Reduced anesthetization during the intracarotid amobarbital (Wada) test in patients taking carbonic anhydrase-inhibiting medications.

PURPOSE: Failure to show adequate anesthetization during the intracarotid amobarbital procedure (IAP or "Wada test") is a rare complication. After an unusually high rate of recent anesthetization failures, we sought to determine the frequency of reduced anesthetization and any common factors underlying these failures. METHODS: We reviewed the records of all patients who underwent IAP tests through the UCLA Seizure Disorder Center between September 1999 and May 2002. Age, date, epileptogenic focus, radiologist, and current medications were all considered. RESULTS: Of a total of 56 patients who underwent our intracarotid amobarbital examination, 11 (19.6%) showed either very rapid recovery (/=8 weeks after discontinuation of such medications.

Contribution of neuropsychology to epilepsy surgery.

Surgical treatment is being used with increasing frequency for patients with intractable epilepsy. Operative success depends to a large degree on the results of a comprehensive pre-operative patient evaluation the main purpose of which is to delineate the epileptogenic lesion. The pre-operative assessment includes video EEG monitoring, structural and functional (fMRI) neuroimaging and neuropsychological evaluation. The likelihood of the success of surgery is increased when all test results point to a single epileptogenic focus. The unique contribution of neuropsychology, which includes standard neuropsychological assessment and intracarotid sodium amytal (Wada) testing, is its capability to predict lateralization and often localization of a brain lesion based on cognitive function and dysfunction, which can be demonstrated also in the absence of a structural lesion. The Wada test is used to determine the cerebral speech dominance, to predict postsurgical amnesia and is found to be useful in predicting laterality of seizure focus in candidates for temporal lobectomy.

Determination of language dominance with near-infrared spectroscopy: comparison with the intracarotid amobarbital procedure.

PURPOSE: To determine the efficacy of near-infrared spectroscopy (NIRS) in identifying the hemisphere associated with language by measuring changes in bilateral lateral inferior frontal blood flow during a word generation task in epilepsy surgery patients and healthy volunteers. METHODS: Sixteen patients who underwent the intracarotid amobarbital procedure (IAP) and eight healthy right-handed/right-footed individuals were tested with NIRS during a word generation paradigm. RESULTS: Increases in lateral inferior frontal total hemoglobin concentrations agreed with the IAP in 11 of 16 patients, including 2 of 3 with right hemisphere (atypical) speech dominance (P = 0.13). NIRS revealed increases in lateral inferior frontal total hemoglobin concentrations congruent with language dominance predicted by handedness/footedness in 18 of 24 subjects, including 100% of healthy right-handed subjects (P = 0.02). CONCLUSION: NIRS is a simple, non-invasive, safe modality for measuring cerebral blood flow. Further research and development of testing procedures and instrumentation are needed before routine implementation in pre-surgical testing.

Affective self-report during the intracarotid sodium amobarbital test: group differences.

Emotional reactions are sometimes observed during the intracarotid sodium amobarbital test. For instance, euphoric/indifference reactions can be seen during right hemisphere inactivation and catastrophic reactions may accompany left hemisphere inactivation. Less dramatic changes can also be detected in affective self-report during left and right hemisphere amobarbital tests, with more negative affect reported during left hemisphere inactivation and either neutral or mildly positive affective states reported during right hemisphere inactivation. The current study not only replicated this effect, but in addition, found significant group differences. The first group (right way) showed a pattern of affective self-report during left and right amobarbital tests entirely consistent with prior findings, while a second group (wrong way) showed results that behaved in a diametrically opposite fashion. A third group (no change) showed little, if any, difference in affective self-report during left and right amobarbital tests. The major factor distinguishing the wrong way group from the other two appeared to be an asymmetrical distribution of left and right temporal lobe lesions in the former group. In contrast, the factor differentiating the right way group from the no change group appeared to be the relative degree of left hemisphere inactivation during the left hemisphere amobarbital test. The results are discussed not only in terms of their impact on theories of cerebral lateralization for emotion, but also in terms of methodological issues in this field.

In vitro and in vivo evaluation of an amylobarbitone/hydroxypropyl-beta-cyclodextrin complex prepared by a freeze-drying method.

The complex formation of amylobarbitone (AMB) with 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CD) was investigated in aqueous solution and in the solid state. The apparent stability constant for complex formation (Kc) calculated by phase solubility and spectral shift methods was 524 M-1 and 568 M-1, respectively. The stoichiometric molar ratio of the complex was estimated to be 1:1 and the solubility of AMB in water was increased about 3 fold. The solid dispersion system of AMB/HP-beta-CD in 1:1 molar ratio was prepared by a freeze-drying method. Differential scanning calorimetry (DSC), x-ray diffractometry, (IR) and 1H NMR spectroscopy were used to confirm that inclusion between the drug and HP-beta-CD occurred. The dissolution behavior of the drug as a physical mixture as well as the prepared complex, showed enhanced drug dissolution properties of the prepared complex compared to the physical mixture or the drug alone. The dissolution rate appeared in the first 2 min, 25 times greater for the complex than for the drug alone. Furthermore, in-vivo study revealed that the duration and hypnotic activity of AMB after its oral administration to mice were improved by inclusion.

Cerebral amobarbital sodium distribution during Wada testing: utility of digital subtraction angiography and single-photon emission tomography.

We aimed to determine if the cerebral distribution of anesthetic during Wada testing is reflected by findings on digital subtraction angiography (DSA) and single-photon emission computed tomography (SPECT) and if the findings on these studies are relevant to the outcome of the Wada test. We carried out selective internal carotid artery (ICA) DSA on 29 patients underwent studies prior to a Wada test. In patients without angiographic cross-filling, amobarbital and a radiotracer were injected into each ICA, beginning with the epileptogenic side. In patients with cross-filling, the ICA ipsilateral to the epileptogenic focus was injected with amobarbital and radiotracer while other was injected with amobarbital alone. We analyzed the DSA studies for cross-filling and filling of the posterior cerebral arteries (PCA). We reviewed the SPECT for activity in the territories of the anterior, middle cerebral, and posterior cerebral arteries. We compared the results of both studies with the success or failure of the neuropsychological portion of the Wada test. In 20 patients without cross-filling, the results of DSA and SPECT were comparable: symmetrical hemisphere activity was seen. In nine patients with cross-filling, SPECT showed bilateral, almost symmetrical activity. Filling or nonfilling of the PCA correlated with activity (or lack of it) in the medial temporal and occipital regions in all patients. The Wada test was considered successful in all patients. The findings on SPECT did not alter interpretation of the Wada test and we suggest that it may not be needed in all patients undergoing Wada testing.

Absence of correlation between amobarbital distribution as assessed with SPECT brain perfusion imaging and behavioral manifestations during the intracarotid amobarbital procedure (Wada test).

1. The IAP is used presurgically in patients with temporal lobe epilepsy to predict the effects on LTM and language of the planned temporal lobectomy. This prognosis presumes that a similar pattern of perfusion will result in anesthesia of the same cerebral regions in most patients. 2. Coinjection of Tc-99m HMPAO with the barbiturate during the IAP has been used to ascertain whether this actually is true, with variable results. Moreover, most studies document only unilateral IAPs and do not report on behavioral performance. 3. The authors coinjected Tc-99m HMPAO and amobarbital in 33 IAPs from 18 patients (15 injected bilaterally, 3 unilaterally) to clarify this and to evaluate the relationship of the perfusion pattern to behavioral performance; SPECT results were also compared to angiographic evaluation obtained at the time of catheter placement. 4. SPECT perfusion data was rated for presence/absence and intensity of perfusion to the ACA, MCA, PCA territories and to H, i or c to the injection site. V, STM and LTM were graded according to a standardized protocol. 5. MCAi was perfused in 100% of cases, ACAi in 91%, PCAi in 21% and Hi in only 6%. Cross-over flow was shown in 9 studies; 50% of the patients in whom both sides were injected (on different days) had crossover, involving the ACAc territory in 80% of cases. As expected, injection on the non-ES was associated with a significantly worse LTM performance than on the ES (p = 0.006). There was no relationship between the perfusion pattern and the V level of the patients (a potential confounding variable in memory/language evaluation) during IAP, nor between perfusion pattern and LTM. STM was significantly adversely affected by the presence of crossover perfusion. Angiography in general overestimated the extent of cerebral perfusion demonstrated by SPECT, most probably because of the markedly different injection conditions. 6. Despite the best efforts to standardize injections, the perfusion pattern has been mostly unpredictable in the patients. Moreover, it has little bearing on their behavioral performance, except for the prediction of poor STM performance (the clinical implications of this remaining dubious). Marked LTM alterations after non-ES injections confirm remote hippocampal effects in the presence of only rare direct perfusion of that region. Tc-99m HMPAO/Amobarbital coinjection was unhelpful from a clinical perspective, most probably because a large part of the effects of amobarbital arise from deafferentation of regions not directly perfused by the anesthetic agent.

Regional cerebral perfusion and amytal distribution during the Wada test.

UNLABELLED: The distribution of sodium amytal and its effect on regional cerebral perfusion during the intracarotid amytal (Wada) test were investigated using high-resolution hexamethyl propyleneamine oxime (HMPAO) SPECT coregistered with the patient's MRI dataset. METHODS: Twenty patients underwent SPECT after intravenous HMPAO injection, and 5 patients had both intravenous and intracarotid injections in a double injection-acquisition protocol. RESULTS: All patients had hypoperfusion in the territories of the anterior and middle cerebral arteries. Basal ganglia perfusion was preserved in 20 of 25 patients. Hypoperfusion of the entire mesial temporal cortex was seen in 9 of 25 patients. Partial hypoperfusion of the whole mesial cortex or hypoperfusion of part of the mesial cortex was seen in 14 of 25 patients. In 2 of 25 patients, mesial temporal perfusion was unaffected. In 5 patients, the double acquisition showed a distribution of HMPAO delivery matching that of hypoperfusion, except for the following: (a) HMPAO was delivered to the basal ganglia and insula, where there was no hypoperfusion; (b) HMPAO was not delivered to the contralateral cerebellum, which did show hypoperfusion; and (c) in 1 patient, perfusion of the mesial temporal cortex was preserved despite intracarotid delivery of HMPAO. CONCLUSION: Some degree of hypoperfusion of medial temporal structures occurs in the great majority of patients during the Wada test. Partial inactivation of memory structures is therefore a credible mechanism of action of the test. The double acquisition protocol provided no evidence that mesial temporal structures are inactivated remotely by diaschisis. Perfusion in the basal ganglia and insular cortex is not affected by amytal.

Functional MRI and the Wada test provide complementary information for predicting post-operative seizure control.

Prediction of post-surgical seizure relief and potential cognitive deficits secondary to anterior temporal lobectomy (ATL) are important to pre-surgical planning. Although the intracarotid amobarbital test (IAT) is predictive of post-ATL seizure outcome, development of non-invasive and more precise means for determining post-ATL seizure relief are needed. We previously reported on a technique utilizing functional MRI (fMRI) to evaluate the relative functional adequacy of mesial temporal lobe structures in preparation for ATL. In the present study, we report follow-up outcome data on eight temporal lobe epilepsy (TLE) patients 1-year post-ATL who were evaluated pre-surgically using IAT and fMRI. Functional memory lateralization using fMRI predicted post-ATL seizure outcome as effectively as the IAT. In general, asymmetry of functional mTL activation favouring the non-epileptic hemisphere was associated with seizure-free status at 1-year follow-up. Moreover, when combined, fMRI and IAT provided complementary data that resulted in improved prediction of post-operative seizure control compared with either procedure alone.

HPLC analysis for amobarbital N-glycosides in urine.

A study was undertaken to determine if humans excrete both amobarbital N-glucuronides and N-glucosides in urine after an oral dose of amobarbital. Amobarbital N-glucuronides were synthesized and characterized. A reverse phase LC method using post-column pH adjustment and UV detection at 240 nm was developed and used for the quantification of the amobarbital N-glucosides and N-glucuronides in human urine. Amobarbital was administered orally to seven male subjects and the total urine was collected for a period of 48-53 h after dosing. After filtration, the urine was injected directly onto the HPLC column to analyze for the presence of metabolites. The previously identified (5S)-amobarbital N-glucoside was detected in all seven subjects. The (5R)-amobarbital N-glucoside was detected at lower concentrations in only four of the subjects. At the levels at which amobarbital N-glucosides were detected, there was no evidence for the formation and excretion of the amobarbital N-glucuronides. Amobarbital N-glucuronidation is not a quantitatively significant pathway for the biodisposition of amobarbital in humans.

Estimation of amobarbital plasma-effect site equilibration kinetics. Relevance of polyexponential conductance functions.

The time delay between drug plasma concentrations and effect has been modeled most commonly by the effect compartment approach, assuming first-order monoexponential equilibrium kinetics between plasma and effect site. So far this assumption has not been rigorously probed. The purpose of the present investigation was to model the delay between amobarbital plasma concentrations and EEG effect using a new approach based on system analysis principles. This approach models the equilibrium between plasma and effect site without assuming a specific kinetic structure. Assuming linear distribution kinetics between plasma and effect site, the relationship between the two variables may be described by a convolution type of linear operation, involving a conductance function phi(t), which is approximated by a sum of exponentials. Six male Wistar-derived rats received an iv infusion of amobarbital at a rate of 10 mg/kg per min until isoelectric periods of 5 sec or longer appeared on the EEG. Frequent arterial blood samples were obtained and EEG was continuously quantified using aperiodic analysis. The amplitudes in the 2.5-30 Hz frequency band were used as EEG effect measure. The delay between plasma concentrations and EEG effect was best modeled by a biexponential conductance function. The use of a biexponential conductance function resulted in a significant further reduction (41 +/- 10%) in hysteresis when compared to a monoexponential function, indicating that the assumption of simple first-order monoexponential equilibration kinetics is inadequate. The use of a biexponential conductance function also resulted in a significantly different shape of the effect site concentration-EEG effect relationship and hence the estimated pharmacodynamic parameters, when compared with a monoexponential function. This relationship showed a biphasic behavior, with EEG effects being maximal at amobarbital concentrations of 29.6 +/- 1.3 mg/L. At 80.2 +/- 2.0 mg/L the EEG effect was reduced 50% below baseline values. A comparison was made with the equilibration between amobarbital plasma and cerebrospinal fluid (CSF) concentrations. Six male Wistar-derived rats received an iv infusion of amobarbital, 10 mg per min for 15 min. Arterial blood and CSF samples were taken simultaneously at regular intervals. The equilibration between plasma and CSF concentrations was best fitted by a monoexponential conductance function. Significant differences in equilibration profiles of CSF and effect site with the plasma site were observed. To reach 50% equilibrium the effect site requires 2.5 +/- 0.3 min and the CSF 3.5 +/- 0.2 min, to reach 95% the values were, respectively, 90 +/- 27 and 15 +/- 1 min. This suggests that CSF is kinetically distinguishable from the effect site.

Biophase equilibration times.

Various methods for describing how quickly a drug equilibrates at the biophase are proposed. The biophase equilibration time (BET) is the time it takes the biophase drug level to reach a given percentage (p) of its predicted steady state in a drug administration that leads to a steady-state condition. The time to reach biophase equilibrium may be defined as the BET value for p = 95, and the 50% biophase equilibration time is obtained when p = 50. Biophase equilibration profiles (BEPs), obtained by plotting p versus BET, give a dynamic representation of the approach to equilibrium and may serve as an indicator of the rate of drug delivery to the biophase. A pharmacodynamic system analysis method is proposed to determine BETs and BEPs from the biophase conduction function. The approach is demonstrated using pharmacodynamic data from the CNS effect of amobarbital evaluated by an aperiodic analysis of EEG recordings. The relevance of the BET and/or BEP principles in optimal computer-controlled drug infusion, drug design, and evaluation of targeted drug delivery is discussed. Both vascular and extravascular drug administrations are considered in the analysis.

Post-mortem drug redistribution--a toxicological nightmare.

Detailed human case data is presented to illustrate the dramatic extent of the phenomenon of post-mortem drug redistribution. The data suggests that there is a post-mortem diffusion of drugs along a concentration gradient, from sites of high concentration in solid organs, into the blood with resultant artefactual elevation of drug levels in blood. Highest drug levels were found in central vessels such as pulmonary artery and vein, and lowest levels were found in peripheral vessels such as subclavian and femoral veins. In individual cases, in multiple blood samples obtained from ligated vessels, concentrations of doxepin and desmethyldoxepin ranged from 3.6 to 12.5 mg/l and 1.2 to 7.5 mg/l, respectively; amobartital, secobarbital and pentobarbital from 4.3 to 25.8 mg/l, 3.9 to 25.3 mg/l and 5.1 to 31.5 mg/l respectively; clomipramine and desmethylclomipramine from 4.0 to 21.5 mg/l and 1.7 to 8.1 mg/l, respectively and flurazepam 0.15 to 0.99 mg/l; imipramine and desipramine from 4.1 to 18.1 mg/l and 1.0 to 3.6 mg/l, respectively. We conclude that this poorly studied phenomenon creates major difficulties in interpretation and undermines the reference value of data bases where the site of origin of post-mortem blood samples is unknown.