The effects of aneurysmal subarachnoid hemorrhage on cerebral vessel diameter and flow velocity.

BACKGROUND: Transcranial Doppler flow velocity is used to monitor for cerebral vasospasm following aneurysmal subarachnoid hemorrhage. Generally, blood flow velocities appear inversely related to the square of vessel diameter representing local fluid dynamics. However, studies of flow velocity-diameter relationships are few, and may identify vessels for which diameter changes are better correlated with Doppler velocity. We therefore studied a large retrospective cohort with concurrent transcranial Doppler velocities and angiographic vessel diameters. METHODS: This is a single-site, retrospective, cohort study of adult patients with aneurysmal subarachnoid hemorrhage, approved by the UT Southwestern Medical Center Institutional Review Board. Study inclusion required transcranial Doppler measurements within 1.1, R2>0.9). Furthermore, velocity and diameter changed (P<0.033) consistent with the signature time course of cerebral vasospasm. CONCLUSIONS: These results suggest that middle cerebral artery velocity-diameter relationships are most influenced by local fluid dynamics, which supports these vessels as preferred endpoints in Doppler detection of cerebral vasospasm. Other vessels showed less influence of local fluid dynamics, pointing to greater role of factors outside the local vessel segment in determining flow velocity.

Fast-onset lidocaine block of rat NaV1.4 channels suggests involvement of a second high-affinity open state.

Local anesthetics (LAs) block resting, open, and inactivated states of voltage-gated Na(+) channels where inactivated states are thought to bind with highest affinity. However, reports of fast-onset block occurring over milliseconds hint at high-affinity block of open channels. Movement of voltage-sensor domain IV-segment 4 (DIVS4) has been associated with high affinity LA block termed voltage-sensor block (VSB) that also leads to a second open state. These observations point to a second high-affinity open state that may underlie fast-onset block. To test for this state, we analyzed the modulation of Na(+) currents by lidocaine and its quaternary derivative (QX222) from heterologously expressed (Xenopus laevis oocytes) rat skeletal muscle µ1 NaV1.4 (rSkM1) with ß1 (WT-ß1), and a mutant form (IFM-QQQ mutation in the III-IV interdomain, QQQ) lacking fast inactivation, in combination with Markov kinetic gating models. 100 µM lidocaine induced fast-onset (τonset≈2 ms), long-lived (τrecovery≈120 ms) block of WT-ß1 macroscopic currents. Lidocaine blocked single-channel and macroscopic QQQ currents in agreement with our previously described mechanism of dual, open-channel block (DOB mechanism). A DOB kinetic model reproduced lidocaine effects on QQQ currents. The DOB model was extended to include trapping fast-inactivation and activation gates, and a second open state (OS2); the latter arising from DIVS4 translocation that precedes inactivation and exhibits high-affinity, lidocaine binding (apparent Kd=25 µM) that accords with VSB (DOB-S2VSB mechanism). The DOB-S2VSB kinetic model predicted fast-onset block of WT-ß1. The findings support the involvement of a second, high-affinity, open state in lidocaine modulation of Na(+) channels.

Psychophysiological Stress Indicators of Heart Rate Variability and Electrodermal Activity With Application in Healthcare Simulation Research.

STATEMENT: Psychological stress arises from a stressor placed on an individual that leads to both emotional and physiological responses. The latter is referred to as psychophysiological stress. Healthcare simulation provides a platform to investigate stress psychobiology and its effects on learning and performance. However, psychophysiological stress measures may be underused in healthcare simulation research. The inclusion of such measures with subjective measures of stress in healthcare simulation research provides a more complete picture of the stress response, thereby furthering the understanding of stress and its impact on learning and performance. The goals of this article were to review 2 commonly used psychophysiological stress measures involving heart rate variability and electrodermal activity reflecting sweat gland activity and to demonstrate their utility in an example pilot study in healthcare simulation research.

In vitro and in vivo properties of 3-tert-butyl-7-(5-methylisoxazol-3-yl)-2-(1-methyl-1H-1,2,4-triazol-5-ylmethoxy)-pyrazolo[1,5-d]-[1,2,4]triazine (MRK-016), a GABAA receptor alpha5 subtype-selective inverse agonist.

3-tert-Butyl-7-(5-methylisoxazol-3-yl)-2-(1-methyl-1H-1,2,4-triazol-5-ylmethoxy)-pyrazolo[1,5-d][1,2,4]triazine (MRK-016) is a pyrazolotriazine with an affinity of between 0.8 and 1.5 nM for the benzodiazepine binding site of native rat brain and recombinant human alpha1-, alpha2-, alpha3-, and alpha5-containing GABA(A) receptors. It has inverse agonist efficacy selective for the alpha5 subtype, and this alpha5 inverse agonism is greater than that of the prototypic alpha5-selective compound 3-(5-methylisoxazol-3-yl)-6-[(1-methyl-1,2,3-triazol-4-hdyl)methyloxy]-1,2,4-triazolo[3,4-a]phthalazine (alpha5IA). Consistent with its greater alpha5 inverse agonism, MRK-016 increased long-term potentiation in mouse hippocampal slices to a greater extent than alpha5IA. MRK-016 gave good receptor occupancy after oral dosing in rats, with the dose required to produce 50% occupancy being 0.39 mg/kg and a corresponding rat plasma EC(50) value of 15 ng/ml that was similar to the rhesus monkey plasma EC(50) value of 21 ng/ml obtained using [(11)C]flumazenil positron emission tomography. In normal rats, MRK-016 enhanced cognitive performance in the delayed matching-to-position version of the Morris water maze but was not anxiogenic, and in mice it was not proconvulsant and did not produce kindling. MRK-016 had a short half-life in rat, dog, and rhesus monkey (0.3-0.5 h) but had a much lower rate of turnover in human compared with rat, dog, or rhesus monkey hepatocytes. Accordingly, in human, MRK-016 had a longer half-life than in preclinical species ( approximately 3.5 h). Although it was well tolerated in young males, with a maximal tolerated single dose of 5 mg corresponding to an estimated occupancy in the region of 75%, MRK-016 was poorly tolerated in elderly subjects, even at a dose of 0.5 mg, which, along with its variable human pharmacokinetics, precluded its further development.

Intraoperative bladder perforation during primary total hip arthroplasty.

We present a unique case of bladder perforation occurring intraoperatively during primary total hip arthroplasty. It is suspected that the patient's aberrant bladder anatomy, with idiopathic erosion of the quadrilateral space, predisposed the patient to bladder injury. Several preoperative risk factors for bladder injury were identified in the literature. These factors include cemented acetabular components, previous history of hip arthroplasty, history of pelvic trauma or intrapelvic surgery, and poor bone quality. Management of bladder injury, should it occur, includes bladder decompression with a Foley catheter, antibiotic administration, hemodynamic monitoring, and urology consult with close follow-up. This case reinforces the importance of urologic preoperative evaluation for anatomic variations of the bladder. In such cases, intraoperative Foley catheters to prevent distension may reduce the risk of perforation.

Physostigmine reverses cognitive dysfunction caused by moderate hypoxia in adult mice.

BACKGROUND: Cognitive changes associated with moderate hypoxia in rodents may result from the diminished functioning of central cholinergic neurotransmission. We designed this study to examine whether treatment with physostigmine (PHY), an acetylcholinesterase inhibitor, could improve the impairment of working memory after hypoxic hypoxia. METHODS: We randomized 90 Swiss Webster, 30-35 g mice (6-8 wks) to three hypoxia groups at fraction of inspired oxygen, FiO2 = 0.10 (1. no treatment; 2. PHY 0.1 mg/kg intraperitoneally administered immediately before; or 3. after hypoxia), or to two room air groups (given either no treatment or PHY after an insult). An object recognition test was used to assess short-term memory function. The object recognition test exploits the tendency of mice to prefer exploring novel objects in an environment when a familiar object is also present. During the 15 min training trial, two identical objects were placed in two defined sites of the box. During the test trial performed 1 h later, one of the objects was replaced by a new object with a different shape. The time spent exploring the two objects was automatically recorded by a video camera and associated software. The performance was analyzed with ANOVA, followed by post hoc comparisons using the Newman-Keuls test when appropriate. P values <0.05 were considered significant. RESULTS: Untreated mice subjected to hypoxia at Fio2 = 0.1 spent significantly less time exploring a novel object on testing day 1 than did untreated mice breathing room air. Performance of the mice subjected to hypoxia, who received physostigmine after, but not before, the insult did not differ from the control group. CONCLUSION: Moderate hypoxia impairs rodents' performance in a working memory task. It appears that changes are transient, because the cognitive functioning of the mice returned to the baseline level 7 days after treatment. Postinsult administration of PHY prevented deterioration of cognitive function. An increased level of acetylcholine in the central nervous system may be responsible for the improved performance of the hypoxia-treated mice.

Isoflurane modulates activation and inactivation gating of the prokaryotic Na+ channel NaChBac.

Voltage-gated Na+ channels (Nav) have emerged as important presynaptic targets for volatile anesthetic (VA) effects on synaptic transmission. However, the detailed biophysical mechanisms by which VAs modulate Nav function remain unclear. VAs alter macroscopic activation and inactivation of the prokaryotic Na+ channel, NaChBac, which provides a useful structural and functional model of mammalian Nav Here, we study the effects of the common general anesthetic isoflurane on NaChBac function by analyzing macroscopic Na+ currents (INa) in wild-type (WT) channels and mutants with impaired (G229A) or enhanced (G219A) inactivation. We use a previously described six-state Markov model to analyze empirical WT and mutant NaChBac channel gating data. The model reproduces the mean empirical gating manifest in INa time courses and optimally estimates microscopic rate constants, valences (z), and fractional electrical distances (x) of forward and backward transitions. The model also reproduces gating observed for all three channels in the absence or presence of isoflurane, providing further validation. We show using this model that isoflurane increases forward activation and inactivation rate constants at 0 mV, which are associated with estimated chemical free energy changes of approximately -0.2 and -0.7 kcal/mol, respectively. Activation is voltage dependent (z ≈ 2e0, x ≈ 0.3), inactivation shows little voltage dependence, and isoflurane has no significant effect on either. Forward inactivation rate constants are more than 20-fold greater than backward rate constants in the absence or presence of isoflurane. These results indicate that isoflurane modulates NaChBac gating primarily by increasing forward activation and inactivation rate constants. These findings support accumulating evidence for multiple sites of anesthetic interaction with the channel.

Plasma ropivacaine levels during awake intracranial surgery.

Plasma ropivacaine levels produced by routine scalp infiltration for field block were assayed in eight patients undergoing awake intracranial surgery. Levels peaked within approximately 13 minutes, indicating rapid systemic absorption of ropivacaine. Potentially toxic plasma drug levels were achieved in three of eight patients, although no untoward effects attributable to elevated levels of ropivacaine were observed. Clinical vigilance is indicated during scalp infiltration with ropivacaine.

The distribution of cocaine in mice differs by age and strain.

Few studies have examined the influence of the age and the strain of mouse on the pharmacokinetics of psychostimulants, or the role of pharmacokinetics in age-related differences in drug responses. The present study compared concentrations of cocaine, and its metabolite, benzoylecgonine (BZE), in the blood and brain of early (P35) and later (P42) periadolescent and adult (P63) CD-1 and C57BL/6 male mice 15 min after acute intraperitoneal injection of cocaine (20 mg/kg). Brain levels of cocaine and BZE after seven daily cocaine injections in CD-1 and C57BL/6 mice beginning on P35 and on P63 were also measured. P35 periadolescents of both strains had lower blood cocaine levels than did the adults, but only C57BL/6 periadolescents had lower brain cocaine levels than the adults. C57BL/6 mice of both ages had higher blood cocaine levels than did the corresponding CD-1 mice. Concomitant with lower cocaine levels, periadolescent CD-1 mice had higher blood BZE levels than the adults, suggesting that periadolescents may metabolize cocaine faster. Brain cocaine levels in P42 C57BL/6 mice were similar to those of adults. Cocaine-induced activity did not differ between periadolescent and adult CD-1 mice after a single injection of cocaine, whereas periadolescent C57BL/6 mice had lower activity levels than did the adults after a single cocaine injection. Periadolescent CD-1 mice exhibited higher levels of locomotor activity following cocaine injection than did periadolescent C57BL/6 mice. Following chronic cocaine administration, cocaine and BZE levels in the brains of periadolescent and adult mice did not differ from each other in either strain. However, brain cocaine levels at both ages were lower in CD-1 mice than in C57BL/6 mice. In conclusion, the age and the strain of mouse significantly affect the levels of cocaine obtained in brain and blood following acute administration. Our data are consistent with the notion that CD-1 and C57BL/6 mice metabolize cocaine faster during the early periadolescent period than as adults. Furthermore, potentially important strain differences between CD-1 and C57BL/6 mice were noted in cocaine levels following acute and chronic cocaine administration, and in locomotor activity following acute cocaine administration.

Anesthetic complications in pediatric patients undergoing cochlear implantation.

OBJECTIVES/HYPOTHESIS: Cochlear implantation (CI) is effective in the treatment of childhood sensorineural hearing loss and is associated with minimal surgical complications. We investigated the incidence of anesthetic complications in young patients undergoing general anesthesia for CI. STUDY DESIGN: Retrospective chart review. METHODS: A retrospective chart review of 123 patients younger than 18 years, who underwent CI between 2007 and 2008, was conducted for identification of intra- and postoperative anesthesia-related complications. The relation of collected variable to the complication events was analyzed using logistic regression. RESULTS: Of the 123 CI procedures, eight patients had nine anesthesia-related complications, yielding a complication rate of 6.5% and included the following: postoperative wheezing/stridor (5 cases), laryngospasm (3 cases), and emesis during inhalational induction (1 case). Divided by age group, 12 patients were <12 months with one complication (8%), 18 patients were between 1 and 2 years with one complication (5.6%), 35 patients were between 2 and 5 years with one complication (3%), 39 patients were between 5 and 12 years with five complications (13%), and 19 patients were older than 12 years with no complication (0%). Logistic regression failed to identify a significant association of any collected variable(s) with the observed complications. The incidence of complications is similar to that previously reported in elderly patients (4.3%) (Pearson χ(2) , P = .523). CONCLUSIONS: General anesthesia is well tolerated by pediatric patients undergoing CI, even under 1 year of age. Significant perioperative complications are primarily respiratory, are usually free of long-term sequelae, and occur with an incidence similar to other reported age groups.

Pentobarbital produces activation and block of {alpha}1{beta}2{gamma}2S GABAA receptors in rapidly perfused whole cells and membrane patches: divergent results can be explained by pharmacokinetics.

Millimolar concentrations of the barbiturate pentobarbital (PB) activate gamma-aminobutyric acid (GABA) type A receptors (GABARs) and cause blockade reported by a paradoxical current increase or "tail" upon washout. To explore the mechanism of blockade, we investigated PB-triggered currents of recombinant alpha(1)beta(2)gamma(2S) GABARs in whole cells and outside-out membrane patches using rapid perfusion. Whole cell currents showed characteristic bell-shaped concentration dependence where high concentrations triggered tail currents with peak amplitudes similar to those during PB application. Tail current time courses could not be described by multi-exponential functions at high concentrations (> or =3,000 microM). Deactivation time course decayed over seconds and was slowed by increasing PB concentration and application time. In contrast, macropatch tail currents manifested eightfold greater relative amplitude, were described by multi-exponential functions, and had millisecond rise times; deactivation occurred over fractions of seconds and was insensitive to PB concentration and application time. A parsimonious gating model was constructed that accounts for macropatch results ("patch" model). Lipophilic drug molecules migrate slowly through cells due to avid partitioning into lipophilic subcellular compartments. Inclusion of such a pharmacokinetic compartment into the patch model introduced a slow kinetic component in the extracellular exchange time course, thereby providing recapitulation of divergent whole cell results. GABA co-application potentiated PB blockade. Overall, the results indicate that block is produced by PB concentrations sixfold lower than for activation involving at least three inhibitory PB binding sites, suggest a role of blocked channels in GABA-triggered activity at therapeutic PB concentrations, and raise an important technical question regarding the effective rate of exchange during rapid perfusion of whole cells with PB.

Nimodipine prevents transient cognitive dysfunction after moderate hypoxia in adult mice.

BACKGROUND: Cognitive changes associated with moderate hypoxia may be related to the elevation of cytosolic calcium (Ca) levels which may, in turn, affect neurotransmitter synthesis and metabolism. We tested whether treatment with nimodipine (NIMO), an L-type Ca channel blocker, would preserve working memory after hypoxic hypoxia. METHODS: We randomized 157 Swiss-Webster, 30 to 35 g mice (6 to 8 wk) to 6 groups, which were exposed to the following gas mixtures for 1 hour: (1) O2 21%; (2) O2 21% followed by 0.1 mg/kg of subcutaneous NIMO; (3) O2 21% followed by vehicle (60% polyethylene glycol/40% methanol); (4) O2 10%; (5) O2 10% then NIMO; (6) O2 10% then vehicle. The Object Recognition Test (ORT) was given once either on Day 1 or Day 7 to assess changes in short-term memory. ORT exploits the tendency of mice to prefer novel over familiar objects. Two identical objects were placed in an arena for 15 minutes of training. During the testing 1 hour later, one of the objects was replaced by a new object. Recognition Index (RI) was used to compare performance. It is defined as the time spent exploring the novel object divided by the time spent exploring both objects, the novel plus the familiar, and this ratio is converted to a percentage. RI was analyzed with analysis of variance. Tukey Honestly Significant Difference tests were used for post hoc comparisons when appropriate. P values <0.05 were considered significant. RESULTS: RI for the control group was 68.3% (SE+/-3.6%). RI was 53.7% (SE+/-3.8%) for the 10% O2 group on the first posttreatment day. O2 saturation (SpO2) for the hypoxic group was 71.7% (SE+/-0.5%). By Day 7, RI for the 10% O2 group increased to 64.2% (SE+/-4.7%), which was not significantly different from control. On Day 1, RI was 68.6% (SE+/-5.2%) for hypoxic rodents treated with NIMO. These results were statistically significant. Low RI indicates impaired working memory and high RI indicates intact working memory. These results suggest that NIMO prevented impairment of working memory after moderate hypoxia. CONCLUSIONS: NIMO reverses the disturbance of short-term working memory caused by moderate hypoxia in mice. The results may have implications for cognitive changes linked to Ca homeostasis in the postoperative period.

Halothane inhibition of recombinant cardiac L-type Ca2+ channels expressed in HEK-293 cells.

BACKGROUND: Volatile anesthetics depress cardiac contractility, which involves inhibition of cardiac L-type calcium channels. To explore the role of voltage-dependent inactivation, the authors analyzed halothane effects on recombinant cardiac L-type calcium channels (alpha1Cbeta2a and alpha1Cbeta2aalpha2/delta1), which differ by the alpha2/delta1 subunit and consequently voltage-dependent inactivation. METHODS: HEK-293 cells were transiently cotransfected with complementary DNAs encoding alpha1C tagged with green fluorescent protein and beta2a, with and without alpha2/delta1. Halothane effects on macroscopic barium currents were recorded using patch clamp methodology from cells expressing alpha1Cbeta2a and alpha1Cbeta2aalpha2/delta1 as identified by fluorescence microscopy. RESULTS: Halothane inhibited peak current (I(peak)) and enhanced apparent inactivation (reported by end pulse current amplitude of 300-ms depolarizations [I300]) in a concentration-dependent manner in both channel types. alpha2/delta1 coexpression shifted relations leftward as reported by the 50% inhibitory concentration of I(peak) and I300/I(peak)for alpha1Cbeta2a (1.8 and 14.5 mm, respectively) and alpha1Cbeta2aalpha2/delta1 (0.74 and 1.36 mm, respectively). Halothane reduced transmembrane charge transfer primarily through I(peak) depression and not by enhancement of macroscopic inactivation for both channels. CONCLUSIONS: The results indicate that phenotypic features arising from alpha2/delta1 coexpression play a key role in halothane inhibition of cardiac L-type calcium channels. These features included marked effects on I(peak) inhibition, which is the principal determinant of charge transfer reductions. I(peak) depression arises primarily from transitions to nonactivatable states at resting membrane potentials. The findings point to the importance of halothane interactions with states present at resting membrane potential and discount the role of inactivation apparent in current time courses in determining transmembrane charge transfer.