Kristin Engelhard

Bio: Kristin Engelhard is an academic researcher from University of Mainz. The author has contributed to research in topics: Traumatic brain injury & Cerebral blood flow. The author has an hindex of 31, co-authored 113 publications receiving 4121 citations. Previous affiliations of Kristin Engelhard include Technische Universität München & University of Illinois at Chicago.

Pathophysiology of traumatic brain injury

Abstract: The knowledge of the pathophysiology after traumatic head injury is necessary for adequate and patient-oriented treatment. As the primary insult, which represents the direct mechanical damage, cannot be therapeutically influenced, target of the treatment is the limitation of the secondary damage (delayed non-mechanical damage). It is influenced by changes in cerebral blood flow (hypo- and hyperperfusion), impairment of cerebrovascular autoregulation, cerebral metabolic dysfunction and inadequate cerebral oxygenation. Furthermore, excitotoxic cell damage and inflammation may lead to apoptotic and necrotic cell death. Understanding the multidimensional cascade of secondary brain injury offers differentiated therapeutic options.

The effect of the alpha 2-agonist dexmedetomidine and the N-methyl-D-aspartate antagonist S(+)-ketamine on the expression of apoptosis-regulating proteins after incomplete cerebral ischemia and reperfusion in rats.

Abstract: In this study, we investigated whether the neuroprotection previously seen with dexmedetomidine or S(+)-ketamine involves regulation of proapoptotic (Bax and p53) and antiapoptotic (Bcl-2 and Mdm-2) proteins. Rats were anesthetized with isoflurane. After surgical preparation of isoflurane was discontinued, animals were randomly assigned to receive fentanyl and nitrous oxide (N(2)O)/oxygen plus 100 microg/kg of dexmedetomidine intraperitoneally 30 min before ischemia (n = 8), 1 mg x kg(-1) x min(-1) of S(+)-ketamine and oxygen/air (n = 8), or fentanyl and N(2)O/oxygen (n = 8; control group). In all three treatment groups, incomplete cerebral ischemia (30 min) was induced by unilateral carotid artery occlusion and hemorrhagic hypotension to a mean arterial blood pressure of 30-35 mm Hg. Four hours after the start of reperfusion, the brains were removed, and the expression of apoptosis-regulating proteins was determined by using immunofluorescence and Western blot analysis. The results were compared with sham-operated animals (n = 8). After cerebral ischemia/reperfusion, the relative protein concentration of Bax was increased by 110% in control animals compared with the dexmedetomidine- and S(+)-ketamine-treated rats and by 140% compared with the sham-operated animals. In animals treated with dexmedetomidine, the expression of Bcl-2 and Mdm-2 was larger compared with control (68% and 210%, respectively) or sham-operated (110% and 180%, respectively) animals. Therefore, it is possible that the neuroprotective properties of dexmedetomidine and S(+)-ketamine seen in previous studies involve ultra-early modulation of the balance between pro- and antiapoptotic proteins.

Effect of the α2-Agonist Dexmedetomidine on Cerebral Neurotransmitter Concentrations during Cerebral Ischemia in Rats

Abstract: Background This study investigates whether neuroprotection seen with dexmedetomidine is associated with suppression of peripheral or central sympathetic tone. Methods Thirty fasted male Sprague-Dawley rats were intubated and ventilated with isoflurane and N2O/O2 (fraction of inspired oxygen = 0.33). Catheters were inserted into the right femoral artery and vein and into the right jugular vein. Cerebral blood flow was measured using laser Doppler flowmetry. Bilateral microdialysis probes were placed into the cortex and the dorsal hippocampus. At the end of preparation, the administration of isoflurane was replaced by fentanyl (bolus: 10 microg/kg; infusion: 25 microg x kg(-1) x h(-1)). Animals were randomly assigned to one of the following groups: group 1 (n = 10): control animals; group 2 (n = 10): 100 microg/kg dexmedetomidine administered intraperitoneally 30 min before ischemia; group 3 (n = 10): sham-operated rats. Ischemia (30 min) was produced by unilateral carotid artery occlusion plus hemorrhagic hypotension to a mean arterial blood pressure of 30-35 mmHg to reduce ipsilateral cerebral blood flow by 70%. Pericranial temperature, arterial blood gases, and pH were maintained constant. Cerebral catecholamine and glutamate concentrations and plasma catecholamine concentrations were analyzed using high-performance liquid chromatography. Results During ischemia, dexmedetomidine suppressed circulating norepinephrine concentrations by 95% compared with control animals. In contrast, brain norepinephrine and glutamate concentrations were increased irrespective of dexmedetomidine infusion before ischemia. Conclusions The current data show that the increase of circulating catecholamine concentrations during cerebral ischemia was suppressed with dexmedetomidine. In contrast, dexmedetomidine does not suppress elevation in brain norepinephrine and glutamate concentration associated with cerebral ischemia. This suggests that the neuroprotective effects of dexmedetomidine are not related to inhibition of presynaptic norepinephrine or glutamate release in the brain.

Influence of propofol on neuronal damage and apoptotic factors after incomplete cerebral ischemia and reperfusion in rats: a long-term observation.

Abstract: BACKGROUND: Propofol reduces neuronal damage from cerebral ischemia when investigated for less than 8 postischemic days. This study investigates the long-term effects of propofol on neuronal damage and apoptosis-related proteins after cerebral ischemia and reperfusion. METHODS: Male Sprague-Dawley rats were randomly assigned as follows: group 1 (n = 32, control): fentanyl and nitrous oxide-oxygen; group 2 (n = 32, propofol): propofol and oxygen-air. Ischemia (45 min) was induced by carotid artery occlusion and hemorrhagic hypotension. Pericranial temperature and arterial blood gases were maintained constant. After 1, 3, 7, and 28 postischemic days, brains were removed, frozen, and sliced. Hippocampal eosinophilic cells were counted. The amount of apoptosis-related proteins Bax, p53, Bcl-2, and Mdm-2 and neurons positive for activated caspase-3 were analyzed. RESULTS: In propofol-anesthetized rats, no eosinophilic neurons were detected, whereas in control animals, 16-54% of hippocampal neurons were eosinophilic (days 1-28). In control animals, the concentration of Bax was 70-200% higher after cerebral ischemia compared with that in animals receiving propofol over time. Bcl-2 was 50% lower in control animals compared with propofol-anesthetized rats during the first 3 days. In both groups, a maximal 3% of the hippocampal neurons were positive for activated caspase-3. CONCLUSIONS: These data show sustained neuroprotection with propofol. This relates to reduced eosinophilic and apoptotic injury. Activated caspase-3-dependent apoptotic pathways were not affected by propofol. This suggests the presence of activated caspase-3-independent apoptotic pathways.

Impaired cerebrovascular autoregulation in patients with severe sepsis and sepsis-associated delirium

Abstract: Sepsis-associated delirium (SAD) increases morbidity in septic patients and, therefore, factors contributing to SAD should be further characterized. One possible mechanism might be the impairment of cerebrovascular autoregulation (AR) by sepsis, leading to cerebral hypo- or hyperperfusion in these haemodynamically unstable patients. Therefore, the present study investigates the relationship between the incidence of SAD and the status of AR during sepsis. Cerebral blood flow velocity was measured using transcranial Doppler sonography and was correlated with the invasive arterial blood pressure curve to calculate the index of AR Mx (Mx>0.3 indicates impaired AR). Mx was measured daily during the first 4 days of sepsis. Diagnosis of a SAD was performed using the confusion assessment method for ICU (CAM-ICU) and, furthermore the predominant brain electrical activity in electroencephalogram (EEG) both at day 4 after reduction of sedation to RASS >-2. 30 critically ill adult patients with severe sepsis or septic shock (APACHE II 32 ± 6) were included. AR was impaired at day 1 in 60%, day 2 in 59%, day 3 in 41% and day 4 in 46% of patients; SAD detected by CAM-ICU was present in 76 % of patients. Impaired AR at day 1 was associated with the incidence of SAD at day 4 (p = 0.035). AR is impaired in the great majority of patients with severe sepsis during the first two days. Impaired AR is associated with SAD, suggesting that dysfunction of AR is one of the trigger mechanisms contributing to the development of SAD. clinicalTrials.gov ID NCT01029080

Traumatic brain injury.

Abstract: In childhood, traumatic brain injury (TBI) poses the unique challenges of an injury to a developing brain and the dynamic pattern of recovery over time, inflicted TBI and its medicolegal ramifications. The mechanisms of injury vary with age, as do the mechanisms that lead to the primary brain injury. As it is common, and is the leading cause of death and disability in the USA and Canada, prevention is the key, and we may need increased legislation to facilitate this. Despite its prevalence, there is an almost urgent need for research to help guide the optimal management and improve outcomes. Indeed, contrary to common belief, children with severe TBI have a worse outcome and many of the consequences present in teenage years or later. The treatment needs, therefore, to be multifaceted and starts at the scene of the injury and extends into the home and school. In order to do this, the care needs to be multidisciplinary from specialists with a specific interest in TBI and to involve the family, and will often span many decades.

Oxidative stress and the amyloid beta peptide in Alzheimer's disease.

Abstract: Oxidative stress is known to play an important role in the pathogenesis of a number of diseases. In particular, it is linked to the etiology of Alzheimer's disease (AD), an age-related neurodegenerative disease and the most common cause of dementia in the elderly. Histopathological hallmarks of AD are intracellular neurofibrillary tangles and extracellular formation of senile plaques composed of the amyloid-beta peptide (Aβ) in aggregated form along with metal-ions such as copper, iron or zinc. Redox active metal ions, as for example copper, can catalyze the production of Reactive Oxygen Species (ROS) when bound to the amyloid-β (Aβ). The ROS thus produced, in particular the hydroxyl radical which is the most reactive one, may contribute to oxidative damage on both the Aβ peptide itself and on surrounding molecule (proteins, lipids, …). This review highlights the existing link between oxidative stress and AD, and the consequences towards the Aβ peptide and surrounding molecules in terms of oxidative damage. In addition, the implication of metal ions in AD, their interaction with the Aβ peptide and redox properties leading to ROS production are discussed, along with both in vitro and in vivo oxidation of the Aβ peptide, at the molecular level.

Neuroinflammation: the devil is in the details.

Abstract: There is significant interest in understanding inflammatory responses within the brain and spinal cord. Inflammatory responses that are centralized within the brain and spinal cord are generally referred to as 'neuroinflammatory'. Aspects of neuroinflammation vary within the context of disease, injury, infection, or stress. The context, course, and duration of these inflammatory responses are all critical aspects in the understanding of these processes and their corresponding physiological, biochemical, and behavioral consequences. Microglia, innate immune cells of the CNS, play key roles in mediating these neuroinflammatory responses. Because the connotation of neuroinflammation is inherently negative and maladaptive, the majority of research focus is on the pathological aspects of neuroinflammation. There are, however, several degrees of neuroinflammatory responses, some of which are positive. In many circumstances including CNS injury, there is a balance of inflammatory and intrinsic repair processes that influences functional recovery. In addition, there are several other examples where communication between the brain and immune system involves neuroinflammatory processes that are beneficial and adaptive. The purpose of this review is to distinguish different variations of neuroinflammation in a context-specific manner and detail both positive and negative aspects of neuroinflammatory processes. In this review, we will use brain and spinal cord injury, stress, aging, and other inflammatory events to illustrate the potential harm and benefits inherent to neuroinflammation. Context, course, and duration of the inflammation are highly important to the interpretation of these events, and we aim to provide insight into this by detailing several commonly studied insults. This article is part of the 60th anniversary supplemental issue.

Ketamine: teaching an old drug new tricks.

Abstract: K etamine has a special position among anesthetic drugs. It was introduced into clinical practice >30 yr ago with the hope that it would function as a “monoanesthetic” drug: inducing analgesia, amnesia, loss of consciousness, and immobility. This dream was not fulfilled because significant side effects were soon reported. With the introduction of other IV anesthetic drugs, ketamine’s role diminished rapidly. However, it is still used clinically for indications such as induction of anesthesia in patients in hemodynamic shock; induction of anesthesia in patients with active asthmatic disease; IM sedation of uncooperative patients, particularly children; supplementation of incomplete regional or local anesthesia; sedation in the intensive care setting; and short, painful procedures, such as dressing changes in burn patients. However, recent insights into ketamine’s anesthetic mechanism of action and its neuronal effects, as well as a reevaluation of its profound analgesic properties, offer the potential of expanding this range of indications. In addition, studies with the S(+) ketamine isomer suggest that its use may be associated with fewer side effects than the racemic mixture. In this article, we review the mechanism of action of ketamine anesthesia, the pharmacologic properties of its stereoisomers, and the potential uses of ketamine for preemptive analgesia and neuroprotection. Several aspects discussed herein have been reviewed previously (l-4).