Population pharmacokinetics of dexmedetomidine during long-term sedation in intensive care patients.

BACKGROUND: Dexmedetomidine is a highly selective and potent α(2)-adrenoceptor agonist registered for sedation of patients in intensive care units. There is little information on factors possibly affecting its pharmacokinetics during long drug infusions in critically ill patients. We characterized the pharmacokinetics of dexmedetomidine in critically ill patients during long-term sedation using a population pharmacokinetic approach. METHODS: Twenty-one intensive care patients requiring sedation and mechanical ventilation received dexmedetomidine with a loading dose of 3-6 µg kg(-1) h(-1) in 10 min and a maintenance dose of 0.1-2.5 µg kg(-1) h(-1) for a median duration of 96 h (range, 20-571 h). Cardiac output (CO), laboratory and respiratory parameters, and dexmedetomidine concentrations in arterial plasma were measured. The pharmacokinetics was determined by population analysis using linear multicompartment models. RESULTS: The pharmacokinetics of dexmedetomidine was best described by a two-compartment model. The population values (95% confidence interval) for elimination clearance, inter-compartmental clearance, central volume of distribution, and volume of distribution at steady state were 57.0 (42.1, 65.6), 183 (157, 212) litre h(-1), 12.3 (7.6, 17.0), and 132 (96, 189) litre. Dexmedetomidine clearance decreased with decreasing CO and with increasing age, whereas its volume of distribution at steady state was increased in patients with low plasma albumin concentration. CONCLUSIONS: The population pharmacokinetics of dexmedetomidine was generally in line with results from previous studies. In elderly patients and in patients with hypoalbuminaemia, the elimination half-life and the context-sensitive half-time of dexmedetomidine were prolonged.

Tinnitus complaint behaviour in long-standing Menière's disorder: its association with the other cardinal symptoms.

OBJECTIVE: To explore factors that determines tinnitus complaint behaviour in patients with chronic long-standing Menière's disorder. DESIGN AND SETTING: A questionnaire-based cross-sectional investigation. This included the Oto-neurological questionnaire, the Hearing Disability and Handicap Scale (HDHS), Hearing Measurement Scale (HMS) on sound localisation and the Dizziness Handicap Questionnaire (DHQ). PARTICIPANTS: Randomly selected 183 members of the Finnish Menière's Federation. INTERVENTION: Postal questionnaire. MAIN OUTCOME MEASURE: International Tinnitus Inventory and impact of tinnitus. RESULTS: The 183 patients,[36 men and 147 women; mean age, 63 years] had their Meniere's disorder-like symptoms, with a mean of 18 years [range, 1-43], 19% of patients ranked tinnitus as their most severe symptom, and 10% experienced tinnitus as causing a severe or very severe impact. Regression analysis indicated that 41% of International Tinnitus Inventory variance and 28% of tinnitus impact variance were explained by the cardinal symptoms of Menière's disorder. Furthermore, 40% of International Tinnitus Inventory and 25% of tinnitus impact variance were explained by symptom-related disabilities (HDHS, HMS and DHQ). Aural pressure, hearing loss and gait problems were the most important predictors of tinnitus complaint. Understanding what people say and limitation of activities because of vertigo were the most important related disabilities. CONCLUSION: Tinnitus shares a significant variance with the other cardinal symptoms in patients with long-standing Menière's disorder. As the impact is significantly related to activity limitations based on hearing disability and vertigo, the results suggest that therapeutic efforts to reduce tinnitus in Menière's disorder should include the alleviation of balance and hearing problems.

Effects of nitric oxide synthase inhibition on dexmedetomidine-induced vasoconstriction in healthy human volunteers.

BACKGROUND: This study aimed to assess the contribution of endothelial nitric oxide synthesis to the net responses of human peripheral blood vessels in vivo to the selective alpha(2)-adrenoceptor agonist dexmedetomidine. METHODS: Two groups of healthy young men were studied. In the first experiment, after brachial plexus block, the responses of digital arteries to systemically administered dexmedetomidine (target plasma concentration 1.2 ng ml(-1)) were studied using a photoplethysmograph (n=10) during i.a. infusions of saline and the nitric oxide synthase (NOS) inhibitor N(G)-monomethyl-L-arginine (L-NMMA) (8 micromol min(-1)). In a separate experiment, after pre-treatment with acetylsalicylic acid, responses to increasing doses of dexmedetomidine (0.01-164 ng min(-1)) in the presence and absence of L-NMMA were compared in dorsal hand veins (DHV) (n=10) using linear variable differential transformers. RESULTS: L-NMMA significantly augmented dexmedetomidine-induced vasoconstriction of digital arteries as assessed by an increase in light transmission through a finger and by a decrease in finger temperature. The mean (95% confidence interval) extent of the additional effect of L-NMMA over the constrictor effect of dexmedetomidine alone was 19% (14-24) (P<0.0001). In DHV, L-NMMA had variable effects on the dexmedetomidine-constriction dose-response curve. In three subjects, the curve was shifted significantly to the left (with a >10-fold difference in ED(50)), but ED(50) was only marginally affected by L-NMMA in the other subjects (difference in ED(50)

I.V. ropivacaine compared with lidocaine for the treatment of tinnitus.

BACKGROUND: I.V. lidocaine has been used to ameliorate tinnitus, but in general its effect has been limited. The longer acting local anaesthetic ropivacaine may be more effective. METHODS: A total of 19 randomized, double-blind, cross-over study patients suffering from chronic tinnitus were given a 30 min i.v. infusion of ropivacaine or lidocaine 1.5 mg kg(-1) at an interval of 2-3 months. The intensity of tinnitus was evaluated on tinnitus handicap inventory (THI) scale and on the visual analogue scale (VAS). Plasma ropivacaine and lidocaine concentrations were determined. RESULTS: In both treatments, the infusion decreased the VAS score significantly. At the end of infusion, a > or =50% reduction in VAS score was observed in five patients by ropivacaine and in one patient by lidocaine, but this effect was sustained for 1 h only in three patients. However, the THI scores did not differ significantly within or between treatments. On the post-infusion day, three patients after ropivacaine and five after lidocaine treatment had > or =30% improvement in the THI score. Four weeks later, one patient after ropivacaine and two after lidocaine had a > or =30% reduction in the THI score. One patient developed seizures soon after ropivacaine infusion from which he recovered uneventfully. His plasma concentration of ropivacaine was 1817 ng ml(-1). The highest individual ropivacaine and lidocaine concentrations were 3483 and 1680 ng ml(-1), respectively. CONCLUSIONS: Temporary clinically significant alleviation of tinnitus was observed only in a few individuals after both i.v. ropivacaine and lidocaine. The toxicity of ropivacaine limits its usefulness.

Value of imaging studies in vertiginous children.

OBJECTIVE: Imaging of the head is expensive and can be stressful for children, some of whom need anesthesia for the procedure. The aim of this study was to determine which vertiginous children benefit most from head imaging. METHODS: We conducted a retrospective chart review of all children aged under 18 years who were referred to the Helsinki University Children's Hospital Radiology Department (tertiary referral center) for head computerized tomography (CT) or magnetic resonance imaging (MRI) over a 1-year period. We analyzed and reviewed the medical records of 87 children who had undergone imaging of the head due to vertigo. RESULTS: Altogether 978 children underwent imaging of the head for various indications. Of these, 87 aged 0-16 years (mean age 8 years) were imaged because of vertigo. Abnormalities were seen in the images of 37 children; 23 were new findings and 14 showed no change in comparison to earlier deviant images. The most common abnormalities in head imaging were brain tumors, infections, multiple sclerosis lesions, and other lesions in T2-weighted images. Of the 23 vertiginous children with a new finding, 19 also had neurological deficits. While four children had no neurological symptoms, three had intense headaches. CONCLUSIONS: Head imaging is necessary for vertiginous children with neurological deficits or persistent headaches or who have sustained a head trauma. If vertigo is the only symptom without trauma, imaging studies will not aid diagnostic work-up.

What is Menière's disease? A contemporary re-evaluation of endolymphatic hydrops.

Menière's disease is a chronic condition with a prevalence of 200-500 per 100,000 and characterized by episodic attacks of vertigo, fluctuating hearing loss, tinnitus, aural pressure and a progressive loss of audiovestibular functions. Over 150 years ago, Prosper Menière was the first to recognize the inner ear as the site of lesion for this clinical syndrome. Over 75 years ago, endolymphatic hydrops was discovered as the pathologic correlate of Menière's disease. However, this pathologic finding could be ascertained only in post-mortem histologic studies. Due to this diagnostic dilemma and the variable manifestation of the various audiovestibular symptoms, diagnostic classification systems based on clinical findings have been repeatedly modified and have not been uniformly used in scientific publications on Menière's disease. Furthermore, the higher level measures of impact on quality of life such as vitality and social participation have been neglected hitherto. Recent developments of high-resolution MR imaging of the inner ear have now enabled us to visualize in vivo endolymphatic hydrops in patients with suspected Menière's disease. In this review, we summarize the existing knowledge from temporal bone histologic studies and from the emerging evidence on imaging-based evaluation of patients with suspected Menière's disease. These indicate that endolymphatic hydrops is responsible not only for the full-blown clinical triad of simultaneous attacks of auditory and vestibular dysfunction, but also for other clinical presentations such as "vestibular" and "cochlear Menière's disease". As a consequence, we propose a new terminology which is based on symptomatic and imaging characteristics of these clinical entities to clarify and simplify their diagnostic classification.

Control of sway using vibrotactile feedback of body tilt in patients with moderate and severe postural control deficits.

We evaluated the effect of the vibrotactile display of body tilt upon the postural stability of vestibulopathic subjects during standing. Two groups were studied: those with moderate and with severe deficits as defined by postural stability test scores. They were studied under conditions of distorted sensory input, and during anterior-posterior perturbations. Seventeen subjects, with uni- or bilateral vestibular deficits, as determined by electronystagmography and vertical axis rotation, were tested using Equitest computerized dynamic posturography (CDP). Based on their performance on the CDP they were divided into two groups having either moderate (nine subjects) or severe (eight subjects) postural control deficits. Their anterior-posterior (A/P) body motion at the waist was measured with a micromechanical rate gyroscope and a linear accelerometer. The resulting tilt estimate was displayed by a vibrotactile array attached to the torso. The vibration served as a tilt feedback to the subject. The subject's performance was evaluated using the root-mean-square (RMS) of both the A/P body motion and center-of-pressure (CoP) estimates. Sensory distortions were introduced using the Equitest Sensory Organization Tests (SOT). These tests are designed to distort A/P sensory inputs while standing. The SOT 5 distorts proprioceptive information about ankle joint movement, while the subject stands eyes-closed on a moving support platform that measures foot pressure. The SOT 6 adds distorted visual information about body movement instead of testing with eyes closed. Perturbations were introduced using the Equitest Motor Control Tests (MCT). These move the support platform forward or backward with small, medium and large displacements in the horizontal plane while measuring subjects' foot pressure responses. We used the medium and large backward tests. Vibrotactile display of body tilt reduced the subjects' A/P sway and improved their balance. The finding was more evident for those subjects with severe deficits than those moderate ones. This trend was found for both SOT 5 and 6, as well as the medium and large MCT. Additionally, during the MCT, the peak deflection and mean recovery time also decreased significantly.

Effect of age and repeated hyperbaric oxygen treatments on vagal tone.

OBJECTIVES: To evaluate the influence of repeated hyperbaric oxygen (HBO2) exposures and age on vagal response to hyperbaric oxygenation, and to evaluate the timing of changes in vagal activity during the treatments. STUDY DESIGN: Open, controlled, non-randomized study. METHODS: Heart rate variability of 23 patients with chronic osteomyelitis or radionecrosis of the jaw or reconstructive surgery of the facial region was studied during repeated treatments. During each treatment, the patients were exposed to HBO2 at 2.5 ATA and heart rate variability was measured using power spectral analysis before compression, three times at 2.5 ATA and during and after decompression. The patients were grouped according to age (Cut-off point 50 years). Statistical analysis was carried out using analysis of variance for repeated measurements. RESULTS: Repeated exposures did not change vagal response to hyperbaric oxygenation. Vagal activity measured by HF power increased significantly in both age groups during the HBO2 exposures but there were no significant difference between the groups in the response. However, the level of HF power was significantly higher in the subjects under 50 years old. Significant differences between consecutive measurements were related to pressure changes. CONCLUSIONS: Repeated therapeutic HBO2exposures are not causing permanent changes in vagal control of the heart. Vagal responsiveness to hyperbaric hyperoxia is preserved in advanced age.

Stimulated expression of cyclooxygenase-2 in porcine heart after bypass circulation and cardioplegic arrest.

OBJECTIVES: Cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) enzymes catalyze the initial step in the formation of prostaglandins, which have a role in the regulation of circulation and in inflammatory reactions. As hypoxia is reported to stimulate the expression of COX-2, we have investigated the effects of bypass circulation and cardioplegic arrest on the expression COX-1 and COX-2 in the myocardium of porcine hearts. METHODS: Anaesthetized pigs were connected to cardiopulmonary bypass and the hearts were arrested by cold crystalloid cardioplegia for 30 min and reperfused thereafter for 90 min. Then the mRNA and protein levels of COX-1 and COX-2 were measured from the transmural specimens of the left ventricular myocardium by Northern and Western blot analyses. Reference specimens were from the hearts of unoperated control pigs and from sham-operated pigs, which were connected to cardiopulmonary bypass for 120 min without any aortic clamping. RESULTS: COX-1 mRNA was expressed in unoperated control porcine hearts, whereas the expression of COX-2 mRNA was weak in control hearts. The expression of COX-2 mRNA increased to 170% of the control level in the hearts of sham-operated pigs and to 180% in arrested hearts, while the level of COX-1 mRNA was not changed. Both COX-1 and COX-2 proteins were detected by Western blot analysis in the myocardial specimens of control hearts. After cardioplegic arrest, the level of COX-2 protein increased to 280% of the control level in arrested hearts, whereas the level of COX-1 protein remained unchanged. CONCLUSIONS: These results indicate that the expression of the COX-2 gene is stimulated in the ventricular myocardium of the porcine heart after bypass circulation and cardioplegic arrest.

Short-lasting drop attacks in Meniere's disease.

OBJECTIVES: To study the vertigo attacks known as Tumarkin attacks or drop attacks (DA). DA are characterized by sudden loss of balance with or without falls but with preserved consciousness, and they are supposedly triggered by changes in the otolith function of Meniere's disease (MD). STUDY DESIGN AND SETTING: Data from 243 consecutive MD patients were collected into a database of an otoneurologic expert system. RESULTS: DA was experienced by 72% (n = 173) of the patients with MD. It correlated with visually provoked vertigo. Gait difficulties, tinnitus, and anxiety were more common in the DA group. Long lasting vertigo attacks were more frequently provoked in the DA subjects by physical strain (58% vs 14%), head movements or changes in head position (71% vs 48%), pressure changes (54% vs 12%), or rapid movements in visual surroundings (65% vs 35%) than in the non-DA subjects. CONCLUSION: DA are common in MD patients. The abrupt occurrence of DA make them poorly tolerated. SIGNIFICANCE: DA are more common in advanced MD.

Database for vertigo.

An interactive database has been developed to assist the diagnostic procedure for vertigo and to store the data. The database offers a possibility to split and reunite the collected information when needed. It contains detailed information about a patient's history, symptoms, and findings in otoneurologic, audiologic, and imaging tests. The symptoms are classified into sets of questions on vertigo (including postural instability), hearing loss and tinnitus, and provoking factors. Confounding disorders are screened. The otoneurologic tests involve saccades, smooth pursuit, posturography, and a caloric test. In addition, findings from specific antibody tests, clinical neurotologic tests, magnetic resonance imaging, brain stem audiometry, and electrocochleography are included. The input information can be applied to workups for vertigo in an expert system called ONE. The database assists its user in that the input of information is easy. If not only can be used for diagnostic purposes but is also beneficial for research, and in combination with the expert system, it provides a tutorial guide for medical students.

Production of diagnostic rules from a neurotologic database with decision trees.

A decision tree is an artificial intelligence program that is adaptive and is closely related to a neural network, but can handle missing or nondecisive data in decision-making. Data on patients with Meniere's disease, vestibular schwannoma, traumatic vertigo, sudden deafness, benign paroxysmal positional vertigo, and vestibular neuritis were retrieved from the database of the otoneurologic expert system ONE for the development and testing of the accuracy of decision trees in the diagnostic workup. Decision trees were constructed separately for each disease. The accuracies of the best decision trees were 94%, 95%, 99%, 99%, 100%, and 100% for the respective diseases. The most important questions concerned the presence of vertigo, hearing loss, and tinnitus; duration of vertigo; frequency of vertigo attacks; severity of rotational vertigo; onset and type of hearing loss; and occurrence of head injury in relation to the timing of onset of vertigo. Meniere's disease was the most difficult to classify correctly. The validity and structure of the decision trees are easily comprehended and can be used outside the expert system.

Comparison between diagnoses of human experts and a neurotologic expert system.

The decision-making ability of a recently developed neurotologic expert system was compared with the diagnoses of six physicians. Five of the physicians were residents and one was a specialist in the field of otolaryngology. The test patients were randomly selected from vertiginous patients referred to an otolaryngology clinic. The expert system and the physicians first had identical information on patient history, symptoms, and tests. During the second phase of the study the physicians were allowed to use the full medical records. The correct diagnoses were certified by an experienced specialist in neurotology. The expert system did better in decision-making when both the expert system and the physicians had identical information on patients. However, when the physicians were allowed to use patient's complete medical records, they surpassed the expert system. The expert system diagnosed 65% of the cases, while the physicians first diagnosed 54% of the cases, and then with complete information, 69% of the cases. From the patients' medical records, the physicians obtained information on the time perspective of the symptoms and the progression of the disease. These aspects will be used to further improve the expert system.

Discovering diagnostic rules from a neurotologic database with genetic algorithms.

Data on patients with Meniere's disease, vestibular schwannoma, traumatic vertigo, sudden deafness, benign paroxysmal positional vertigo, or vestibular neuritis were retrieved from the database of otoneurologic expert system ONE for the development and testing of a genetic algorithm (GA). The accuracy of the diagnostic rules in solving the test cases was 81%, 91%, 92%, 95%, 96%, and 98% for the respective diseases. The best rules retrieved from the GA were described by a set of questions with the most likely answers. The most important questions concerned the duration of hearing loss and the occurrence of head injury. The validity and structure of the rules created with a GA can be analyzed in detail. For rare diseases, some other reasoning process can be used, for example, case-based reasoning.

Otoneurological expert system.

An otoneurological expert system was developed to help collect data and diagnose both central and peripheral diseases causing vertigo. Patient history and otoneurological and other examination results are used in the reasoning process. The case history data can be either mandatory or supportive. Mandatory questions are used to confirm a diagnosis, and conflicting answers are used to reject an unlikely disease. Supportive questions support or suppress a diagnosis, but their presence is not obligatory. The reasoning procedure of the otoneurological expert system scores every question independently for different diagnoses, depending on how well they agree with the symptom entity of a disease. Diagnostic criteria are set for each disease. Graphic displays illustrate the linear and nonlinear correlation between the symptoms and diseases. Emphasis is placed on diminishing the possibility of a wrong decision rather than maximizing the likelihood of reaching only one right decision, so that even rare diseases can be taken into consideration.

Otoneurological expert system for vertigo.

We have developed an otoneurological expert system (ONE) to aid the diagnostics of vertigo, to assist teaching and to implement a database for research. The ONE database is set to harvest data on patient history, signs and test results necessary for diagnostic work with vertiginous patients. A method based on pattern recognition was used in the reasoning process. Questions about symptoms, signs and test results are weighted and scored for each disease and the most likely disease is recognized from defined disease profiles. Missing information and uncertainties are solved with a method resembling fuzzy logic. ONE was validated by comparing diagnoses assessed by physicians with those provided by the system. It proved to be a valid decision-maker by solving 65% of the cases correctly, while the physicians' mean was 69%. To improve ONE further, a follow-up should be implemented for the patients, since diagnosing sudden deafness and Meniere's disease during the first visit is often impossible. We aim to obtain new information on diseases involving vertigo by applying adaptive computer applications, such as genetic algorithms, to the reasoning process.

Usefulness of imputation for the analysis of incomplete otoneurologic data.

The usefulness of imputation in the treatment of missing values of an otoneurologic database for the discriminant analysis was evaluated on the basis of the agreement of imputed values and the analysis results. The data consisted of six patient groups with vertigo (N=564). There were 38 variables and 11% of the data was missing. Missing values were filled in with the means, regression and Expectation-Maximisation (EM) imputation methods and a random imputation method provided the baseline results. Means, regression and EM methods agreed on 41-42% of the imputed missing values. The level of agreement between these and the random method was 20-22%. Despite the moderate agreement between the means, regression and EM methods, the discriminant functions were similar and accurate (prediction accuracy 83-99%). The discriminant functions obtained from the randomly imputed data were also accurate having prediction accuracy 88-97%. Imputation seems to be a useful method for treating the missing data in this database. However, a lot of data was missing in otoneurologic tests, which are likely to be of less importance in the diagnosis of vertiginous patients. Consequently, the disagreement of the methods did not affect clearly the discriminant analysis, and, therefore, future research requires more complete data and advanced imputation methods.

Postural instability in Meniere's disease.

In order to characterize the postural instability by duration of Meniere's disease (MD) we present the results of 180 MD patients tested on posturography. The duration of the disease varied from 4 weeks to 36 years. The patients were clinically examined and they had filled a questionnaire concerning their symptoms. Postural instability was examined by a force platform posturography and the results are expressed as sway velocities (SV). There was no statistically significant difference in the mean SV between groups of different duration of MD. The number of the patients with normal eyes open SV declined by duration of the illness from 73% to 38% but the decline was not statistically significant. The mean age in the different duration groups of MD varied from 47 to 61 years. In general 58% of the patients had their eyes open SV in normal range and 55% when measured eyes closed. When examining the SV between the 4 different hearing stages of MD we found that those belonging into the group III (pure tone average [PTA] 41-70 dB) had significantly higher eyes open and eyes closed SV's than the patients in the group I (PTA under 25 dB).