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Background: In patients with non-communicating hydrocephalus impairment of cerebral compliance can occur pre- but also intraoperatively., Methodology: In such patients (n = 6) undergoing endoscopic third ventriculostomy (ETV), the present study aimed to investigate the effect of ETCO2 (e.g 40 mmHg and 60 mmHg) and positive end-expiratory pressure (PEEP) (e.g. 6 cm and 12 cm H2O) on intraventricular pressure (IVP)., Findings: Before but not after ETV, hypercapnia in contrast to PEEP increased IVP., Before Etv: (PEEP-6/ ETCO2-40: 2.6 ± 2.4 mmHg) vs. (PEEP-6/ ETCO2-60: 12 ± 6.4 mmHg*); (PEEP-12/ ETCO2-40: 4.2 ± 4.1 mmHg) vs. (PEEP-12/ ETCO2-60: 13.7 ± 7.6 mmHg*), * significant, P ≤ 0.05., After Etv: (PEEP-6/ ETCO2-40: 2.0 ± 1.2 mmHg) vs. (PEEP-6/ ETCO2-60: 4.4 ± 3.1 mmHg); (PEEP-12/ ETCO2-40: 1.6 ± 1.3 mmHg) vs. (PEEP-12/ ETCO2-60: 6.6 ± 2.6 mmHg), * significant, P ≤ 0.05)., Conclusion: Patients with non-communicating hydrocephalus showed that hypercapnia but not PEEP increases significantly IVP before but not after ETV., Competing Interests: Conflict of interest Conflict of interest statement: Authors state no conflict of interest., (© 2019 Werner Tiefenthaler et al., published by De Gruyter.)

A 79-year-old critically ill woman presented with remarkable prolongation of activated partial thromboplastin time and thrombin time combined with high levels of anti-factor IIa activity 26 days after coronary artery bypass grafting. Coagulation disorder was associated with severe bleeding. Cause of coagulopathy was accidental administration of argatroban in an unknown dosage. Clearance of argatroban was significantly prolonged because of a liver function disorder related to septic multiorgan failure. Argatroban reversal was performed with prothrombin complex concentrate.

Background: Bispectral index (BIS) monitoring of depth of anesthesia has pioneered the field for more recent monitoring devices like the A-line ARX Index (AAI) or the state (SE) and response entropy (RE) monitoring devices. Following an observational design the present study aimed to simultaneously compare in the same patient recorded BIS, AAI and entropy values., Methods: Data from patients (n = 32) undergoing minor gynecological operations were analyzed. For all patients, standardized anesthesia was used. Before induction of anesthesia AEP electrodes, BIS and entropy sensors were simultaneously placed on the forehead and recordings were started at 3 minutes before induction and continued until patient transfer to the postanesthesia care unit. Markers were set at defined landmarks., Results: Anesthesia reduced mean BIS, AAI and entropy values. During uneventful, and even more pronounced, during eventful anesthesia BIS/ entropy and BIS/ AAI values showed better correlation than did AAI and entropy values. The prediction probability (Pk) of AAI (0.824 ± 0.036) and RE (0.786 ± 0.040) or SE (0.781 ± 0.040) for preanesthesia awake, postanesthesia awake or anesthesia was comparable and significantly greater than that of BIS (0.705 ± 0.047). However, only 20% of BIS, AAI and entropy values simultaneously categorized the state of the patient as awake, inadequate anesthesia, optimal anesthesia or deep anesthesia., Conclusion: The prediction probability (Pk) of entropy and AAI was comparable and better than that of BIS. However, agreement between BIS, AAI and entropy measurements on patient state was poor., Competing Interests: Conflict of interest: Authors state no conflict of interest.

Background: Effective treatment of trauma-induced coagulopathy is important; however, the optimal therapy is still not known. We aimed to compare the efficacy of first-line therapy using fresh frozen plasma (FFP) or coagulation factor concentrates (CFC) for the reversal of trauma-induced coagulopathy, the arising transfusion requirements, and consequently the development of multiple organ failure., Methods: This single-centre, parallel-group, open-label, randomised trial was done at the Level 1 Trauma Center in Innsbruck Medical University Hospital (Innsbruck, Austria). Patients with trauma aged 18-80 years, with an Injury Severity Score (ISS) greater than 15, bleeding signs, and plasmatic coagulopathy identified by abnormal fibrin polymerisation or prolonged coagulation time using rotational thromboelastometry (ROTEM) were eligible. Patients with injuries that were judged incompatible with survival, cardiopulmonary resuscitation on the scene, isolated brain injury, burn injury, avalanche injury, or prehospital coagulation therapy other than tranexamic acid were excluded. We used a computer-generated randomisation list, stratification for brain injury and ISS, and closed opaque envelopes to randomly allocate patients to treatment with FFP (15 mL/kg of bodyweight) or CFC (primarily fibrinogen concentrate [50 mg/kg of bodyweight]). Bleeding management began immediately after randomisation and continued until 24 h after admission to the intensive care unit. The primary clinical endpoint was multiple organ failure in the modified intention-to-treat population (excluding patients who discontinued treatment). Reversal of coagulopathy and need for massive transfusions were important secondary efficacy endpoints that were the reason for deciding the continuation or termination of the trial. This trial is registered with ClinicalTrials.gov, number NCT01545635., Findings: Between March 3, 2012, and Feb 20, 2016, 100 out of 292 screened patients were included and randomly allocated to FFP (n=48) and CFC (n=52). Six patients (four in the FFP group and two in the CFC group) discontinued treatment because of overlooked exclusion criteria or a major protocol deviation with loss of follow-up. 44 patients in the FFP group and 50 patients in the CFC group were included in the final interim analysis. The study was terminated early for futility and safety reasons because of the high proportion of patients in the FFP group who required rescue therapy compared with those in the CFC group (23 [52%] in the FFP group vs two [4%] in the CFC group; odds ratio [OR] 25·34 [95% CI 5·47-240·03], p<0·0001) and increased needed for massive transfusion (13 [30%] in the FFP group vs six [12%] in the CFC group; OR 3·04 [0·95-10·87], p=0·042) in the FFP group. Multiple organ failure occurred in 29 (66%) patients in the FFP group and in 25 (50%) patients in the CFC group (OR 1·92 [95% CI 0·78-4·86], p=0·15)., Interpretation: Our results underline the importance of early and effective fibrinogen supplementation for severe clotting failure in multiple trauma. The available sample size in our study appears sufficient to make some conclusions that first-line CFC is superior to FFP., Funding: None., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

An increase of extensively drug-resistant Pseudomonas aeruginosa (XDR-PA) in various clinical specimens among intensive care unit patients (n = 7) initiated an outbreak investigation consisting of patient data analyses, control of adherence to infection control guidelines, microbiologic surveys, and molecular-based studies. XDR-PA was detected in a jointly used aroma-oil nursing bottle for aromatherapy. We implemented the restriction of oil sharing among patients. Hence, the outbreak was controlled successfully., (Copyright © 2017 Association for Professionals in Infection Control and Epidemiology, Inc. Published by Elsevier Inc. All rights reserved.)

Central venous catheters are usually positioned using the Seldinger technique with a guidewire. This article reports a case where the guidewire was inserted via the left subclavian vein with the landmark technique. The guidewire became kinked, pierced the vessel wall and became stuck forming several loops within the adjacent tissue of the vein. Several attempts were made to remove the guidewire by interventional radiology but were unsuccessful. Due to the critical condition of the patient an operation was considered too perilous and the guidewire was finally left in situ. No formation of local venous thrombosis could be detected.

In cardiosurgery patients atherosclerotic debris displaced from the cannulation site but also from the opposite aortic wall by the "sandblast-like" effect of the high-pressure jet emanating from the cannula is a potential source of intraoperative arterial embolization and consequently postoperative neurologic dysfunction. The present study examined the extent to which shear stress exerted on the intact aortic intima by an aortic cannula jet stream can cause endothelial lesions that promote thrombogenesis and consequently thrombembolism. A single-stream, straight-tip aortic cannula was used in a porcine cardiopulmonary bypass (CPB) model. Following a 120-minute CPB pump run, a 60-minute stabilization period was allowed before sacrificing the pigs (N.=40) for histological evaluation of the ascending aorta and the brain. Opposite the cannulation site endothelial lesions (diameter: 3.81±1.3 mm; depth: 0.017±0.003 mm) were present in 22.5% (9/40) of aortic specimens. Cerebral thrombembolic lesions were not found. The present study showed that single-stream, straight-tip aortic cannulas caused jet lesions of the formerly intact aortic endothelium opposite the cannulation site in 22.5% of cases in a porcine CPB model.

Background: Lornoxicam like other non-steroidal anti-inflammatory drugs (NSAIDs) is widely used for postoperative pain therapy. Evaluation of the effect of lornoxicam on cerebral processing of surgical pain was thus the aim of the present functional magnetic resonance imaging (fMRI) study., Methods: An fMRI-compatible pain model that mimics surgical pain was used to induce pain rated 4-5 on a visual analogue scale (VAS) at the anterior margin of the right tibia in volunteers (n=22) after i.v. administration of saline (n=11) or lornoxicam (0.1 mg kg(-1)) (n=11)., Results: Lornoxicam, which significantly reduced pain sensation [VAS: mean (sd) 4.6 (0.7) vs 1.2 (1.5)], completely suppressed pain-induced activation in the SII/operculum, anterior cingulate cortex, insula, parietal (inferior), prefrontal (inferior, medial), temporal (inferior, medial/superior) lobe, cerebellum, and contralateral (e.g. left-sided) postcentral gyrus (SI). Only the hippocampus and the contralateral superior parietal lobe (BA 7) were activated., Conclusions: As compared with saline, lornoxicam typically suppressed pain-induced brain activation in all regions except the hippocampus. Furthermore, de novo activation was found in the contralateral, superior parietal lobe (BA 7).

To assess the effect of caffeine on the functional MRI signal during a 2-back verbal working memory task, we examined blood oxygenation level-dependent regional brain activity in 15 healthy right-handed males. The subjects, all moderate caffeine consumers, underwent two scanning sessions on a 1.5-T MR-Scanner separated by a 24- to 48-h interval. Each participant received either placebo or 100 mg caffeine 20 min prior to the performance of the working memory task in blinded crossover fashion. The study was implemented as a blocked-design. Analysis was performed using SPM2. In both conditions, the characteristic working memory network of frontoparietal cortical activation including the precuneus and the anterior cingulate could be shown. In comparison to placebo, caffeine caused an increased response in the bilateral medial frontopolar cortex (BA 10), extending to the right anterior cingulate cortex (BA 32). These results suggest that caffeine modulates neuronal activity as evidenced by fMRI signal changes in a network of brain areas associated with executive and attentional functions during working memory processes.

The significant risk of cerebral embolism during cardiopulmonary bypass (CPB) makes monitoring of embolic events advisable already when developing new operation and coagulation management strategies for example in CPB animal models. The present study therefore evaluated in a porcine CPB model the feasibility of bilateral epicarotid Doppler signal recording and the quality of manual or automatic emboli detection. A total of 42 recordings (e.g. right carotid artery (n = 20), left carotid artery (n = 22)) were evaluated. The frequency of emboli counts was comparable for both carotid arteries. Automatic emboli detection, however, found significantly more embolic events per pig than did post-hoc manual off-line analysis of the recordings (172 +/- 217 vs. 13 +/-10). None of the brains, however, showed any emboli or infarction area either in cross-examination or in histological evaluation. In conclusion, the present study showed the feasibility of using an epicarotid Doppler device for bilateral emboli detection in a porcine CPB model. Automatic on-line emboli detection, however, reported more embolic events than did post hoc, off-line manual analysis. Possible reasons for this discrepancy are discussed.

The pig is a suitable animal model for researching blood coagulation and fibrinolysis. The present study therefore aimed to investigate in porcine blood the applicability of commercially available tests of coagulation and thrombelastography (ROTEM) and above all to determine normal values for coagulation parameters (e.g. prothrombin time (PT), activated partial thromboplastin time (aPTT), thrombin-antithrombin complexes (TAT), fibrinogen, antithrombin III (AT III), D-dimers, protein C). Except for the FibTEM and aPTT tests, all commercially available coagulation tests used were fully applicable for porcine blood. Normal values and reference intervals for porcine blood are given. As compared to the human reference intervals for the coagulation parameters investigated, porcine blood was found to be hypercoagulable.

This paper investigates the possible antinociceptive effect of systemically administered ciprofloxacin and gentamicin and its influence on intrathecal morphine-induced antinociception. Using thermal nociceptive tests (hot-plate test and tail-flick test) and a motor function test (catalepsy test) in male Sprague-Dawley rats (n=5-9/dose), the following observations were made: ciprofloxacin administered intraperitoneally in the dose range 4-64 mg/kg demonstrated a modest antinociceptive effect in both nociceptive tests. Solvent of ciprofloxacin (intraperitoneally) and saline (intraperitoneally), given as a control, showed no effect. Gentamicin, administered at a dose of 0.1-4 mg/kg intraperitoneally, demonstrated a significant (P<0.05) antinociceptive effect in the tail-flick test but not in the hot-plate test. However, opioid antagonists caused no significant change in the antibiotics. Furthermore, ciprofloxacin intraperitoneally produced a significant left-shift in the hot-plate test (ED50 saline-morphine=2.86 [CI 95%: 2.2, 4.32]microg; ED50 ciprofloxacin-morphine=0.87 (CI 95% 0.68, 1.21) microg, P<0.05) and in the tail-flick test (ED50 saline-morphine=1.98 (CI 95%: 1.21, 2.84) microg; ED50 ciprofloxacin-morphine=0.37 (CI 95%: 0.23, 0.44) microg; P<0.05) for intrathecal morphine-induced antinociception. From a comparison of these data with the predicted ciprofloxacin-morphine value (hot-plate test: 1.61 (CI 95%: 1.18, 2.51]microg; tail-flick test: 0.82 (CI 95%: 0.52, 1.92) microg) we estimate that ciprofloxacin and morphine produce at least additive effects (P>0.05). This was reversed with intraperitoneal naloxone (P<0.05). Gentamicin intraperitoneally did not influence the antinociception achieved with intrathecal administration of morphine (hot-plate test: ED50 gentamicin-morphine=2.71 (CI 95%: 2.35; 3.2) microg; tail-flick test: ED50 gentamicin-morphine=2.43 (CI 95%: 1.58; 5.22]microg; P>0.05). These data show that intraperitoneal administration of ciprofloxacin and gentamicin produces a modest antinociceptive effect in the hot-plate test and tail-flick test. Ciprofloxacin, but not gentamicin, can interact at least additively to increased naloxone-reversible morphine intrathecal antinociception. Differences in the ability to penetrate the blood-brain barrier between the two antibiotics could explain the lack of effect from gentamicin in the hot plate and on morphine-induced antinociception.

Background: The aim of the present investigation was to survey former participants (n=869) of a cadaver workshop using a mail questionnaire to assess the demographic data and the impact of these courses on daily practice., Methods: The deadline for acceptance of return mail was 60 days. Descriptive statistics were employed for analysis of results., Results: The response rate was 36.7% and the course was judged to be recommendable by 98.2%. The average course attendant was board certified and had spent a mean time of 9+/-6 years in anesthesiology. The highest quality and degree of subsequent practicability in daily routine was attributed to peripheral nerve block training on cadavers. Of the course participants two-thirds performed regional anesthesia procedures more often following attendance. The majority of course attendants had to defray at least a part of the course fee themselves, and one-third was required to invest leisure time to attend., Conclusion: Attendance of a cadaver workshop increased knowledge of clinical anatomy and enhanced performance of regional anesthesia procedures. Courses of this format constitute a currently underestimated adjunct to contemporary regional anesthesia education.

We report a case of life-threatening mediastinal hematoma in a 6-mo-old girl during surgical correction of scaphocephaly. The hematoma was caused by extravascular infusion via the proximal lumen of a dislocated triple-lumen central venous catheter (CVC). Worsening symptoms of hypovolemia and ventilation problems prompted performance of transesophageal echocardiography, which reliably and quickly allowed us to exclude pericardial tamponade and detect a mediastinal hematoma. The anesthesiologist should be alert when a patient with a CVC develops acute cardiopulmonary or respiratory symptoms. Repeated aspirations of blood, especially after major positional changes and before giving large quantities of fluid or blood, should be performed to detect secondary malposition of the CVC.

Background: Surgical pain typically combines superficial and deep pain. We wished to generate pain that resembled surgical pain, reliably and reproducibly, in volunteers., Methods: We constructed a computer-controlled pneumatic device to apply pressure to the anterior tibia. The reproducibility of the pain was tested by rating the pressure that caused pain rated 4-5 on a visual analogue scale (VAS) on days 0, 7, and 24 in 10 volunteers. The effect of remifentanil (0.025, 0.05, 0.075, and 0.1 microg kg-1 min-1) on pain tolerance in another set of volunteers (n=11) was used as an indirect measure of the reliability of pain production., Results: The pressure needed (0.7 (0.3) to 0.9 (0.4) atm (mean (SD)) to induce pain rated 4-5 (VAS) did not vary, showing long-term reproducibility of the method. When pressure was applied to cause increasing pain in volunteers (n=11) 0.05 microg kg-1 min-1 remifentanil increased pain tolerance by 50%. An approximate doubling of the dose (0.1 microg kg-1 min-1) increased pain tolerance significantly more. The linear logarithmic dose-effect relationship shows that the device causes pain reliably, and this can be reduced with opioid treatment., Conclusion: This pneumatic device can apply pain reliably and reproducibly.

Unlabelled: Parkinson's disease patients with long-term L-dopa syndrome may benefit from an implanted cerebral stimulation device. When advanced life support demands cardioversion or defibrillation in these patients, undesired effects of monophasic electroshocks might occur in brain tissue adjacent to the stimulation electrodes (e.g., thermal injury), but also in the stimulation device itself. Thus, in this animal study (n = 6 pigs), we investigated the effects of repeated defibrillation (2 x 200 J [n = 1] and 2 x 360 J [n = 5]) at the implantation site of cerebral stimulation electrodes and on stimulation device function. Repeated external cardiac defibrillation did not cause acute histopathologic changes typical of thermal injury to brain tissue adjacent to the cerebral stimulation electrodes. Functionality of the stimulator device after defibrillation, however, ranged from normal to total loss of function. Therefore, when defibrillation is performed, the greatest possible distance between the defibrillation site and the stimulator device implantation site should be considered. Subsequent testing of the stimulator device's function is mandatory., Implications: Repeated cardiac defibrillation did not cause histopathologic changes typical of thermal injury at the implantation site of cerebral stimulation electrodes. The function of the stimulator device after defibrillation, however, ranged from normal to total loss of function.

The MEDLINE database was used to survey the period January 1964 to July 2003 for the number of publications relating to telemedicine (n = 5911), as well as their distribution by country (n = 42). Publications per million inhabitants were then correlated with each country's population density, gross national product, human development index (HDI) and number of PCs per 1000 inhabitants. Telemedicine publications made up 0.05% of all medical publications cited in MEDLINE. American and European countries along with others classified as industrialized produced 97% of all telemedicine publications. In terms of publications per million inhabitants, Norway and Finland took the lead. There were significant correlations between telemedicine publications per capita and HDI (r = -0.60), number of PCs per 1000 inhabitants (r = 0.73) and gross national product per capita (r = 0.69), but not population density (r = -0.12).

Aim of the Study: Participation in courses for health and hospital management is increasingly becoming a conditio sine qua non for candidates for executive positions in the health professions. The aim of this study was thus to evaluate the two-semester university course for health and hospital management offered by the University of Innsbruck since 1994., Methods: A structured telephone survey was conducted to poll the participants (n = 184) of previous courses concerning time invested, cost-benefit ratio, quality of the course as well as implementation of course content., Results: The university courses (n = 7) for health and hospital management of the University of Innsbruck evaluated in this study were rated in the upper half of the of the five-part scale (scores 2 to 3) for overall quality, cost-benefit ratio and implementation of course content. Only approx. 25 % of the course participants reported that the course had a positive influence on their career. The relatively high course fee was borne in part by the local hospital operator, a fact that had a certain influence on the selection of course participants. Participation in the course was largely made possible by exemptions from job duties (approx. 75 %) and to a lesser extent by vacation time (approx. 20 %) or time off for overtime (approx. 5 %). Of total absences from the course (3.18 +/- 3.41 d) 75 % was for job-related reasons, 6 % for illness and 19 % for other reasons. Overall, participants were absent more often, the larger the number of personnel in their department or clinic., Conclusion: All in all, the courses were considered important and recommendable, particularly with regard to communication, organization, time management and cost awareness. Streamlining (i. e. more content in less time), stronger practical orientation and a switch from mainly local to more international speakers would be important steps toward improving course quality. Thanks to its demonstrated quality, it can be said that the university course for health and hospital management held by the University of Innsbruck and evaluated in this study is certainly a worthwhile course offered in a still emerging market, namely one that will come under increasing pressure from the candidates for executive positions in the health professions to provide what is best for their careers and the health services industry in general.

Background: Cerebral blood flow is affected by painful stimuli, and analgesic agents may alter the response of cerebral blood flow to pain. We set out to quantify the effects of remifentanil and nitrous oxide on blood flow changes caused by experimental pain., Methods: We simulated surgical pain in 10 conscious volunteers using increasing mechanical pressure to the tibia. We measured changes in cerebral blood flow velocity in the middle cerebral artery (CBFV(MCA)) caused by the pain, using transcranial Doppler sonography. We gave increasing doses of remifentanil (0.025, 0.05 and 0.1 micro g kg(-1) min(-1)) or nitrous oxide [20%, 35% and 50% end-tidal concentration (FE'(N(2)O))] and compared these effects on blood flow changes., Results: Nitrous oxide increased CBFV(MCA) only when given at 50% FE'(N(2)O). Remifentanil did not affect CBFV(MCA). Pain increased CBFV(MCA). Both agents attenuated this pain-induced change in CBFV(MCA) with the exception of nitrous oxide at 20% FE'(N(2)O)., Conclusions: Inhalation of nitrous oxide or adminstration of remifentanil attenuated pain-induced changes in CBFV(MCA).

We compared the costs of a dynamic, robotic telepathology service for intraoperative frozen sections with the cost of a once-weekly visiting pathologist service established between the small Reutte Hospital, located in north-western Tyrol, and the department of pathology of the University of Innsbruck. Telepathology required either 15 min or 30 min per case in order to make a diagnosis, depending on the type of tissue and the operator's experience in handling the telepathology system. Costs were calculated for a five-year period. The main costs of the telepathology service were for set-up, whereas the main costs of the visiting pathologist service concerned personnel. The threshold at which telepathology was cheaper than the visiting pathologist service was 46 cases per month (15 min for diagnosis) or 135 cases per month (30 min for diagnosis). The present case-load (eight cases per month) at the study hospital was below this threshold.

Telemedicine and new media (e.g. the Internet, tele-teaching and tele-learning) are increasingly being used in medicine. We surveyed the awareness and acceptance of these developments on the part of medical students (n =750) at the University of Innsbruck. A 16-item questionnaire was handed out in randomly chosen medical classes and collected immediately after completion, which resulted in a response rate of 99.9%. Nearly all of the students used the Internet regularly (68%) or at least sometimes (30%). Telemedicine was already known to most of the students, mainly from articles in magazines and newspapers (41%), but the great majority of them (95%) reported that they did not know about the telemedicine lectures offered by the University of Innsbruck. Most students (75%) thought that they would benefit from tele-teaching or tele-learning. The survey suggested that medical schools should offer more special lectures, as well as undergraduate or postgraduate qualifications in telemedicine. The marketing of such opportunities needs to be improved.

The accuracy of telepathology diagnosis and conventional diagnosis of frozen sections was compared, using the diagnosis established on paraffin-embedded tissue as a reference. Out of a total of 270 cases, remote frozen-section diagnosis was correct in 227 cases (84.1%) and incorrect in 23 cases (8.5%). The latter comprised 12 false positive diagnoses of malignancy (4.4%) and 11 false negative diagnoses (4.1%). A diagnosis was not possible in 20 cases (7.4%). In contrast, the conventional frozen-section diagnosis was correct in 269 cases (99.6%) and incorrect in 1 case (0.4%), the latter being a false negative diagnosis. The average time needed to make a remote diagnosis was 14.2 min (SD 9). Manual examination was not found to be essential for remote frozen-section diagnosis. Overall slide quality was rated as 'satisfactory' to 'fair' by the six pathologists concerned. An improvement in the quality of slides is necessary to guarantee an acceptable level of accuracy of remote frozen-section diagnosis; a shortening of the time needed for diagnosis is a further requirement for the successful implementation of a routine telepathology frozen-section service.

Unlabelled: Phase-contrast magnetic resonance imaging measurements of systolic cerebrospinal fluid peak velocity (CSFVPeak) in the aqueduct of Sylvius have been shown to be sensitive enough to detect even minor changes in cerebral compliance. Clinically relevant changes in cerebral compliance can be caused by changes in cerebral blood volume (CBV). Changes in arterial carbon dioxide partial pressure, which correlate well with end-tidal carbon dioxide concentration (ETCO(2)), cause changes in CBV. In this study, we investigated the effect of hypercapnia-induced changes in CBV on systolic CSFVPeak in anesthetized patients (n = 8). Hypercapnia (ETCO(2) = 60 mm Hg) increased systolic CSFVPeak in the aqueduct of Sylvius as compared with normocapnia (ETCO(2) = 40 mm Hg) (hypercapnia: -5.67 +/- 0.74 cm/s versus normocapnia: -3.54 +/- 0.98 cm/s). In addition to the already known decrease in systolic CSFVPeak, changes in cerebral compliance can also prompt an increase in systolic CSFVPeak., Implications: Magnetic resonance imaging measurements of systolic cerebrospinal fluid peak velocity (CSFVPeak) in the aqueduct of Sylvius are sensitive enough to detect even minor changes in cerebral compliance. We investigated the effect of hypercapnia-induced changes in cerebral blood volume on systolic CSFVPeak in anesthetized patients. Hypercapnia (end-tidal carbon dioxide concentration = 60 mm Hg) increased systolic CSFVPeak.

Remifentanil is increasingly used in the context of anesthesia, e.g., in patients presenting for MRI examinations, not only as an analgesic but also to replace nitrous oxide. Therefore, a comparative analysis of the effects of commonly used doses of remifentanil and of nitrous oxide on cerebral hemodynamics is warranted. The present study used contrast-enhanced magnetic resonance (MR) perfusion measurement to compare the effects of nitrous oxide (N(2)O/O(2) = 50%; n = 9) and remifentanil (0.1 microg/kg/min; n = 10) on regional cerebral blood flow (rCBF), regional cerebral blood volume (rCBV), and regional mean transit time (rMTT) in spontaneously breathing human volunteers. Remifentanil increased rCBF above all in basal ganglia, whereas in supratentorial gray matter the increase in rCBF was equal or even more pronounced when using nitrous oxide. In contrast, nitrous oxide produced a greater increase in rCBV in gray-matter regions than did remifentanil. In summary, nitrous oxide increased rCBV in all gray-matter regions more than did remifentanil. However, the increase in rCBF, especially in basal ganglia, was typically less pronounced than during infusion of remifentanil.

Conflicting results reported on the effects of hyperoxia on cerebral hemodynamics have been attributed mainly to methodical and species differences. In the present study contrast-enhanced magnetic resonance imaging (MRI) perfusion measurement was used to analyze the influence of hyperoxia (fraction of inspired oxygen (FiO2) = 1.0) on regional cerebral blood flow (rCBF) and regional cerebral blood volume (rCBV) in awake, normoventilating volunteers (n = 19). Furthermore, the experiment was repeated in 20 volunteers for transcranial Doppler sonography (TCD) measurement of cerebral blood flow velocity in the middle cerebral artery (CBFV(MCA)). When compared to normoxia (FiO2 = 0.21), hyperoxia heterogeneously influenced rCBV (4.95 +/- 0.02 to 12.87 +/- 0.08 mL/100g (FiO2 = 0.21) vs. 4.50 +/- 0.02 to 13.09 +/- 0.09 mL/100g (FiO2 = 1.0). In contrast, hyperoxia diminished rCBF in all regions (68.08 +/- 0.38 to 199.58 +/- 1.58 mL/100g/min (FiO2 = 0.21) vs. 58.63 +/- 0.32 to 175.16 +/- 1.51 mL/100g/min (FiO2 = 1.0)) except in parietal and left frontal gray matter. CBFV(MCA) remained unchanged regardless of the inspired oxygen fraction (62 +/- 9 cm/s (FiO2 = 0.21) vs. 64 +/- 8 cm/s (FiO2 = 1.0)). Finding CBFV(MCA) unchanged during hyperoxia is consistent with the present study's unchanged rCBF in parietal and left frontal gray matter. In these fronto-parietal regions predominantly fed by the middle cerebral artery, the vasoconstrictor effect of oxygen was probably counteracted by increased perfusion of foci of neuronal activity controlling general behavior and arousal.

Purpose: Propofol is a potential vector of infection, because it contains no preservative. Thus, the manufacturer's specific recommendations for preparing injections or infusions go beyond the guidelines commonly used in our operating rooms for preparing other iv drugs. The purpose of the present study was to determine whether in the daily routine of an operating theatre a modified propofol handling technique can prevent contamination as effectively as do the manufacturer's handling recommendations., Methods: A total of 160 consecutive neurosurgical patients were allocated to either Group I (manufacturer's handling recommendations: i.e., 1) disinfecting propofol vials and ampoules before filling syringes; 2) replacing empty syringes; 3) discarding all material at the end of surgery); or Group II (modified propofol handling protocol: i.e., 1) refilling empty syringes; 2) renewing only the infusion line to the patient)., Results: Total contamination rates were comparable in both groups (Group I: 14/160 (8.75%), Group II: 13/160 (8.13%) (chi2= 0.074; P=0.96). Frequency of contamination was not different between groups; either in sample 1 taken at the beginning of the procedure, (Group I: 5/80 (6.25%) vs Group II: 6/80 (7.5%); chi2=0.098; P=0.76) or in sample 2, taken at the end, (Group I: 9/80 (11.25%) vs Group II: 7/80 (8.75%); chi2=0.278; P=0.598)., Conclusion: We conclude that in the daily routine of the operating theatre following a modified propofol handling protocol prevents contamination of propofol syringes as effectively as does adhering to the manufacturer's specific handling recommendations. However, neither of the tested guidelines completely prevented contamination.

Anesthesia for diagnostic procedures, e.g., MRI measurements, has increasingly used sevoflurane and nitrous oxide in recent years. Sevoflurane and nitrous oxide are known cerebrovasodilatators, however, which potentially interferes with MRI examination of cerebral hemodynamics. To compare the effects of relevant equianesthetic concentrations (0.4 MAC) of both drugs on regional cerebral blood flow (rCBF) and regional cerebral blood volume (rCBV) we used contrast-enhanced magnetic resonance imaging (MRI) perfusion measurement, which has the advantage of providing regional anatomic resolution. Sevoflurane increased rCBF more than did nitrous oxide in all regions except in parietal and frontal gray matter. Nitrous oxide, by contrast, increased rCBV in most of the gray matter regions more than did sevoflurane. In summary we show that, in contrast to nitrous oxide, sevoflurane supratentorially reversed the anterior-posterior gradient in rCBF and typically redistributed rCBF to infratentorial gray matter. In contrast, nitrous oxide increased rCBV more than did sevoflurane. Both inhalational anesthetics had a drug-specific influence on cerebral hemodynamics, which is of importance when interpreting MRI studies of cerebral hemodynamics in anesthetized patients.

Background: Sailing is becoming increasingly popular as a form of holiday recreation. The purpose of the present study was to profile the heart rate characteristics of non-professional crew members on a Mediterranean sailboat trip. Additionally, the practicability of transferring electronic data via the Internet while sailing offshore was also studied., Methods: Seven healthy male non-professional crew members responsible for steering and navigating the boat during the observation period were studied using continuous electrocardiographic recording (Holter). Manually measured blood pressure, side effects and sailing data were taped half-hourly., Results: While sailing we observed that the heart rate increased typically into the 120-170 beats/min range, mean arterial pressure remained stable between 80-90 mmHg. Heart rate changes and the incidence of supraventricular arrhythmias correlated with activity on board, boat speed and wind velocity. No subject showed ventricular arrhythmias during sailing. The minimal blood pressure changes correlated only with activity on board., Conclusions: All these results indicate that sailboating on vacation, even in a non-professional status, does not promote disease-relevant changes in heart rhythm on trips in mild to moderate seas. Additionally, we were able to demonstrate that the online transfer of electronic data via the Internet from a sailboat offshore is possible, easy and inexpensive.

Nitrous oxide and isoflurane have cerebral vasodilatory effects. The use of isoflurane in neuroanaesthesia is widely accepted, whereas the use of nitrous oxide in neuroanaesthesia is still the subject of debate. In the present study, contrast-enhanced magnetic resonance (MR) perfusion measurement was used to compare the effects of 0.4 MAC nitrous oxide (n=9) and 0.4 MAC isoflurane (n=9) on regional cerebral blood flow (rCBF), regional cerebral blood volume (rCBV) and regional mean transit time (rMTT) in spontaneously breathing human volunteers. Nitrous oxide increased rCBF and rCBV in supratentorial regions more than did isoflurane. Isoflurane, by contrast, increased rCBF and rCBV in basal ganglia more than did nitrous oxide. An increased rMTT was caused by a relatively greater increase in rCBV than in rCBF supratentorially by isoflurane and infratentorially by nitrous oxide. In conclusion, nitrous oxide increases rCBF and rCBV predominantly in supratentorial grey matter, whereas isoflurane increases rCBF and rCBV predominantly in infratentorial grey matter.

Both sevoflurane and isoflurane are used in moderate concentrations in neuroanesthesia practice. The limiting factors for using higher concentrations of inhalational anesthetics in patients undergoing neurosurgery are the agents' effects on cerebral blood flow (CBF) and cerebral blood volume (CBV). In particular, an increase in CBV, which is a key determinant of intracranial pressure, may add to the neurosurgical patient's perioperative risk. To compare the effects of a subanesthetic concentration (0.4 minimum alveolar concentration) of sevoflurane or isoflurane on regional CBF (rCBF), regional CBV (rCBV) and regional mean transit time (rMTT), contrast-enhanced magnetic resonance imaging perfusion measurements were made in spontaneously breathing human volunteers. Absolute changes in rCBF, regional CBV, and rMTT during administration of either drug in regions of interest outlined bilaterally in white and grey matter were nonparametrically (Mann-Whitney test) analyzed. Sevoflurane increased rCBF in practically all regions (absolute change, 4.44 +/- 2.87 to 61.54 +/- 2.39 mL/100g per minute) more than isoflurane did (absolute change, 12.91 +/- 2.52 to 52.67 +/- 3.32 mL/100g per minute), which decreased frontal, parietal, and white matter rCBF (absolute change, -1.12 +/- 0.59 to -14.69 +/- 3.03 mL/100g per minute). Regional CBV was higher in most regions during isoflurane administration (absolute change, 0.75 +/- 0.03 to 4.92 +/- 0.16 mL/100g) than during sevoflurane administration (absolute change, 0.05 +/- 0.14 to 3.57 +/- 0.14 mL/100g). Regional mean transit time was decreased by sevoflurane (absolute change, -0.18 +/- 0.05 to -0.60 +/- 0.04 s) but increased by isoflurane (absolute change, 0.19 +/- 0.03 to 0.69 +/- 0.04 s). In summary, regional CBV was significantly lower during sevoflurane than during isoflurane administration, although sevoflurane increased rCBF more than isoflurane, which even decreased rCBF in some regions. For sevoflurane and, even more pronouncedly, for isoflurane, the observed changes in cerebral hemodynamics cannot be explained by vasodilatation alone.

Changes in both blood flow and blood oxygenation determine the functional MRI (fMRI) signal. In the present study factors responsible for blood oxygenation (e.g., FiO(2)) were held constant so that changes in pixel count would above all reflect changes in regional cerebral blood flow (rCBF). Continuous positive airway pressure (CPAP) breathing at 12 cm H(2)O, which was previously shown to influence rCBF, was applied in human volunteers (n = 19) to investigate the sensitivity of fMRI for changes in rCBF caused by increased mean airway pressure. Increasing the mean airway pressure decreased the pixel count in the primary visual cortex (median (range)): baseline: 219 (58-425) pixels vs. CPAP (12 cm H(2)O): 92 (0-262) pixels). These findings indicate that fMRI is sensitive to detect a reduced rCBF-response in the primary visual cortex. The underlying mechanism is likely to be a reduced basal rCBF due to constriction and/or compression of postcapillary venoles during CPAP breathing. These findings are important for interpreting fMRI results in awake and in artificially respirated patients, in whom positive airway pressure is used to improve pulmonary function during the diagnostic procedure.

Contrast-enhanced magnetic resonance imaging (MRI) measurement of cerebral perfusion is a diagnostic procedure increasingly gaining access to clinical practice not only in spontaneously breathing patients but also in mechanically ventilated patients. Effects of increased mean airway pressure on cerebral perfusion are entirely possible. Therefore, the present study used continuous positive airway pressure (CPAP) (12 cm H2O) to study the effects of increased mean airway pressure on cerebral perfusion in volunteers. CPAP significantly reduced regional cerebral blood flow (rCBF) and regional cerebral blood volume (rCBV) but increased regional mean transit time (rMTT) and regional cerebrovascular resistance (rCVR). Active vasoconstriction (e.g., arterial) and/or passive compression of capillary and/or venous vessel areas are the most likely underlying mechanisms. The number of interhemispheric differences in rCBF, rCBV, rMTT, and rCVR found at baseline rose when mean airway pressure was increased. These results, although obtained in volunteers, should be taken into consideration for the interpretation of contrast-enhanced MRI perfusion measurements in mechanically ventilated patients with an increased positive airway pressure.

We have used contrast media-enhanced perfusion magnetic resonance imaging MRI to measure regional cerebral blood flow (rCBF), regional cerebral blood volume (rCBV), regional mean transit time (rMTT) and regional cerebrovascular resistance (rCVR) in volunteers at baseline and during infusion of remifentanil (0.1 microgram kg-1 min-1). Remifentanil increased rCBF and rCBV in white and grey matter (striatal, thalamic, occipital, parietal, frontal) regions, with a parallel decrease in rMTT in those regions with the exception of occipital grey matter. rCVR was decreased in all regions studied. The relative increase in rCBF was greater than that in rCBV. Cerebral haemodynamics were increased significantly in areas less rich in mu-opioid receptors with a tendency towards more pronounced increases in rCBF and rCBV in pain-processing areas. Furthermore, interhemispheric differences in rCBF, rCBV and rMTT found prior to drug administration were almost eliminated during infusion of remifentanil. We conclude that, apart from direct and indirect cerebrovascular effects of remifentanil, these findings are consistent with cerebral excitement and/or disinhibition.

Inhaled anesthetics exert metabolically mediated effects on cerebral blood vessels both directly and indirectly. We investigated the effects of a 0.4 minimum alveolar subanesthetic concentration of sevoflurane on regional cerebral blood flow (rCBF), regional cerebral blood volume (rCBV), regional cerebrovascular resistance (rCVR), and regional mean transit time (rMTT) in volunteers by means of contrast-enhanced magnetic resonance imaging perfusion measurement. Sevoflurane increased rCBF by 16% to 55% (control, 55. 03 +/- 0.33 to 148.83 +/- 1.9 mL. 100 g(-1). min(-1); sevoflurane, 71.75 +/- 0.36 to 193.26 +/- 2.14 mL. 100 g(-1). min(-1)) and rCBV by 7% to 39% (control, 4.66 +/- 0.03 to 10.04 +/- 0.12 mL/100 g; sevoflurane, 5.04 +/- 0.03 to 13.6 +/- 0.15 mL/100 g); however, sevoflurane decreased rMTT by 7% to 18% (control, 3.75 +/- 0.04 to 5. 39 +/- 0.04 s; sevoflurane, 3.4 +/- 0.03 to 4.44 +/- 0.03 s) and rCVR by 22% to 36% (control, 0.74 +/- 0.01 to 1.9 +/- 0.2 mm Hg/[mL. 100 g(-1). min(-1)]; sevoflurane, 0.54 +/- 0.01 to 1.41 +/- 0.01 mm Hg/[mL. 100 g(-1). min(-1)]). Interhemispheric differences in rCBF, rCBV, and rCVR were markedly reduced after the administration of sevoflurane. These findings are consistent with the known direct vasodilating effect of sevoflurane. The decrease in rMTT further shows that rCBF increases more than does rCBV. Furthermore, we can show that the observed increase in rCBF during inhalation of sevoflurane is not explained by vasodilation alone.

Unlabelled: Remifentanil, a short-acting potent mu-opioid agonist proposed for intraoperative analgesia but also for postoperative pain therapy, has not been investigated with regard to the effects of the drug on cerebral capacity in awake humans. We assessed cerebral capacity noninvasively by means of phase-contrast magnetic resonance imaging measurement of systolic cerebrospinal fluid peak velocity in the aqueduct of Sylvius before and during infusion of remifentanil (0.1 microg. kg(-1). min(-1) IV) in normocapnic humans. Remifentanil had no significant effect on systolic cerebrospinal fluid peak velocity as compared with baseline (mean +/- SD): baseline, -4.3 +/- 1.3 cm/s versus remifentanil (0.1 microg. kg(-1). min(-1)): -4.7 +/- 1.0 cm/s. Small-dose remifentanil (0.1 microg. kg(-1). min(-1)) did not influence cerebral capacity in healthy, awake volunteers free of intracranial pathology., Implications: Knowledge about the influence of remifentanil on cerebral capacity is crucial before routine use of the drug in neuroanesthesia. Thus, we assessed the influence of remifentanil on cerebral capacity noninvasively by means of phase-contrast magnetic resonance imaging measurement of systolic cerebrospinal fluid peak velocity in the aqueduct of Sylvius in humans.

Fluvoxamine, a selective serotonin reuptake inhibitor (SSRI), significantly potentiates analgesia when administered in animals together with opioids. The aim of the present study was to investigate the effects of fluvoxamine on sufentanil antinociception and tolerance. Following animal care committee approval, the effects of continuous infusions of fluvoxamine and sufentanil were studied in behavioural tests (hot-plate test, tail-flick test, catalepsy test) in Sprague-Dawley rats with a jugular vein catheter. Saline was administered as a control. The time-effect curves for continuous intravenous sufentanil indicate dose-related antinociception and rapid development of tolerance in the hot-plate and tail-flick tests. Co-administration of fluvoxamine with continuous sufentanil enhances antinociception and attenuates development of tolerance, most clearly seen in the tail-flick test. Fluvoxamine alone and saline were not effective. No animal showed catalepsy. As a side effect we observed a marked loss of body weight. The IC50 values of sufentanil binding with and without fluvoxamine addition are 0.56+/-0.17 nM and 0.3+/-0.15 nM, respectively, indicating no direct effect on the occupancy of sufentanil on the mu-receptor by this serotonin reuptake inhibitor. In conclusion, we were able to show that the combination of an opioid with an SSRI at low doses improves analgesia and decreases development of tolerance in nociceptive tests in rats. The clinical implications of these promising results in an animal model, however, await further investigation.

Hyperoxia can improve oxygen delivery in patients exposed to hypocapnia for neurosurgical procedures but this effect may be modified by regional differences in the degree of hypocapnic vasoconstriction. Using functional magnet resonance imaging (fMRI), we have investigated the influence of hyperoxia on blood flow and blood oxygenation in the primary visual cortex in hypocapnic volunteers. Consecutive fMRI measurements were performed in 10 awake, male volunteers during hypocapnia (mean PE'CO2 3.3 (SD 0.1) kPa) and normocapnia (PE'CO2 5.3 (0.1) kPa) at FIO2 values of 0.21 and 1.0, respectively. Hypocapnia significantly reduced the pixel count in the primary visual cortex (median 169 (quartiles 34-246) vs 21 (0-40) pixels at an FIO2 of 0.21). Additional hyperoxia had no influence on this reduction in pixel count (16 (0-28) pixels at FIO2 1.0 vs 21 (0-40) pixels at FIO2 0.21). Hyperoxia did not influence hypocapnic vasoconstriction in the primary visual cortex. These data suggest that in the primary visual cortex, administration of oxygen alone may not be sufficient to improve oxygen delivery under hypocapnic conditions.

Background: Cerebrospinal fluid (CSF) outflow to intra- and extracranial subarachnoid spaces caused by arterial inflow to the brain predominantly compensates systolic increases in cerebral blood volume. Phase-contrast magnetic resonance imaging is a new tool for noninvasive assessment of CSF displacement by measuring CSF peak velocity (CSFV(Peak)). The authors tested this new tool in an experimental human model of increased intracranial pressure and reduced cerebral capacity by means of continuous positive airway pressure (CPAP) breathing., Methods: The authors investigated systolic CSFV(Peak) in the aqueduct of Sylvius in 11 awake, normocapnic (end-tidal carbon dioxide [ET(CO2)] = 40 mmHg) volunteers without CPAP and at two different CPAP levels (6 and 12 cm H2O) by means of electroencephalography-gated phase-contrast magnetic resonance imaging., Results: Administration of 6 cm H2O CPAP did not change systolic CSFV(Peak) (-4.9+/-2.8 cm/s vs. control: -5.1+/-2.7 cm/s), whereas 12 cm H2O CPAP significantly reduced systolic CSFV(Peak) (-4.0+/-1.8 cm/s vs. control: -5.1+/-2.7 cm/s; P < 0.05)., Conclusions: These findings in awake volunteers show that monitoring CSFV(Peak) in the aqueduct of Sylvius is a sensitive method for detecting even minor impairment of cerebral capacity caused by experimentally induced increases in intracranial pressure.

We investigated transcutaneous partial CO2 and O2 pressures and respiratory rate in unpremedicated elderly patients of ASA physical status 1 to 3 who underwent cataract surgery under retrobulbar anaesthesia. In group A no air suction was used. In group B suction was applied under the sterile drapes to avoid rebreathing of CO2. In group A transcutaneous partial CO2 pressure and respiratory rate significantly increased compared with baseline, whereas in group B they remained constant. In both groups transcutaneous partial O2 pressure and oxygen saturation as measured by pulse oximetry significantly rose after insufflating oxygen 31.min-1. Heart rate and mean arterial blood pressure remained constant. Our results demonstrate that the application of suction near the patient's head prevents CO2 rebreathing and subsequent hypercapnia associated with an elevated respiratory rate. The use of suction makes it unnecessary to raise oxygen administration. Suction combined with monitoring of partial CO2 pressure using transcutaneous sensors should be used in all ophthalmological operations under retrobulbar anaesthesia.

The work input of an institutional review board, the satisfaction or dissatisfaction of project applicants with its decisions, as well as the amount of time needed for preparatory and follow-up work for projects submitted to the board were surveyed in a questionnaire. An analysis of the status quo provided proposals for improvement, with the aim of increasing the satisfaction of all parties involved. Questionnaires were returned by 41.4% (101/244) of the specialist doctors surveyed. Of these, 42 were doctors who had submitted projects for review and whose evaluation was used for the study. The proportion of trained "clinical review doctors" was 14.3%. Analysis of work input showed that 13.5 +/- 15.2 hours were invested before submitting a project and 6.3 +/- 9.3 hours in the follow-up. Although the board's work was given a satisfactory grading with a score of 2.8 +/- 1.0, the surveyed satisfaction/importance profile showed marked deficits in many areas, primarily in organization and communication, as well as in the examination and evaluation of projects. The suggestions for improvement above all requested the introduction of a review system employing specialists from outside the institution or from other disciplines, standardization of project submission, optimization of organization and improvement in communication. In summary, the institutional review board plays an important role in clinical research. The acceptance of a review board's work, however, can only be improved when the suggestions for improvement are realized step by step. The results of this evaluation and the proposed solutions can also help other boards improve their work. At any rate, it would be desirable to take a new look in several years' time at how the proposals worked out in this study have been implemented.

1. Benzodiazepines potentiate morphine antinociception at the spinal level via GABAergic mechanisms. At the supraspinal level, the inhibitory effect of midazolam on morphine antinociception cannot be easily explained by GABAA receptor activation. Since excitatory amino acids play a role in central transmission, we investigated the effect of dizocilpine (MK 801) on this interaction in spinal cord and brain. 2. In rats with an intrathecal or intracerebroventricular catheter, the mechanisms of the antinociceptive effect of benzodiazepine-morphine combinations were tested during thermal nociceptive tests. 3. The principal findings of this study were that at the spinal level, midazolam potentiation of morphine antinociception can be antagonized by the NMDA antagonist, MK 801 (10 micrograms), as assessed by hot-plate and tail-flick tests. When drugs were administered supraspinally, midazolam inhibited morphine antinociception only in the hot-plate test, an effect also inhibited by MK 801. In the tail-flick assay, midazolam failed to influence the morphine response. 4. The NMDA antagonist significantly affected midazolam antinociception at the spinal level, but was not effective following i.c.v. administration of the drugs. MK 801 had no effect on morphine antinociception after i.t. and i.c.v. administration of the drugs. 5. The paradoxical effect of midazolam on morphine antinociception and its reversal by MK 801 might be due to modulation at various levels of the neuraxis and/or modulation of different pathways mediated via both GABAA and NMDA receptor mechanisms.

The mechanisms for the combined antinociceptive effect of midazolam and morphine administered at spinal (intrathecal, i.t.) and supraspinal (intracerebroventricular, i.c.v.) levels were investigated in rats. Nociceptive test results showed that co-administration of midazolam and morphine at the spinal level potentiated morphine-induced antinociception, and that this interaction was blocked by intraperitoneal (i.p.) naloxone and reversed by i.t. bicuculline and i.p. flumazenil. Also, bicuculline and flumazenil blocked midazolam-induced antinociception at the spinal level, and naloxone completely reversed morphine antinociception. In contrast, when drugs were injected intracerebroventricularly, midazolam inhibited the antinociceptive effect of morphine (as determined by the hot-plate test). The inhibitory effects of i.c.v. midazolam upon i.c.v. morphine antinociception were partly blocked by flumazenil and bicuculline. Midazolam-induced antinociception was increased by bicuculline and decreased by flumazenil; naloxone i.p. blocked both i.c.v. morphine antinociception and i.c.v. morphine-midazolam antinociception. Results after i.t. injection may be due to an interaction between morphine and midazolam/GABAA receptor-activated systems. At the supraspinal level, this interaction may also activate other systems that are distinct from those governing the individual action of each agonist.