Lesion development in Marburg's type of acute multiple sclerosis: from inflammation to demyelination.

We report a patient who suffered from acute inflammatory CNS demyelination and underwent two consecutive diagnostic stereotactic brain biopsies during the early disease course. The first lesion was drawn 33 days after the onset of disseminated neurological symptoms. Macrophages and T lymphocytes diffusely infiltrated small vessel walls and the white matter. mRNA for tumor necrosis factor alpha (TNFalpha) and inducible nitric oxide synthase (iNOS) was abundantly expressed. Myelin sheaths were entirely preserved. The second biopsy 76 days later showed confluent demyelinating lesions with a diffuse infiltration of macrophages that were positive for myelin debris, activation markers and TNFalpha and iNOS mRNA. IgG and C9neo deposits were found along myelin sheaths. The patient had received intravenous immunoglobulins (IVIG) prior to biopsy. Findings from this single patient affirm that demyelination follows the migration of inflammatory cells from the circulation into the white matter with subsequent inflammation and demyelination. Inflammation alone may be sufficient to cause significant clinical deficits without demyelination. Inflammatory mediators such as TNFalpha and NO are involved at very early stages in the pathogenetic process. IVIG treatment may lead to the deposition of immunoglobulins and to the activation of the complement cascade, but the clinical relevance of this particular finding remains uncertain.

Pharmacokinetic optimisation of the treatment of bacterial central nervous system infections.

Central nervous system (CNS) infections caused by bacteria with reduced sensitivity to antibacterials are an increasing worldwide challenge. In successfully treating these infections the following conditions should be considered: (i) Antibacterials do not distribute homogeneously in the central nervous compartments [cerebrospinal fluid (CSF), extracellular space of the nervous tissue, intracellular space of the neurons, glial cells and leucocytes]. Even within the CSF, after intravenous administration, a ventriculo-lumbar concentration gradient is often observed. (ii) Valid parameters of drug entry into the CSF are the CSF: serum concentration ratio in steady state and the CSF: serum ratio of the area under the concentration-time curves (AUCCSF/AUCS). Frequently, the elimination half-life (t1/2 beta) in CSF is longer than t1/2 beta in serum. (iii) For most antibacterials, lipophilicity, molecular weight and serum protein binding determine the drug entry into the CSF and brain tissue. With an intact blood-CSF and blood-brain barrier, the entry of hydrophilic antibacterials (beta-lactam antibacterials, glycopeptides) into the CNS compartments is poor and increases during meningeal inflammation. More lipophilic compounds [metronidazole, quinolones, rifampicin (rifampin) and chloramphenicol] are less dependent on the function of the blood-CSF and blood-brain barrier. (iv) Determination of the minimal inhibitory concentrations (MIC) of the causative organism is necessary for optimisation of treatment. (v) For rapid sterilisation of CSF, drug concentrations of at least 10 times MIC are required. The minimum CSF concentration: MIC ratio ensuring successful therapy is unknown. Strategies to achieve optimum antibacterial concentrations in the presence of minor disturbances of the blood-CSF and blood-brain barrier include, the increased use of low toxicity antibacterials (e.g., beta-lactam antibiotics), the use of moderately lipophilic compounds, and the combination of intravenous and intraventricular administration. Antibacterials which do not interfere with bacterial cell wall synthesis delay and/or decrease the liberation of proinflammatory bacterial products, delay or inhibit tumour necrosis factor release, and may reduce brain oedema in experimental meningitis. Conclusive evidence of the reduction of neuronal damage by this approach, however, is lacking.

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.

Beta-trace protein concentration in cerebrospinal fluid is decreased in patients with bacterial meningitis.

Although meninges represent a major site of biosynthesis, beta-trace protein (beta-trace) has not been studied in the cerebrospinal fluid (CSF) of meningitis patients. We measured beta-trace in lumbar CSF of normal controls (n = 27) and in patients with various neurological diseases (n = 92) by an immunonephelometric assay. The mean concentration of beta-trace in CSF of control patients was 16.6+/-3.6 mg/l. In bacterial meningitis (n = 41), CSF beta-trace was significantly decreased (8.7+/-3.9 mg/l; P< 0.001), whereas in spinal canal stenosis it was elevated (29.2+/-10.3 mg/l; P= 0.002). In viral meningoencephalitis (n = 12), beta-trace CSF concentrations were normal. Beta-trace concentrations remained below the normal range even after curing of bacterial meningitis, and normalisation of CSF leucocytes and blood-CSF barrier function. Beta-trace may be a useful tool for studying the pathophysiology of bacterial meningitis.

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.

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.

[Embolic complications in bacterial endocarditis]. / Embolische Komplikationen bei bakterieller Endokarditis.

Embolic complications are a major prognostic determinant in the clinical course of infective endocarditis (IE) with an incidence of about 30-50%. In order to analyze risk factors leading to embolism in native (NVE) and prosthetic valve endocarditis (PVE), we reviewed 177 consecutive patients; 43% were female, 57% male, PVE occurred in 24% of all patients all left-sided, among the NVE were 11% right-sided IE. Major embolic complications occurred in 40% of all patients. In NVE, a higher rate of embolic events (45% vs. 26%; p < 0.05), and a larger vegetation size compared to PVE was observed (14 +/- 6 mm vs. 11 +/- 5 mm; p < 0.05). The most important risk factor for embolic complications in NVE was Staphylococcus aureus (odds ratio 6.4). Furthermore, double valve endocarditis, fever, and mitral valve endocarditis were associated with the risk for embolism. In case of severe regurgitation the rate of embolic complications was reduced (54% vs. 77%; p < 0.05). In PVE, fever was a risk factor for embolic events. Staphylococcus aureus was also a frequent microorganism in embolism (45% vs. 22%). The in-hospital mortality was significantly increased in case of embolism (NVE 40% vs. 11%; p < 0.001; PVE 36% vs. 9% p < 0.05). About 50% of all embolic events occurred before admission. In NVE, due to high in-hospital mortality, the rate of patients with embolism undergoing surgery was lower (57% vs. 72%; p < 0.05); whereas in PVE no significant difference was observed. In patients with NVE, aspirin therapy because of coronary artery disease appeared to reduce the rate of embolic complications (11% vs. 47%). However, the low number of patients on aspirin (9%) does not allow recommendations regarding a potential benefit. In conclusion, identification of risk factors leading to embolism in IE may be useful in considering early surgical therapy. However, the high rate of embolic complications before hospital admission indicates a need for improving the diagnostic delay in the prehospital phase.

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).

Soluble adhesion molecules in sera of patients with leprosy: levels of soluble intercellular adhesion molecule-1 (sICAM-1) rapidly decrease during multi-drug therapy.

The clinicopathological spectrum of leprosy is associated with an altered immunological reaction. The expression of adhesion molecules on endothelial cells directs the cellular traffic to sites of local skin and nerve inflammation. Soluble forms of adhesion molecules, which are released upon cytokine activation, can be detected in the circulation and may reflect ongoing tissue inflammation. We determined the serum levels of sICAM-1, sE-selectin and sL-selectin in 74 patients with leprosy (tuberculoid form, n = 23; lepromatous form, n = 36; acute leprous reaction, n = 16) and 15 healthy age- and sex-matched control donors. Patients with lepromatous leprosy had significantly higher levels of sICAM-1 (564 +/- 174 versus 450 +/- 92 versus 334 +/- 57 ng/ml) and E-selectin (90 +/- 31 versus 74 +/- 29 versus 50 +/- 10 ng/ml) than patients with tuberculoid leprosy and normal donors (P < 0.01). No differences between groups were detected for L-selectin. Patients with leprous reactions had similar high levels to lepromatous patients. Twenty lepromatous patients were re-examined after 4 weeks of therapy. A significant decrease in sICAM-1 serum levels was observed after 1 month of anti-mycobacterial treatment, which was accompanied by a reduction of mycobacteria in skin biopsies (P < 0.01). Patients with leprous reactions (n = 13) also demonstrated a drop in sICAM-1 after anti-inflammatory therapy. sE-selectin and sL-selectin serum values decreased only in lepromatous patients after therapy. It can be concluded that soluble adhesion molecules like sICAM-1 and sE-selectin are promising activity markers in patients with leprosy, which may be useful for treatment monitoring.

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.

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.

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.

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.

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).

[Life threatening embolism caused by central venous catheter fragments in psychiatric patients]. / Lebensbedrohliche Embolien durch Venenkatheterfragmente bei psychiatrischen Patienten.

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.

[Intensive care treatment of psychiatric patients]. / Intensivmedizinische Behandlungen bei psychiatrisch kranken Patienten.

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.