[Laboratory diagnosis of infections of the central nervous system].
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AIDS-Related Opportunistic Infections↗
Biomedical subjects
R Nau
Publications and source records attributed to R Nau.
Lipophilicity at pH 7.4 and molecular size govern the entry of the free serum fraction of drugs into the cerebrospinal fluid in humans with uninflamed meninges.
Physicochemical properties of drugs were related to their ability to enter the cerebrospinal fluid (CSF) in humans by reevaluation of previously reported studies. Either the quotients of the drug concentrations in CSF and serum at steady state (CCSFSS/CSSS) or, since in most cases CSF passage was studied after a short-term infusion, the ratios of the areas under the concentration-time curves in CSF and serum (AUCCSF/AUCS) were taken as measures of CSF passage. AUCS and CSSS were corrected for binding to serum proteins (AUCSf, CSssf). Of the drugs studied the quotient of the octanol/water partition coefficient at pH 7.4 (PC) as a measure of lipophilicity and the square root of the molecular weight (MW1/2) correlated with AUCCSF/AUCS (Spearman's rank correlation coefficient rS = 0.78, P < 0.01) and with AUCCSF/AUCSf (rS = 0.90, P < 0.01). PC.MW-1/2 was related to AUCCSF/AUCSf (or CCSFSS/CSssf, respectively) by the equation: AUCCSF/AUCSf = 0.96 + 0.091.1n(PC.MW-1/2). For 0.0001 < or = PC.MW-1/2 < or = 1.0 this function may be of value for the prediction of CSF penetration in humans when the physicochemical properties of a drug are known and when active transport or metabolism are negligible.
Cerebrospinal Fluid↗
Rifampin for therapy of experimental pneumococcal meningitis in rabbits.
Rifampin at a maximally effective dose was less active than ceftriaxone (both drugs at 10 mg/kg of body weight.h) in a rabbit model of pneumococcal meningitis (delta log10 CFU/ml.h, -0.40 +/- 0.13 versus -0.77 +/- 0.18; P < 0.01). The bactericidal activity of rifampin decreased at concentrations in cerebrospinal fluid greater than those that are clinically achievable, and use of rifampin in combination with ofloxacin had no synergistic or additive effect.
Animals↗
Kinetics of ofloxacin and its metabolites in cerebrospinal fluid after a single intravenous infusion of 400 milligrams of ofloxacin.
Ofloxacin has been reported to diffuse readily into the cerebrospinal fluid (CSF) in subjects with both inflamed and uninflamed meninges. However, with moderately susceptible bacteria, ofloxacin concentrations in CSF may be subtherapeutic after administration of an intravenous (i.v.) dose of 200 mg. For this reason, the kinetics of a higher dose of ofloxacin in CSF was studied with humans. Six patients with occlusive hydrocephalus caused by cerebrovascular diseases who had undergone external ventriculostomy received 400 mg of ofloxacin i.v. over 30 min. Serum and CSF samples were drawn repeatedly. Serum from 12 healthy volunteers was sampled repeatedly after they had received 400 mg of ofloxacin i.v. over 60 min. Ofloxacin, ofloxacin-N-oxide, and N-desmethyl-ofloxacin concentrations were determined by high-pressure liquid chromatography with fluorescence detection. The maximum ofloxacin concentrations in the serum of the patients ranged from 7.36 to 11.6 mg/liter (mean, 9.55 mg/liter), the apparent volume of distribution/body weight was 0.96 to 1.19 liters/kg (mean, 1.11 liters/kg), and the total body clearance was 115 to 280 ml/min (mean, 192 ml/min). In healthy volunteers, the volume of distribution/body weight and the total body clearance were higher and amounted to 1.27 +/- 0.18 liters/kg and 217 +/- 43 ml/min (means +/- standard deviations), respectively. These differences were attributed to the older ages of the patients than the volunteers. In the CSF of patients, maximum concentrations of 1.00 to 2.85 mg/liter (mean, 2.04 mg/liter) were observed 0.5 to 4 h following the completion of the ofloxacin infusion. Ofloxacin elimination from CSF was slightly slower than that from serum (half-lives, 4.33 to 10.02 versus 4.27 to 9.14 h). The overall penetration of ofloxacin into CSF, as expressed by the ratios of the areas under the concentration-curves, amounted to 0.59 to 0.81 (mean, 0.65). The more hydrophilic metabolites ofloxacin-N-oxide and N-desmethyl-ofloxacin passed less readily than ofloxacin into the CSF. In conclusion, the concentrations in CSF attained after a single i.v. infusion of 400 mg of ofloxacin in the absence of meningeal inflammation appear to be high enough to inhibit the growth of most staphylococci and members of the family Enterobacteriaceae, which are often involved in CSF shunt infection. Yet, in view of pharmacodynamic studies suggesting a peak concentration in CSF of at least 10-fold the MIC, the use of ofloxacin for central nervous systems infections is optimal only with highly susceptible pathogens (MIC, less than or equal to 0.12 mg/liter).
Aged↗
[Bacterial CNS infections in adults in Southern Lower Saxony. A retrospective study of the Göttingen Neurologic University Clinic].
All 155 patients with suspected bacterial central nervous system (CNS) infections treated from 1986 to 1991 at the Department of Neurology, University of Göttingen, were evaluated in a retrospective study. According to the clinical symptoms presented at admission, 7 cases were classified as encephalitis, 44 as meningitis, 15 as radiculitis, 19 as ventriculitis, 61 as meningoencephalitis and 9 as meningoradiculitis. In 78% of these cases, the causative bacteria were either isolated from cerebrospinal fluid (CSF), or other relevant sources (blood, wound swabs) or identified by serological methods; (all cases of CNS borreliosis, and 3 of the 5 cases of listeriosis were identified by means of the last mentioned method). CNS infections caused by staphylococci and Borrelia burgdorferi were most frequent, followed by those due to pneumococci, meningococci and other streptococci. CNS infections caused by Mycobacterium tuberculosis, Listeria monocytogenes, Haemophilus influenzae and enterobacteriaceae were less frequent. In comparison to the CNS infections due to other bacteria, the pneumococcal and meningococcal meningitic infections were associated with more pronounced CSF alterations (on the average, there were higher white blood cell counts, and higher CSF protein and lactate). Pneumococci predominated in older patients and those with an impaired immune system, or infections of organs neighboring the CNS. Meningococci were most frequent in young and previously healthy individuals. All patients with CNS listeriosis had predisposing conditions. Meningococcal meningitis was either fatal or resolved with or without minimal neurological deficits. Infections caused by staphylococci or pneumococci were associated with a high percentage of neurologic sequelae.
Adolescent↗
[Life threatening embolism caused by central venous catheter fragments in psychiatric patients].
Central venous catheters are sometimes the cause of life-threatening complications. In two patients with underlying psychiatric disorders we observed an embolism as a result of catheter fragments. The first patient was a 30-year-old woman with a borderline personality disorder and several previous episodes of self-mutilation, psychogenic seizures and disturbances of consciousness. She cut her central venous line positioned in the external jugular vein when she was unattended. The intravasal fragment dislocated into the right ventricle and had to be removed by a forceps used for myocardial biopsies. The second patients was a 34-year-old mentally retarded male with a history of psychomotoric and grand mal seizures who suffered from a prolonged disturbance of consciousness with uncontrolled motor activity after four grand mal seizures. Despite physical restraint, the tip of his central venous catheter inserted through the subclavian vein broke and embolized in the right atrium. The embolus was removed by thoracotomy. To avoid these complications central venous lines should be used only when critically needed in uncooperative patients or those who display disturbance of consciousness and uncontrolled motor activity.
Adult↗
[Intensive care treatment of psychiatric patients].
In a retrospective analysis we studied the frequency and cause of intensive care measures for psychiatric patients. All inpatients seen in the Department of Psychiatry, University of Göttingen, between 1985 and 1990 who either were treated in an intensive care unit (ICU) or died during treatment were included. 218 patients fulfilled these criteria, representing 2.4% of all psychiatric inpatients. In the sample as a whole, addiction (29%) and neurotic disorder (27%) were the largest diagnostic groups, followed by organic psychoses (15%). In comparison with other psychiatric diagnoses, addictive and organic disorders were overrepresented. The patients originally seen in the Department of Psychiatry (n = 70) were admitted to the ICU for various reasons (24% alcoholic delirium, 17% electrolyte disturbances and dehydration, 16% pneumonia, 11% suicide attempts, 7% thrombosis, etc.). Reasons for admission directly to the ICU (n = 138) with subsequent referral to the Department of Psychiatry were generally either suicide attempts (53%) or complications of addiction (32%). Thirty-six per cent of all patients required tracheal intubation. Patients with endogenous psychoses required mechanical ventilation more often than patients with other psychiatric diagnoses. Sixteen deaths occurred in this period of time, most often in patients with organic psychoses (n = 6). These results illustrate a high incidence of severe medical disorders in psychiatric inpatients. They emphasize the necessity of intensive collaboration between psychiatrists and intensive care physicians.
Adult↗
Pharmacokinetic quantification of the exchange of drugs between blood and cerebrospinal fluid in man.
Various parameters which may be useful in quantification of drug transit from blood into CSF and vice versa after a short duration infusion are compared here by recalculating previously published data from our group. Due to the slower entry into and elimination from the CSF compartment as compared to the central compartment, the ratio of drug concentrations in CSF and serum sampled at the same time increase with time after an infusion. Therefore, concentration quotients of simultaneously drawn blood and CSF are inadequate to characterise CSF penetration. The ratio of the areas under the concentration-time curves in a body fluid and serum (AUCbody fluid/AUCs) is an established measure to quantify overall penetration from the central into a peripheral compartment. AUCCSF/AUCs is closely correlated with the quotient of the maximum CSF and serum concentrations (CmaxCSF/CmaxS) (rs = 0.87, n = 42, P < 0.001) and with the rate constant of distribution in CSF (CLin/VCSF) (rs = 0.80, n = 42, P < 0.001). Since CmaxCSF/CmaxS depends on the mode of drug administration, it is suggested that AUCCSF/AUCs be used to quantify overall drug transit into CSF. CLin/VCSF is of use when CSF can only be sampled once, or when the velocity of the transit of a drug into CSF is to be described. The CSF exit rate constant (CLout/VCSF) characterises elimination from CSF independent of the elimination from serum and may be applied to estimate the formation rate of CSF; in the present study it averaged 20 ml/h.
Blood↗
Inverse correlation between disappearance of intrathecally injected 111In-DTPA from CSF with CSF protein content and CSF-to-serum albumin ratio.
By means of cerebrospinal fluid (CSF) scintigraphy with 111In-DTPA injected following lumbar puncture in 18 patients after meningitis (12), with traumatic head injury (4), cholesteatoma (1) or a communicating hydrocephalus (1) the hypothesis of whether slow movement of CSF may contribute to the elevation of CSF protein and albumin content in neurological diseases other than spinal block was tested. The ratios of the count rates over the head (geometric mean of anterior and posterior view) at 23-25 h to 4-6 h after 111In-DTPA application (C24 h/C5 h) and the ratio 47-49 h to 23-25 h after injection (C48 h/24 h) were taken as measures of the velocity of 111In-DTPA disappearance from CSF. Both the CSF protein content and the CSF-to-serum albumin ratio correlated with C24 h/C5 h and C48 h/C24 h. Assuming log-linear elimination between 24 and 48 h the elimination half-life of 111In-DTPA was estimated to be 12.4-131.1 h (median = 31.7 h). It was concluded that slow CSF kinetics probably are involved in the elevation of CSF protein content in several neurological diseases.
Adolescent↗
Netilmicin cerebrospinal fluid concentrations after an intravenous infusion of 400 mg in patients without meningeal inflammation.
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Adult↗
Intoxication in manic patients following chaotic self-administration of lithium.
Intoxication is a serious complication of lithium therapy. Suicides attempted by depressive patients or excessive serum levels due to reduced renal elimination are typical causes of these intoxications. So far, lithium intoxications following excessive intake by patients with manic disorders have not been reported. We present 4 case histories of manic patients in whom the diagnosis of lithium intoxication was delayed, even though their affective disorders and medication were known. Lithium should be determined immediately on a routine basis in all patients who, on the basis of their history, are known to receive or who, considering the underlying mental illness, possibly receive lithium therapy.
Adult↗
Passage of cefotaxime and ceftriaxone into cerebrospinal fluid of patients with uninflamed meninges.
Cefotaxime and ceftriaxone have proven to be effective in pyogenic infections of the central nervous system. Since in some bacterial central nervous system infections the blood-cerebrospinal fluid (CSF) barrier is either minimally impaired or recovers in the course of the illness, we studied the penetration of both antibiotics in the absence of inflamed meninges. Patients who had undergone external ventriculostomies for noninflammatory occlusive hydrocephalus received either cefotaxime (2 g/30 min) or ceftriaxone (2 g/30 min) to treat extracerebral infections. Serum and CSF were drawn repeatedly after the first dose. With ceftriaxone, they were also drawn after the last dose. The concentrations of cefotaxime, its metabolite desacetylcefotaxime, and ceftriaxone were determined by high-performance liquid chromatography with UV detection. Maximum concentrations of cefotaxime in CSF were reached 0.5 to 8 h (median = 3 h; n = 6) after the end of the infusion and ranged from 0.14 to 1.81 mg/liter (median = 0.44 mg/liter; n = 6). Maximum levels of ceftriaxone in CSF ranging from 0.18 to 1.04 mg/liter (median = 0.43 mg/liter; n = 5) were seen 1 to 16 h (median = 12 h; n = 5) after the infusion. The elimination half-life of cefotaxime in CSF was 5.0 to 26.9 h (median = 9.3 h; n = 5), and that of ceftriaxone was 15.7 to 18.4 h (median = 16.8 h; n = 3). It is concluded that after a single dose of 2 g, maximal concentrations of cefotaxime and ceftriaxone in CSF do not differ substantially. The long elimination half-lives guarantee uniform concentrations in CSF. These concentrations reliably inhibit highly susceptible bacteria but cannot be relied on to inhibit staphylococci and penicillin G-resistant Streptococcus pneumoniae.
Aged↗
Cannulation of the lateral saphenous vein--a rapid method to gain access to the venous circulation in anaesthetized guinea pigs.
Previously published methods of venous puncture in guinea pigs did not provide reliable venous access for more than a few minutes, and therefore surgical intervention was necessary to cannulate the femoral or external jugular vein or the vena cava. In the present report cannulation of the Vena saphena lateralis via the Vena plantaris lateralis or of the Vena saphena medialis is described by inserting a 22 gauge teflon catheter. These catheters are commercial products. The method is timesaving and inexpensive. Successful cannulation was accomplished in 34 of 35 guinea pigs. No lethal incidents occurred.
Animals↗
Pharmacokinetics of glycerol administered orally in healthy volunteers.
Of the three standard osmotherapeutics glycerol, mannitol and sorbitol, glycerol (CAS 56-81-5) alone can be applied orally. As only limited pharmacokinetic data after oral administration are available, studies were performed in 10 healthy subjects (2 female, 8 male, body weight 58-90 kg, age 23-47 years). After 12 h of fasting the subjects drank a single dose of 1.2 g/kg glycerol (Glycerol 85% DAB 9, flavoured with lemon juice). For the first 90 min venous blood was sampled every 15 min, for the following 6.5 h every 30 min. Glycerol serum concentrations were determined by an enzymatic procedure. Intestinal absorption was rapid. Maximum glycerol serum levels ranging from 1285-2238 mg/l (median = 1770 mg/l) were observed 1-2 h after ingestion. On the assumption of full intestinal absorption total body clearance was 0.18-0.26 l/h.kg, and the apparent volume of distribution 0.18-0.34 l/kg. The terminal elimination half-life ranged from 0.61-1.18 h. The concentration-time curves were not adequately described by linear pharmacokinetic models. In all subjects glycerol serum concentrations were high enough to induce increases of serum osmolality of at least 10 mosmol/kg. No signs of haemolysis or haemodilution were observed.
Administration, Oral↗
[Subarachnoid hemorrhage with pulmonary edema and electrocardiographic changes. The differential diagnosis of myocardial infarct].
A 32-year-old man (weight 132 kg, height 190 cm) suddenly became unconscious and cyanosed with an unrecordable pulse and ventricular flutter on ECG. After resuscitation, the blood pressure was 200/100 mm Hg; the patient moved his arms and legs at times, but he did not regain consciousness. Focal neurological signs and meningism were not demonstrable. Subsequent ECGs showed a raised ST segment, followed later by terminal T wave inversion; marked pulmonary oedema was present clinically and radiologically. The creatine kinase activity was 344 U/l. As lateral myocardial infarction was suspected, the patient received heparin (1000-1700 IU/h) and nitroglycerin intravenously. Because the CK-MB isoenzyme failed to rise significantly and there was no reduction of R wave on the ECG, a CT scan of the brain was performed: this showed brain oedema as well as severe subarachnoid haemorrhage in the basal subarachnoid space, the posterior horn of the lateral ventricles and over the cerebral hemispheres. Despite implantation of an epidural pressure gauge, hyperventilation and administration of dexamethasone, osmotic diuretics and thiopental, the patient died 14 days after collapsing. At autopsy the heart showed no signs of myocardial infarction. The cause of the subarachnoid haemorrhage was a ruptured aneurysm of the anterior communicating artery.
Adult↗
Temporary reversal of serum to cerebrospinal fluid glycerol concentration gradient after intravenous infusion of glycerol.
Glycerol 50 g infused i.v. over 2 to 6 h is widely used to treat cerebral oedema in patients with acute stroke. Its transit through the blood-cerebrospinal fluid barrier in subjects with uninflamed meninges has now been examined. In 7 patients with an external ventriculostomy for occlusive hydrocephalus, each of whom was given 500 ml of a 10% solution IV over 4 h, serum and CSF were repeatedly sampled during and after the infusion and glycerol was measured enzymatically. The highest serum glycerol level of 191-923 mg/l was observed at the end of the infusion. The maximum CSF glycerol of 18.7-110.8 mg/l was attained 0-1 h after the end of the infusion. Elimination both from serum and CSF approximated a single-exponential decay; the elimination half-life from serum was 0.29-0.56 h compared to 1.03-3.68 h from CSF. In six of the seven cases there was a temporary reversal of the serum/CSF concentration gradient during glycerol elimination. The ratios of the AUCs of CSF and serum, which describe the overall penetration of glycerol into CSF, ranged from 0.09-0.31. In conclusion, the serum level of glycerol produced by giving 50 g IV glycerol over 4 h may not be sufficiently high reliably dehydrate to brain tissue in many patients, and the slow elimination of glycerol from the CSF may be related to the so-called rebound phenomenon.
Adult↗
Results of four technical investigations in fifty clinically brain dead patients.
Fifty consecutive patients (aged 19-77 years, median 56 years) with primary cerebral diseases and the clinical signs of absent cortical and brainstem function were subjected to electroencephalography (EEG), brainstem acoustic evoked potentials (BAEP), extracranial Doppler ultrasonography (ECD) and arterial digital subtraction angiography (DSA). In the majority of cases the results of the technical tests agreed with the clinical signs and were suggestive of brain death. However, in one patient EEG revealed clear bioelectrical activity. In 6 cases, doubts existed about whether the EEG was isoelectric; in 3 of the 6 cases biological activity might have been present. In 31 of 42 patients ECD showed a typical pattern of intracranial circulatory arrest, in 9 of 42 ECD revealed a pattern suggestive of the cessation of cerebral blood flow. In four patients BAEP recordings compatible with brain death were recorded 2-3 days before intracranial circulatory arrest. In 2 patients with isoelectric EEG and absent BAEP arterial DSA demonstrated residual perfusion. The findings are discussed in view of the conceptional differences concerning brain death. It is concluded that the strict application of the concept of death of the whole brain requires angiographic demonstration of absent intracerebral blood flow.
Adult↗
Relationships between dopamine infusions and intracranial hemodynamics in patients with raised intracranial pressure.
Dopamine, 1-10 micrograms/kg body weight/min was infused in 6 patients suffering from cerebrovascular diseases with elevated intracranial pressure and a critical cerebral perfusion pressure. Dopamine decreased intracranial pressure in 3 and increased it moderately in the other 3 patients. In all patients, the dopamine-induced rise of mean arterial pressure led to an increase of cerebral perfusion pressure. Transcranial Doppler ultrasonographic recordings of the middle cerebral artery in patients whose intracranial pressure declined revealed a decrease of the pathologically elevated cerebrovascular resistance, and an augmentation of cerebral blood supply. In conclusion, dopamine infusions may improve cerebral hemodynamics in some patients with severe brain edema. Such patients can be identified by intracranial pressure and Doppler monitoring.
Blood Flow Velocity↗