[The disaster task force medical officer as a pivotal decision maker in the superordinate pandemic hospital capacity management : A field report covering the initial COVID-19 surge in a Bavarian district]. / Der Ärztliche Leiter Führungsgruppe Katastrophenschutz als zentrale Entscheidungsinstanz bei der Steuerung regionaler Krankenhauskapazitäten in der Pandemie : Ein Erfahrungsbericht zur ersten Welle der COVID-19-Pandemie in einem bayerischen Regierungsbezirk.

BACKGROUND AND OBJECTIVE: During the initial phase of the COVID-19 pandemic the government of the state of Bavaria, Germany, declared a state of emergency for its entire territory for the first time in history. Some areas in eastern Bavaria were among the most severely affected communities in Germany, prompting authorities and hospitals to build up capacities for a surge of COVID-19 patients. In some areas, intensive care unit (ICU) capacities were heavily engaged, which occasionally made a redistribution of patients necessary. MATERIAL AND METHODS: For managing COVID-19-related hospital capacities and patient allocation, crisis management squads in Bavaria were expanded by disaster task force medical officers ("Ärztlicher Leiter Führungsgruppe Katastrophenschutz" [MO]) with substantial executive authority. The authors report their experiences as MO concerning the superordinate patient allocation management in the district of Upper Palatinate (Oberpfalz) in eastern Bavaria. RESULTS: By abandoning routine patient care and building up additional ICU resources, surge capacity for the treatment of COVID-19 patients was generated in hospitals. In parts of the Oberpfalz, ICU capacities were almost entirely occupied by patients with corona virus infections, making reallocation to other hospitals within the district and beyond necessary. The MO managed patient pathways in an escalating manner by defining local (within the region of responsibility of a single MO), regional (within the district), and cross-regional (over district borders) reallocation lanes, as needed. When regional or cross-regional reallocation lanes had to be established, an additional management level located at the district government was involved. Within the determined reallocation lanes, emitting and receiving hospitals mutually agreed on any patient transfer without explicitly involving the MO, thereby maintaining the established interhospital routine transfer procedures. The number of patients and available treatment resources at each hospital were monitored with the help of a web-based treatment capacity registry. If indicated, reallocation lanes were dynamically revised according to the present situation. To oppose further virus spreading in nursing homes, the state government prohibited patient allocation to these facilities, which led to considerably longer hospital length of stay of convalescent elderly and/or dependent patients. In parallel to the flattening of the COVID-19 incidence curve, routine hospital patient care could be re-established in a stepwise manner. CONCLUSION: Patient allocation during the state of emergency by the MO sought to keep up routine interhospital reallocation procedures as much as possible, thereby reducing management time and effort. Occasionally, difficulties were observed during patient allocations crossing district borders, if other MO followed different management principles. The nursing home blockade and conflicting financial interests of hospitals posed challenges to the work of the disaster task force medical officers.

Etomidate and propylene glycol activate nociceptive TRP ion channels.

BACKGROUND: Etomidate is a preferred drug for the induction of general anesthesia in cardiovascular risk patients. As with propofol and other perioperatively used anesthetics, the application of aqueous etomidate formulations causes an intensive burning pain upon injection. Such algogenic properties of etomidate have been attributed to the solubilizer propylene glycol which represents 35% of the solution administered clinically. The aim of this study was to investigate the underlying molecular mechanisms which lead to injection pain of aqueous etomidate formulations. RESULTS: Activation of the nociceptive transient receptor potential (TRP) ion channels TRPA1 and TRPV1 was studied in a transfected HEK293t cell line by whole-cell voltage clamp recordings of induced inward ion currents. Calcium influx in sensory neurons of wild-type and trp knockout mice was ratiometrically measured by Fura2-AM staining. Stimulated calcitonin gene-related peptide release from mouse sciatic nerves was detected by enzyme immunoassay. Painfulness of different etomidate formulations was tested in a translational human pain model. Etomidate as well as propylene glycol proved to be effective agonists of TRPA1 and TRPV1 ion channels at clinically relevant concentrations. Etomidate consistently activated TRPA1, but there was also evidence for a contribution of TRPV1 in dependence of drug concentration ranges and species specificities. Distinct N-terminal cysteine and lysine residues seemed to mediate gating of TRPA1, although the electrophile scavenger N-acetyl-L-cysteine did not prevent its activation by etomidate. Propylene glycol-induced activation of TRPA1 and TRPV1 appeared independent of the concomitant high osmolarity. Intradermal injections of etomidate as well as propylene glycol evoked severe burning pain in the human pain model that was absent with emulsification of etomidate. CONCLUSIONS: Data in our study provided evidence that pain upon injection of clinical aqueous etomidate formulations is not an unspecific effect of hyperosmolarity but rather due to a specific action mediated by activated nociceptive TRPA1 and TRPV1 ion channels in sensory neurons.

Irritant volatile anesthetics induce neurogenic inflammation through TRPA1 and TRPV1 channels in the isolated mouse trachea.

BACKGROUND: Irritating effects of volatile general anesthetics on tracheal nerve endings and resulting spastic reflexes in the airways are not completely understood with respect to molecular mechanisms. Neuropeptide release and neurogenic inflammation play an established role. METHODS: The basal and stimulated calcitonin gene-related peptide (CGRP) release from the isolated superfused mouse trachea was analyzed as an index of sensory neuron activation, applying irritant (desflurane and isoflurane) and nonirritant (sevoflurane) volatile anesthetics as stimuli. Various gas concentrations (0.5-, 1-, or 2-fold minimum alveolar concentration [MAC]) and different O2 atmospheres were used for tracheal stimulation at 38°C. Null mutants of the capsaicin receptor TRPV1 and of the chemoreceptor TRPA1, as well as double knockout mice, were used as tissue donors. RESULTS: Desflurane and, less so, isoflurane caused a concentration-dependent tracheal CGRP release, both saturating at 1 MAC (human), that is, 6% and 1.25%, respectively. With desflurane, the O2 concentration (25% or 94%) did not make a difference. Sevoflurane 1 MAC did not activate tracheal CGRP release. TRPV1 mice showed 75% reduced desflurane responses, and TRPA1 and double-null mutants showed no responses at all. CONCLUSIONS: Our results confirm the clinical experience that desflurane is more irritating than isoflurane at equal anesthetic gas concentration, whereas sevoflurane does not activate tracheobronchial sensory nerves to release neuropeptides and induce neurogenic inflammation. Both irritant receptor channels, TRPA1 more than TRPV1, are involved in mediating the adverse effects that may even extend to systemic proinflammatory sequelae.

Local anesthetic-like inhibition of voltage-gated Na(+) channels by the partial µ-opioid receptor agonist buprenorphine.

BACKGROUND: Opioids induce analgesia mainly by inhibiting synaptic transmission via G protein-coupled opioid receptors. In addition to analgesia, buprenorphine induces a pronounced antihyperalgesia and is an effective adjuvant to local anesthetics. These properties only partially apply to other opioids, and thus targets other than opioid receptors are likely to be employed. Here we asked if buprenorphine inhibits voltage-gated Na(+) channels. METHODS: Na(+) currents were examined by whole cell patch clamp recordings on different recombinant Na(+) channel α-subunits. The effect of buprenorphine on unmyelinated mouse C-fibers was examined with the skin-nerve preparation. Data are presented as mean ± SEM. RESULTS: Buprenorphine induced a concentration-dependent tonic (IC(50) 33 ± 2 µM) and use-dependent block of endogenous Na(+) channels in ND7/23 cells. This block was state-dependent and displayed slow on and off characteristics. The effect of buprenorphine was reduced on local anesthetic insensitive Nav1.4-mutant constructs and was more pronounced on the inactivation-deficient Nav1.4-WCW mutant. Neuronal (Nav1.3, Nav1.7, and Nav1.8), cardiac (Nav1.5), and skeletal muscle (Nav1.4) α-subunits displayed small differences in tonic block, but similar degrees of use-dependent block. According to our patch clamp data, buprenorphine blocked electrically evoked action potentials in C-fiber nerve terminals. Buprenorphine was more potent than other opioids, including morphine (IC(50) 378 ± 20 µM), fentanyl (IC(50) 95 ± 5 µM), sufentanil (IC(50) 111 ± 6 µM), remifenatil (IC(50) 612 ± 17 µM), and tramadol (IC(50) 194 ± 9 µM). CONCLUSIONS: Buprenorphine is a potent local anesthetic and blocks voltage-gated Na(+) channels via the local anesthetic binding site. This property is likely to be relevant when buprenorphine is used for pain treatment and for local anesthesia.

Activation of TRPA1 by membrane permeable local anesthetics.

BACKGROUND: Low concentrations of local anesthetics (LAs) suppress cellular excitability by inhibiting voltage-gated Na⁺ channels. In contrast, LAs at high concentrations can be excitatory and neurotoxic. We recently demonstrated that LA-evoked activation of sensory neurons is mediated by the capsaicin receptor TRPV1, and, to a lesser extent by the irritant receptor TRPA1. LA-induced activation and sensitization of TRPV1 involves a domain that is similar, but not identical to the vanilloid-binding domain. Additionally, activation of TRPV1 by LAs involves PLC and PI(4,5)P2-signalling. In the present study we aimed to characterize essential structural determinants for LA-evoked activation of TRPA1. RESULTS: Recombinant rodent and human TRPA1 were expressed in HEK293t cells and investigated by means of whole-cell patch clamp recordings. The LA lidocaine activates TRPA1 in a concentration-dependent manner. The membrane impermeable lidocaine-derivative QX-314 is inactive when applied extracellularly. Lidocaine-activated TRPA1-currents are blocked by the TRPA1-antagonist HC-030031. Lidocaine is also an inhibitor of TRPA1, an effect that is more obvious in rodent than in human TRPA1. This species-specific difference is linked to the pore region (transmembrane domain 5 and 6) as described for activation of TRPA1 by menthol. Unlike menthol-sensitivity however, lidocaine-sensitivity is not similarly determined by serine- and threonine-residues within TM5. Instead, intracellular cysteine residues known to be covalently bound by reactive TRPA1-agonists seem to mediate activation of TRPA1 by LAs. CONCLUSIONS: The structural determinants involved in activation of TRPA1 by LAs are disparate from those involved in activation by menthol or those involved in activation of TRPV1 by LAs.

TRPA1 and substance P mediate colitis in mice.

BACKGROUND & AIMS: The neuropeptides calcitonin gene-related peptide (CGRP) and substance P, and calcium channels, which control their release from extrinsic sensory neurons, have important roles in experimental colitis. We investigated the mechanisms of colitis in 2 different models, the involvement of the irritant receptor transient receptor potential of the ankyrin type-1 (TRPA1), and the effects of CGRP and substance P. METHODS: We used calcium-imaging, patch-clamp, and neuropeptide-release assays to evaluate the effects of 2,4,6-trinitrobenzene-sulfonic-acid (TNBS) and dextran-sulfate-sodium-salt on neurons. Colitis was induced in wild-type, knockout, and desensitized mice. RESULTS: TNBS induced TRPA1-dependent release of colonic substance P and CGRP, influx of Ca2+, and sustained ionic inward currents in colonic sensory neurons and transfected HEK293t cells. Analysis of mutant forms of TRPA1 revealed that TNBS bound covalently to cysteine (and lysine) residues in the cytoplasmic N-terminus. A stable sulfinic acid transformation of the cysteine-SH group, shown by mass spectrometry, might contribute to sustained sensitization of TRPA1. Mice with colitis had increased colonic neuropeptide release, mediated by TRPA1. Endogenous products of inflammatory lipid peroxidation also induced TRPA1-dependent release of colonic neuropeptides; levels of 4-hydroxy-trans-2-nonenal increased in each model of colitis. Colitis induction by TNBS or dextran-sulfate-sodium-salt was inhibited or reduced in TRPA1-/- mice and by 2-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl)-N-(4-isopro-pylphenyl)-acetamide, a pharmacologic inhibitor of TRPA1. Substance P had a proinflammatory effect that was dominant over CGRP, based on studies of knockout mice. Ablation of extrinsic sensory neurons prevented or attenuated TNBS-induced release of neuropeptides and both forms of colitis. CONCLUSIONS: Neuroimmune interactions control intestinal inflammation. Activation and sensitization of TRPA1 and release of substance P induce and maintain colitis in mice.

The general anesthetic propofol excites nociceptors by activating TRPV1 and TRPA1 rather than GABAA receptors.

Anesthetic agents can induce a paradox activation and sensitization of nociceptive sensory neurons and, thus, potentially facilitate pain processing. Here we identify distinct molecular mechanisms that mediate an activation of sensory neurons by 2,6-diisopropylphenol (propofol), a commonly used intravenous anesthetic known to elicit intense pain upon injection. Clinically relevant concentrations of propofol activated the recombinant transient receptor potential (TRP) receptors TRPA1 and TRPV1 heterologously expressed in HEK293t cells. In dorsal root ganglion (DRG) neurons, propofol-induced activation correlated better to expression of TRPA1 than of TRPV1. However, pretreatment with the protein kinase C activator 4ß-phorbol 12-myristate 13-acetate (PMA) resulted in a significantly sensitized propofol-induced activation of TRPV1 in DRG neurons as well as in HEK293t cells. Pharmacological and genetic silencing of both TRPA1 and TRPV1 only partially abrogated propofol-induced responses in DRG neurons. The remaining propofol-induced activation was abolished by the selective γ-aminobutyric acid, type A (GABA(A)) receptor antagonist picrotoxin. Propofol but not GABA evokes a release of calcitonin gene-related peptide, a key component of neurogenic inflammation, from isolated peripheral nerves of wild-type but not TRPV1 and TRPA1-deficient mice. Moreover, propofol but not GABA induced an intense pain upon intracutaneous injection. As both the release of calcitonin gene-related peptide and injection pain by propofol seem to be independent of GABA(A) receptors, our data identify TRPV1 and TRPA1 as key molecules for propofol-induced excitation of sensory neurons. This study warrants further investigations into the role of anesthetics to induce nociceptor sensitization and to foster postoperative pain.