Model-based setting of inspiratory pressure and respiratory rate in pressure-controlled ventilation.

Mechanical ventilation carries the risk of ventilator-induced-lung-injury (VILI). To minimize the risk of VILI, ventilator settings should be adapted to the individual patient properties. Mathematical models of respiratory mechanics are able to capture the individual physiological condition and can be used to derive personalized ventilator settings. This paper presents model-based calculations of inspiration pressure (pI), inspiration and expiration time (tI, tE) in pressure-controlled ventilation (PCV) and a retrospective evaluation of its results in a group of mechanically ventilated patients. Incorporating the identified first order model of respiratory mechanics in the basic equation of alveolar ventilation yielded a nonlinear relation between ventilation parameters during PCV. Given this patient-specific relation, optimized settings in terms of minimal pI and adequate tE can be obtained. We then retrospectively analyzed data from 16 ICU patients with mixed pathologies, whose ventilation had been previously optimized by ICU physicians with the goal of minimization of inspiration pressure, and compared the algorithm's 'optimized' settings to the settings that had been chosen by the physicians. The presented algorithm visualizes the patient-specific relations between inspiration pressure and inspiration time. The algorithm's calculated results highly correlate to the physician's ventilation settings with r = 0.975 for the inspiration pressure, and r = 0.902 for the inspiration time. The nonlinear patient-specific relations of ventilation parameters become transparent and support the determination of individualized ventilator settings according to therapeutic goals. Thus, the algorithm is feasible for a variety of ventilated ICU patients and has the potential of improving lung-protective ventilation by minimizing inspiratory pressures and by helping to avoid the build-up of clinically significant intrinsic positive end-expiratory pressure.

Efficient computation of interacting model systems.

Physiological processes in the human body can be predicted by mathematical models. Medical Decision Support Systems (MDSS) might exploit these predictions when optimizing therapy settings. In critically ill patients depending on mechanical ventilation, these predictions should also consider other organ systems of the human body. In a previously presented framework we combine elements of three model families: respiratory mechanics, cardiovascular dynamics and gas exchange. Computing combinations of moderately complex submodels showed to be computationally costly thus limiting the applicability of those model combinations in an MDSS. A decoupled computing approach was therefore developed, which enables individual evaluation of every submodel. Direct model interaction is not possible in separate calculations. Therefore, interface signals need to be substituted by estimates. These estimates are iteratively improved by increasing model detail in every iteration exploiting the hierarchical structure of the implemented model families. Simulation error converged to a minimum after three iterations. Maximum simulation error showed to be 1.44% compared to the original common coupled computing approach. Simulation error was found to be below measurement noise generally found in clinical data. Simulation time was reduced by factor 34 using one iteration and factor 13 using three iterations. Following the proposed calculation scheme moderately complex model combinations seem to be applicable for model based decision support.

Hierarchical parameter identification in models of respiratory mechanics.

Potential harmful effects of ventilation therapy could be reduced by model-based predictions of the effects of ventilator settings to the patient. To obtain optimal predictions, the model has to be individualized based on patients' data. Given a nonlinear model, the result of parameter identification using iterative numerical methods depends on initial estimates. In this work, a feasible hierarchical identification process is proposed and compared to the commonly implemented direct approach with randomized initial values. The hierarchical approach is exemplarily illustrated by identifying the viscoelastic model (VEM) of respiratory mechanics, whose a priori identifiability was proven. To demonstrate its advantages over the direct approach, two different data sources were employed. First, correctness of the approach was shown with simulation data providing controllable conditions. Second, the clinical potential was evaluated under realistic conditions using clinical data from 13 acute respiratory distress syndrome (ARDS) patients. Simulation data revealed that the success rate of the direct approach exponentially decreases with increasing deviation of the initial estimates while the hierarchical approach always obtained the correct solution. The average computing time using clinical data for the direct approach equals 4.77 s (SD = 1.32) and 2.41 s (SD = 0.01) for the hierarchical approach. These investigations demonstrate that a hierarchical approach may be beneficial with respect to robustness and efficiency using simulated and clinical data.

[Primary neurogenic and myogenic disorders of posture]. / Primär neurogene und myogene Störungen der Körperhaltung.

Disturbance of posture may occur in a variety of neurological disorders and occasionally is the presenting or even the only sign. In the majority of cases, the head or the trunk or both are bent forward (bent spine syndrome, dropped head syndrome). A feature of these primary neurogenic or myogenic postural disturbances that is in contrast to antalgic contraction or ankylosis is that they are not fixed, but the trunk or head are easily erected by the examiner and show a characteristic sagging. Neuromuscular disorders are a frequent cause. They may be confined to the paraspinal muscles. Axial computed tomography of the spine, electromyography of the involved muscles, and muscle biopsy help to make the diagnosis. However, also central movement disorders may lead to a sagging of the head or trunk or of both due to a lessened tone of the head and trunk extensors. This is frequently seen in the various parkinsonian syndromes which may, however, occur in association with a focal myopathy of the paraspinal muscles. Occasionally, sagging of the trunk is seen as a side effect of neuropharmacologic medication. Sagging of the trunk or head should be differentiated from a pathologically increased innervation of the ventral muscles in dystonic movement disorders such as antecollis or camptocormia. Pathologic reclination of the head or trunk or both is a rare disturbance of posture. It may occur in dystonia (retrocollis) or, occasionally, as a consequence of musculotendinous contractures secondary to certain neuromuscular disorders such as the rigid spine syndrome.

Fatal subarachnoid hemorrhage after carotid stenting.

BACKGROUND AND PURPOSE: Cerebral hyperperfusion syndrome with intracerebral hemorrhage (ICH) following carotid angioplasty and stent placement (CAS) of the internal carotid artery (ICA) is well known. We report the occurrence of fatal subarachnoid hemorrhage in a patient undergoing CAS. CASE REPORT: A 77-year-old woman experiencing a left-hemispheric transient ischemic attack underwent CAS for a 95% stenosis of the left ICA. CAS was performed without acute complications. At 5 hours the patient suddenly deteriorated. Her level of consciousness changed and she developed neck stiffness. CT of the brain revealed diffuse SAH with acute hydrocephalus. CONCLUSIONS: Like ICH, SAH may develop as a severe complication after CAS. There are no reliable clinical symptoms preceding this fatal complication. However, several factors such as long-standing severe carotid stenosis with contralateral occlusion and increasing blood pressure after CAS accompanied by the extensive use of antithrombotic agents may predispose to this fatal complication.

Progressive arm weakness and tonic hand spasm from multifocal motor neuropathy in the brachial plexus.

A 50-year-old waitress presented with a 10-year history of progressive weakness in her right arm without atrophy and with tonic hand spasms suggesting a central motor disorder. Electromyography, however, disclosed chronic neurogenic changes including fasciculations and atypical cramps. Isolated motor conduction block in the right brachial plexus suggested a variant of multifocal motor neuropathy. Strength recovered and cramps disappeared after intravenous immunoglobulins. Motor neuropathies may thus manifest with features of central motor disorders.

Thrombolytic therapy within 3 to 6 hours after onset of ischemic stroke: useful or harmful?

BACKGROUND: The use of recombinant tissue plasminogen activator (rtPA) within 3 hours after onset of an ischemic stroke is an established therapy. Because the use of intravenous rtPA beyond a time window of 3 hours after stroke onset is still a matter of debate, we sought to review the evidence for the use of thrombolytic therapy in a time window up to 6 hours after onset of symptoms of ischemic stroke. SUMMARY OF REVIEW: The meta-analyses of the major trials (National Institute of Neurological Disorders and Stroke rtPA Stroke Study, European Cooperative Acute Stroke Study [ECASS] I, ECASS II) showed a benefit of thrombolytic therapy with intravenous rtPA even within 6 hours after onset of symptoms of ischemic stroke. The rate of intracerebral hemorrhage was slightly increased in the 6-hour time window compared with the 3-hour time window (odds ratio, 3.23 versus 2.68), but this was without statistical significance because of wide confidence intervals. A positive effect of 37% relative odds reduction with the use of a dichotomization of < or =2 versus > or =3 on the modified Rankin Scale remains for rtPA treatment within 6 hours. However, the Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke (ATLANTIS) Study, in which a 3- to 5-hour time window was used, failed to show a benefit of rtPA. Still, when the results of ATLANTIS are included into meta-analyses such as the Cochrane Library, the positive effect of rtPA treatment in the 6-hour time window remains, with a "number needed to treat" value of 11. Treating patients only within a 3- to 6-hour time window would lead to a number needed to treat value of 25. CONCLUSIONS: Consequently, from our point of view it appears unjustified to limit thrombolytic therapy to 3 hours. Because of lack of approvals for 3 to 6 hours, thrombolytic therapy within this time window should be done only as part of an institutional protocol after extensive information is obtained from the patient and the patient's relatives. Better methods for patient selection are required; in particular, newer MRI techniques, such as diffusion- and perfusion-weighted imaging, can play a key role. The aim is to qualify and individualize the time window according to the findings in each patient's imaging results rather than to use a strictly time-defined therapeutic window.

Role for Bcl-xL in delayed eosinophil apoptosis mediated by granulocyte-macrophage colony-stimulating factor and interleukin-5.

Eosinophils are potent inflammatory cells involved in allergic reactions. Inhibition of apoptosis of purified eosinophils by certain cytokines has been previously shown to be an important mechanism causing tissue eosinophilia. To elucidate the role of Bcl-2 family members in the inhibition of eosinophil apoptosis, we examined the expression of the known anti-apoptotic genes Bcl-2, Bcl-xL, and A1, as well as Bax and Bcl-xS, which promote apoptosis in other systems. We show herein that freshly isolated human eosinophils express significant amounts of Bcl-xL and Bax, but only little or no Bcl-2, Bcl-xS, or A1. As assessed by reverse transcription-polymerase chain reaction, immunoblotting, flow cytometry, and immunocytochemistry, we show that spontaneous eosinophil apoptosis is associated with a decrease in Bcl-xL mRNA and protein levels. In contrast, stimulation of the cells with granulocyte-macrophage colony-stimulating factor (GM-CSF) or interleukin-5 (IL-5) results in maintenance or upregulation of Bcl-xL mRNA and protein levels. Moreover, Bcl-2 protein is not induced by GM-CSF or IL-5 in purified eosinophils. Bcl-2 protein is also not expressed in tissue eosinophils as assessed by immunohistochemistry using two different eosinophilic tissue models. Furthermore, Bcl-xL antisense but not scrambled phosphorothioate oligodeoxynucleotides can partially block the cytokine-mediated rescue of apoptotic death in these cells. These data suggest that Bcl-xL acts as an anti-apoptotic molecule in eosinophils.

Direct demonstration of delayed eosinophil apoptosis as a mechanism causing tissue eosinophilia.

Nasal polyps, which often occur in association with allergic rhinitis and asthma, are characterized by a marked infiltration of eosinophils. Using a method for detecting eosinophils with DNA strand breaks, we found direct evidence for inhibition of eosinophil apoptosis in this model of tissue eosinophilia. By using Southern blot analysis linked to reverse transcription-PCR, we detected a mRNA signal specific for IL-5 in all nasal polyps. The identification of IL-5 as a major eosinophil survival factor was confirmed by ELISA measurements using tissue homogenates. Moreover, immunohistochemical analysis of the nasal polyp tissues demonstrated that IL-5 was localized in lymphocytes, mast cells, and eosinophils. Treatment of the eosinophil-infiltrated tissue with neutralizing anti-IL-5 mAb induced eosinophil apoptosis and decreased tissue eosinophilia. Therefore, IL-5 may represent an important cytokine responsible for the delay of the death process in eosinophils in nasal polyps. In addition, a previously suggested IL-4-dependent specific recruitment of eosinophils into the inflamed tissue could be excluded by our studies. Taken together, these findings suggest a novel mechanism by which eosinophils specifically accumulate in pathologic human tissues.

Disposition of glutathione monoethyl ester in the rat: glutathione ester is a slow release form of extracellular glutathione.

Glutathione monethyl ester (GSHE) is though to deliver glutathione (GSH) directly and intact into cell cytosol and therefore might have therapeutic potential in states of GSH deficiency. To better understand the disposition of GSHE, the pharmacokinetics of GSHE and GSH were compared in rats. Fifteen min after an i.v. dose of 5 mmol/kg GSHE, the plasma concentration of GSHE was 7.2 +/- 1.2 mmol/l and the plasma concentration of GSH had increased from 0.009 +/- 0.002 to 2.5 +/- 0.3 mmol/l. The areas under the plasma concentration time curves of GSH were identical after either the administration of GSHE or GSH, but the mean residence time of GSH in plasma was significantly longer after GSHE. The concentration of GSHE in liver reached a peak of 0.66 +/- 0.09 mumol/g. Intrahepatic concentrations of cysteine and GSH increased from 53 +/- 15 to 319 +/- 41 nmol/g and from 5.5 +/- 0.4 to 7.8 +/- 1.5 mumol/g, respectively, and remained elevated for 2 hr. Similar increases occurred after administration of GSH. However, the concentrations of cysteine and GSH peaked earlier and had returned to baseline by 2 hr. Qualitatively similar results were obtained in rats pretreated with L-buthionine-[S, R]-sulfoximine that partially inhibits GSH synthesis. GSHE added to rat plasma at a concentration of 10 mM was hydrolyzed to GSH at a rate of 0.1 mumol/min. Our data indicate that GSHE is not readily taken up by the liver, but is hydrolyzed by esterases in plasma and thereby gradually releases GSH in the extracellular space.(ABSTRACT TRUNCATED AT 250 WORDS)

Supplementation of N-acetylcysteine fails to increase glutathione in lymphocytes and plasma of patients with AIDS.

Because glutathione (GSH) in plasma and lymphocytes of HIV-infected patients is low, adjunct therapy with N-acetylcysteine (NAC) to restore GSH homeostasis has been proposed. To investigate the effect of NAC on the GSH status we treated six patients with AIDS with 1.8 g/day of NAC for 2 weeks. During treatment the plasma concentration of cysteine, a precursor for GSH synthesis, increased significantly. Nevertheless, there was no significant increase in GSH in plasma and peripheral blood mononuclear cells. The failure of sulfhydryl supplementation to increase GSH suggests that the low concentrations of the tripeptide are not the result of an increased consumption secondary to an oxidant stress, but rather the consequence of a decreased rate of synthesis of GSH in HIV infection.

Effect of oral glutathione monoethyl ester and glutathione on circulating and hepatic sulfhydrils in the rat.

Glutathione (GSH) plays an important role in the detoxification of reactive metabolites of oxygen and xenobiotics and as a source of cysteine. Since several clinical situations characterized by low circulating and intracellular GSH have been identified, there is a growing interest in pharmacological interventions to correct a deranged sulfhydril status. Therefore, the systemic bioavailability of orally administered GSH and glutathione monoethyl ester (GSHE) was examined in the rat. Following the intraduodenal administration of 0.5 mmol/kg of GSH and GSHE there was no significant increase in the concentrations of cysteine and GSH in plasma, but hepatic cysteine and GSH increased significantly, albeit transiently. Five mmol/kg of GSH and GSHE significantly increased circulating and hepatic cysteine and GSH. Following the administration of 0.5 and 5 mmol/kg of GSHE low concentrations of the ester were found in plasma and the liver, indicating that GSHE is not readily absorbed from the gastrointestinal tract, although it is not a substrate for gamma-glutamyl-transferase. GSHE resulted in a delayed release of cysteine and GSH compared to GSH, such that the concentrations of GSH and cysteine in liver and plasma were significantly higher 2 h after administration of GSHE than after GSH. The data indicate that the bioavailability of GSH and GSHE is low in the rat. Orally administered GSH and GSHE do not affect the circulating concentrations of GSH and cysteine unless very high doses are administered, but increase hepatic cysteine and GSH at lower doses because of the efficient extraction by the liver of cysteine originating from the breakdown of GSH and GSHE in the gut.

Prednisolone stimulates hepatic glutathione synthesis in mice. Protection by prednisolone against acetaminophen hepatotoxicity in vivo.

Mediators of inflammation modulate the extent of hepatocellular necrosis following the administration of hepatotoxins. Since corticosteroids interfere with the generation of some of these mediators they might thus protect against the hepatotoxicity of drugs such as acetaminophen. To test this hypothesis mice were pretreated with two doses of prednisolone (10 and 20 mg/kg i.p., 17 and 2 h, respectively) prior to a hepatotoxic dose of 375 mg/kg acetaminophen and the metabolism and toxicity of acetaminophen were assessed. Twenty-four hours after acetaminophen the activity of ALT in plasma (737 vs. 6775 U/l) and the extent of hepatocellular necrosis (4 vs. 45% necrotic hepatocytes) were significantly lower in prednisolone-pretreated mice. Prednisolone pretreatment resulted in decreased covalent binding of the toxic metabolite in vivo and an increased urinary excretion of glutathione-derived conjugates of acetaminophen, indicating an enhanced detoxification of the reactive metabolite by glutathione. Nevertheless, hepatic glutathione was less depleted by acetaminophen in the prednisolone group, indicating an increased capacity to resynthesize glutathione. This was confirmed in experiments with diethyl maleate which depletes hepatic glutathione without causing cell injury. Following the administration of diethyl maleate to fed and fasted mice, hepatic glutathione was depleted to the same extent after 45 min, but was significantly higher after 2.5 h in prednisolone-pretreated mice. The present results indicate that prednisolone increases the capacity to replete depleted hepatic glutathione stores in mice.