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R Nau

Publications and source records attributed to R Nau.

At least 73 records · Page 4Linked to original sources
PubMed1997

[Treatment of patients with thromboses of the basilar artery and locked-in syndrome. An ethical dilemma].

Decisions regarding the extent of treatment of severely ill patients can be an ethical dilemma when life-prolonging intensive care contradicts the goal of avoiding unnecessary suffering on the part of the patient. Here we present the results of a written survey of physicians on neurological intensive care units in Germany regarding the treatment of patients with basilar artery thrombosis and locked-in syndrome. 52% of the 93 physicians who replied advocated not treating severe infections with antibiotics, 38% were in favor of stopping intensive care. In contrast, 55% recommended intubating the patient in the presence of swallowing disturbances and imminent aspiration. 58% were in favor of discussing these problems in detail with the patient, and 87% advocated discussing them with relatives. Nearly all physicians (97%) recommended using adequate amounts of opiates and benzodiazepines. In very rare cases, 99% would agree to the use of passive euthanasia and 19% to active euthanasia. These findings illustrate the current disagreement on some of the important treatment decisions among physicians on neurological intensive care units. An open exchange of views on these questions could facilitate the appropriate consideration of ethical matters in the treatment of these patients.

Adult↗
PubMed1997

Slow elimination of mannitol from human cerebrospinal fluid.

OBJECTIVE: The rise of intracranial pressure above the pre-treatment level (rebound phenomenon) is considered, in part, a consequence of osmotherapeutics penetrating into the intracranial compartments. METHODS: The kinetics of mannitol in the ventricular CSF were studied in 10 patients with cerebrovascular stroke after a single i.v. infusion of 37.5 g over 15 min. RESULTS: Maximum mannitol CSF concentrations (mean = 51.1 mg.1-1) were reached 2-12 h after termination of the infusion. Mean t1/2CSF (18.3 h) by far exceeded t1/2S (3.71 h). AUCCSF/AUCS, as a measure of mannitol CSF penetration, ranged from 0.037 to 0.390. CONCLUSION: The slow elimination of mannitol from CSF implies a high risk of accumulation in the central nervous compartments after repeated dosing.

Aged↗
PubMed1997

Increased glutamine synthetase immunoreactivity in experimental pneumococcal meningitis.

Glutamine synthetase (GS), glial fibrillary acidic protein (GFAP) immunohistochemistry and neuronal apoptotic cell death were evaluated in a rabbit model of pneumococcal meningitis. Meningitis caused an increase of GS immunoreactivity in the cerebral cortex, but not in the hippocampal formation. GFAP immunoreactivity remained unchanged. This may represent a protective mechanism for cortical neurons. The inability of hippocampal GS to counteract the detrimental effects of glutamate may be the cause of neural apoptosis observed in the dentate gyrus during meningitis.

Animals↗
PubMed1997

Elimination of blood-derived macrophages inhibits the release of interleukin-1 and the entry of leukocytes into the cerebrospinal fluid in experimental pneumococcal meningitis.

Parameters of inflammation during pneumococcal meningitis were determined in rabbits after monocyte elimination by dichloromethylene diphosphonate (Cl(2)MDP)-containing mannosylated liposomes in comparison with untreated controls. Monocyte depletion reduced the migration of white blood cells into the cerebrospinal fluid (CSF) (medians: 42 versus 2146/mm3 at 18 h, 323 versus 7413/mm3 at 24 h p.i., p < 0.01). CSF IL-1beta concentrations were lower in depleted animals (379 versus 3282 pg/ml, 24 h p.i., p < 0.01), whereas TNF-alpha concentrations were not different. Monocyte-depleted animals lost body temperature during the experiment carried out in anaesthesia (p = 0.01) indicating that macrophages are necessary for thermogenesis during meningitis.

Animals↗
PubMed1997

Limited efficacy of pentoxifylline as anti-inflammatory agent in experimental pneumococcal meningitis.

Dexamethasone appears to show some adverse side-effects as adjunctive anti-inflammatory agent in bacterial meningitis. For this reason, we tested the anti-inflammatory and neuroprotective effect of pentoxifylline administered 15 min before starting antibiotic treatment with ceftriaxone (n = 10) versus antibiotic therapy alone (n = 9) in the rabbit model of pneumococcal meningitis. Pentoxifylline lowered the medians of leucocyte density, tumour necrosis factor-alpha (TNF-alpha) and lactate in the cerebrospinal fluid (CSF), but only leucocyte migration into the subarachnoid space was significantly inhibited 8 h after initiation of therapy (P = 0.01). CSF protein, brain water content, and the entry of ceftriaxone into CSF were not influenced by pentoxifylline. The density of neuronal apoptoses in the dentate gyrus was slightly lower in animals receiving pentoxifylline than in those treated with ceftriaxone only. The median concentration of neuron-specific enolase in CSF was lower in the pentoxifylline-treated group, but the difference was not significant. In conclusion, pentoxifylline showed some anti-inflammatory activity in pneumococcal meningitis, but the substance failed significantly to reduce neuronal damage.

Animals↗
PubMed1997

Trovafloxacin delays the antibiotic-induced inflammatory response in experimental pneumococcal meningitis.

This study evaluates the ability of the new fluoroquinolone trovafloxacin to attenuate the inflammatory burst known to occur after initiation of antibiotic treatment in pneumococcal meningitis. After exposure to trovafloxacin or ceftriaxone for 3 h in vitro, Streptococcus pneumoniae was injected intracisternally (i.c.) into rabbits every 3 h over 9 h (n = 6 for each antibiotic). Ceftriaxone-treated S. pneumoniae induced consistently higher CSF leucocyte counts (median 2568/microL versus 543/microL at 6 h; P = 0.03; 4560/microL versus 2207/microL at 18 h; P = 0.03) than trovafloxacin-treated bacteria. Meningitis induced in rabbits by i.c. injection of live S. pneumoniae was treated with equal doses of trovafloxacin or ceftriaxone i.v. (ten per group). The bactericidal rates of both antibacterial agents in CSF were almost identical. In comparison with ceftriaxone, trovafloxacin resulted in lower tumour necrosis factor (TNF) and interleukin 1beta (IL-1beta) CSF levels 2 h after the initiation of treatment (TNF levels, median 26 U/mL versus 141 U/mL; P = 0.02; IL-1beta levels 455 pg/mL versus 1399 pg/mL; P = 0.02). Twelve hours after initiation of therapy, however, TNF and IL-1beta were higher in trovafloxacin-treated animals (TNF, 61 U/mL versus 7 U/mL; P = 0.001; IL-1beta, 4320 pg/mL versus 427 pg/mL; P = 0.006). The increase in CSF lactate was less during trovafloxacin therapy than with ceftriaxone (median: 2.0 mmol/L versus 4.0 mmol/L; P = 0.03). In conclusion, S. pneumoniae treated in vitro with trovafloxacin induced less CSF leucocytosis than ceftriaxone-treated S. pneumoniae. After i.c. inoculation of live S. pneumoniae, trovafloxacin therapy delayed, but did not inhibit, the release of the proinflammatory cytokines TNF and IL-1beta, probably by slowing the liberation of bacterial cell wall components into the subarachnoid space.

Adult↗
PubMed1997

Kinetics of piperacillin and tazobactam in ventricular cerebrospinal fluid of hydrocephalic patients.

Its broad antibacterial spectrum qualifies the combination of piperacillin and tazobactam for therapy of nosocomial bacterial central nervous system (CNS) infections. Since these infections sometimes are accompanied by only minor dysfunction of the blood-cerebrospinal fluid (CSF) barrier, patients with noninflammatory occlusive hydrocephalus who had undergone external ventriculostomy were studied (n = 9; age range, 48 to 75 years). After administration of the first dose of piperacillin (6 g)-tazobactam (0.5 g) over 30 min intravenously, serum and CSF were drawn repeatedly and analyzed by high-performance liquid chromatography. Pharmacokinetics were determined by noncompartmental analysis. Maximum concentrations of piperacillin in CSF ranged from 8.67 to <0.37 mg/liter (median, 3.42 mg/liter), and those of tazobactam ranged from 1.37 to 0.11 mg/liter (median, 0.45 mg/liter). CSF maxima were observed, in median, 1.5 and 2 h after the end of the infusion. Elimination in CSF was considerably slower than in serum (median half-life at beta phase for piperacillin, 5.9 h in CSF versus 1.47 h in serum; for tazobactam, 6.1 h versus 1.34 h). For tazobactam, the ratio of the area under the concentration-time curve (AUC) in CSF to the AUC in serum was approximately three times as high as that for piperacillin (medians, 0.106 versus 0.034). In view of the tazobactam concentrations in CSF observed in this study, the practice of using a constant concentration of 4 mg of tazobactam per liter for MIC determination is inadequate for intracranial infections. Larger amounts of tazobactam than the standard dose of 0.5 g three times daily may be necessary for CNS infections.

Aged↗
PubMed1996

Estimation of steady state antibiotic concentration in cerebrospinal fluid from single-dose kinetics.

OBJECTIVE: Assuming linear kinetics, the mean CSF concentrations of an antibacterial in steady state (CssCSF) can be estimated, when the area under the concentration-time curve in CSF after the first dose is known. For this purpose we propose the function CssCSF = AUCCSF.Anticipated dose/Dosing Interval. Applied dose. RESULTS: Together with the MIC and MBC of the causative pathogen, the estimate is of value in the choice of antibacterial drug and the dosing regimen in central nervous system infections.

Anti-Bacterial Agents↗
PubMed1996

Anti-inflammatory treatment influences neuronal apoptotic cell death in the dentate gyrus in experimental pneumococcal meningitis.

Apoptotic neuronal death and the increase of neuron-specific enolase (NSE) in cerebrospinal fluid (CSF) were studied in a rabbit model of experimental pneumococcal meningitis after treatment with antimicrobial (ceftriaxone) and antiinflammatory agents (dexamethasone, monoclonal antibodies against the beta-subunit of beta 2-integrins [anti-CD18 mAb]). Twenty-four hours after infection, apoptotic cell death was found solely in the granular cell layer of the dentate gyrus. Neurons with DNA fragmentation were quantified with the in situ tailing (IST) reaction. Dexamethasone and anti-CD18 mAb inhibited the NSE increase in CSF significantly (p = 0.003, p = 0.011). After administration of dexamethasone the density of apoptotic neurons was significantly higher than in control animals receiving only ceftriaxone (p = 0.044). The median of the density of apoptotic neurons was lower in the dentate gyrus in animals receiving anti-CD18 mAb and ceftriaxone vs those receiving only ceftriaxone, although the difference did not reach statistic significance (p = 0.058). In conclusion, apoptotic cell death occurs in the dentate gyrus during the early phase of bacterial meningitis. The extent was influenced by antiinflammatory therapy. The systemic administration of glucocorticoids increased the quantity of apoptotic neurons in the dentate gyrus but reduced overall neuronal damage as indicated by low levels of NSE concentration in CSF.

Animals↗
PubMed1996

Focal neurologic deficits in infective endocarditis and other septic diseases.

INTRODUCTION: Focal neurologic deficits in sepsis frequently result from parenchymal lesions due to cerebral embolism. The aim of this study was to characterize clinical, laboratory and radiologic patterns of those patients. PATIENTS AND METHODS: Medical records of 30 patients with focal neurologic symptoms during sepsis were analyzed retrospectively. RESULTS: 24 patients (22 with infective endocarditis) had ischemic stroke. Cerebrospinal fluid (CSF) analyses revealed inflammation in 11 of 12 patients. Patients who died (11/24) suffered more frequently from secondary intracerebral hemorrhage (p = 0.0031), which was significantly associated with intravenous high-dose anticoagulation (p = 0.0059). Six patients had slowly progressive focal neurologic deficits without evidence for stroke. All showed CSF inflammation and three developed multiple cerebral abscesses. CONCLUSIONS: There are two distinctive groups of patients with focal neurologic deficits during sepsis. One presents with stroke and CNS inflammation (septic embolic focal encephalitis). The other group develops slowly progressive focal neurologic deficits and sometimes multiple cerebral abscesses (septic metastatic focal encephalitis).

Adult↗
PubMed1996

Cerebrospinal fluid ceftazidime kinetics in patients with external ventriculostomies.

Ceftazidime has proven to be effective for the treatment of bacterial meningitis caused by multiresistant gram-negative bacteria. Since nosocomial central nervous system infections are often accompanied by only a minor dysfunction of the blood-cerebrospinal fluid (CSF) barrier, patients with noninflammatory occlusive hydrocephalus who had undergone external ventriculostomy were studied (n = 8). Serum and CSF were drawn repeatedly after the administration of the first dose of ceftazidime (3 g over 30 min intravenously), and concentrations were determined by high-performance liquid chromatography by using UV detection. The concentrations of ceftazidime in CSF were maximal at 1 to 13 h (median, 5.5 h) after the end of the infusion and ranged from 0.73 to 2.80 mg/liter (median, 1.56 mg/liter). The elimination half-lives were 3.13 to 18.1 h (median, 10.7 h) in CSF compared with 2.02 to 5.24 h (median, 3.74 h) in serum. The ratios of the areas under the concentration-time curves in CSF and serum (AUCCSF/AUCS) ranged from 0.027 to 0.123 (median, 0.054). After the administration of a single dose of 3 g, the maximum concentrations of ceftazidime in CSF were approximately four times higher than those after the administration of 2-g intravenous doses of cefotaxime (median, 0.44 mg/liter) and ceftriaxone (median, 0.43 mg/liter) (R. Nau, H. W. Prange, P. Muth, G. Mahr, S. Menck, H. Kolenda, and F. Sörgel, Antimicrob. Agents Chemother. 37:1518-1524, 1993). The median AUCCSF/AUCS ratio of ceftazidime was slightly below that of cefotaxime (0.12), but it was 1 order of magnitude above the median AUCCSF/AUCS of ceftriaxone (0.007) (Nau et al., Antimicrob. Agents Chemother. 37:1518-1524, 1993). The concentrations of ceftazidime observed in CSF were above the MICs for most Pseudomonas aeruginosa strains. However, they are probably not high enough to be rapidly bactericidal. For this reason, the daily dose should be increased to 12 g in cases of P. aeruginosa infections of the central nervous system when the blood-CSF barrier is minimally impaired.

Adult↗
PubMed1995

Effect of a recombinant N-terminal fragment of bactericidal/permeability-increasing protein (rBPI23) on cerebrospinal fluid inflammation induced by endotoxin.

Endotoxin triggers the subarachnoid inflammation of gram-negative meningitis. This study examined the ability of a recombinant N-terminal fragment of bactericidal/permeability-increasing protein (rBPI23) to block endotoxin-induced meningitis in rabbits. Intracisternal (ic) injection of 10-20 ng of meningococcal endotoxin induced high cerebrospinal fluid (CSF) concentrations of tumor necrosis factor (TNF) and CSF pleocytosis and increased CSF lactate concentrations. ic administration of rBPI23 significantly reduced meningococcal endotoxin-induced TNF release into CSF (P < .005), lactate concentrations (P < .001), and CSF white blood cell counts (P < .01). No such effect was observed in animals receiving intravenous rBPI23. Concentrations of rBPI23 in CSF were high after ic administration but low or undetectable after systemic administration. Thus, high concentrations of rBPI23 can effectively neutralize meningococcal endotoxin in CSF, but low CSF concentrations after systemic administration currently limit its potential usefulness as adjunctive drug treatment in gram-negative meningitis.

Animals↗
PubMed1995

Activity of fosfomycin in a rabbit model of experimental pneumococcal meningitis.

Fosfomycin is an antibacterial substance of low molecular weight and negligible binding to plasma proteins exhibiting in-vitro activity against most pathogens involved in bacterial meningitis including pneumococci. Due to these properties the drug has been recommended for therapy of central nervous system (CNS) infections. For this reason, fosfomycin at doses of 10, 40, 80 and 160 mg/kg/h iv, was investigated in the rabbit model of pneumococcal meningitis. Bacterial counts in cerebrospinal fluid (CSF) before, and 2, 5 and 8 h after initiation of therapy were quantitated by plating on blood agar. Fosfomycin concentrations in serum and CSF were determined by the agar well diffusion method. The MIC and MBC of fosfomycin for the Streptococcus pneumoniae type 3 strain used was 4 and 32 mg/L, respectively. The MIC of ceftriaxone was 0.016 mg/L. In vitro, both drugs showed an additive effect (fractional inhibitory concentration index = 0.75). In vivo at each dose tested, fosfomycin was less active than ceftriaxone (means +/- S.D.): delta log cfu/mL/h at 10 mg/kg/h + 0.130 +/- 0.062 (n = 2), at 40 mg/kg/h -0.217 +/- 0.185 (n = 3), at 80 mg/kg/h -0.270 +/- 0.121 (n = 3), at 160 mg/kg/h -0.331 +/- 0.118 (n = 3) vs -0.647 +/- 0.193 at 10 mg/kg/h ceftriaxone (n = 3). CSF penetration of fosfomycin as estimated by the CSF-to-serum concentration ratio at 8 h was 0.55 +/- 0.22 (n = 11). For bactericidal activity CSF concentrations of at least ten times the MIC were necessary. Coadministration of both drugs (1 mg/kg/h ceftriaxone + 40 mg/kg/h fosfomycin) tended to be more active than either drug alone (in-vivo drug interaction = 1.3). In conclusion, fosfomycin at very high doses reduced bacterial counts in CSF. However, fosfomycin CSF concentrations usually observed in patients with meningitis receiving fosfomycin were not bactericidal in this model. At all doses tested the bactericidal rate was lower than that of ceftriaxone. Fosfomycin is therefore unsuitable as a single agent, but may be used as a reserve antibiotic in combination with a newer cephalosporin for pneumococcal meningitis unresponsive to conventional therapy.

Animals↗
PubMed1995

Quinolone antibiotics in therapy of experimental pneumococcal meningitis in rabbits.

Using a rabbit model of pneumococcal meningitis, we compared the pharmacokinetics and bactericidal activities in cerebrospinal fluid (CSF) of older (ciprofloxacin, ofloxacin) and newer (levofloxacin, temafloxacin, CP-116,517, and Win 57273) quinolones with those of the beta-lactam ceftriaxone. All quinolones penetrated into the inflamed CSF better than ceftriaxone, and the speed of entry into CSF was closely related to their degrees of lipophilicity. At a dose of 10 mg/kg.h, which in the case of the quinolones already in use in clinical practice produced concentrations attainable in the sera and CSF of humans, ciprofloxacin had no antipneumococcal activity (delta log10 CFU/ml.h, +0.20 +/- 0.14). Ofloxacin (delta log10 CFU/ml.h, -0.13 +/- 0.12), temafloxacin (delta log10 CFU/ml.h, -0.19 +/- 0.18), and levofloxacin (delta log10 CFU/ml.h, -0.24 +/- 0.16) showed slow bactericidal activity (not significantly different from each other), while CP-116,517 (delta log10 CFU/ml.h, -0.59 +/- 0.21) and Win 57273 (delta log10 CFU/ml.h, -0.72 +/- 0.20) showed increased bactericidal activities in CSF that was comparable to that of ceftriaxone at 10 mg/kg.h (delta log10 CFU/ml.h, -0.80 +/- 0.17). These improved in vivo activities of the newer quinolones reflected their increased in vitro activities. All quinolones and ceftriaxone showed positive correlations between bactericidal rates in CSF and concentrations in CSF relative to their MBCs. Only when this ratio exceeded 10 did the antibiotics exhibit rapid bactericidal activities in CSF. In conclusion, in experimental pneumococcal meningitis the activities of new quinolones with improved antipneumococcal activities were comparable to that of ceftriaxone.

4-Quinolones↗
PubMed1995

[Treatment of ischemic cerebral infarct with glycerine].

Ischemic brain edema promotes focal cerebral ischemia by increasing intracranial pressure and thereby reducing perfusion pressure, obstructing capillaries and prolonging transport routes within ischemic tissue. There is clinical and experimental evidence that osmotic agents counteract these mechanisms. Moreover, glycerol may act as a free radical scavenger, antioxidant, and activator of plasma prostaglandin (PGI2), resulting in vasodilation. Improvements in ischemic brain energy metabolism after glycerol administration has also been postulated. Results of clinical trials on glycerol treatment of acute ischemic stroke were not conclusive: some demonstrated improved survival in the acute stage, in others survivors benefited in terms of neurological status and/or daily living activities. Other trials did not reveal any superiority of glycerol treatment over placebo. Glycerol is given intravenously as a 10% solution or orally. By the oral route higher intravascular glycerol concentration can be achieved with smaller quantities of fluid. Possible side effects include elevation of blood glucose level with subsequent lactate acidosis in the ischemic brain, serum hyperosmolarity after long-term glycerol administration and--when given intravenously--volume overload in patients with congestive heart failure and hemolysis that may cause renal failure.

Administration, Oral↗