Biomedical subjects
Publications and source records attributed to E Pfenninger.
Emergency room management means time management. A time and four color based algorithm is described to improve workflow, follow up of diagnostic procedures and initial treatment. As a result introducing the time based interdisciplinary emergency algorithm within 60 minutes all necessary treatment and diagnostic procedures were completed. This algorithm is an effective tool to improve emergency room treatment.
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UNLABELLED: Two surveys initiated by the Neuroanesthesia Research Group of the German Society of Anesthesia and Intensive Care Medicine examined the practice of intraoperative monitoring during intracranial procedures in Germany in 1991 and 1997. Questionnaires were mailed to departments that were registered members of the German Society of Anesthesia and Intensive Care Medicine and that provided neuroanesthesia service on a routine basis in 1991. In 1997, the survey was repeated in the 1991 respondents. In 1991, 68 departments and in 1997, 44 departments returned completed questionnaires, indicating a response rate of 87% for 1991 and of 65% for 1997. Compared with 1991, the standards for monitoring, such as surveillance of oxygenation, ventilation, circulation, and body temperature, were universally applied in adult and pediatric patients in 1997. Overall, there was a 20% increase in neuromuscular blockade monitoring and in the use of electroencephalography and evoked potentials in 1997 compared with 1991. Further brain-specific monitoring was rarely provided in 1997. Overall, jugular venous oximetry was used in 20% and transcranial Doppler ultrasonography in 15% of responding hospitals. To detect venous air embolism in sitting patients, 75% of all responding hospitals used precordial Doppler ultrasonography in both years, whereas transesophageal echocardiography was more often used in 1997 (38%) as compared with 1991 (17%). IMPLICATIONS: Standards of anesthetic monitoring were surveyed in neuroanesthesia in Germany in 1991 and 1997. Central nervous system monitoring was not the standard of practice.
Hypertonic-hyperoncotic saline solutions (HHS) have been used for small-volume resuscitation and to treat intracranial hypertension and cerebral edema in neurocritical care. Little is known on the response of brain cells to direct exposure in HHS, which may occur in blood-brain barrier disruption. We studied the effects of HHS on healthy and glutamate-injured brain cells in vitro. To model a hypertonic-hyperoncotic environment, rat hippocampal neurons and cerebral astrocytes were exposed to hypertonic saline and hydroxyethyl starch (HES) added to medium for 15 minutes (final osmolarity: 350 mOsm/L in the neuronal, 373 mOsm/L in the glial medium; 2.5 mg/mL HES in both media). To simulate excitotoxicity, cells were exposed to 100 microM glutamate for 8 minutes before exposure to HHS. Cell viability was analyzed by morphology and vital dye staining; intracellular water space (WS) and glucose use were measured by scintillation spectrometry using 3-O-methyl[14C]-D-glucose and [3H]2-deoxy-D-glucose ([3H]2-DG). After 24 hours, exposure to HHS added to medium caused a 30% reduction in viability of healthy neurons (P < .05), but did not exacerbate the glutamate-induced 50% decrease in neuronal survival. One hundred percent astrocyte viability remained unchanged. The WS of astrocytes and surviving neurons was negligibly altered. Exposure to HHS added to medium caused a 35% reduction in [3H]2-DG in healthy and glutamate-injured neurons (P < .05), but did not affect [3H]2-DG in astrocytes. Our data show that HHS may potentially injure hippocampal neurons. Preserved WS values imply that live cells maintained volume regulation capabilities, indicating a lack of dehydration 24 hours after exposure to HHS. Impaired glucose use predisposes neurons to disturbed metabolism, which may influence neuronal outcome after brain injury.
UNLABELLED: This survey collected and analyzed data on the current practice of clinical neuroprotection in neuroanesthesia in Germany. METHODS: The data were collected by a questionnaire sent to departments of anesthesiology in Germany in 1997 which provided care for neurosurgical patients on a routine basis, and which were registered members of the German Society of Anesthesiology and Intensive Care Medicine (DGAI). Since the questions concerning "neuroprotective therapy" were linked to a general survey on clinical neuroanesthesia performed by the scientific neuroanesthesia working group of the DGAI, the only departments that were assessed were those which had participated in an earlier study on neuroanesthesia in 1991. RESULTS: Of the completed questionnaires 63% could be included in the analysis. Approximately 75,000 cases were thus evaluated. Therapy varied considerably between departments. Following head trauma 69% of injured patients were managed with enhanced cerebral perfusion pressure (CPP) within the range of 70-90 mmHg. If necessary, CPP increase was induced by vasopressors (exogenous supply of catecholamines in 100% of instances) and the administration of fluids (97% of instances). The most commonly used therapeutic approaches to treat intracranial hypertension were mannitol (95% of instances), hyperventilation (91% of instances), cerebrospinal fluid drainage (89% of instances), and barbiturates (86% of instances). Tris (hydroxymethyl)-aminomethane was administered in almost 49%, mild hypothermia in 37%, and hypertonic-hyperoncotic solutions in 28% of patients treated for an increase in intracranial pressure. Following intracranial aneurysm surgery "triple-H" therapy was used in 74% of patients, applied as hemodilution in 94% and as hypervolemia and hypertension in 87% of instances. Mild hypothermia was employed as a method of neuroprotection in 54% of the departments involved. It was used in 83% of patients during perioperative care and in 52% of patients during intensive care therapy. Specific neuroprotective drugs were applied in 68% of departments, with barbiturates (38% of instances), nimodipine (23% of instances), and corticosteroids (10% of instances) as the main agents named. These brain-protective medications were administered especially in intracranial hypertension in 30%, in intracranial aneurysms in 21%, and in subarachnoid hemorrhages subsequent to head trauma in 18% of instances described. CONCLUSION: These findings demonstrate that the neuroprotective therapy administered in anesthesiological departments in Germany is not yet standardized, i.e., there is a wide variation. Although outcome was not assessed with this survey, it is conceivable that algorithms based on logical approaches in the sense of evidence-based medicine could serve as tools to reduce morbidity and mortality.
In previous studies, racemic ketamine improved neurological outcome after experimental brain injury and S(+)-ketamine demonstrated neuroprotective effects in neurons after damage in vitro. We compared the expression of regeneration-associated proteins in rat hippocampal neurons after glutamate injury and treatment with S(+)-ketamine versus racemic ketamine. Following an 8 minute exposure to 100 microM glutamate, neurons were maintained untreated or in the presence of S(+)-ketamine or racemic ketamine (10(-4) M, 10(-5) M, 10(-6) M) for one week. Growth-associated protein-43 (GAP-43) and synaptosomal-associated protein-25 (SNAP-25) was analyzed by Western Blotting, the mitochondrial transmembrane potential (MTP) by fluorescence imaging, and [3H]2-deoxy-D-glucose ([3H]2-DG) uptake by scintillation spectrometry. Seven days after exposure, GAP-43 decreased to 15% and SNAP-25 to 30% in the glutamate-injured, untreated neurons. The MTP declined to 50% and [3H]2-DG to 30%. Both S(+)-ketamine and racemic ketamine at 10(-4) M and 10(-5) M minimized the decline in MTP, almost maintaining it at control value. Additionally, S(+)-ketamine and racemic ketamine decreased the reduction in [3H]2-DG. S(+)-ketamine at 10(-4) M and 10(-5) M and racemic ketamine at 10(-4) M reduced the decline in SNAP-25 to 60% of controls (P < .05). However, S(+)-ketamine at 10(-4) M and 10(-5) M only reversed the decrease in GAP-43 to 50% and 40% of controls, respectively (P < .05). We conclude that the synthesis of a growth-associated protein related to plasticity and repair in the adult nervous system is increased by S(+)-ketamine but is not increased by racemic ketamine.
The intravenous anaesthetic ketamine is a racemic mixture of two equimolar doses of enantiomers. After stereoselective separation, the right-handed S(+)-isomer is now clinically available. Since anaesthetic and analgesic pharmacological studies have shown that S(+)-ketamine is approximately two times as potent as racemic ketamine, the clinical effects of S(+)-ketamine were evaluated in comparison to ketamine-racemate at dose relation of 1:2 in several therapeutic investigations. The studies disclosed that both drugs caused a similar activation of the endocrine stress response and a comparable stimulation of the sympathoadrenergic system. However, application of S(+)-ketamine was associated with a remarkably smoother emergence period, a profound postoperative analgesia, a more rapid recovery of cerebral functions, and a greater preference by the study persons. The incidence of psychotomimetic phenomena appeared to be negligibly less after S(+)-ketamine in comparison to racemic ketamine, but their quality was described as far less unpleasant. Clinical use of S(+)-ketamine administered at one-half of the usual dose is thus not only associated with a reduction of undesirable adverse effects without altering ketamine's anaesthetic and analgesic potency, but also offers distinctive improvements due to the reduced drug load. Moreover, increasing experimental evidence supports a remarkable neuroprotective effect of S(+)-ketamine, which may become a promising drug for new therapeutic approaches to neuroprotection.
OBJECTIVE: To evaluate the long-term effects of lactic acidosis and to examine a potential neuroprotective role of basic fibroblast growth factor (bFGF) on hippocampal neurons. DESIGN: Long-term observation in a cell-culture study. SETTING: University research laboratory. SUBJECTS: Adult, differentiated, primary rat hippocampal neurons. INTERVENTIONS: Neurons were exposed to medium acidified with 20 mM lactic acid, pH 6.2, for a 10-min period, and maintained untreated or in the presence of bFGF (500 pg/mL, 1 ng/mL, 10 ng/mL, 20 ng/mL) applied after exposure. MEASUREMENTS AND MAIN RESULTS: Viability was analyzed by a dye inclusion/enzyme activity test and morphology by phase contrast and immunofluorescence microscopy. [3H]Arachidonic acid (AA) release was measured by liquid scintillation spectrometry. All cultures appeared to be unchanged during the first days after exposure to lactic acidosis. Neurodegeneration became apparent within 3 days. Seven days after exposure, cell survival decreased to 60% in lactic acidosis-injured, untreated cultures. Morphologic damage appeared as a 50% reduction in axonal and 25% reduction in dendritic arborizations. AA release increased to four-fold enhanced levels relative to control values. bFGF (1, 20, and 10 ng/ mL) enhanced neuronal viability (p < .05), and 10 ng/mL bFGF induced a maximal increase in live cells to 80% of controls. Axonal arborizations increased to 50% and dendritic arborizations to 75% of controls after 10 ng/mL bFGF (p< .05). bFGF in a dose of 20 ng/ mL enhanced axonal branching to 40% and dendrites in number and branching to 50% of controls (p< .05). bFGF (500 pg/mL, and 1 and 10 ng/mL) decreased enhanced AA (p < .05), and 10 ng/mL bFGF maximally reduced increased AA to two-fold enhanced values relative to controls. CONCLUSIONS: In vulnerable neurons, exposure to moderate lactic acidosis induces a process of cell injury with long latency. bFGF applied postinjury reduces the delayed neurodegeneration and may have neuroprotective efficacy in new therapeutic strategies to ischemia-induced cerebral injury.
THAM (trometamol; tris-hydroxymethyl aminomethane) is a biologically inert amino alcohol of low toxicity, which buffers carbon dioxide and acids in vitro and in vivo. At 37 degrees C, the pK (the pH at which the weak conjugate acid or base in the solution is 50% ionised) of THAM is 7.8, making it a more effective buffer than bicarbonate in the physiological range of blood pH. THAM is a proton acceptor with a stoichiometric equivalence of titrating 1 proton per molecule. In vivo, THAM supplements the buffering capacity of the blood bicarbonate system, accepting a proton, generating bicarbonate and decreasing the partial pressure of carbon dioxide in arterial blood (paCO2). It rapidly distributes through the extracellular space and slowly penetrates the intracellular space, except for erythrocytes and hepatocytes, and it is excreted by the kidney in its protonated form at a rate that slightly exceeds creatinine clearance. Unlike bicarbonate, which requires an open system for carbon dioxide elimination in order to exert its buffering effect, THAM is effective in a closed or semiclosed system, and maintains its buffering power in the presence of hypothermia. THAM rapidly restores pH and acid-base regulation in acidaemia caused by carbon dioxide retention or metabolic acid accumulation, which have the potential to impair organ function. Tissue irritation and venous thrombosis at the site of administration occurs with THAM base (pH 10.4) administered through a peripheral or umbilical vein: THAM acetate 0.3 mol/L (pH 8.6) is well tolerated, does not cause tissue or venous irritation and is the only formulation available in the US. In large doses, THAM may induce respiratory depression and hypoglycaemia, which will require ventilatory assistance and glucose administration. The initial loading dose of THAM acetate 0.3 mol/L in the treatment of acidaemia may be estimated as follows: THAM (ml of 0.3 mol/L solution) = lean body-weight (kg) x base deficit (mmol/L). The maximum daily dose is 15 mmol/kg for an adult (3.5L of a 0.3 mol/L solution in a 70kg patient). When disturbances result in severe hypercapnic or metabolic acidaemia, which overwhelms the capacity of normal pH homeostatic mechanisms (pH < or = 7.20), the use of THAM within a 'therapeutic window' is an effective therapy. It may restore the pH of the internal milieu, thus permitting the homeostatic mechanisms of acid-base regulation to assume their normal function. In the treatment of respiratory failure, THAM has been used in conjunction with hypothermia and controlled hypercapnia. Other indications are diabetic or renal acidosis, salicylate or barbiturate intoxication, and increased intracranial pressure associated with cerebral trauma. THAM is also used in cardioplegic solutions, during liver transplantation and for chemolysis of renal calculi. THAM administration must follow established guidelines, along with concurrent monitoring of acid-base status (blood gas analysis), ventilation, and plasma electrolytes and glucose.
A key question in cellular neuroprotection is how pharmacologic agents may protect neurons when applied after injury in clinically relevant concentrations. Of special importance is the N-methyl-D-aspartate (NMDA) antagonist ketamine, which offers the potential for regulation of intracellular calcium levels and pathophysiological NO induction by blocking excessive NMDA-receptor stimulation. This may reduce progressive neuronal degeneration and cell death. Initial evidence for ketamine's neuroprotective effects came from cell culture studies demonstrating increased neuronal and astroglial viability, preserved cellular morphology, and reduced cell swelling subsequent to anoxia-hypoxia or glutamate injury and ketamine application. Moreover, ketamine was found to protect cellular energy status after ischaemic insults and maintained ATP production, glucose metabolism, and mitochondrial transmembrane potentials. Subsequent studies have revealed ketamine's regulating effects on intracellular ion homeostasis, thus stabilising neuronal electrophysiological functions. In addition, ketamine was reported to maintain a glutamate-associated induction of intrinsic-neuronal protective nerve growth factors, and recent evidence suggests that S(+)-ketamine has a greater neuroprotective potential than ketamine racemate. S(+)-ketamine demonstrated a unique neuroregenerative potential that was associated with greater re-outgrowth of axonal neurites after mechanical injury and increased expression of growth-associated proteins after glutamate damage. S(+)-ketamine has a two- to four-fold higher affinity for the phencyclidine receptor of the NMDA receptor complex than ketamine racemate, and it is conceivable that the induction of a differentiated pattern of genes induces cellular growth activities via ketamine-mediated NMDA-receptor activation or blockade. However, further investigations elucidating ketamine's effects in animals and humans have to be performed before final decisions regarding a potential application of ketamine as a neuroprotective agent in the clinical setting can be made.
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OBJECTIVE: Axons of adult central nervous system neurons fail to regenerate after diffuse axonal injury in head trauma. Basic fibroblast growth factor (bFGF) has been reported to enhance neuritic extensions after neuronal injury in immature nerve cells. To investigate the effects of bFGF on adult neurons and axonal reoutgrowth, differentiated nerve cells were axonally transected and bFGF was applied. DESIGN: Cell culture study with primary rat hippocampal neurons. MATERIALS AND METHODS: After axotomy, hippocampal cultures were maintained untreated or in the presence of 0.5, 1, 10, or 20 ng/mL bFGF and evaluated over a 7-day period after injury. MEASUREMENTS AND MAIN RESULTS: Seven days after injury, axotomy decreased cell survival to 65%, increased [3H]arachidonic acid release 1.8-fold from prelabeled cells, and showed negligible effects on neuronal dendrites. bFGF reduced this neurodegeneration at all doses applied. bFGF at 10 ng/mL most efficiently increased live cells to 85% and decreased [3H]arachidonic acid release from prelabeled cells to control values (p < 0.01, vs. damaged cells). Furthermore, 10 ng/mL bFGF induced axonal branching and the longest axonal re-extensions from 60 +/- 8 to 377 +/- 10 microns 7 days after injury (p < 0.01, vs. damaged cells). CONCLUSIONS: bFGF increased cell survival and supported axonal re-elongations in adult hippocampal neurons in vitro when applied after axotomy. bFGF may play a role in new therapeutic concepts for the management of axonal injury after head trauma.
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During development in culture, basic fibroblast growth factor (bFGF) protected immature primary hippocampal neurons against glutamate-induced neurotoxicity. We investigated the effects of bFGF on mature, differentiated rat hippocampal neurons cultured for 10-12 days after an 8-min exposure to 500 microM glutamate. Seven days post-injury, hippocampal cells demonstrated severe reductions in cellular viability and axonal and dendritic outgrowth, which were accompanied by a marked increase in [3H]arachidonic acid (ARA) release from prelabelled neurons. bFGF applied post-injury attenuated cell death and cytoarchitectural destruction at all concentrations used (500 pg/ml, 1, 10, 20 ng/ml). However, neurite elongation and branching processes were only significantly protected by 10 ng/ml bFGF. [3H]ARA release decreased in a dose-related fashion within a concentration range of 1-10 ng/ml bFGF. 20 ng/ml bFGF was not superior to 10 ng/ml bFGF. Therefore, bFGF's neurotropic actions appear to be concentration-dependent. Our data suggest that bFGF applied post-injury may have a neuroprotective potential for mature, differentiated, completely polarized hippocampal neurons.
There is a difference in the relative anesthetic potency of the isomers of ketamine. Neuroprotective differences may therefore also exist. After an 8-min exposure to 500 microM glutamate or axonal transection, cultured rat hippocampal neurons were maintained untreated or in the presence of ketamine-racemate, S(+)-ketamine, or R(-)-ketamine (10(-4) M, 10(-5) M, 10(-6) M). Cell survival was examined by dye inclusion/esterase activity, morphology by phase contrast and immunofluorescence microscopy, and [3H]arachidonic acid (ARA) release by liquid scintillation spectrometry. Seven days after glutamate exposure, survival decreased to 30% in the damaged, untreated group. Extracellular [3H]ARA increased fivefold. Dendritic length and branching decreased to a quarter and axonal extensions to the half. Ketamine-racemate 10(-4) M increased survival to 65%, and induced longer dendrites (P < or = 0.05). S(+)-Ketamine 10(-4) M increased survival to 80%, reduced [3H]ARA threefold, and preserved cytoskeletal arborizations (P < or = 0.05). Axotomy decreased survival to 60% and caused a minor increase in [3H]ARA after 7 days. Survival was 80% after 10(-4) M ketamine-racemate and 90% after 10(-4) M S(+)-ketamine (P < or = 0.05). Only S(+)-ketamine supported axonal reoutgrowth and decreased [3H]ARA (P < or = 0.05). R(-)-Ketamine was ineffective after both types of injury. Ketamine-racemate and S(+)-ketamine attenuated injury after glutamate exposure or axonal transection in hippocampal neurons in vitro. Neuroregenerative effects were uniquely demonstrated by S(+)-ketamine.
OBJECTIVE: To assess the effects of graded doses of vasopressin vs. saline on median fibrillation frequency and defibrillation success in a porcine model of cardiopulmonary resuscitation. DESIGN: Prospective, randomized, controlled trial. SETTING: Animal laboratory in a university medical center. SUBJECTS: Twenty-eight domestic pigs (body weight between 26 and 31 kg), aged 12 to 14 wks. INTERVENTIONS AND MAIN RESULTS: After 4 mins of ventricular fibrillation and 3 mins of closed-chest cardiopulmonary resuscitation, the animals were allocated to receive either 0.2 U/kg of vasopressin (n = 7), 0.4 U/kg of vasopressin (n = 7), 0.8 U/kg of vasopressin (n = 7), or 10 mL of saline (n = 7, control group). Using radiolabeled microspheres, myocardial blood flow rates during cardiopulmonary resuscitation-before drug administration and 90 secs and 5 mins after drug administration-were as follows in the four groups (mean +/- SEM): 18.8 +/- 0.9, 17.2 +/- 1.1, and 14.6 +/- 1.4 mL/min/100 g in the control group; 17.8 +/- 2.2, 49.6 +/- 6.3 (p < .01 vs. control group), and 29.4 +/- 3.1 mL/min/100 g (p < .05 vs. control group) in the group receiving 0.2 U/kg of vasopressin; 17.1 +/- 1.0, 52.4 +/- 7.5 (p < .01 vs. control group), and 52.2 +/- 5.8 mL/min/100 g (p < .001 vs. control group) in the group receiving 0.4 U/kg of vasopressin; and 18.1 +/- 1.6, 94.9 +/- 9.2 (p < .001 vs. control group), and 57.2 +/- 6.3 mL/min/100 g (p < .001 vs. control group) in the group receiving 0.8 U/kg of vasopressin. Using spectral analysis, median frequencies of ventricular fibrillation-before drug administration and 90 secs and 5 mins after drug administration-were as follows in the four groups: 9.6 +/- 0.4, 8.5 +/- 0.8, and 7.2 +/- 1.0 Hz in the control group; 9.7 +/- 0.5, 12.9 +/- 0.8 (p < .01 vs. control group), and 12.7 +/- 0.8 Hz (p < .001 vs. control group) in the group receiving 0.2 U/kg of vasopressin; 10.3 +/- 0.2, 12.7 +/- 0.9 (p < .01 vs. control group), and 12.8 +/- 0.7 Hz (p < .001 vs. control group) in the group receiving 0.4 U/kg of vasopressin; and 10.0 +/- 0.9, 14.1 +/- 0.9 (p < .001 vs. control group), and 12.5 +/- 0.9 Hz (p < .001 vs. control group) in the group receiving 0.8 U/kg of vasopressin at the same points in time. Median frequency before the first defibrillation attempt was 12.3 +/- 0.4 Hz in the resuscitated animals (n = 19) and 8.2 +/- 1.2 Hz in the nonresuscitated animals (n = 9) (p < .001). CONCLUSIONS: This study contributes to the characterization of the effect of increasing global myocardial blood flow on median fibrillation frequency after administration of graded doses of vasopressin in a porcine model of ventricular fibrillation. Interventions such as vasopressor treatment that increase fibrillation frequency improve the chance of successful defibrillation.
This article was written to give researchers and clinicians a short synopsis of ethical and thorough design, conduct, analysis, publication, and interpretation of randomised controlled clinical trials according to the European quality standards of Good Clinical Practice (GCP). The paper consists of two parts. In the first part we introduce important elements of study design, especially study hypothesis, criteria of inclusion and study population, sample size calculation, validity considerations, bias and confounding, randomisation, stratification, and masking of treatment assignment. Different treatment allocation like multiple parallel groups, factorial experiment, cross-over, and sequential design are presented. Requirements of ethical standards according to the Declaration of Helsinki are discussed for their necessity in any experimentation in humans. Principles of informed consent are demonstrated with emphasis on special conditions in anaesthesia, emergency medicine, and intensive care research. In the second part of this article we explain issues of baseline assessment, experimental intervention, data recording, and data monitoring, particularly of negative or hazardous treatment effects. Topics of data analysis and reporting of trial results in publications are illustrated with regard to their influence on subsequent interpretation.
This article was written to give researchers and clinicians a short synopsis of ethical and thorough design, conduct, analysis, publication, and interpretation of randomised controlled clinical trials according to the European quality standards of Good Clinical Practice (GCP). The paper consists of two parts. In the first part we introduce important elements of study design, especially study hypothesis, criteria of inclusion and study population, sample size calculation, validity considerations, bias and confounding, randomisation, stratification, and masking of treatment assignment. Different treatment allocation like multiple parallel groups, factorial experiment, cross-over, and sequential design are presented. Requirements of ethical standards according to the Declaration of Helsinki are discussed for their necessity in any experimentation in humans. Principles of informed consent are demonstrated with emphasis on special conditions in anaesthesia, emergency medicine, and intensive care research. In the second part of this article we explain issues of baseline assessment, experimental intervention, data recording, and data monitoring, particularly of negative or hazardous treatment effects. Topics of data analysis and reporting of trial results in publications are illustrated with regard to their influence on subsequent interpretation.