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Biomedical subjects

M Leuwer

Publications and source records attributed to M Leuwer.

At least 19 recordsLinked to original sources
PubMed2002

Hydroxyethyl starch and modified fluid gelatin maintain plasma volume in a porcine model of septic shock with capillary leakage.

OBJECTIVE: To compare the effects of different volume replacement therapies on maintenance of plasma volume in septic shock and capillary leakage syndrome. DESIGN AND SETTING: Prospective randomized, controlled animal laboratory study in a university animal laboratory. MEASUREMENTS AND RESULTS: Twenty-five fasted, anaesthetized, mechanically ventilated and multi-catheterized pigs (20.8+/-1.8 kg) received 1 g/kg body weight faeces into abdominal cavity to induce sepsis and were observed over 8 h. Five animals each received volume replacement therapy with modified fluid gelatin 4% or 8% (MFG4%, MFG8%), 6% HES 200/0.5, or Ringer's solution and were compared to controls receiving 6% HES 200/0.5. Infusion rate was titrated to maintain a central venous pressure of 12 mmHg. Plasma volume was determined using (51)Cr-labelled erythrocytes and standard formulae. Albumin escape rate was calculated using technetium (99m)Tc-labelled albumin. Colloid osmotic pressure, systemic haemodynamics and oxygenation were obtained before and 4 and 8 h after induction of sepsis. Plasma volume was reduced in the Ringer's solution group (-46%) but was maintained in HES (+/-0%), MFG4% (+4%), MFG8% (+23%) groups. Albumin escape rate increased in HES (+52%), MFG4% (+47%), MFG8% (+54%) and the Ringer's solution group (+41%) compared to controls. CONCLUSION: In this porcine septic shock model with concomitant capillary leakage syndrome, confirmed by an increased albumin escape rate, the artificial colloids HES, MFG4%, and MFG8% maintained plasma volume and colloid osmotic pressure. These results suggest the intravascular persistency of artificial colloids in the presence of albumin leakage. An editorial regarding this article can be found in the same issue (http://dx.doi.org/10.1007/s00134-002-1283-9)

Albumins↗
PubMed2002

Voltage-dependent block of neuronal and skeletal muscle sodium channels by thymol and menthol.

BACKGROUND AND OBJECTIVE: Thymol is a naturally occurring phenol derivative used in anaesthetic practice as a stabilizer and preservative of halothane, usually at a concentration of 0.01%. Although analgesic effects have long been described for thymol and its structural homologue menthol, a molecular basis for these effects is still lacking. We studied the blocking effects of thymol and menthol on voltage-activated sodium currents in vitro as possible molecular target sites. METHODS: Whole cell sodium inward currents via heterologously (HEK293 cells) expressed rat neuronal (rat type IIA) and human skeletal muscle (hSkM1) sodium channels were recorded in the absence and presence of definite concentrations of either thymol or menthol. RESULTS: When depolarizing pulses to 0 mV were started from a holding potential of -70 mV, half-maximum blocking concentrations (IC50) for the skeletal muscle and the neuronal sodium channel were 104 and 149 mumol for thymol and 376 and 571 mumol for menthol. The blocking potency of both compounds increased at depolarized holding potentials with the fraction of inactivated channels. The estimated dissociation constant Kd for thymol and menthol from the inactivated state was 22 and 106 mumol for the neuronal and 23 and 97 mumol for the skeletal muscle sodium channel, respectively. CONCLUSIONS: The results suggest that antinociceptive and local anaesthetic effects of thymol and menthol might be mediated via blockade of voltage-operated sodium channels with the phenol derivative thymol being as potent as the local anaesthetic lidocaine.

Analgesics↗
PubMed2001

Structural requirements of phenol derivatives for direct activation of chloride currents via GABA(A) receptors.

Propofol directly activates gamma-aminobutyric acid (GABA(A)) receptors in the absence of the natural agonist. This mechanism is supposed to contribute to its sedative-hypnotic actions. We studied the effects of seven structurally related phenol derivatives on chloride inward currents via rat alpha1beta2gamma2 GABA(A) receptors, heterologously expressed in HEK 293 cells in order to find structural determinants for this direct agonistic action. Only compounds with the phenolic hydroxyl attached directly to the benzene ring and with aliphatic substituents in ortho position to the phenolic hydroxyl activated chloride currents in the absence of GABA. Concentrations required for half-maximum effect were 980 microM for 2-methylphenol, 230 microM for 2,6-dimethylphenol, 200 microM for thymol, and 23 microM for propofol. Drug-induced chloride currents showed no desensitisation during the 2-s application. These results show that the position of the aliphatic substituents with respect to the phenolic hydroxyl group is the crucial structural feature for direct GABA(A) activation by phenol derivatives.

Animals↗
PubMed2001

Phenol derivatives accelerate inactivation kinetics in one inactivation-deficient mutant human skeletal muscle Na(+) channel.

Altered inactivation kinetics in skeletal muscle Na(+) channels due to mutations in the encoding gene are causal for the alterations in muscle excitability in nondystrophic myotonia. Na(+) channel blockers like lidocaine and mexiletine, suggested for therapy of myotonia, do not reconstitute inactivation in channels with defective inactivation in vitro. We examined the effects of four methylated and/or halogenated phenol derivatives on one heterologously expressed inactivation-deficient Paramyotonia congenita-mutant (R1448H) muscle Na(+) channel in vitro. All these compounds accelerated delayed inactivation of R1448H-whole-cell currents during a depolarization and delayed accelerated recovery from inactivation. The potency of these effects paralleled the potency of the drugs to block the peak current amplitude. We conclude that the investigated phenol derivatives affect inactivation-deficient Na(+) channels more specifically than lidocaine and mexiletine. However, for all compounds, the effect on inactivation was accompanied by a substantial block of the peak current amplitude.

Cell Line↗
PubMed2001

The anesthetic propofol modulates gating in paramyotonia congenita mutant muscle sodium channels.

We examined the effects of propofol on a paramyotonia congenita mutant skeletal muscle sodium channel in vitro, because life-threatening complications resulting from severe muscle rigidity during induction of anesthesia have been observed using other anesthetics in patients with hereditary sodium channel myopathies. Our hypothesis was that propofol might interact directly with mutant channels, causing enhanced muscle excitability in affected patients. Whole-cell voltage-clamp experiments were performed on HEK 293 cells expressing R1448H mutant sodium channels. Propofol blocked sodium inward current at clinical concentrations (5 micromol/L) when depolarizing pulses were started from holding potentials close to the physiological resting potential (-70 mV). Higher propofol concentrations (>/=25 micromol/L) accelerated pathologically delayed inactivation kinetics and delayed pathologically enhanced recovery from inactivation. Our in vitro results show that inactivation-deficient sodium channels are specifically targeted and blocked by propofol. This might reduce enhanced muscle excitability experienced by affected patients in vivo.

Amino Acid Substitution↗
PubMed2001

Effects of C1 inhibitor and r-SP-C surfactant on oxygenation and histology in rats with lavage-induced acute lung injury.

OBJECTIVE: To assess the effects of C1 inhibitor (INH) administration and r-SP-C surfactant application on oxygenation and lung histology in an acute respiratory distress syndrome model. DESIGN AND SETTING: Randomized, controlled experimental study in an animal research laboratory. MATERIAL: 36 adult male Sprague-Dawley rats. INTERVENTIONS: Animals were subjected to repetitive lung lavage. Four experimental groups and two control groups were studied: groups 1 and 2 served as controls. Animals of groups 3-6 received 200 U/kg body weight C1-INH (group 3), 25 mg/kg r-SP-C surfactant (group 4) or both (group 5) at 60 min postlavage (pl). Animals of group 6 were treated with 200 U/kg C1-INH1 at 10 min pl. Animals of group 1 were killed 60 min (min) pl, animals of groups 2-6 were killed at 210 min pl. Thereafter the lungs were excised for histological examination. MEASUREMENTS AND RESULTS: Hyaline membrane formation, intra-alveolar neutrophil (PMN) accumulation and intra-alveolar/perivascular haemorrhage were graded semiquantitatively (0-4). Blood gases were determined 120, 150, 180 and 210 min pl. At 210 min pl pO(2) in group 4 (456+/-74 mmHg) and group 5 (387+/-155 mmHg) was significantly higher than in controls (72+/-29 mmHg) or after C1-INH monotherapy (group 3: 120+/-103, group 6: 63+/-12 mmHg). PMN infiltration after C1-INH monotherapy was significantly less severe than in controls. The combination of r-SP-C surfactant and C1-INH led to significantly lower PMN infiltration than surfactant monotherapy. CONCLUSION: In this lavage-induced acute respiratory distress syndrome model the administration of C1-INH might be followed by a higher clinical efficacy of exogenously supplied recombinant SP-C surfactant.

Animals↗
PubMed2001

General anesthesia for interventional neuroradiology: propofol versus isoflurane.

STUDY OBJECTIVE: To compare recovery of psychomotor and cognitive ability after isoflurane and propofol-based general anesthesia. DESIGN: Prospective, blinded interventional study. SETTING: University hospital. PATIENTS: 24 ASA physical status I and II patients undergoing embolization procedures for intracranial vascular lesions. INTERVENTIONS: Isoflurane anesthesia or propofol anesthesia was given to patients. MEASUREMENTS: Awakening time; early recovery (5 minutes, 15 minutes, 30 minutes) was assessed using orientation and Steward tests; medium recovery (30 minutes, 60 minutes, 120 minutes) was tested using Controlled World Association (COWAT) and Digit Span tests; late recovery (4 hours, 24 hours) was assessed using a Verbal Learning and Memory Test and three subtests of a computerized attention test battery. MAIN RESULTS: Awakening time and early recovery of motor and respiratory function did not differ between groups. The propofol group scored worse in COWAT and Digit Span tests up to 60 minutes after anesthesia. Both groups showed an impairment of higher cognitive functions up to 24 hours after anesthesia. CONCLUSIONS: Both isoflurane- and propofol-based anesthesia allow early extubation and recovery of basic psychomotor functions. More sophisticated tests show a decline of cognitive functions up to 24 hours after isoflurane- as well as propofol-based anesthesia. Because both anesthetics show similar recovery of psychomotor functions after long duration anesthesia, other factors such as subjective well-being and costs may be considered when deciding between these two anesthetics.

Adolescent↗
PubMed2001

Postoperative reading speed does not indicate implicit memory in elderly cardiac patients after propofol and remifentanyl anaesthesia.

BACKGROUND: A recent study in young patients undergoing propofol-alfentanil-nitrous oxide anaesthesia demonstrated implicit memory for stories presented during operation using a postoperative reading speed task. In this study we investigated whether patients who tolerate only small amounts of anaesthetics are prone to develop implicit and explicit memories about intraoperative events. METHODS: Thirty patients with poor physical status (ASA III-IV) undergoing cardioverter defibrillator implantation were included in the study. Patients were premedicated with intravenous midazolam and anaesthesia was maintained using propofol and remifentanil infusions. During surgery one of two audio-tapes containing two short stories was played to the patients. Reading speed for the stories played during surgery and two similar stories from the other tape was tested 4 h later. Explicit memory was tested at 4 h and 24 h after audiotape presentation using a structured interview and a forced-choice recognition test pertaining to the story content. Thirty additional awake subjects served as controls. RESULTS: Although half of the patients seemed to be awake one or more times during the operation, no explicit memories of intraoperative events were reported. The forced-choice recognition of the stories was at chance level. No effect on reading speed was found in either the patients or the control subjects. CONCLUSIONS: The possible reasons for reduced explicit and implicit memory performance in elderly patients are age and poor physical status of the patients and the modality change between study and test phases. A non-anaesthetised control group of the same age and physical status should therefore be included in all studies of implicit memory.

Acoustic Stimulation↗
PubMed2001

Structural requirements for voltage-dependent block of muscle sodium channels by phenol derivatives.

We have studied the effects of four different phenol derivatives, with methyl and halogen substituents, on heterologously expressed human skeletal muscle sodium channels, in order to find structural determinants of blocking potency. All compounds blocked skeletal muscle sodium channels in a concentration-dependent manner. The methylated phenol 3-methylphenol and the halogenated phenol 4-chlorophenol blocked sodium currents on depolarization from -100 mV to 0 mV with IC(50) values of 2161 and 666 microM respectively. Methylation of the halogenated compound further increased potency, reducing the IC(50) to 268 microM in 2-methyl-4-chlorophenol and to 150 microM in 3,5-dimethyl-4-chlorophenol. Membrane depolarization before the test depolarization increased sodium channel blockade. When depolarizations were started from -70 mV or when a 2.5 s prepulse was introduced before the test pulse inducing slow inactivation, the IC(50) was reduced more than 3 fold in all compounds. The values of K(D) for the fast-inactivated state derived from drug-induced shifts in steady-state availability curves were 14 microM for 3,5-dimethyl-4-chlorophenol, 19 microM for 2-methyl-4-chlorophenol, 26 microM for 4-chlorophenol and 115 microM for 3-methylphenol. All compounds accelerated the current decay during depolarization and slowed recovery from fast inactivation. No relevant frequency-dependent block after depolarizing pulses applied at 10, 50 and 100 Hz was detected for any of the compounds. All the phenol derivatives that we examined are effective blockers of skeletal muscle sodium channels, especially in conditions that are associated with membrane depolarization. Blocking potency is increased by halogenation and by methylation with increasing numbers of methyl groups.

Cell Line↗
PubMed2001

Propofol blocks human skeletal muscle sodium channels in a voltage-dependent manner.

UNLABELLED: Propofol decreases muscle tone in the absence of neuromuscular blocking drugs. This effect probably cannot be attributed solely to central nervous depression. We studied the effects of propofol on heterologously expressed skeletal muscle sodium channels. Our hypothesis was that the decrease in muscle tone may partly be attributed to an interaction of propofol with sarcolemmal sodium channels. Cells were voltage clamped and whole-cell sodium inward currents were recorded in the absence and presence of propofol. When depolarizing pulses to 0 mV were started from a holding potential close to the normal resting potential of muscle (-70 mV), or when a 2.5-s prepulse inducing slow inactivation was applied before the test pulse at -100 mV, a significant reduction in the peak current amplitude was achieved by 10 and 5 microM propofol, respectively (P < 0.001). Half-maximum blocking concentrations with these protocols were 23 and 22 microM. Blocking potency increased at depolarized membrane potentials with the fraction of inactivated channels; the estimated dissociation constant K(d) from the inactivated state was 4.6 microM. These results suggest that propofol significantly blocks sarcolemmal sodium channels at clinically relevant concentrations while maintaining potentials close to the physiological resting potential. IMPLICATIONS: Voltage-gated sodium channels mediate the initiation and propagation of action potentials along the sarcolemma. Results from our study show that those channels are targeted and blocked in a concentration- and voltage-dependent manner by propofol. This mechanism may contribute to the reduction in muscle excitability.

Action Potentials↗
PubMed2001

Using intranasal midazolam spray to prevent claustrophobia induced by MR imaging.

OBJECTIVE: Up to 37% of patients undergoing MR imaging examinations experience moderate to severe levels of anxiety that necessitate the termination of the procedure in 5-10% of patients. Although the clinical use of MR imaging has increased, effective procedures to handle claustrophobia are lacking. We evaluated the effectiveness of intranasally administered midazolam spray in preventing claustrophobic responses of patients undergoing MR imaging. SUBJECTS AND METHODS: Fifty-four patients scheduled for MR imaging were included in this prospective study. Anxiety and sedation of patients were evaluated before drug administration, immediately before MR imaging, and at the end of the procedure. The Spielberger State-Trait Anxiety Inventory, the visual analogue scale of anxiety, and a five-point sedation scale were used. Half the patients received intranasal spray applications of 4 mg midazolam, whereas the other patients received a placebo, in a randomized, double-blind study design (six sprayings of 0.5% midazolam solution or NaCl 0.9%, respectively). The intensity of the sensation of burning of the nasal mucosa was rated by patients using a three-point scale (no, slight, or strong burning). The quality of scan images was evaluated by a radiologist using a five-point scale (0 = extremely poor, 5 = excellent). RESULTS: No cancellations occurred with patients who received midazolam, whereas four of 27 patients receiving placebo panicked and terminated the scanning procedure. The initial anxiety and sedation scores did not differ between the groups. Patients who received midazolam spray were more sedated and less anxious immediately before entering the MR scanner and reported a more intense slight transient burning of the nasal mucosa than those in the placebo group. The quality of the MR image was higher in the midazolam group. CONCLUSION: A sizeable reduction in MR imaging-related anxiety and improved MR image quality were seen with patients who received intranasal midazolam spray. With the exception of transient burning of the nasal mucosa, no adverse effects were reported. This simple and safe method is useful in sedating patients for MR imaging and other minor procedures.

Administration, Intranasal↗
PubMed2000

Absorption and hemodynamic effects of airway administration of adrenaline in patients with severe cardiac disease.

BACKGROUND: If intravenous access cannot be attained during resuscitation of adult patients, endotracheal application of at least 2 mg of adrenaline is recommended. However, the effects of this intervention have not yet been demonstrated in adults. OBJECTIVE: To demonstrate the effects of adrenaline administered through the airways. DESIGN: Prospective clinical trial. SETTING: Operating theater at university hospital. PATIENTS: 34 patients receiving implantable cardioverter defibrillators under general anesthesia. INTERVENTION: When mean arterial pressure decreased below 80 mm Hg, 100 times the effective central intravenous dose of adrenaline (mean +/- SD, 1.3+/-0.6 mg [range, 0.7 to 3 mg]) was administered over 5 seconds into the endotracheal tube or through a bronchial catheter. Ten forced ventilations followed. MEASUREMENTS: Hemodynamic variables were recorded with a polygraph recorder. Adrenaline levels were measured in 13 patients. RESULTS: Plasma levels and arterial pressure increased in all patients (P < 0.002). Higher plasma levels (P < 0.039) and greater arterial pressure (P < 0.001) were achieved with this method than with intravenous injection. The effects of adrenaline did not differ between the two airway routes. Sustained ventricular arrhythmia did not occur. CONCLUSION: These substantial effects support the standard recommendation to consider the airways as an alternate route for at least 2 mg of adrenaline during resuscitation.

Absorption↗
PubMed2000

Evaluation of noninvasive determinants for capillary leakage syndrome in septic shock patients.

OBJECTIVE: Capillary leakage syndrome (CLS) is a frequent complication in sepsis, characterized by loss of intravasal fluids leading to generalized edema and hemodynamic instability despite massive fluid therapy. In spite of its importance no standardized diagnostic criteria are available for CLS. DESIGN: Prospective clinical study. SETTING: 1,800-bed university hospital PATIENTS: Six septic shock patients with CLS were compared to six control patients. MEASUREMENTS AND RESULTS: CLS was clinically determined by generalized edema, positive fluid balance, and weight gain. Plasma volume was measured by indocyanine green, red blood cell volume by chromium-51 labeled erythrocytes, and colloid osmotic pressure before and 90 min after the administration of 300 ml 20% albumin. Extracellular water (ECW) was measured using the inulin distribution volume and bioelectrical impedance analysis. Red blood cells averaged 20.2 +/- 1.0 ml/ kg body weight in CLS patients and 23.3 +/- 4.1 in controls. ECW was higher in CLS patients than in controls (40.0 +/- 6.9 vs. 21.7 +/- 3.71; p< 0.05). ECW of inulin was correlated with that measured by bioelectrical impedance analysis (r = 0.74, p< 0.01). The increase in colloid osmotic pressure over the 90 min was less in CLS patients than in controls (1.1 +/- 0.3 vs. 2.8 +/- 1.3 mmHg;p< 0.05). CONCLUSION: These results suggest that measurements of an increased ECW using bioelectrical impedance analysis combined with a different response of colloid osmotic pressure to administration of albumin can discriminate noninvasively between patients with and those without CLS.

Adult↗
PubMed2000

Endoluminal grafting of abdominal aortic aneurysms: experience with the Talent endoluminal stent graft.

The aim of this study was to evaluate the Talent endoluminal stent graft (TESG) in treating abdominal aortic aneurysms (AAA). The TESG is a polyester-covered nitinol endograft (proximal diameters 20-38 mm and iliac limb diameters 8-22 mm). Twenty-two men were treated with the TESG via bilateral femoral arteriotomies. Pre-implantation, coil embolization of various vessels arising from the aneurysm was performed in 6 patients. Plain radiographs and spiral CT angiograms (CTA) were carried out at 7 days, 3, 6, and 12 months following TESG implantation or re-intervention. Median aortic and iliac diameters were 27 mm (range 20-34 mm) and 14 mm (range 10-19 mm). The corresponding graft diameters were 30 mm (range 24-38 mm) and 14 mm (range 12-20 mm). No patient was rejected purely on the basis of too large aortic or iliac diameters. Eight patients required custom-made grafts. Graft implantation was successful in all patients. There were no blood transfusions, distal embolic episodes, or conversions to open surgery. Re-intervention was necessary in 1 patient. Complications included one fatal myocardial infarction, one inguinal hematoma, and two superficial wound infections. The aneurysm thrombosed completely following implantation in 14 patients and at 3 or 6 months in 4 other patients. One patient with endoleak is awaiting his 3-month control and 2 patients show tiny endoleaks but reduction of aneurysm size. The mean aneurysm size decreased significantly from 58 +/- 10 to 53 +/- 13 mm (p < 0.0005). Due to the large sizes available and the option of custom-made grafts, the TESG helps widen the spectrum of patients who can be treated with endoluminal grafting. The treatment is associated with a significant reduction in aneurysm size.

Aged↗
PubMed2000

Acute vascular rejection is associated with systemic complement activation in a pig-to-primate kidney xenograft model.

The introduction of h-DAF transgenic porcine organs into pre-clinical pig-to-primate discordant xenotransplantation has led to complete and reliable abrogation of hyperacute xenograft rejection (HAR). Despite additional heavy immunosuppression however, most xenografts are still lost due to acute vascular rejection (AVR), with current treatment protocols being of only limited value. In a life-supporting model of pig-to-primate kidney transplantation, unmodified (n=8) or h-DAF-transgenic (n=9) porcine kidneys were transplanted into cynomolgus monkeys under cyclophosphamide (CyP), cyclosporine and low-dose steroid immunosuppression. Longest recipient survival was 11 days in the control group and 68 days in the h-DAF transgenic group. Stable initial graft function with recipient survival >4 days was generated in eight animals (two controls and six transgenics). In these animals, plasma complement levels were analyzed during ongoing AVR. Compared with baseline levels, a two-fold increase in C3a levels and a four-fold increase in sC5b-9 levels were measured. In parallel to systemic complement activation, increased deposition of C3 and C5b-9 along with massive staining for recipient IgM immunoglobulins was detected in the xenografts on immunohistochemistry. We conclude that acute vascular xenograft rejection of porcine kidneys in cynomolgus monkeys is associated with classical pathway complement activation following binding of induced recipient anti-porcine antibodies. This complement activation can be observed despite membrane bound expression of human complement regulators in the porcine xenografts. Therefore, additional short-term fluid phase complement inhibition seems necessary for the future development of protocols designed for treatment of AVR in the pig-to-primate combination.

Acute Disease↗