Entry of tromethamine into the cerebrospinal fluid of humans after cerebrovascular events.

OBJECTIVE: The intravenous administration of tromethamine (INN, trometamol) lowers the intracranial pressure in patients with brain edema. One postulated mechanism of action is the increase of the pH of the cerebrospinal fluid. METHODS: To study tromethamine kinetics in serum and cerebrospinal fluid, nine patients with external ventriculostomies and normal serum creatinine values received 60 mmol intravenous tromethamine (Tris 36.34%, pH 11) over 30 minutes. Serum and cerebrospinal fluid were drawn repeatedly, and concentrations were determined by HPLC. RESULTS: Maximum serum concentrations (Cmax) ranged from 211 to 426 mg/L (median, 302 mg/L). The volume of distribution was 0.34 to 0.86 L/kg body weight (median, 0.53 L/kg), and the elimination half-life in serum (t1/2beta) 3.22 to 8.44 hours (median, 4.53 hours). Cerebrospinal fluid Cmax values ranging from 0.68 to 34.14 mg/L (median, 3.88 mg/L) were observed 1 to 12 hours after the end of the tromethamine infusion (median, 2 hours). AUC(CSF)/AUC(S) as a measure of overall cerebrospinal fluid penetration was 0.015 to 0.46 (median, 0.068). Cerebrospinal fluid Cmax and AUC(CSF)/AUC(S) depended on the function of the blood-cerebrospinal fluid barrier. Cerebrospinal fluid t1/2 (8.52 to 14.2 hours; median, 11.2 hours) was substantially longer than the t1/2beta in serum. In vitro, cerebrospinal fluid concentrations < or =30 mg/L did not influence cerebrospinal fluid pH. CONCLUSION: Tromethamine cerebrospinal fluid concentrations will be high enough to increase the pH of the cerebrospinal fluid only at large doses and in patients with a pronounced disruption of the blood-cerebrospinal fluid barrier.

Disposition and elimination of meropenem in cerebrospinal fluid of hydrocephalic patients with external ventriculostomy.

The broad antibacterial spectrum and the low incidence of seizures in meropenem-treated patients qualifies meropenem for therapy of bacterial meningitis. The present study evaluates concentrations in ventricular cerebrospinal fluid (CSF) in the absence of pronounced meningeal inflammation. Patients with occlusive hydrocephalus caused by cerebrovascular diseases, who had undergone external ventriculostomy (n = 10, age range 48 to 75 years), received 2 g of meropenem intravenously over 30 min. Serum and CSF were drawn repeatedly and analyzed by liquid chromatography-mass spectroscopy. Pharmacokinetics were determined by noncompartmental analysis. Maximum concentrations in serum were 84.7 +/- 23.7 microg/ml. A CSF maximum (CmaxCSF) of 0.63 +/- 0.50 microg/ml (mean +/- standard deviation) was observed 4.1 +/- 2.6 h after the end of the infusion. CmaxCSF and the area under the curve for CSF (AUCCSF) depended on the AUC for serum (AUCS), the CSF-to-serum albumin ratio, and the CSF leukocyte count. Elimination from CSF was considerably slower than from serum (half-life at beta phase [t1/2beta] of 7.36 +/- 2.89 h in CSF versus t1/2beta of 1.69 +/- 0.60 h in serum). The AUCCSF/AUCS ratio for meropenem, as a measure of overall CSF penetration, was 0.047 +/- 0.022. The AUCCSF/AUCS ratio for meropenem was similar to that for other beta-lactam antibiotics with a low binding to serum proteins. The concentration maxima of meropenem in ventricular CSF observed in this study are high enough to kill fully susceptible pathogens. They may not be sufficient to kill bacteria with a reduced sensitivity to carbapenems, although clinical success has been reported for patients with meningitis caused by penicillin-resistant pneumococci and Pseudomonas aeruginosa.

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.