Prof. dr. M. Hollmann
Academisch Medisch Centrum, Anesthesiologie, Amsterdam
Nederland
Focus of Research
- Effects of anesthetics on intracellular signaling transduction, especially Local Anesthetic interactions with G protein coupled receptor signaling
- Modulation of NMDA receptor signaling
- Ketamine & Magnesium in pain therapy
- Clinical "alternative" effects of Local Anesthetics, especially modulation of inflammatory and hemostatic responses, effects on gastro-intestinal motility, cognitive function, bronchial hyperreactivity and wound healing
Research Interests:
1. Anesthetics & Intracellular Signaltransduction
Effects of different anesthetics (local anesthetics, volatile anesthetics, ketamine) on G protein-coupled receptor (GPCR) and glutamate (e.g. NMDA receptor) signaling with special emphasis on less known properties (so called “alternative” effects) of local anesthetics (e.g. anti-inflammatory, anti-thrombotic, anti-hyperalgesic, neuroprotective actions) and their underlying mechanisms. In a translational approach these effects were studied from a very basic level, e.g. anesthetic interactions with specific G protein subunits (in a completely reconstituted system – baculovirus vector expression in Sf9 insect cells), via recombinant expression systems (Xenopus oocytes) and human polymorphonuclear cells to the clinical setting. Most likely based on their modulatory action on inflammation and coagulation, local anesthetics when applied continuous intravenously in the perioperative period were shown to improve outcome.
2. Pharmacological Cardioprotection
This is one the key aspects of research activities at L.E.I.C.A. Cardioprotective actions of anesthetics (e.g. volatile anesthetics, opiates) are evaluated under various experimental conditions for their effectiveness and mechanisms of action.
3. Pharmacological Modulation of transalveolar Ion transport
These projects are performed in collaboration with the Departments of Anesthesiology and Sports Medicine at the University of Heidelberg, Germany. The effects of different anesthetics (e.g. ketamine) on transalveolar ion transport and fluid shift in various experimental models is investigated. Detailed mechanisms of action and involvement of epithelial sodium channels (ENac) will be determined.
4. Pathophysiology and Treatment of Cerebral Air Embolism
Gas embolism, defined as the entry of gas into vascular structures, can occur in many clinical environments as an iatrogenic complication and in diving medicine. In most cases gas embolism is in fact an air embolism, although the medical use of other gases (such as carbon dioxide) can also result in this condition. Air bubbles may reach any organ, but their effect on the cerebral and cardiac circulation is particularly deleterious because these organs are highly vulnerable for hypoxia. In a clinical situation most venous gas emboli occur in patients in whom a central venous catheter has been placed. The greatest risks for arterial gas embolism occur with cardiac surgery with cardiopulmonary bypass, craniotomy performed with the patients in the sitting position, and hip replacement procedures. Hyperbaric oxygen therapy has been advocated as a therapy for gas embolism, whereby the patient breathes 100% oxygen at a pressure above that of the atmosphere at sea level. The increased ambient pressure (decreases the size of the gas bubbles) and the resulting systemic hyperoxia improves oxygenation of hypoxic tissue. Questions have been raised about the effect of HBO therapy in relation to timing of treatment. Most investigators agree, however, that early, rather than late, treatment is most appropriate for air embolism. Unfortunately, data supporting this statement are more anecdotal than scientific. Animal studies reported that lidocaine reduces brain infarct size, preserves cerebral blood flow, reduces cerebral edema and preserves neuro-electrical function. These results in brain-injured animals showed that lidocaine improves cerebral function. In close cooperation with the Diving Medical Center , Royal Netherlands Navy, we study lidocaine as a brain protective drug and the use of hyperbaric oxygen therapy, in particular different time delays before treatment. We use a validated animal model of cerebral air embolism. We employ microsensor technology to measure brain oxygenation and intracranial pressure combined with a microdialysis technique to measure brain glucose and lactate levels.
5. Molecular Mechanisms of neurotoxicity of anesthetics
Toxic effects of local and general anesthetics were evaluated in different human cell culture models. The apoptotic pathways of different local anesthetics and various general anesthetics (ketamine, midazolam, propofol) were elucidated in neuronal (SHEP) and lymphoma (Jurkat) cells. Llocal anesthetic in clinical concentrations induce apoptosis via the mitochondrial pathway (protected by Bcl 2 overexpression and Caspase 9 deficiency) independently of the death-receptor pathway (FADD and Caspase 8 deficiency).