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Background: Continuous infusion of numerous parenteral medications is common practice in intensive care units (ICU). In contrast to some countries, there is a lack of clearly defined standardized concentrations in Germany, especially for high-risk medications designated for infusion therapy., Objectives: The goal was to collect representative data of standardized concentrations commonly used for continuous infusion in German ICUs. Results should be used to draft nationwide recommendations for standardized continuous infusions., Materials and Methods: To determine the nationwide acceptance and preference for medications designated for continuous infusion, a questionnaire was developed and sent to the directors of 1816 ICUs in Germany. The questionnaire comprised suggestions of 59 medicinal products with 73 concentrations. In addition, participants could make their own proposals on medications and concentrations preferably used. Evaluation was performed with SurveyMonkey® and Microsoft® Excel®., Results: A total of 312 (17%) ICUs answered the survey. Data analyses indicate a very high acceptance rate for rate-controlled continuous infusion with standardized concentrations. More than 90% (50%) of participating physicians routinely use the top 10 (top 25) medicines listed for continuous infusion. For most medicines, one concentration could be identified., Conclusions: Our survey results generate a suitable basis for a nationwide list with standardized concentrations of medicines intended for continuous infusion (usually 50 mL). Publication of such a list by the corresponding expert committees is likely to be met with broad acceptance and implementation into clinical practice can be expected., (© 2022. The Author(s).) more...

Background: Critically ill patients are particularly susceptible to adverse drug events. International studies show that pharmaceutical care has a positive impact on patient and drug therapy safety. Nationally, the integration of pharmacists into the multidisciplinary team and participation in ward rounds is required. The aim of this work is to assess the scope and extent of pharmaceutical care in intensive care units (ICU) in Germany., Method: In a literature and database search, 13 relevant pharmaceutical activities were identified. Based on this, an online survey with 27 questions on the implementation of pharmaceutical care in ICU was prepared by a panel of experts. The survey was sent to heads of German ICUs., Results: Of the participants, 35.3% (59/167) have established regular pharmaceutical care. Drug information (89.7% [52/58]), pharmaceutical interventions with change of therapy (e.g., ward rounds; 67,2% [39/58]), regular evaluation of prescriptions (medication analysis; 65.5% [38/58]) as well as the monitoring of medication (e.g., side effects, effectiveness, costs; 63.8% [37/58]) were most frequently mentioned. The participants with pharmaceutical care (58/168) graded 7 of 13 but those without (104/168) only two  activities as 'essential/indispensable'., Conclusion: Only a few ICU in Germany have already integrated ward pharmacists into the multidisciplinary team. Once a pharmaceutical service has been established, a greater role/importance is assigned to several pharmaceutical activities., (© 2022. The Author(s).) more...

Safety of Pharmacotherapy in Emergencies Abstract. Emergency pharmacotherapy is one of the most commonly used medical procedures. At the same time, pharmacotherapy in an emergency is always a potentially dangerous action. Medication errors are even among the most frequently registered errors in medicine. Due to the special circumstances in emergency medicine, special precautions are required to ensure the safety of drug therapy. In addition to the important background information, this article presents procedures that are recognized and applicable in daily routine to increase safety in pharmacotherapy. more...

Background: The number of students using neuro enhancement to improve their performance and to prevent test anxiety is increasing. The acupuncture point Heart 7 (HT7) has been described as being prominent in reducing states of anxiety., Methods: We conducted a randomized placebo-controlled, two-armed pilot trial to investigate the efficacy of a single-point acupuncture treatment at bilateral HT7 compared to sham laser acupuncture on test anxiety. Test anxiety was induced applying the standardised protocol of the Trier Social Stress Test. Outcome measures included saliva samples analysed for cortisol and amylase, anxiety questionnaires and heart rate variability., Results: Twenty-five male subjects (age 28 ± 5 years) were allocated to either verum acupuncture (n = 12) or sham laser acupuncture (n = 13). Cortisol peaked 20 min after the stress test (2-fold, 18.11 ± 2 nmol/l) and amylase 10 min after (2-fold, 259 ± 49 U/ml) with no difference between groups. There were no differences between groups regarding either anxiety questionnaires or physiological parameters. Compared to reference data (3-fold increase in cortisol), increase in stress hormones and heart rate seemed somewhat reduced., Conclusions: Acupuncture may be a possible approach for the treatment of anxiety. Due to the lack of a no control treatment group, we cannot determine the magnitude of possible specific needle effects at HT7 to promote specific effects in the neuroendocrine system. Finally this study only examines the efficacy of a single time treatment., Competing Interests: Dr. Fleckenstein is the Deputy Head of the Scientific Chapter of the German Medical Acupuncture Society DAEGfA. He received honoraria for academic teaching and counselling. This does not alter our adherence to PLOS ONE policies on sharing data and materials. more...

Candidemia is frequent in critically ill patients, especially in combination with an acute kidney injury (AKI). Echinocandins generally are recommended for therapy of such infections. Recent studies found no need for dosage adjustment in patients with end-stage renal disease receiving hemodialysis, or patients with AKI receiving continuous venovenous hemofiltration. The aim of this in vitro study was to examine the adsorption of anidulafungin to the surface of the hemofilter during continuous venovenous hemodialysis (CVVHD) and its effect on anidulafungin concentrations. The concentration of anidulafungin in the dialyzed fluid, and the dialysate during CVVHD in vitro was examined using three different dialyzed fluids (saline; saline with 40 g/L human albumin; and a mixture of human erythrocytes and fresh frozen plasma). After the end of dialysis, the hemofilter was opened and portions of the filter capillaries were also analyzed to determine the amount of anidulafungin adsorbed. When dialyzing saline, about 99% of the anidulafungin used adsorbed to the hemofilter capillaries; in the experiments with saline with 40 g/L albumin, about 60% adsorbed to the hemofilter's surface, and when blood was dialyzed, 35% was found adsorbed after analyzing the filter capillaries. Anidulafungin was not detectable in the dialysate of any of the experiments, consequently the dialysis clearance was 0 mL/min. In conclusion, during CVVHD in vitro we found remarkable adsorption of anidulafungin to the hemofilter's surface, yet the effect on the tissue concentration needs further examination., (© 2017 International Center for Artificial Organs and Transplantation and Wiley Periodicals, Inc.) more...

Background: Estimate the expenditure of computer-related worktime resulting from the use of clinical decision support systems (CDSS) to prevent adverse drug reactions (ADR) among patients undergoing chronic pain therapy and compare the employed check systems with respect to performance and practicability., Methods: Data were collected retrospectively from 113 medical records of patients under chronic pain therapy during 2012/2013. Patient-specific medications were checked for potential drug-drug interactions (DDI) using two publicly available CDSS, Apotheken Umschau (AU) and Medscape (MS), and a commercially available CDSS AiDKlinik® (AID). The time needed to analyze patient pharmacotherapy for DDIs was taken with a stopwatch. Measurements included the time needed for running the analysis and printing the results. CDSS were compared with respect to the expenditure of time and usability. Only patient pharmacotherapies with at least two prescribed drugs and fitting the criteria of the corresponding CDSS were analyzed. Additionally, a qualitative evaluation of the used check systems was performed, employing a questionnaire asking five pain physicians to compare and rate the performance and practicability of the three CDSSs., Results: The AU tool took a total of 3:55:45 h with an average of 0:02:32 h for 93 analyzed patient regimens and led to the discovery of 261 DDIs. Using the Medscape interaction checker required a total of 1:28:35 h for 38 patients with an average of 0:01:58 h and a yield of 178 interactions. The CDSS AID required a total of 3:12:27 h for 97 patients with an average time of analysis of 0:01:59 h and the discovery of 170 DDIs. According to the pain physicians the CDSS AID was chosen as the preferred tool., Conclusions: Applying a CDSS to examine a patients drug regimen for potential DDIs causes an average extra expenditure of work time of 2:09 min, which extends patient treatment time by 25 % on average. Nevertheless, the authors believe that the extra expenditure of time employing a CDSS is outweighed by their benefits, including reduced ADR risks and safer clinical drug management. more...

Objective: Pain after thoracotomy is associated with intense discomfort leading to impaired pulmonary function., Design: Prospective, non-randomized trial from April 2009 to September 2011., Setting: Department of Thoracic Surgery, single-center., Participants: Thoracic surgical patients., Interventions: Comparison of thoracic epidural analgesia (TEA) with the On-Q® PainBuster® system after thoracotomy., Measurements and Main Results: The TEA group (n=30) received TEA with continuous 0.2% ropivacaine at 4 mL-to-8 mL/h, whereas Painbuster® patients (n=32) received 0.75% ropivacaine at 5 mL/h until postoperative day 4 (POD4). Basic and on-demand analgesia were identical in both groups. Pain was measured daily on a numeric analog scale from 0 (no pain) to 10 (worst pain) at rest and at exercise. There were no significant differences regarding demographic and preoperative data between the groups, but PainBuster® patients had a slightly lower relative forced expiratory volume in 1 second (FEV1) (71±20% versus 86±21%; p=0.01). Most common surgical procedures were lobectomies (38.8%) and atypical resections (28.3%) via anterolateral thoracotomy. Most common primary diagnoses were lung cancer (48.3%) and tumor of unknown origin (30%). At POD1, median postoperative pain at rest was 2.1 (1; 2.8) in the TEA group and 2 (1.5; 3.8; p=0.62) in the PainBuster® group. At exercise, median pain was 4.3 (3.5; 3.8) in the TEA group compared to 5.0 (4.0; 6.5; p=0.07). Until POD 5 there were decreases in pain at rest and exercise but without significant differences between the groups., Conclusions: Sufficient analgesia after thoracotomy can be achieved with the intercostal PainBuster® system in patients, who cannot receive TEA., (Copyright © 2014 Elsevier Inc. All rights reserved.) more...

Background: Transcranial color-coded sonography (TCCS) has proved to be a fast and reliable tool for the detection of middle cerebral artery (MCA) occlusions in a hospital setting. In this feasibility study on prehospital sonography, our aim was to investigate the accuracy of TCCS for neurovascular emergency diagnostics when performed in a prehospital setting using mobile ultrasound equipment as part of a neurological examination., Methods: Following a '911 stroke code' call, stroke neurologists experienced in TCCS rendezvoused with the paramedic team. In patients with suspected stroke, TCCS examination including ultrasound contrast agents was performed. Results were compared with neurovascular imaging (CTA, MRA) and the final discharge diagnosis from standard patient-centered stroke care., Results: We enrolled '232 stroke code' patients with follow-up data available in 102 patients with complete TCCS examination. A diagnosis of ischemic stroke was made in 73 cases; 29 patients were identified as 'stroke mimics'. MCA occlusion was diagnosed in ten patients, while internal carotid artery (ICA) occlusion/high-grade stenosis leading to reversal of anterior cerebral artery flow was diagnosed in four patients. The initial working diagnosis 'any stroke' showed a sensitivity of 94% and a specificity of 48%. 'Major MCA or ICA stroke' diagnosed by mobile ultrasound showed an overall sensitivity of 78% and specificity of 98%., Conclusions: The study demonstrates the feasibility and high diagnostic accuracy of emergency transcranial ultrasound assessment combined with neurological examinations for major ischemic stroke. Future combination with telemedical support, point-of-care analysis of blood serum markers, and probability algorithms of prehospital stroke diagnosis including ultrasound may help to speed up stroke treatment. more...

Background and Purpose: The primary aim of this study was to investigate the diagnostic accuracy and time frames for neurological and transcranial color-coded sonography (TCCS) assessments in a prehospital '911' emergency stroke situation by using portable duplex ultrasound devices to visualize the bilateral middle cerebral arteries (MCAs)., Methods: This study was conducted between May 2010 and January 2011. Patients who had sustained strokes in the city of Regensburg and the surrounding area in Bavaria, Germany, were enrolled in the study. After a '911 stroke code' call had been dispatched, stroke neurologists with expertise in ultrasonography rendezvoused with the paramedic team at the site of the emergency. After a brief neurological assessment had been completed, the patients underwent TCCS with optional administration of an ultrasound contrast agent in cases of insufficient temporal bone windows or if the agent had acute therapeutic relevance. The ultrasound studies were performed at the site of the emergency or in the ambulance during patient transport to the admitting hospital. Relevant timelines, such as the time from the stroke alarm to patient arrival at the hospital and the duration of the TCCS, were documented, and positive and negative predictive values for the diagnosis of major MCA occlusion were assessed., Results: A total of 113 patients were enrolled in the study. MCA occlusion was diagnosed in 10 patients. In 9 of these 10 patients, MCA occlusion could be visualized using contrast-enhanced or non-contrast-enhanced TCCS during patient transport and was later confirmed using computed tomography or magnetic resonance angiography. One MCA occlusion was missed by TCCS and 1 atypical hemorrhage was misdiagnosed. Overall, the sensitivity of a 'field diagnosis' of MCA occlusion was 90% [95% confidence interval (CI) 55.5-99.75%] and the specificity was 98% (95% CI 92.89-99.97%). The positive predictive value was 90% (95% CI 55.5-99.75%) and the negative predictive value was 98% (95% CI 92.89-99.97%). The mean time (standard deviation) from ambulance dispatch to arrival at the patient was 12.3 min (7.09); the mean time for the TCCS examination was 5.6 min (2.2); and the overall mean transport time to the hospital was 53 min (18)., Conclusion: Prehospital diagnosis of MCA occlusion in stroke patients is feasible using portable duplex ultrasonography with or without administration of a microbubble contrast agent. Prehospital neurological as well as transcranial vascular assessments during patient transport can be performed by a trained neurologist with high sensitivity and specificity, perhaps opening an additional therapeutic window for sonothrombolysis or neuroprotective strategies., (Copyright © 2012 S. Karger AG, Basel.) more...

Background: To obtain reliable and accurate measurements of the intraocular pressure (IOP) in children often requires sedation or anaesthesia. Therefore, we investigated the effects of oral midazolam on IOP in children., Methods: In a prospective study, IOP was measured in 72 eyes of 36 cooperative children without glaucoma requiring general anaesthesia (mean age 3.5±1.3 years, body weight ≤20 kg) by using a Perkins hand-held tonometer. Measurements of IOP were performed before, and 15 and 30 min after sedation with orally administered midazolam (1 mg/kg) given as preoperative medication, and 5 and 15 min after induction of general anaesthesia. The individual IOP courses were analysed., Results: In all of the cooperative children, IOP measurement was possible after sedation with midazolam. Mean IOP was 11.2±0.3 mmHg before sedation, 10.9±0.2 mmHg at 15 min, and 10.7±0.3 mmHg 30 min after administration of midazolam. This small decrease was not statistically significant, whilst the IOP decline at 5 and 15 min after induction of general anaesthesia was statistically significant (p<0.0001)., Conclusion: Sedation with midazolam can be assumed to be an applicable, well-tolerated, safe method for IOP measurements in children. more...

Background: Acid aspiration induces lung injury by causing an intense inflammatory reaction. Neutrophils are attracted by various cytokines, such as TNFbeta, and release reactive oxygen species, which then cause acute lung injury. Endothelin antagonists, such as bosentan, have been found to possess anti-inflammatory properties., Materials and Methods: We performed a prospective, randomised, controlled study to evaluate the effects of bosentan in a rat model of acid-induced lung injury. Sprague-Dawley rats underwent sevoflurane anaesthesia; lung injury was then induced by instillation of 1.2mL/kg, 0.1M hydrochloric acid. The lungs were ventilated for 6h and then randomised into three groups: bosentan 30mg/kg body weight, 90mg/kg body weight or sodium chloride, each applied immediately after acid aspiration via a gastric tube., Results: After induction of acute lung inflammation, the production of reactive oxygen species by PMN following stimulation with FMLP increased significantly. Comparison of pre-treatment and post-treatment in the 90mg/kg bosentan treatment group did not show a significant increase of reactive oxygen species following stimulation with FMLP. A comparison of the absolute difference of the MESF demonstrated a significant difference between the control group and the group treated with 90mg/kg bosentan., Conclusions: Bosentan administration at 90mg/kg body weight reduced the release of reactive oxygen species after 360min in acid aspiration-induced lung injury in rats. more...

Background: Acid aspiration is a serious complication that can occur during general anesthesia. Studies show that beta-agonists have beneficial effects on lung injury. Therefore, we tested the effect of the nebulized beta-agonist fenoterol on lung variables in a rodent model of acid-induced lung injury., Methods: In a prospective, randomized, and controlled study, we evaluated the effects of fenoterol inhalation on lung oxygenation, inflammation, and pulmonary histology in a rat model of acid-induced lung injury. Sprague-Dawley rats underwent sevoflurane anesthesia with tracheotomy and carotid catheter insertion. Lung injury was induced by instillation of 0.4 mL/kg 0.1 M hydrochloric acid. The lungs were ventilated for 6 h and randomized to receive either fenoterol inhalation 10 microg or saline inhalation, both at 15 and 180 min after acid aspiration. Mean arterial blood pressures and peak airway pressures were documented, arterial blood gases were determined at 30, 90, 180, 270, and 360 min, and postmortem histology was subsequently examined. Additionally, fenoterol concentrations in bronchoalveolar lavage fluid (BALF) and plasma were determined by liquid chromatography/tandem mass spectroscopy. After 360 min tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 were determined in the BALF, and lungs were dried for determination of the wet/dry ratio., Results: Inhalation treatment with 10 microg fenoterol significantly increased oxygenation after 270 and 360 min when compared with placebo. Fenoterol-treated rats showed a significant decrease in IL-6 and TNF-alpha levels and in the wet/dry weight ratio of the lungs. The histologic appearance showed significantly less interstitial edema and leukocyte infiltration in the fenoterol group. The concentration of fenoterol was 10.3 microg/L (median) in the BALF and <1 microg/L in the plasma., Conclusions: Fenoterol inhalation improved oxygenation after 270 and 360 min, attenuated the release of TNF-alpha and IL-6, and diminished the lung edema and infiltration of polymorphonuclear leukocytes. more...

Providing an acute pain service means accumulation of a large amount of data. The alleviation of data collection, improvement of data quality and data analysis plays a pivotal role. The electronic medical record (EMR) is gaining more and more importance in this context and is continuously spreading in clinical practice. Up to now only a few commercial softwares are available that specifically fit to the needs of an acute pain service. Here we report the development and implementation of such a program (Schmerzvisite, Medlinq, Hamburg, Germany) in the acute pain service of a University Hospital. more...

Background: To test whether portable duplex ultrasound devices can be used in a prehospital '911' emergency situation to assess intracranial arteries., Methods: Non-contrast-enhanced transcranial duplex ultrasound studies were performed either immediately at the site of the emergency (i.e. private home) or after transfer into the emergency helicopter/ambulance vehicle., Results: A total of 25 patients were enrolled. In 5/25 cases, intracranial vessels could not be visualized due to insufficient quality of the temporal bone window. In 20/25 cases, bilateral visualization and Doppler flow measurements of the middle cerebral artery could be assessed in a mean time less than 2 min., Conclusion: Emergency assessment of intracranial arteries using portable duplex ultrasound devices is feasible shortly after arrival at the patient's site., (2008 S. Karger AG, Basel.) more...

Pediatric transfusion therapy is complex since there is a remarkable physiological change from neonate to child. Here we report the blood transfusion management of a 6-year-old male child after abdominal trauma. Particular normovolemia with ringer/hetastarch, the estimation of the maximal allowable blood loss, target transfusion hematocrit, transfusion with platelets and FFP are discussed. more...

Post-operative pain therapy of chronic pain patients poses a challenge. Here we report the perioperative management of a 39-year-old male under chronic therapy with oxycodon, gabapentin and tolperison. Particular the pharmacointeractions regarding premedication and postoperative dose finding of opioids with intravenous PCIA are discussed. more...

We report on a case of a patient with migraine and depression treated with citalopram and sumatriptan. The drug evaluation is presented using the actual summaries of product characteristics (SPC, "Fachinformationen"). Particular the individual perioperative anaesthesiological risk assessment regarding the pharmacodynamic and pharmacointeractions is discussed. more...

Background/aims: The clearance of moxifloxacin is reported to be unaltered in the presence of renal insufficiency. There is little information about the clearance of intravenous moxifloxacin in renal replacement therapies during intensive care. The aim of this study was to determine the clearance of moxifloxacin during continuous veno-venous haemofiltration (CVVHF) in vitro., Methods: The elimination of moxifloxacin (reservoir with 600 mL of washed human erythrocytes, 100 mL of NaHCO3 and various amounts of Ringer solution and human albumin to give a total volume of 1000 mL, pH 7.35 +/- 0.5; haematocrit 41 +/- 2) during CVVHF in vitro with two filter conditions (during priming, after priming), three protein concentrations (human albumin: 0 g/L, 20 g/L, 40 g/L) and two filtration velocities [(i) standard condition: blood flow at 100 mL/min and turnover of 2 L/h; (ii) blood flow at 50 mL/min and turnover of 1 L/h] were investigated., Results: A new filter needs 20 min of priming before moxifloxacin reaches a steady relative filtration rate. The sieving coefficient with 0 g/L albumin was 1.07, with 20 g/L 0.90 and with 40 g/L 0.80. Under standard filtration conditions (i) the renal clearance was between 26.7 and 35.7 mL/min, and under the altered conditions (ii) it was 15.2 mL/min., Conclusion: During CVVHF in vitro we found filtration clearances of moxifloxacin of the same order as its renal clearance in healthy subjects. The high sieving coefficient, nearly independent of blood protein concentration, would suggest that moxifloxacin is filtered almost as freely as creatinine. These results do not indicate a need for dose adjustment under appropriate haemofiltration conditions and normal hepatic function. more...

Study Objectives: To evaluate the effect of pentoxifylline treatment on gas exchange and mortality immediately after bilateral instillation of hydrochloric acid., Design: Randomized, prospective, placebo-controlled trial., Setting: Animal laboratory of a university hospital., Subjects: Twenty-four, adult, male Sprague-Dawley rats., Methods: Sevoflurane-anesthetized rats (n = 12 in each group) underwent tracheostomy and insertion of a cannula into a hind paw vein and the left carotid artery. All animals received volume-controlled mechanical ventilation (zero positive end-expiratory pressure; fraction of inspired oxygen, 0.21). Acute lung injury was induced by instillation of 0.4 mL/kg 0.1 mol/L hydrochloric acid. The animals were randomized into two groups. The pentoxifylline group (n = 12) received a bolus of 20 mg/kg IV pentoxifylline after aspiration, followed by a continuous infusion of 6 mg/kg/h. The placebo group (n = 12) received an equivalent volume of saline solution. Arterial blood samples were collected for blood gas analysis 15 min and 0 min prior to aspiration and 30, 90, 180, 270, and 360 min after aspiration. Hemodynamic parameters, temperature, and ECG were recorded simultaneously. The primary end point was 6 h after aspiration. All surviving rats were killed by IV administration of pentobarbital. To assess morphologic changes due to lung injury, all animals underwent CT in inspiratory hold at the end of the experiment., Measurements and Results: No difference in baseline measurements was observed. In pentoxifylline-treated rats, Pao(2) was significantly increased (p < 0.05) at 30, 90, 180, 270, and 360 min. Mortality at 6 h was 17% in the pentoxifylline group vs 67% in the placebo group. Placebo-treated rats showed significant abnormalities in CT lung scans compared with the pentoxifylline group., Conclusions: Acid aspiration impairs gas exchange and induces hypotension. Pentoxifylline administration shortly after acid instillation results in significant alleviation of impaired oxygenation, stabilization of BP with higher heart rates, and improved survival after 6 h. more...

To elucidate potential stereoselective effects of single barbiturate isomers, we compared the inhibitory potency of single thiopentone enantiomers, two isomer-enriched mixtures of methohexitone and racemic mixtures of both barbiturates on the fMLP-induced neutrophil oxidative response. A suppression of the response to 50% compared to control required a 100-fold therapeutic concentration of methohexitone, while therapeutic concentrations of the thiopentone racemate led to a significant inhibition (relative fluorescence of neutrophils 0.46 +/- 0.03 compared to fMLP controls). The racemate of thiopentone produced significantly greater inhibition than the single enantiomers. Stereoselectivity in favor of one isomer could not be shown for both barbiturates. The greater inhibition by the thiopentone racemate might suggest two separate binding sites for the enantiomers which are positively coupled., (Copyright 2004 S. Karger AG, Basel) more...

Trauma patients with accidental hypothermia have adverse outcomes when compared with normothermic patients. Studies with a small number of mild hypothermic volunteers suggested that convective warming is more effective than warming with 12 volt resistive heating blankets. In a laboratory study, we compared the warming effectiveness of two electric blankets and convective air warming. The average speed of convective rewarming during anaesthesia in patients is approximately 0.6 degree C per hour. Accordingly, calibration of the dummy was performed with increasing amounts of water during convective warming until we reached a temperature gain of 0.6 degree C per hour. The following warming experiments were performed: 12 volt electric warming blanket (SH6012, Hella); 12 volt electric warming blanket (Thermamed, whole-body blanket); convective air warming (Warm Touch, Mallinckrodt, whole-body blanket). Each experiment was repeated four times. The temperature development was measured and recorded online. Convective warming increased the dummy temperature 0.6 degree C per hour, Thermamed 0.3 degree C per hour (P<0.001 versus convective warming) and two Hella blankets 0.2 degree C per hour (P<0.001 versus convective warming). Our laboratory investigation confirmed the superiority of convective warming over resistive heating. Efforts should be made to incorporate convective warming into the out-of-hospital treatment of trauma patients. more...

Background and Objective: Diabetes mellitus associated with hypertension often causes perioperative complications. The alpha1-adrenoceptor antagonist/5-hydroxytryptamine-1A receptor agonist urapidil is an approved drug used in hypertension and hypertensive emergencies. 5-Hydroxytryptamine-1A (5-HT1A) receptor agonists impair glucose metabolism. To evaluate a possible dose-dependent hyperglycaemic effect of urapidil due to its 5-HT1A receptor agonistic properties, the effect of three doses of urapidil on hyperglycaemia in the streptozotocin diabetic rat was investigated., Methods: Male Wistar-Kyoto rats were made diabetic by streptozotocin and randomly allocated to the following daily treatments for 7 days (n = 6 each): urapidil 6 mg kg(-1), urapidil 20 mg kg(-1), urapidil 60 mg kg(-1), insulin 4 IU kg(-1) subcutaneously. One diabetic group and one non-diabetic healthy group served as controls., Results: Treatment for 7 days with urapidil 20 mg kg(-1) and urapidil 60 mg kg(-1) reduced mean glucose concentrations significantly (urapidil-20: 15.6 +/- 1.1 mmol L(-1), P = 0.023; urapidil-60: 15.8 +/- 0.8 mmol L(-1), P = 0.04) compared with diabetic controls (20.9 +/- 0.8 mmol L(-1)), whereas those after urapidil 6 mg kg(-1) were similar to diabetic controls. Insulin treatment normalized blood glucose concentrations., Conclusions: The alpha1-adrenoceptor antagonist/5-HT1A receptor agonist urapidil has no hyperglycaemic effect on experimental diabetes mellitus, even in high doses, despite its 5-HT1A receptor agonistic properties. more...

Naftidrofuryl, a 5-hydroxytryptamine 2 (5-HT 2 ) serotonergic receptor antagonist with vasodilator effects, has successfully been used for intermittent claudication, some forms of dementia, and glaucoma. Recently, an additional mode of action of naftidrofuryl (i.e., mixed endothelin receptor antagonism) has been suggested. However, in the current study naftidrofuryl was unable to block endothelin-3-induced free intracellular calcium increases, in contrast to a mixed endothelin receptor antagonist, bosentan. The inhibition of forskolin-induced renin secretion by endothelin-3 in primary cultures of mouse juxtaglomerular cells and by endothelin-1 in the isolated perfused rat kidney could not be blocked by naftidrofuryl. Naftidrofuryl was unable to block marked endothelin-1-induced renal vasoconstriction in isolated perfused rat kidney. In contrast, naftidrofuryl markedly attenuated serotonin-induced renal vasoconstriction and nearly completely blocked serotonin's renin inhibitory properties in isolated perfused rat kidney. The present results suggest that naftidrofuryl is a potent antagonist of serotonin's renal effects, but has no endothelin receptor-blocking properties. more...

Based on recent evidence that renin gene and cyclooxygenase-2 (COX-2) expression in the rat kidney cortex increase in parallel under a variety of conditions, this study aimed to characterize the causal linkage between COX-2 and renin expression. Therefore, we semi-quantitated renocortical renin and COX-2 gene expression when the renin-angiotensin system (RAS) was inhibited by the angiotensin II (Ang II) AT1 receptor antagonist candesartan (15 mg/kg per day) and when COX-2 activity was blocked by celecoxib (20 mg/kg twice a day) in three rat strains (Sprague-Dawley, WKY and SHR) at ages of 5, 9 and 15 weeks. We observed that candesartan increased renin mRNA in all rats at all ages, the amplitude of stimulation being inversely related to age. Candesartan increased COX-2 mRNA in all three strains at 5 weeks, and in SD and WKY rats also at 9 weeks. In 9-week-old SHR and in 15-week-old rats of all three strains candesartan did not influence COX-2 mRNA levels. For all rat strains, strain-specific strong linear correlations existed between renocortical COX-2 and renin mRNA levels, both with and without candesartan treatment. The additional feeding of candesartan-treated rats with celecoxib did not change renin mRNA or COX-2 mRNA levels, whilst the renal excretion of sodium and renal cortical prostaglandin E2 concentration decreased by 26% and 60%, respectively. In summary, these findings, obtained when the renin system was activated by AT1 receptor blockade, indicate that Ang II is not required to stimulate COX-2 expression and that COX-2 activity is not required to stimulate renin expression. However, the renocortical expression of renin and of COX-2 appear to be highly coordinated under basal conditions and during inhibition of RAS, suggesting the existence of a common denominator for renin and COX-2 expression that remains to be elucidated. more...

Our study aimed to characterize the mechanisms underlying the attenuated cardiovascular responsiveness toward the renin-angiotensin system during sepsis. For this purpose, we determined the effects of experimental Gram-negative and Gram-positive sepsis in rats. We found that sepsis led to a ubiquitous upregulation of NO synthase isoform II expression and to pronounced hypotension. Despite increased plasma renin activity and plasma angiotensin (Ang) II levels, plasma aldosterone concentrations were normal, and the blood pressure response to exogenous Ang II was markedly diminished in septic rats. Mimicking the fall of blood pressure during sepsis by short-term infusion of the NO donor sodium nitroprusside in normal rats did not alter their blood pressure response to exogenous Ang II. Therefore, we considered the possibility of an altered expression of Ang II receptors during sepsis. It turned out that Ang II type 1 receptor expression was markedly downregulated in all organs of septic rats. Further in vitro studies with rat renal mesangial cells showed that NO and a combination of proinflammatory cytokines (interleukin-1beta, tumor necrosis factor-alpha, and interferon-gamma) downregulated Ang II type 1 receptor expression in a synergistic fashion. In summary, our data suggest that sepsis causes a systemic downregulation of Ang II type 1 receptors that is likely mediated by proinflammatory cytokines and NO. We suggest that this downregulation of Ang II type 1 receptors is the main reason for the attenuated responsiveness of blood pressure and of aldosterone formation to Ang II and, therefore, contributes to the characteristic septic shock. more...

Background: Triple therapy including two antibiotics and a proton pump inhibitor is a rational approach to the treatment of Helicobacter pylori induced peptic ulcer disease. The interaction of antimicrobial therapy and acid suppression is not yet well elucidated., Aims: To investigate the effects of proton pump inhibitors on roxithromycin levels in plasma and gastric tissue under steady-state conditions in volunteers., Methods: In two crossover studies omeprazole 20 mg b.d., lansoprazole 30 mg b.d., roxithromycin 300 mg b.d., and the combination of roxithromycin with either omeprazole or lansoprazole were administered to 12 healthy volunteers over 6 days. Blood plasma levels of the drugs were measured. In addition, roxithromycin concentrations were also determined in gastric juice and gastric tissue obtained during endoscopy., Results: The proton pump inhibitors and roxithromycin did not alter the blood plasma pharmacokinetics of each other. When compared to roxithromycin administered alone, its combination with a proton pump inhibitor significantly increased the roxithromycin concentrations in gastric juice (3.0-5.0 microg/mL vs. 0.3-0.4 microg/mL) and gastric tissue (antrum: 3.8-4.0 vs. 2.8 microg/g, fundus: 5.9-7.4 vs. 4.2-4.4 microg/g)., Conclusions: Proton pump inhibitors and roxithromycin do not alter the systemic bioavailability of each other. However, proton pump inhibitors increase the local concentration of roxithromycin in the stomach which may contribute to the clinically proven synergic beneficial action in eradication therapy of H. pylori. more...

Angiotensin-converting enzyme inhibitors and alpha1-adrenoceptor antagonists improve glucose disposal in diabetes mellitus. We compared the effect of the antihypertensive hybrid drug urapidil [alpha1-adrenoceptor antagonist serotonin 1A (5-hydroxytryptamine 1A, 5-HT1A) receptor agonist] on hyperglycemia in streptozotocin diabetic rats with the angiotensin-converting enzyme inhibitor ramipril. 5-HT1A receptor agonists induce hyperglycemia. This could be an important disadvantage during treatment of diabetes mellitus with urapidil. Diabetes was induced by streptozotocin (70 mg/kg i.p.). Treatment for 7 days (ramipril 10 mg/kg p.o.; urapidil 20 mg/kg p.o.) significantly decreased mean blood glucose values (urapidil: 15.7+/-0.9 mmol/l, P=0.007; ramipril: 15.0+/-0.8 mmol/l, P=0.038 vs. diabetic control group: 18.7+/-1.0 mmol/l). Both drugs reduced significantly blood pressure, urinary glucose, water consumption, and food requirement. Serotonin concentration in the brain (medulla oblongata, pituitary) was not affected. A normalization comparable with healthy control rats was observed only in a diabetic control group with insulin therapy. In conclusion, our results demonstrate that the antihypertensive drug urapidil has no detrimental effect on hyperglycemia compared with the angiotensin-converting enzyme inhibitor ramipril in experimental diabetes mellitus despite its 5-HT1A receptor agonistic properties. more...

Objective: To determine the plasma elimination of methohexitone in patients with critically elevated intracranial pressure (ICP) who received the drug in high doses for several days., Design: Drug-monitoring study., Setting: Intensive care unit at a university hospital., Patients: Twelve intensive care unit patients with brain injuries who received methohexitone as a final therapeutic approach after routine therapy had proved to be insufficient in controlling critically elevated ICP., Measurements and Main Results: Plasma samples were taken during methohexitone infusion, before cessation, and in distinct, short increments after discontinuation of the infusion. Methohexitone was determined in plasma by reverse-phase high-pressure liquid chromatography and photometric detection. The median duration of infusion of methohexitone was 137 hrs (minimum, 27 hrs; maximum, 445 hrs), with a median infusion rate of 62.5 microg/kg/min (minimum, 22.5 microg/kg/min; maximum, 116.2 microg/kg/min). Plasma concentrations of methohexitone at burst suppression under concomitant analgesic sedation ranged from 1.6 to 17.3 microg/mL (median, 4.7 microg/mL). After cessation of methohexitone infusion, the decline of plasma concentrations followed a biexponential function. Clearance rates, volume of distribution at steady state, context-sensitive half-time, and initial and terminal elimination half-times were calculated. Pharmacokinetic data showed remarkable interindividual variability that could not be correlated to the infusion rate, to the duration of the infusion, or to obvious differences in physiology or the disease states of these patients. Even in patients with high plasma concentrations who received the drug for a considerable length of time, the initial decline in plasma concentration was exponential, indicating redistribution., Conclusions: We conclude that the elimination kinetics of methohexitone after long-term, high-dose infusion in critically ill patients with brain injuries may favor the use of methohexitone over thiopentone for controlling critically elevated ICP by allowing for a more timely neurologic examination after cessation. more...

Angiotensin II receptors have recently been subclassified as type-1 or type-2 receptors. The in vitro and in vivo effects of blocking the angiotensin II type-1 receptor with ZD7155, an angiotensin II type-1 selective receptor antagonist, have been studied in angiotensin II-mediated increases in cytosolic calcium in rat mesangial cells, in angiotensin II-induced renal and systemic vasoconstriction, and in angiotensin II-mediated regulation of renin secretion and renal renin gene expression. ZD7155 completely blocked the ability of angiotensin II to elicit an increase in free intracellular calcium concentrations in rat mesangial cells. In isolated perfused rat kidneys, ZD7155 completely abolished the angiotensin II-induced vasoconstriction and increased renin secretion to 700% of baseline levels. Furthermore, ZD7155 decreased systolic blood pressure by 16 mm Hg, increased plasma renin activity 3.7-fold, and stimulated renal renin gene expression 4.2-fold in Sprague-Dawley rats in vivo. Our results suggest that ZD7155 is a potent antagonist of the angiotensin II type-1 receptor, which mediates angiotensin II-induced increases of free intracellular calcium concentrations in (e.g., renal mesangial cells), constriction of the renal and systemic vasculature, and inhibition of renin secretion and synthesis. more...

The endothelin peptide family consists of the 21 amino acid isoforms endothelin-1, endothelin-2, endothelin-3, and sarafotoxin (a snake venom). Endothelin-1 has been isolated from the supernatant of endothelial cells and has subsequently been shown to be the most potent vasoconstrictor known to date and to be positively inotropic. This review summarizes some of the current literature pertaining to circulatory and myocardial effects of endothelins. Exogenously administered endothelin-1 has been demonstrated to increase peripheral resistance and blood pressure in a dose-dependent manner. However, during the first minutes of intravenous administration endothelins also decrease peripheral resistance and blood pressure, presumably due to the release of vasodilatory compounds such as nitric oxide, prostacyclin, and atrial natriuretic peptide. Endothelins appear to be involved in the pathogenesis of salt-dependent and renovascular animal models of experimental hypertension. Although endothelins appear to contribute to basal vascular tone, the role of endothelins in the pathophysiology of human hypertension remains unclear. In addition, a role has been suggested for endothelins in specific vascular lesions and inflammatory conditions (e.g., restenosis after coronary angioplasty, atherosclerotic coronary lesions, acute myocardial infarction, and vasculitis, glomerulonephritis). Endothelins are positively inotropic peptides in cardiac myocyte and papillary muscle preparations. They have also been demonstrated to induce hypertrophy of cardiac myocyte and may play an important role in ventricular processes that lead to chronic cardiac failure. The pathophysiological relevance of the endothelin system in human disease states is elucidated using selective (ET[A]) and nonselective (ET[A/B]) inhibitors of the endothelin receptors. more...

This study was done to investigate the influence of Gram-negative and Gram-positive sepsis on the expression of the three isoforms of nitric oxide synthase (NOS) gene in rat liver and kidney. Male Sprague-Dawley rats were treated with lipopolysaccharide (LPS, 10 mg/kg i.v.) as an in vivo model for Gram-negative sepsis or lipoteichoic acid (LTA, 10 mg/kg i.v.) as an in vivo model for Gram-positive sepsis. Animals were killed 12 h and 24 h after i.v. treatment. NOS mRNA of the three isoforms was determined by RNase protection assay. NOS II gene expression was strongly induced after LPS or LTA treatment in rat liver and kidney, indicating the efficacy of this treatment to induce sepsis. We found no change of NOS I gene expression after LPS or LTA injection in rat liver and kidney. NOS III gene expression was increased about 8-fold 12 h and about 5-fold 24 h after induction of sepsis in the rat liver whereas in the kidney there was no significant increase in NOS III gene expression. After correction for length NOS III mRNA was about 4- and 40-fold more abundant 12 h and 24 h after LPS treatment than NOS II mRNA in the liver, respectively. Twelve and 24 h after LTA treatment NOS III mRNA was about 18- and 140-fold more abundant than NOS II in the liver. These findings suggest that NOS III is an even more potent source of NO than NOS II in the liver after stimulation with LPS or LTA. more...

There is accumulating evidence from in vitro studies suggesting that the genes of endothelin-1, PDGF, and VEGF are, like the erythropoietin gene, regulated by oxygen tension and by divalent cations. Hypoxia-induced stimulation of, such as endothelin-1, PDGF or VEGF might be involved in the pathogenesis of acute or chronic renal failure, and in renal "inflammatory" diseases (glomerulonephritis, vasculitis, allograft rejection). Hypoxia (8% O2) for six hours caused a 55-fold/1.6-fold increase of renal erythropoietin/endothelin-1 gene expression, whereas endothelin-3, PDGF-A, PDGF-B, and VEGF gene expression was unchanged. Carbon monoxide (0.1%) treatment for six hours stimulated renal erythropoietin gene expression 140-fold; however, endothelin-1, endothelin-3, PDGF-A, PDGF-B, and VEGF gene expression was not affected. Finally, cobalt treatment (60 mg/kg CoCl2) increased only renal erythropoietin/PDGF-B gene expression 5-fold/1.65-fold. These findings suggest that hypoxia is a rather weak stimulus for renal endothelin-1 gene expression, and that renal PDGF and VEGF gene expression in vivo is not sensitive to tissue hypoxia, in contrast to cell culture experiments. The in vivo regulation of endothelin-1, PDGF, and VEGF differs substantially from that of erythropoietin, suggesting that the basic gene regulatory mechanisms may not be the same. more...

Technical problems during anaesthesia are important causes of anaesthesia-related deaths and brain damage. During general endotracheal anaesthesia for ophthalmic surgery (41-year-old man, ASA 1) we observed an increase in inspiratory pressure without other clinical changes. Disconnection and ventilation with a resuscitation bag showed normal inspiratory pressures. Inspection demonstrated an obstruction due to an aneurysm of the inner layer of the inspiratory tubing. The classification of this rare blockage of ventilation differs in the literature (pressure, hypoventilation, hypercarbia). In addition, it demonstrates the principal problem of clinical decision-making during anaesthesia based on monitoring information. Strategies for responding to alarms indicating hazards of ventilation must be based on immediate restoration of sufficient ventilation, and not primarily on detecting the cause. more...