary hypothesis of the study is that acoustic neuroma (AN) surgery and microvascular decompression (MVD) of cranial nerves increase the risk of postoperative nausea and vomiting (PONV). METHODS: We designed a retrospective case-control study matched on age, sex, and year of surgery (≤2005 and >2005). Year of surgery was noted as a potential confounder, because routine antiemetic prophylaxis was strongly encouraged at the study site in 2005. Cases of PONV in the recovery room were matched to controls in a 1:2 manner using a perioperative database. Charts were then reviewed for the following data: American Society of Anesthesiologists grade, smoking status, craniotomy location, craniotomy indication, and type of anesthetic administered. RESULTS: The final analysis included 117 cases that were matched with 185 controls. Patients had a mean age of 50 years (SD=13), and 65% were female. Overall, the majority of craniotomies were supratentorial (70%) and performed for tumor resection (41%). On multivariable analysis, MVD [odds ratio (OR)=6.7; 95% confidence interval (CI), 2.0-22.7; P=0.002], AN (OR=3.3; 95% CI, 1.0-11.0; P=0.05), and epilepsy surgery (OR=2.8; 95% CI, 1.1-7.5; P=0.04) were associated with an increased likelihood of PONV when compared with tumor surgery. There was effect modification of total intravenous anesthesia by location of surgery (P-interaction=0.02). The benefit of total intravenous anesthesia on PONV was observed in supratentorial (OR=0.41; 95% CI, 0.17-0.96; P=0.04) but not infratentorial location (OR=2.6; 95% CI, 0.78-8.7; P=0.11). CONCLUSIONS: MVD and AN resection were associated with an increased likelihood of PONV compared with craniotomies performed for other tumor resection.

A comparison of the systemic toxicity of lidocaine versus its quaternary derivative QX-314 in mice.

PURPOSE: We recently showed that the quaternary lidocaine derivative, QX-314, produces long-lasting local anesthesia with a slow onset in animal models in vivo. As quaternary agents do not rapidly penetrate biological membranes or the blood-brain barrier, QX-314 may represent a local anesthetic with decreased systemic toxicity compared with conventional tertiary aminoamines. To test this hypothesis, we conducted an in vivo animal study in mice to compare QX-314 with lidocaine in terms of its relative central nervous system (CNS) and cardiac toxicity. METHODS: With approval from the institutional Animal Care Committee, we used the "up-and-down" method to determine the relative potencies (ED(50)) of lidocaine and QX-314 for CNS and cardiac toxicity in adult CD-1 mice (weight, 20 to 35 g). The animals were administered either intravenous lidocaine or QX-314 (dose range, 7.5 to 30 mg·kg(-1)) and were observed for signs of CNS toxicity (convulsions, ataxia, loss of righting reflex, and/or death). We also observed animals for electrocardiographic evidence of toxic effects on cardiac automaticity, conductivity, and rhythmicity. RESULTS: The ED(50) of lidocaine for CNS toxicity as determined by the "up-and-down" method was 19.5 mg·kg(-1) (95% confidence interval [CI], 17.7 to 21.3 mg·kg(-1); n = 6) compared with 10.7 mg·kg(-1) for QX-314 (95% CI, 9.1 to 12.3 mg·kg(-1); n = 6) (potency ratio, 1.8). Similarly, the ED(50) of lidocaine for electrocardiographic evidence of cardiac toxicity was significantly higher than that of QX-314 (ED(50) of lidocaine, 21.2 mg·kg(-1); 95% CI, 19.0 to 23.4 mg·kg(-1); n = 6 vs ED(50) of QX-314, 10.6 mg·kg(-1); 95% CI, 8.4 to 12.8 mg·kg(-1); n = 6) (potency ratio, 2.0). CONCLUSIONS: In this in vivo animal study, the relative potencies of QX-314 for systemic CNS and cardiac toxicity were significantly higher than those of lidocaine. These data do not support the hypothesis that QX-314 is a safer local anesthetic compared with lidocaine in terms of systemic toxicity. Whereas our results do not exclude the possibility that QX-314 may represent a clinically useful agent to produce long-lasting local anesthesia and nociceptive blockade after a single shot in humans, its systemic toxicity relative to conventional tertiary aminoamide local anesthetics and the underlying mechanisms warrant further study.

Lumbar intrathecal administration of the quaternary lidocaine derivative, QX-314, produces irritation and death in mice.

BACKGROUND: We recently found that peripheral administration of the quaternary lidocaine derivative, QX-314, produces long-lasting sensory and motor blockade in animals. The goal of this study was to test whether intrathecal QX-314 has similar properties. METHODS: We conducted a randomized, double-controlled, blinded study with female CD-1 mice. Animals in the treatment group received lumbar intrathecal QX-314 (0.5-10 mM; volume, 2 microl; each concentration, n = 6). Normal saline and lidocaine (70 mM) served as negative and positive controls (each group, n = 12), respectively. Animals were tested for up to 3 h for lumbosacral neural blockade and observed for adverse effects. RESULTS: No animal injected with saline and 11 of 12 (92%) animals injected with lidocaine displayed reversible lumbosacral motor blockade (P < 0.001). QX-314 (5 mM) produced motor blockade in four of the six (67%) and sensory blockade in five of the six animals (83%; P < 0.05 vs. saline). However, six of the six mice (100%) at 5 mM QX-314 and five of the six (83%) at 10 mM exhibited marked irritation; one of the six animals at 5 mM (17%) and two of the six at 10 mM (33%) died. We observed no neural blockade without adverse effects in any animal injected with QX-314. All animals injected with saline and 11 of the 12 (92%) animals injected with lidocaine demonstrated normal behavior. CONCLUSION: Lumbar intrathecal QX-314 concentration-dependently produced irritation and death in mice, at lower concentrations than those associated with robust motor blockade. Although QX-314 did produce long-lasting neural blockade, these findings indicate that QX-314 is unlikely to be a suitable candidate for spinal anesthesia in humans.

Analgesic properties of the novel amino acid, isovaline.

BACKGROUND: Isovaline, a nonproteinogenic alpha-amino acid rarely found in the biosphere, is structurally similar to the inhibitory neurotransmitters glycine and gamma-aminobutyric acid. Because glycine(A) and gamma-aminobutyric acid receptor agonists are antiallodynic, we hypothesized that isovaline produces antinociception in mice. METHODS: All experiments were performed on female CD-1 mice using a blinded, randomized, and controlled design. The effects of RS-isovaline were studied on nociceptive responses to (1) formalin injection into the hindpaw; (2) glutamate injection into the hindpaw; and (3) strychnine injection either into the lumbar intrathecal space or cisterna magna. We determined the effects of IV RS-isovaline (50, 150, or 500 mg/kg; n = 10/dose) or intrathecal RS-, R-, and S-isovaline, glycine, and beta-alanine into the lumbar intrathecal space (5-microL volumes of 60, 125, 250, and 500 mM; n = 9/dose/group) on the response to formalin in the paw. The response to 20 microL intraplantar glutamate (750 mM) was compared with glutamate (750 mM) coadministered with isovaline. We also determined the response to intraplantar strychnine. Lumbar intrathecal (100 microM) or intracisternal (200 microM) injections of strychnine into the lumbar intrathecal space or the cisterna magna were used to induce allodynia as a measure of glycine inhibitory dysfunction. The effects of intrathecal or intracisternal strychnine were compared with isovaline coapplied with the strychnine (n = 8/group). RESULTS: In the formalin paw test, IV isovaline did not change phase I but decreased phase II responses in a dose-dependent manner (50% effective dose = 66 mg/kg, n = 10, P < 0.01). There was no effect on rotarod performance, appearance, or behavior of the mouse, and no respiratory depression. Intrathecal isovaline, glycine, and beta-alanine attenuated phase I and II responses (P < 0.01 for each drug). In contrast to beta-alanine and glycine, isovaline at maximally effective doses did not produce scratching, biting, or agitation. Intrathecal RS- and S-isovaline attenuated phase I (P < 0.05 for each group) and RS-, R-, and S-isovaline attenuated phase II responses (P < 0.05 for each group), with no significant difference between the efficacies of R- and S-enantiomers. Localized strychnine-induced glycine inhibitory dysfunction was greatly reduced by intracisternal (P < 0.01) and intrathecal (P < 0.01) isovaline. Although intraplantar strychnine did not induce peripheral allodynia, high doses of isovaline did not block the peripheral allodynia induced by glutamate. CONCLUSIONS: Isovaline reduced responses in mouse pain models without producing acute toxicity, possibly by enhancing receptor modulation of nociceptive information.

Effects of local tramadol administration on peripheral glutamate-induced nociceptive behaviour in mice.

PURPOSE: The use of peripheral tramadol to block pain has been advocated. However, since its actions in the periphery have not been elucidated fully, we tested the hypothesis that peripheral tramadol blocks peripheral glutamate-induced nociceptive behaviour in mice. METHODS: First, we compared the duration of paw licking after intraplantar (ipl.) glutamate administration, with and without tramadol, using a randomized blinded controlled design. Next, we established the half maximal effective concentrations (EC(50s)) for local tramadol and reference compound lidocaine in the hot water tail-flick latency test and the glutamate-induced paw allodynia assay. RESULTS: Tramadol reduced glutamate-induced paw licking from 33 +/- 12 sec to 4 +/- 4 sec (mean +/- SD; t test, P < 0.05; n = 6 per group). The tramadol and lidocaine EC(50) nerve conduction blocks in the tail did not differ significantly (84 +/- 24 mM vs 69 +/- 5 mM, respectively). Although tramadol reduced glutamate-induced allodynia (EC(50), 46 +/- 13 mM), lidocaine was more potent (EC(50), 13 +/- 5 mM; Dixon's up-and-down method; P < 0.05). Tramadol was 2.5 times as effective at blocking nerve conduction in the tail compared with allodynia in the paw. CONCLUSIONS: Local tramadol administration blocked nociceptive behaviour in mice induced by peripheral glutamate. Compared with lidocaine, the relative potency of tramadol was lower for blocking glutamate-induced allodynia than for sensory nerve conduction blockade, suggesting the activation of a pronociceptive receptor system in the periphery.

QX-314 produces long-lasting local anesthesia modulated by transient receptor potential vanilloid receptors in mice.

BACKGROUND: The quaternary lidocaine derivative QX-314 is now known to produce long-lasting local anesthesia despite its positive charge. However, recent research suggests that the transient receptor potential vanilloid receptor agonist, capsaicin, should reduce the onset and offset times, whereas the transient receptor potential vanilloid receptor antagonist, capsazepine, should delay the onset time of sensory blockade by QX-314. METHODS: Sensory blockade in the tail of the conscious mouse was investigated using QX-314 2.5% in combination with capsaicin 0.1% and/or capsazepine (50 microg/ml). After tail injection, onset and offset times of local anesthesia were measured using the hot water tail-flick latency test. RESULTS: Capsaicin reduced the onset time of local anesthesia by QX-314 by more than 75% (Mann-Whitney test, P = 0.007; n = 10 per group) with no effect on the offset time of QX-314. For QX-314 without capsaicin, the onset and offset times were 23 min (interquartile range 15-30 min) and 300 min (interquartile range 285-375 min), respectively. For QX-314 with capsaicin, the onset and offset times were 4 min (interquartile range 3-8 min) and 360 min (interquartile range 285-435 min), respectively. In the antagonist study, capsazepine without added capsaicin decreased QX-314's efficacy, as 6 out of 9 mice did not develop sensory blockade after 90 min (Fisher exact test, P = 0.009). CONCLUSION: We have confirmed in a sensory blockade model that QX-314 is a local anesthetic with a slow onset and a long duration of reversible blockade. Capsaicin, a transient receptor potential vanilloid receptor agonist, accelerated QX-314's onset kinetics, whereas capsazepine, a transient receptor potential vanilloid receptor antagonist, decreased QX-314's efficacy. These observations raise the possibility that endovanilloids may modulate cell entry of QX-314.

A novel wavelet-based index to detect epileptic seizures using scalp EEG signals.

In this paper, we propose a novel wavelet-based algorithm for the detection of epileptic seizures. The algorithm is based on the recognition of rhythmic activities associated with ictal states in surface EEG recordings. Using a moving-window analysis, we first decomposed each EEG segment into a wavelet packet tree. Then, we extracted the coefficients corresponding to the frequency band of interest defined for rhythmic activities. Finally, a normalized index sensitive to both the rhythmicity and energy of the EEG signal was derived, based on the resulting coefficients. In our study, we evaluated this combined index for real-time detection of epileptic seizures using a dataset of approximately 11.5 hours of multichannel scalp EEG recordings from three patients and compared it to our previously proposed wavelet-based index. In this dataset, the novel combined index detected all epileptic seizures with a false detection rate of 0.52/hr.

Electroconvulsive therapy: a model for seizure detection by a wavelet packet algorithm.

Electroconvulsive therapy (ECT) is an effective treatment for severe depression. In this paper, we have used an algorithm based on wavelet packet (WP) analysis of EEG signals to detect seizures induced by ECT. After determining dominant frequency bands in the ictal period during ECT, the energy ratio of these bands was computed using the corresponding WP coefficients. This ratio was then used as an index to recognize seizure periods. Four different approaches to detect ECT seizures were employed in 41 EEG recordings from nine patients. Sensitivity in ECT seizure detection ranged from 76 to 95% while the false detection rate ranged from 6 to 13.

The quaternary lidocaine derivative, QX-314, produces long-lasting local anesthesia in animal models in vivo.

BACKGROUND: QX-314 is a quaternary lidocaine derivative considered to be devoid of clinically useful local anesthetic activity. However, several reports document that extracellular QX-314 application affects action potentials. Hence, the authors tested the hypothesis that QX-314 could produce local anesthesia in animal models in vivo. METHODS: The authors tested QX-314 (10, 30, and 70 mM) in three standard in vivo local anesthetic animal models, using a randomized, blinded experimental design with negative (placebo) and positive (70 mM lidocaine) controls. The guinea pig intradermal wheal assay (n = 29) was used to test for peripheral inhibition of the cutaneous trunci muscle reflex, the mouse tail-flick test (n = 30) was used to test for sensory blockade, and the mouse sciatic nerve blockade model (n = 45) was used to test for motor blockade. RESULTS: In all three animal models, QX-314 concentration-dependently and reversibly produced local anesthesia of long duration, at concentrations equivalent to those clinically relevant for lidocaine. In the guinea pig intradermal wheal assay, QX-314 produced peripheral nociceptive blockade up to 6 times longer than lidocaine (650 +/- 171 vs. 100 +/- 24 min [mean +/- SD]; n = 6 per group; P < 0.0001). In the mouse tail-flick test, QX-314 produced sensory blockade up to 10 times longer than lidocaine (540 +/- 134 vs. 50 +/- 11 min; n = 6 per group; P < 0.0001). Finally, in the mouse sciatic nerve model, QX-314 produced motor blockade up to 12 times longer compared with lidocaine (282 +/- 113 vs. 23 +/- 10 min; n = 9 or 10 per group; P < 0.0001). The onset of QX-314-mediated blockade was consistently slower compared with lidocaine. Animals injected with saline exhibited no local anesthetic effects in any of the three models. CONCLUSION: In a randomized, controlled laboratory study, the quaternary lidocaine derivative, QX-314, concentration-dependently and reversibly produced long-lasting local anesthesia with a slow onset in animal models in vivo. The authors' results raise the possibility that quaternary ammonium compounds may produce clinically useful local anesthesia of long duration in humans and challenge the conventional notion that these agents are ineffective when applied extracellularly.

Quantifying cortical activity during general anesthesia using wavelet analysis.

This paper reports on a novel method for quantifying the cortical activity of a patient during general anesthesia as a surrogate measure of the patient's level of consciousness. The proposed technique is based on the analysis of a single-channel (frontal) electroencephalogram (EEG) signal using stationary wavelet transform (SWT). The wavelet coefficients calculated from the EEG are pooled into a statistical representation, which is then compared to two well-defined states: the awake state with normal EEG activity, and the isoelectric state with maximal cortical depression. The resulting index, referred to as the wavelet-based anesthetic value for central nervous system monitoring (WAV(CNS)), quantifies the depth of consciousness between these two extremes. To validate the proposed technique, we present a clinical study which explores the advantages of the WAV(CNS) in comparison with the BIS monitor (Aspect Medical Systems, MA), currently a reference in consciousness monitoring. Results show that the WAV(CNS) and BIS are well correlated (r = 0.969) during periods of steady-state despite fundamental algorithmic differences. However, in terms of dynamic behavior, the WAV(CNS) offers faster tracking of transitory changes at induction and emergence, with an average lead of 15-30 s. Furthermore, and conversely to the BIS, the WAV(CNS) regains its preinduction baseline value when patients are responding to verbal command after emergence from anesthesia. We conclude that the proposed analysis technique is an attractive alternative to BIS monitoring. In addition, we show that the WAV(CNS) dynamics can be modeled as a linear time invariant transfer function. This index is, therefore, well suited for use as a feedback sensor in advisory systems, closed-loop control schemes, and for the identification of the pharmacodynamic models of anesthetic drugs.

Seizure detection by a novel wavelet packet method.

We describe a novel wavelet-based method for the detection of seizure in patients with temporal lobe epilepsy. This method uses local discriminant bases and cross- data entropy algorithms to identify nodes of a wavelet packet dictionary that best discriminate preictal from ictal EEG signals. The algorithms are based on relative entropy criterion as a measure of discrepancy between different classes of signals. The frequency bands associated with these nodes were in the range of interest for seizure events. After selecting two bands, we determined the ratio of energies at the level of wavelet packet chosen by the cross-data entropy algorithm. Preliminary results demonstrate that the wavelet packet energy ratio could serve as a robust criterion in seizure detection.

Under "real world" conditions, desflurane increases drug cost without speeding discharge after short ambulatory anesthesia compared to isoflurane.

PURPOSE: To compare the measured "real world" perioperative drug cost and recovery associated with desflurane- and isoflurane-based anesthesia in short (less than one hour) ambulatory surgery. METHODS: We conducted a prospective, randomized, blinded trial with patients undergoing arthroscopic meniscectomy under general anesthesia. Following iv induction, patients received either isoflurane (group I; n = 25) or desflurane (group D; n = 20) for maintenance. The primary outcome variable was total perioperative drug cost per patient in Canadian dollars. Secondary outcome variables included volatile agent consumption and cost, adjuvant anesthetic and postanesthesia care unit (PACU) drug cost, readiness for PACU discharge, and incidence of adverse events. RESULTS: Total perioperative drug cost per patient was 14.58 +/- 6.83 Canadian dollars (mean +/- standard deviation) for group I, and 21.47 +/- 5.18 Canadian dollars for group D (P < 0.001). Isoflurane consumption per patient was 6.0 +/- 3.0 mL compared to 18.6 +/- 7.7 mL for desflurane (P < 0.0001); corresponding costs were 0.83 +/- 0.42 Canadian dollars vs 7.61 +/- 3.15 Canadian dollars (P < 0.0001). There were no differences in adjuvant anesthetic or PACU drug cost. All but one patient from each group were deemed ready for PACU discharge at 15 min postoperatively (Aldrete score >or= 9). One patient in group D experienced postoperative nausea. No other adverse events were noted. CONCLUSIONS: Measured total perioperative drug cost for a short ambulatory procedure (less than one hour) under general anesthesia was higher when desflurane rather than isoflurane was used for maintenance, essentially due to volatile agent cost. Desflurane use did not translate into faster PACU discharge under "real world" conditions.

Propofol reduces cognitive impairment after electroconvulsive therapy.

BACKGROUND: Cognitive impairments are the main complication after electroconvulsive therapy (ECT). Modification of treatment parameters has been shown to affect the magnitude of these impairments, but the role of anesthetic type remains unclear. This study tested whether there is a difference in cognitive impairments immediately after ECT with propofol compared to thiopental anesthesia. METHODS: This randomized, double-blind, crossover study included 15 patients receiving right unilateral ECT for depression. Patients received propofol or thiopental on alternating ECTs up to 6 treatments. Immediate and delayed verbal memory, motor speed, reaction speed, visuospatial, and executive functions were assessed 45 minutes after each ECT. Differences were assessed with repeated measures analysis of variance. RESULTS: Cognitive impairments were reduced after ECT with propofol compared to thiopental. Time to emergence was quicker and EEG seizure duration was shorter after propofol treatments. There was no significant correlation between seizure duration and neuropsychological test performance. CONCLUSIONS: Our results indicate that cognitive impairments in the early recovery period after ECT are reduced with propofol compared to thiopental anesthesia. We suggest that, in addition to ECT parameters, the type of anesthetic agent should be considered to reduce cognitive impairments after ECT.

The effect of repeated isoflurane anesthesia on spatial and psychomotor performance in young and aged mice.

UNLABELLED: Exposure to general anesthesia may contribute to postoperative cognitive impairment in elderly patients, but the relationship remains poorly understood. We investigated whether aged mice, 18-19 mo, are more susceptible to postanesthetic cognitive impairment than young mice, 3-4 mo, using spatial memory (Barnes maze) and psychomotor (rotarod) tasks. Initially we studied the effect of a single anesthetic episode on asymptotic maze performance. We then tested whether repeated anesthesia would impair spatial memory and psychomotor performance to a greater extent in aged mice. Mice were anesthetized with isoflurane (1.4% atm) for 30 min; controls received 90% oxygen. Anesthesia, administered during the asymptotic period of maze learning, did not impair performance tested the following day (P > 0.05). Repeated anesthesia, 2-3 h after each session, did not impair overall maze or rotarod performance in young or aged mice (P > 0.05). Spatial learning appeared to be facilitated by anesthesia, F(1,204) = 7.97, P < 0.01 for pooled results. Asymptotic performance-when learning had stabilized-remained unimpaired in both the maze and rotarod tasks. These results suggest that an age-related risk of anesthetic-induced impairment appears to be limited to acquisition of a novel motor skill and that anesthesia alone does not lead to prolonged cognitive impairments in aged mice. IMPLICATIONS: This study demonstrates that repeated isoflurane general anesthesia impaired psychomotor performance in aged mice during the initial learning period; however, spatial learning improved and, overall, spatial memory and psychomotor performance were unimpaired. Thus, general anesthesia alone does not appear to result in prolonged cognitive deficits in aged mice.

Quantifying uncertainty bounds in anesthetic PKPD models.

A major challenge faced when designing controllers to automate anesthetic drug delivery is the large variability that exists between and within patients. This intra- and inter-patient variability have been reported to lead to instability. Hence, defining and quantifying uncertainty bounds provides a mean to validate the control design, ensure its stability and assess performance. In this work, the intra- and inter-patient variability measured from thiopental induction data is used to define uncertainty bounds. It is shown that these bounds can be reduced by up to 40% when using a patient-specific model as compared to a population-normed model. It is also shown that identifying only the overall static gain of the patient system already decreases significantly this uncertainty.