Papers by Robert Werdehausen
Anesthesiology, 2015
Impaired cardiac repolarization, indicated by prolonged QT interval, may cause critical ventricul... more Impaired cardiac repolarization, indicated by prolonged QT interval, may cause critical ventricular arrhythmias. Many anesthetics increase the QT interval by blockade of rapidly acting potassium rectifier channels. Although xenon does not affect these channels in isolated cardiomyocytes, the authors hypothesized that xenon increases the QT interval by direct and/or indirect sympathomimetic effects. Thus, the authors tested the hypothesis that xenon alters the heart rate-corrected cardiac QT (QTc) interval in anesthetic concentrations. The effect of xenon on the QTc interval was evaluated in eight healthy volunteers and in 35 patients undergoing abdominal or trauma surgery. The QTc interval was recorded on subjects in awake state, after their denitrogenation, and during xenon monoanesthesia (FetXe > 0.65). In patients, the QTc interval was recorded while awake, after anesthesia induction with propofol and remifentanil, and during steady state of xenon/remifentanil anesthesia (FetXe > 0.65). The QTc interval was determined from three consecutive cardiac intervals on electrocardiogram printouts in a blinded manner and corrected with Bazett formula. In healthy volunteers, xenon did not alter the QTc interval (mean difference: +0.11 ms [95% CI, -22.4 to 22.7]). In patients, after anesthesia induction with propofol/remifentanil, no alteration of QTc interval was noted. After propofol was replaced with xenon, the QTc interval remained unaffected (417 ± 32 ms vs. awake: 414 ± 25 ms) with a mean difference of 4.4 ms (95% CI, -4.6 to 13.5). Xenon monoanesthesia in healthy volunteers and xenon/remifentanil anesthesia in patients without clinically relevant cardiovascular disease do not increase QTc interval.
Regional Anesthesia and Pain Medicine, 2007
ABSTRACT
European Journal of Anaesthesiology, 2013
ABSTRACT Background and Goal of study: Xenon (Xe) anaesthesia is associated with stable blood pre... more ABSTRACT Background and Goal of study: Xenon (Xe) anaesthesia is associated with stable blood pressure and rapid recovery from general anaesthesia. Thus, it appears favourable to apply Xe‐based anaesthesia in patients at cardiovascular risk, e.g., during carotid endarterectomy. However, volatile anaesthetics frequently interfere with routine neuromonitoring, like somatosensory evoked potentials (SSEP). Thus, we test the hypothesis that SSEP amplitude and latency were not altered during Xe anaesthesia in patients prior to carotid endarterectomy.Material and methods: Following IRB‐approval, general anesthesia was induced in 20 unpremedicated patients by intravenous propofol (Prop)/ remifentanil and rocuronium. Patients were intubated and mechanically ventilated (FiO2 0.35) to normocapnia. Invasive arterial pressure, heart rate, and Narcotrend® depth of anaesthesia were continuously recorded. Arterial pressure was maintained by titration of intravenous norepinephrine. Median nerve SSEP amplitudes and latencies were repeatedly assessed over both hemispheres. Following recording of reference values during Prop, Xe was administered targeting end‐tidal 60% in oxygen. Values during Xe were compared to Prop prior to surgical stimulation. Statistics: Mean ±SD, Student's t‐test, P< 0.05.Results and Discussion: Mean arterial pressure (Prop 91 mmHg ±15; Xe 93±10), heart rate (Prop 57 min‐1 ±12; Xe 54±13), and anesthetic depth (Prop 38±6; Xe 38±6) did not differ between groups. Intravenous norepinephrine demand was significant larger during Prop (Prop: 0.067 μg kg‐1 min‐1 ± 0.042 Xe: 0,028 ± 0.021; P< 0.001). SSEP amplitudes were decreased by Xe (Prop: 3.6 μV ±1.7; Xe: 1.4±0.7; P< 0.001), while SSEP latencies were not altered (Prop: 22.9 ms ±2; Xe: 22.6±2.9; P=0.49) A too low SSEP amplitude during Xe anaesthesia rendered SSEP monitoring impossible in one case, which had a baseline amplitude during Prop below 0.5 μV.Conclusion: Anaesthetic concentrations of Xe decrease SSEP amplitude to 43 percent of baseline while SSEP latencies remain unaltered, thus preserving the value of SSEP monitoring as a tool for guiding surgical strategy.
Anesthesiology, 2012
Background: Lidocaine exerts antinociceptive effects when applied systemically. The mechanisms ar... more Background: Lidocaine exerts antinociceptive effects when applied systemically. The mechanisms are not fully understood but glycinergic mechanisms might be involved. The synaptic glycine concentration is controlled by glycine transporters. Whereas neurons express two types of glycine transporters, astrocytes specifically express glycine transporter 1 (GlyT1). This study focuses on effects of lidocaine and its major metabolites on GlyT1 function. Methods: The effects of lidocaine and its metabolites monoethylglycinexylidide (MEGX), glycinexylidide, and N-ethylglycine on GlyT1 function were investigated in uptake experiments with [ 14 C]-labeled glycine in primary rat astrocytes. Furthermore, the effect of lidocaine and its metabolites on glycine-induced currents were investigated in GlyT1-expressing Xenopus laevis oocytes. Results: Lidocaine reduced glycine uptake only at toxic concentrations. The metabolites MEGX, glycinexylidide, and N-ethylglycine, however, significantly reduced glycine uptake (P Ͻ 0.05). Inhibition of glycine uptake by a combination of lidocaine with its metabolites at a clinically relevant concentration was diminished with increasing extracellular glycine concentrations. Detailed analysis revealed that MEGX inhibits GlyT1 function (P Ͻ 0.05), whereas Nethylglycine was identified as an alternative GlyT1 substrate (EC 50 ϭ 55 M). Conclusions: Although lidocaine does not function directly on GlyT1, its metabolites MEGX and glycinexylidide were shown to inhibit GlyT1-mediated glycine uptake by at least two different mechanisms. Whereas glycinexylidide was demonstrated to be an alternative GlyT1 substrate, MEGX was shown to inhibit GlyT1 activity in both primary astrocytes and in GlyT1-expressing Xenopus laevis oocytes at clinically relevant concentrations. These findings provide new insights into the possible mechanisms for the antinociceptive effect of systemic lidocaine.
European Journal of Anaesthesiology, 2011
British journal of pharmacology, 2014
The non-selective sodium channel inhibitor mexiletine has been found to be effective in several a... more The non-selective sodium channel inhibitor mexiletine has been found to be effective in several animal models of chronic pain and has become popular in the clinical setting as an orally available alternative to lidocaine. It remains unclear why patients with monogenic pain disorders secondary to gain-of-function SCN9a mutations benefit from a low systemic concentration of mexiletine, which does not usually induce adverse neurological side effects. The aim of this study was, therefore, to investigate the biophysical effects of mexiletine on the L858F primary erythromelalgia NaV 1.7 mutation in vitro. Human wild-type and L858F-mutated NaV 1.7 channels were expressed in HEK293A cells. Whole-cell currents were recorded by voltage-clamp techniques to characterize the effect of mexiletine on channel gating properties. While the concentration-dependent tonic block of peak currents by mexiletine was similar in wild-type and L858F channels, phasic block was more pronounced in cells transfect...
PloS one, 2015
The Nav1.7 voltage-gated sodium channel, encoded by SCN9A, is critical for human pain perception ... more The Nav1.7 voltage-gated sodium channel, encoded by SCN9A, is critical for human pain perception yet the transcriptional and post-transcriptional mechanisms that regulate this gene are still incompletely understood. Here, we describe a novel natural antisense transcript (NAT) for SCN9A that is conserved in humans and mice. The NAT has a similar tissue expression pattern to the sense gene and is alternatively spliced within dorsal root ganglia. The human and mouse NATs exist in cis with the sense gene in a tail-to-tail orientation and both share sequences that are complementary to the terminal exon of SCN9A/Scn9a. Overexpression analyses of the human NAT in human embryonic kidney (HEK293A) and human neuroblastoma (SH-SY5Y) cell lines show that it can function to downregulate Nav1.7 mRNA, protein levels and currents. The NAT may play an important role in regulating human pain thresholds and is a potential candidate gene for individuals with chronic pain disorders that map to the SCN9A...
Brain, 2012
à These authors contributed equally to this work.
Neuroscience letters, Jan 20, 2015
Glycinergic inhibitory neurotransmission plays a pivotal role in the development of neuropathic p... more Glycinergic inhibitory neurotransmission plays a pivotal role in the development of neuropathic pain. The glycine concentration in the synaptic cleft is controlled by the glycine transporters GlyT1 and GlyT2. GlyT1 is expressed throughout the central nervous system, while GlyT2 is exclusively located in glycinergic neurons. Aim of the present study was to investigate whether GlyTs are also expressed in the peripheral sensory nervous system and whether their expression is modulated in experimental neuropathic pain. Neuropathic pain was induced in male Wistar rats by Chronic Constriction Injury (CCI) and verified by assessment of mechanical allodynia (von Frey method). Expression patterns of GlyTs and the glycine binding subunit NR1 of the N-methyl-d-aspartate (NMDA) receptor in the spinal cord and dorsal root ganglia (DRG) were analyzed by Western blot analysis, PCR and immunohistochemistry. While both GlyT1 and GlyT2 were detected in the spinal cord, only GlyT1, but not GlyT2, was d...
Molecular pain, 2015
MicroRNAs (miRNAs) are involved in the neuroplastic changes which induce and maintain neuropathic... more MicroRNAs (miRNAs) are involved in the neuroplastic changes which induce and maintain neuropathic pain. However, it is unknown whether nerve injury leads to altered miRNA expression and modulation of pain relevant target gene expression within peripheral nerves. In the present study, expression profiles of miR-1 and the pain-relevant targets, brain derived neurotrophic factor (BDNF) and Connexin 43 (Cx43), were studied in peripheral neuropathic pain, which was induced by chronic constriction injury (CCI) of the sciatic nerve in rats. The expression of miR-1 was investigated in the sciatic nerve, dorsal root ganglion (DRG) and the ipsilateral spinal cord by qPCR. Changes of BDNF and Cx43 expression patterns were studied using qPCR, Western blot analysis, ELISA and immunohistochemistry. In sciatic nerves of naïve rats, expression levels of miR-1 were more than twice as high as in DRG and spinal cord. In neuropathic rats, CCI lead to a time-dependent downregulation of miR-1 in the scia...
PAIN, 2015
Glycine transporter 1 (GlyT1) plays a crucial role in regulating extracellular glycine concentrat... more Glycine transporter 1 (GlyT1) plays a crucial role in regulating extracellular glycine concentrations and might thereby constitute a new drug target for the modulation of glycinergic inhibition in pain signaling. Consistently with this view, inhibition of GlyT1 has been found to induce antinociceptive effects in various animal pain models. We have shown previously that the lidocaine metabolite N-ethylglycine (EG) reduces GlyT1-dependent glycine uptake by functioning as an artificial substrate for this transporter. Here we show that EG is specific for GlyT1 and that in rodent models of inflammatory and neuropathic pain, systemic treatment with EG results in an efficient amelioration of hyperalgesia and allodynia without affecting acute pain. There was no effect on motor coordination or the development of inflammatory edema. No adverse neurologic effects were observed following repeated high-dose application of EG.EG concentrations both, in blood and spinal fluid, correlated with an increase of glycine concentration in spinal fluid. The time courses of the EG and glycine concentrations corresponded well with the antinociceptive effect. Additionally, we found that EG reduced the increase in neuronal firing of wide-dynamic-range neurons caused by inflammatory pain induction. These findings suggest that systemically applied lidocaine exerts antihyperalgesic effects via its metabolite EG in vivo, by enhancing spinal inhibition of pain processing through GlyT1 modulation and subsequent increase of glycine concentrations at glycinergic inhibitory synapses. EG and other substrates of GlyT1, therefore, may be a useful therapeutic agent in chronic pain states involving spinal disinhibition.This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Neuroscience, Jan 31, 2009
It has been proposed that alterations in spinal inhibitory neurotransmission are critically invol... more It has been proposed that alterations in spinal inhibitory neurotransmission are critically involved in the pathophysiology of neuropathic pain. The mechanisms by which a relief from inhibitory tone contributes to pathological pain are not fully understood. Hitherto it is still under debate whether there is a loss of inhibitory neurons in the spinal cord in neuropathic pain. The aim of the present study was to evaluate whether a specific loss of glycinergic neurons is necessary to develop hyperalgesia and allodynia in the chronic constriction injury (CCI) model of neuropathic pain. The experiments were performed in bacterial artificial chromosome (BAC) transgenic mice which specifically express enhanced green fluorescent protein under the control of the promotor of the glycine transporter 2 gene, which is a reliable marker for glycinergic neurons. Thus, possible technical inconsistencies due to immunoreactivity in fixed tissues could be ruled out. Twelve days after CCI, in neuropath...
Regional anesthesia and pain medicine
Stimulating catheters have been introduced into clinical practice to confirm perineural localizat... more Stimulating catheters have been introduced into clinical practice to confirm perineural localization of the catheters. The muscular twitch induced over the catheter may be used to evaluate nerve function intraoperatively. Therefore, the function of the sciatic nerve was evaluated during major cancer surgery of the femur. A 7-year-old boy (29 kg) was scheduled for hip rotationplasty for resection of an osteosarcoma of the left femur under general anesthesia and postoperative pain therapy with an epidural stimulating catheter. In hip rotationplasty the femur is resected, the lower limb and foot are rotated 180 degrees and the tibia plateau is attached to the pelvic acetabulum to form a new hip joint. During preparation of the left thigh and the sciatic nerve, motor responses to stimulation of the catheter were preserved, but the stimulation threshold increased. After vascular anastomosis the foot remained cold, therefore ropivacaine was applied epidurally and subsequently a warming of...
Regional anesthesia and pain medicine
Skin-temperature increase is a reliable but late indicator of success during regional-anesthesia ... more Skin-temperature increase is a reliable but late indicator of success during regional-anesthesia techniques. The goal of this study is to determine the distribution of skin-temperature changes during different regional techniques. Does skin temperature increase in the whole area innervated by the blocked neural structures or only in certain regions within this area with the capability to react preferentially to sympathetic block (i.e., vessel-rich skin)? Although onset time may vary between different regional-anesthetic techniques, we hypothesized that the distribution of skin warming is equal. Skin temperature was assessed continuously by infrared thermography in 24 patients who received either combined femoral-nerve and sciatic-nerve block, epidural anesthesia, or spinal anesthesia. Apart from differences in time of onset, no differential spatial distribution of skin-temperature changes could be detected. The earliest and greatest rise of skin temperature occurred at the great toe...
Regional Anesthesia and Pain Medicine, 2011
Background: Neurotoxic properties of local anesthetics can rarely lead to irreversible neuronal d... more Background: Neurotoxic properties of local anesthetics can rarely lead to irreversible neuronal damage as in cauda equina syndrome. Clinically, local anesthetics are often combined with adjuvants to improve or prolong the anesthetic effect, whereas the impact of such adjuvants on lidocaineinduced apoptosis is unclear. Therefore, we investigated the influence of different adjuvants on the neurotoxicity of lidocaine.
Background: In contrast to most common general anesthetics xenon anesthesia does not decrease sys... more Background: In contrast to most common general anesthetics xenon anesthesia does not decrease systemic vascular resistance and cardiac output [1]. Although the observed hemodynamic stability is associated with unchanged sympathetic outflow to muscle, ...
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Papers by Robert Werdehausen