Inositol 1,4,5-trisphosphate synthesis in mononuclear white blood cells of malignant hyperthermia-susceptible and normal human beings, following in vitro exposure to halothane, caffeine and ryanodine.

Despite a plethora of findings associated with the pathophysiology of malignant hyperthermia (MH), the in vitro contracture test (IVCT) is the only reliable test for diagnosis of this heterogeneous syndrome in man. An increase of 1,4,5-IP3 (inositol 1,4,5-trisphosphate), a second messenger involved in cellular calcium homeostasis, has been observed in muscle tissue of MH susceptible (MHS) patients. The aim of this study was to evaluate if the known differences of 1,4,5-IP3 content in muscle tissue might be reproduced in mononucleated white blood cells (MWBCs). Subsequently, MWBCs of 23 healthy controls and 12 patients with a clinical suspicion for MH disposition were isolated and screened for 1,4,5-IP3 content. An IVCT according to the protocol of the European Malignant Hyperpyrexia Group (EMHG) was performed on muscle specimens of 12 patients. Eight MHN and four MHS individuals were diagnosed. Additionally, 1,4,5-IP3 synthesis in MWBCs was detected following in vitro exposure to IVCT test substances halothane (2%), caffeine (1-30mM), and ryanodine (1-5 microM). A broad inter-individual variability of 1,4,5-IP3 content was observed in MWBCs of all volunteers, but no differences were detected between MHS and MHN individuals. These findings are in strong contrast to those observed in muscle tissue. In vitro exposure of isolated MWBCs to halothane, caffeine and ryanodine yielded no statistically significant differences between groups. A time- and concentration-dependent increase in cellular 1,4,5-IP3 content could be induced in some but not all individuals of both groups. Since no correlation was obtained between induction of 1,4,5-IP3-synthesis following in vitro exposure of MWBCs to MH test substances and MH disposition, this study was terminated. We conclude from our data that the detection of 1,4,5-IP3 synthesis in MWBCs is not suitable for diagnosis of MH disposition. It remains questionable whether an altered 1,4,5-IP3 metabolism in MWBCs is involved in pathologic cascades of MH. Therefore, other cell tissues should be evaluated in further studies to clarify the role of the 1,4,5-IP3 metabolism in MH.

Topography of clonidine-induced electroencephalographic changes evaluated by principal component analysis.

BACKGROUND: Principal component analysis is a multivariate statistical technique to facilitate the evaluation of complex data dimensions. In this study, principle component analysis was used to reduce the large number of variables from multichannel electroencephalographic recordings to a few components describing changes of spatial brain electric activity after intravenous clonidine. METHODS: Seven healthy volunteers (age, 26 +/- 3 [SD] yr) were included in a double-blind crossover study with intravenous clonidine (1.5 and 3.0 microg/kg). A spontaneous electroencephalogram was recorded by 26 leads and quantified by standard fast Fourier transformation in the delta, theta, alpha, and beta bands. Principle component analysis derived from a correlation matrix calculated between all electroencephalographic leads (26 x 26 leads) separately within each classic frequency band. The basic application level of principle component analysis resulted in components representing clusters of electrodes positions that were differently affected by clonidine. Subjective criteria of drowsiness and anxiety were rated by visual analog scales. RESULTS: Topography of clonidine-induced electroencephalographic changes could be attributed to two independent spatial components in each classic frequency band, explaining at least 85% of total variance. The most prominent effects of clonidine were increases in the delta band over centroparietooiccipital areas and decreases in the alpha band over parietooccipital regions. Clonidine administration resulted in subjective drowsiness. CONCLUSIONS: Data from the current study supported the fact that spatial principle component analysis is a useful multivariate statistical procedure to evaluate significant signal changes from multichannel electroencephalographic recordings and to describe the topography of the effects. The clonidine-related changes seen here were most probably results of its sedative effects.

Targeted disruption of cd39/ATP diphosphohydrolase results in disordered hemostasis and thromboregulation.

CD39, or vascular adenosine triphosphate diphosphohydrolase, has been considered an important inhibitor of platelet activation. Unexpectedly, cd39-deficient mice had prolonged bleeding times with minimally perturbed coagulation parameters. Platelet interactions with injured mesenteric vasculature were considerably reduced in vivo and purified mutant platelets failed to aggregate to standard agonists in vitro. This platelet hypofunction was reversible and associated with purinergic type P2Y1 receptor desensitization. In keeping with deficient vascular protective mechanisms, fibrin deposition was found at multiple organ sites in cd39-deficient mice and in transplanted cardiac grafts. Our data indicate a dual role for adenosine triphosphate diphosphohydrolase in modulating hemostasis and thrombotic reactions.

[In memory of August Bier (1861-1949)]. / Zur Erinnerung an August Bier (1861-1949).

"A professor is a gentleman of different opinion" this striking and sarcastic remark, which the surgeon August Bier often quoted in his lectures, can be applied to the pioneer of the lumbar and intravenous local anesthesia himself. Bier, born in 1861, in many ways influenced surgery, anesthesia and general medicine with his contributions through the decades. A student of the Kieler surgeon Friedrich von Esmarch, he habilitated after only two years. 1899 he received a call to the university in Greifswald, went to Bonn University in 1903 and finally in 1907 became the successor of Ernst von Bergmann in the acclaimed Klinik in der Ziegelstrasse in Berlin. The philosophic thoughts of Heraklit and Hippokrates influenced his own teleologic view of medicine and his (Reizkörper) and hyperemia therapy. He kept his interest in both subjects as well as in homeopathy throughout his life; an interest few of his surgical colleagues shared. His Chirurgische Operationslehre (Surgical Theory) however, which appeared in countless editions, met with undiluted consent. His publications on philosophic questions are still of interest today, as are his concepts on forestry which he could apply to his own estate in Sauen. When Bier was emerited in 1932 he was almost completely retired and lived on his estate. He dies there in 1949 at the age or 88, respected world-wide as a bionomic thinker, surgeon and expert on forestry. In the following we wish to point out the lesser known aspects of the surgeon August Bier, who enriched our special field by introducing spinal and intravenous anesthesia into it at the turn of the century. It is not possible to acknowledge all of the achievements of this restlessly working, sometimes difficult surgeon, this scientist to whom always could be applied: "A professor is a gentleman of different opinion!"

Rhabdomyolysis following severe physical exercise in a patient with predisposition to malignant hyperthermia.

A 21-year-old man suffered from exertional heat stroke with impaired consciousness and rhabdomyolysis after strenuous physical exercise. Within two weeks the patient recovered completely without any specific therapy. Based on the symptoms and laboratory investigations, this episode suggested a moderate form of malignant hyperthermia. An in vitro contracture test was performed and a predisposition to malignant hyperthermia was diagnosed; other muscular diseases were excluded by histological examination. At present, the in vitro contracture test is the only method used to determine susceptibility to malignant hyperthermia and should be performed when the diagnosis is suggested on clinical grounds.

Transmyocardial laser revascularization induces cerebral microembolization.

BACKGROUND: Transmyocardial laser revascularization may vaporize fluid in the left heart, allowing bubbles to form. This study aimed to determine whether the laser pulse resulted in cerebral emboli and to examine changes in middle cerebral artery flow velocity and jugular bulb oxygen saturation (SjO2) during transmyocardial laser revascularization. METHODS: Twelve patients (American Society of Anesthesiologists physical status III) were studied after the authors received institutional review board approval and the patients' informed consent. Monitored variables included mean arterial blood pressure (measured in millimeters of mercury), heart rate (measured as beats/min), and partial pressure of carbon dioxide (measured in millimeters of mercury). A 5-MHz transesophageal-sonography system was used to record intraventricular events after laser injection. Mean blood flow velocity (Vmean; measured in centimeters per second) was monitored in the middle cerebral artery using transcranial Doppler sonography, and SjO2 (expressed as a percentage) was measured using a fiberoptic thermodilution catheter placed in the right jugular bulb. Data were recorded before, during, and for 4 min after laser injection. RESULTS: After laser injection, intraventricular echogenic contrast was seen in transesophageal-sonography, and 2-4 s later high-intensity signals (microemboli) appeared in the transcranial Doppler sonography spectra. As long as mean arterial pressure remained stable during the observation period, Vmean and SjO2 did not change. CONCLUSIONS: These data show that microemboli can be detected after laser injection in the middle cerebral artery, although they do not effect Vmean and SjO2. The results suggest that these microemboli do not induce a global oxygen imbalance.

The effects of propofol on cerebral blood flow in correlation to cerebral blood flow velocity in dogs.

This study correlates the effects of propofol on cerebral blood flow (CBF) and middle cerebral artery blood flow velocity in dogs. CBF was measured using radioactive microspheres. Cerebral oxygen consumption (CMRO2) was measured with each CBF determination. Blood flow velocity was measured through a transtemporal window using a pulsed 8 MHz transcranial Doppler ultrasound system (TCD). Electroencephalogram (EEG) was continuously recorded over both cerebral hemispheres. Cardiac output (CO) was measured using an electromagnetic flow probe placed on the pulmonary artery. Baseline measures were made in all dogs (n = 11) with 0.7% isoflurane end tidal and 50% N2O in O2. There were two treatment groups. In group 1 (n = 6), propofol (0.8 mg/kg/min) was infused and a second measurement made at induction of EEG burst suppression (12 +/- 2 min). CBF and CMRO2 decreased by 70% and mean blood flow velocity decreased by 60%. Blood pressure, heart rate, and CO did not change. Propofol infusion was discontinued and all parameters were measured following recovery of EEG to baseline activity (48 +/- 9 min). CBF and blood flow velocity increased 35 and 25%, respectively, and CMRO2 increased by 32% during this period. A second propofol infusion (0.8 mg/kg/min) was started and all cerebral and systemic hemodynamic parameters were again determined at induction of EEG burst suppression (12 +/- 2 min). CBF decreased 35% and blood flow velocity decreased 25% to levels seen during the first propofol infusion. Over the entire study, changes in CBF correlated with changes in blood flow velocity (r = 0.86, p < 0.05). In group 2 (n = 5), four control measures were made at the same time intervals as in group 1. Baseline CBF and blood flow velocity were lower in group 2 compared to group 1 but these measures did not change over time. Our results show that propofol produces marked decreases in CBF in dogs and that these changes are closely correlated with CBF velocity.

Dose-dependent blood flow velocity changes in the Basal cerebral arteries following low-dose ketamine.

The effects of low-dose ketamine on blood flow velocity and pulsatility index (PI) in the basal cerebral arteries were studied in two groups of healthy volunteers (group A: 0.25 mg/kg, n = 10; group B: 0.5 mg/kg, n = 10) by means of a 2 MHz pulsed transcranial Doppler ultrasonic system (TCD) for an observation period of 70 min. In addition, mean arterial pressure (MAP), heart rate (HR), end-tidal CO2 (petCO2), and oxygen saturation (saO2) were recorded. The mean blood flow velocity (Vmean) increased significantly by 28% in group A and by 68% in group B within 2-9 min. In group B, the PI was reduced by 32% for a period of 2-7 min (p < 0.05). MAP (group A: -20%; group B: -26%) and HR (group A: -39%; group B: -54%) increased significantly (p < 0.05). Vmean and PI were significantly different between groups A and B, suggesting a dose-dependent stimulation of cerebral hemodynamics. The flow velocity increases cannot be entirely explained by systemic hemodynamic changes since there was no intergroup difference with respect to MAP and HR. No significant differences were observed with regard to petCO2 and saO2. With the assumption that the diameter of the insonated vessel is not changed by ketamine, the dose-dependent increase in Vmean with a concomitant decrease in PI may be interpreted as indicating an increase in cerebral blood flow.

[Pulmonary changes in cranio-cerebral injuries and respiration with high oxygen concentrations]. / Lungenveränderungen Schädel-Hirn-Verietzter und Beatmung mit hohen Sauerstoffkonzentrationen

In 131 cases of craniocerebral trauma it was shown in what respect definite changes in the lungs, demonstrated by clinical course, radiographs and blood gas analyses, occurred in proportion to the severity of the trauma. The causes of these changes were considered and the possibility of complicating the course of the illness by administering oxygen in high concentrations was investigated. In 98 patients was an indication for treatment with a respirator. 41 patients were so treated for longer than 5 days (mean 17.7 days). The need for respirator treatment rose with the increasing severity of the trauma. Frequency and severity of tracheobronchial aspiration increased in proportion to the depth of unconsciousness. It occurred in 50-60% of cases with severe trauma. Minor pulmonary lesions developed in 13% of those patients who only had minor disturbances of consciousness. Patients who had aspirated had lower arterial oxygen tensions than those who had not aspirated. In a high percentage of cases considerable improvement could be achieved, despite lung changes. In patients treated with the respirator mean inspiratory oxygen concentrations of 75% were necessary to achieve arterial oxygen tensions of 150-200 mm Hg. No evidence of oxygen toxicity was found, despite long periods of treatment with high oxygen concentrations. Very often cases of craniocerebral injury are followed both by tracheobronchial aspiration, causing lung damage, hypoxia and acidosis, and by disturbances of coagulation. These disorders are to be considered as most important, each needing specific therapy.