RESUMO
BACKGROUND: Postdural puncture headache (PDPH) occurs in up to 11% of patients after spinal anesthesia and in more than 80% after dural perforation upon epidural anesthesia. It represents a severe anesthesiological complication in obstetric patients. If conservative medication measures do not result in a timely relief of symptoms, the current guidelines recommend the early implementation of an epidural blood patch; however, although performing an epidural blood patch is effective to treat PDPH, potential side effects include neurological complications, spinal hematoma and infections. Assumed to reduce cerebral vasodilatation as a potential pathophysiological driver of PDPH, the transnasal block of the sphenopalatine ganglion with local anesthetics is discussed as an alternative approach. METHODS: In this case study a modification of this technique is reported using a mucosal atomization device (MAD) for off-label nasal administration of lidocaine in two obstetric patients suffering from PDPH. Up to now there is no experience with this modified technique in obstetric anesthesiology. RESULTS: The first patient (25-year-old secundigravida, body mass index [BMI] 54.7â¯kg/m2) displayed a pronounced PDPH with nausea and vomiting during the first day after a cesarean section under spinal anesthesia (3 attempts). The second patient (32-year-old tertiagravida, BMI 27.3â¯kg/m2) was readmitted to hospital due to PDPH 4 days after a natural birth under epidural anesthesia. Whereas conservative measures and therapeutic attempts with nonopioid analgesics and caffeine did not result in a sufficient treatment success, intranasal lidocaine administration via a MAD led to an immediate and persisting symptom relief. Both patients could be discharged from hospital after 24â¯h of surveillance and did not report any relevant side effects of the lidocaine administration. CONCLUSION: The described noninvasive and simple procedure represents a valuable addition to previously known treatment options for PDPH and a potential alternative to an epidural blood patch in obstetric patients with PDPH. Prospective studies are needed to validate the findings.
Assuntos
Anestesiologia , Cefaleia Pós-Punção Dural , Administração Intranasal , Adulto , Placa de Sangue Epidural , Cesárea , Feminino , Humanos , Lidocaína , Cefaleia Pós-Punção Dural/terapia , GravidezRESUMO
OBJECTIVES: To determine the neuroprotective efficacy of the inert gas xenon following traumatic brain injury and to determine whether application of xenon has a clinically relevant therapeutic time window. DESIGN: Controlled animal study. SETTING: University research laboratory. SUBJECTS: Male C57BL/6N mice (n = 196). INTERVENTIONS: Seventy-five percent xenon, 50% xenon, or 30% xenon, with 25% oxygen (balance nitrogen) treatment following mechanical brain lesion by controlled cortical impact. MEASUREMENTS AND MAIN RESULTS: Outcome following trauma was measured using 1) functional neurologic outcome score, 2) histological measurement of contusion volume, and 3) analysis of locomotor function and gait. Our study shows that xenon treatment improves outcome following traumatic brain injury. Neurologic outcome scores were significantly (p < 0.05) better in xenon-treated groups in the early phase (24 hr) and up to 4 days after injury. Contusion volume was significantly (p < 0.05) reduced in the xenon-treated groups. Xenon treatment significantly (p < 0.05) reduced contusion volume when xenon was given 15 minutes after injury or when treatment was delayed 1 or 3 hours after injury. Neurologic outcome was significantly (p < 0.05) improved when xenon treatment was given 15 minutes or 1 hour after injury. Improvements in locomotor function (p < 0.05) were observed in the xenon-treated group, 1 month after trauma. CONCLUSIONS: These results show for the first time that xenon improves neurologic outcome and reduces contusion volume following traumatic brain injury in mice. In this model, xenon application has a therapeutic time window of up to at least 3 hours. These findings support the idea that xenon may be of benefit as a neuroprotective treatment in patients with brain trauma.
Assuntos
Lesões Encefálicas/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Xenônio/uso terapêutico , Administração por Inalação , Animais , Encéfalo/fisiopatologia , Lesões Encefálicas/fisiopatologia , Modelos Animais de Doenças , Marcha/fisiologia , Locomoção/fisiologia , Masculino , Camundongos Endogâmicos C57BL , Fármacos Neuroprotetores/administração & dosagem , Resultado do Tratamento , Xenônio/administração & dosagemRESUMO
OBJECTIVE: To determine the effect of peridural analgesia on long-term survival in patients who underwent surgical treatment of colorectal carcinoma. BACKGROUND: Clinical and animal studies suggest a potential benefit of peridural analgesia on morbidity and mortality after cancer surgery. The effect of peridural analgesia on long-term outcome after surgery for colorectal cancer remains undefined. METHODS: From 2003 to 2009, there were 749 patients who underwent surgery for colorectal carcinoma under general anesthesia with or without peridural analgesia. Clinical data were reviewed retrospectively and analyzed with multivariate analysis and Kaplan-Meier plots. RESULTS: There were 442 patients who received peridural analgesia and 307 patients who did not receive peridural analgesia. A substantial survival benefit was observed in patients who received peridural analgesia (5-year survival rate: peridural analgesia, 62%; no peridural analgesia, 54%; P < 0.02). The hazard rate for death was decreased by 27% in patients who received peridural analgesia. When peridural analgesia was included simultaneously in a Cox model with the confounding factors age, American Society of Anesthesiologists classification, and stage, there was a significant survival benefit in patients who received peridural analgesia. In patients with America Society of Anesthesiologists classification 3 to 4, there was significantly greater survival with peridural analgesia than without peridural analgesia (P < 0.009). CONCLUSIONS: Peridural analgesia may improve survival in patients underwent surgery for colorectal carcinoma. The survival benefit with peridural analgesia was greater in patients who had greater medical morbidity.
Assuntos
Analgesia Epidural/efeitos adversos , Carcinoma/mortalidade , Carcinoma/cirurgia , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/cirurgia , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Sistema de Registros , Estudos Retrospectivos , Taxa de Sobrevida , Fatores de TempoRESUMO
BACKGROUND: With modern intensive care medicine, even older patients and those with pre-existing conditions can survive critical illnesses and major operations; however, unreflected application of intensive care treatment might lead to a state called chronic critical illness. Today, withholding treatment and/or treatment withdrawal precede many deaths in the intensice care unit (ICU). We looked at changes in measures at the end of life and withholding or withdrawal of treatment in the ICU of a German tertiary hospital in 2017/2018 compared to 2011/2012. METHODS: In this retrospective explorative study, we analyzed end of life practices in adult patients who died in an intermediate care unit (IMC)/ICU of Klinikum Hanau in 2017/2018. We compared these data with data from the same hospital in 2011/2012 RESULTS: Of the 1246 adult patients who died in Klinikum Hanau in 2017/2018, 433 (35%) died in an ICU or IMC unit. Deceased ICU patients were 74.0⯱ 12.5 years and 86.6% were older than 60 years. At least one life-sustaining measure was withheld in 278 (76.2%) and withdrawn in 159 (46.3%) of patients. More than three quarters of patients (nâ¯= 276, 75.6%) had a do not resuscitate (DNR) order and in about half of the patients invasive ventilation (nâ¯= 175, 49.9%) or renal replacement therapy (nâ¯= 191, 52.3%) was limited. In 113 patients (31.0%) catecholamine treatment was withdrawn, in 72 (19.7%) patients invasive ventilation and in 49 (13.4%) patients renal replacement therapy. Compared to 2011/2012, we saw an increase by ~15% (absolute increase) in withholding and withdrawal of treatment and observed an effect of documents like advance directive or healthcare proxy. CONCLUSION: In 76.2% of deceased ICU patients withholding treatment and in 43.6% treatment withdrawal preceded death. Compared to 2011/2012 treatment was withheld or withdrawn more often. Compared to 2011/2012, we saw an increase (~15% absolute) in withholding and withdrawal of treatment. After withholding or withdrawal of treatment, most patients died within 3 and 2 days, respectively.
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Diretivas Antecipadas , Ordens quanto à Conduta (Ética Médica) , Humanos , Centros de Atenção Terciária , Estudos Retrospectivos , MorteRESUMO
Sepsis, a general inflammatory response to microbiological infection, is still a major cause of high mortality rates in intensive care units. This mortality rate strongly correlates with sepsis-induced impairment of organ blood supply as a consequence of disturbed capillary circulation and vascular leakage. Within this pathophysiological process, endothelial cell function plays a key role. Recent studies provide evidence that degradation of the glycocalix on the luminal cell membrane is an early step in septic vascular endothelial cell disorder and its shed compounds, such syndecan-1, heparan sulfate, intercellular-adhesion-molecule-1 (ICAM-1), and vascular-cell-adhesion-molecule-1 (VCAM-1), can be quantified in the plasma. The plasma concentrations of heparan sulfate and syndecan-1 strongly correlate with severity of sepsis and with inflammatory markers such as interleukin-6 (IL-6). Furthermore, a nonspecific deterioration of the glycocalix occurs during major abdominal surgery and during ischemia/reperfusion after vascular surgery. Both surgical treatments cause vascular leakage and, consequently, tissue edema, similar to that triggered by inflammatory impairment of the endothelial cell barrier. So far, no specific therapeutic strategies exist to maintain glycocalix integrity; hence, conserving endothelial function. Detection of glycocalix compounds in the plasma can be utilized as diagnostic markers to evaluate sepsis-induced endothelial damage and to estimate severity of sepsis. In the future, efforts will be made to prevent glycocalix damage during sepsis or major surgery. As a result, this will possibly preserve organ function and improve patient outcome.
Assuntos
Endotélio Vascular/metabolismo , Glicocálix/metabolismo , Sepse/metabolismo , HumanosRESUMO
BACKGROUND: Modern intensive care methods led to an increased survival of critically ill patients over the last decades. But an unreflected application of modern intensive care measures might lead to prolonged treatment for incurable diseases, and an inadaequate or too aggressive therapy can prolong the dying process of patients. In this study, we analysed end-of-life decisions regarding withholding and withdrawal of intensive care measures in a German intensive care unit (ICU) of a communal tertiary hospital. METHODS: Patient datasets of all adult patients dying in an ICU or an intermediate care unit (IMC) in a tertiary communal hospital (Klinikum Hanau, Germany) between 01.01.2011 and 31.12.2012 were analysed for withholding and withdrawal of intensive care measures. RESULTS: During the two-year period, 1317 adult patients died in Klinikum Hanau. Of these, 489 (37%) died either in an ICU/IMC unit. The majority of those deceased patients (n = 427, 87%) was 60 years or older. In 306 (62%) of 489 patients, at least one life-sustaining measure was withheld or withdrawn. In 297 (61%) of 489 patients dying in ICU/IMC, any type of therapy was withheld, and in 139 patients (28%), any type of therapy was withdrawn. Mostly, cardiopulmonary resuscitation (n = 427, 87%) was 60 years or older. In 306 (62%) of 489 patients, at least one life-sustaining measure was withheld or withdrawn. In 297 (61%) of 489 patients dying in ICU/IMC, any type of therapy was withheld, and in 139 patients (28%), any type of therapy was withdrawn. Mostly, cardiopulmonary resuscitation (n = 427, 87%) was 60 years or older. In 306 (62%) of 489 patients, at least one life-sustaining measure was withheld or withdrawn. In 297 (61%) of 489 patients dying in ICU/IMC, any type of therapy was withheld, and in 139 patients (28%), any type of therapy was withdrawn. Mostly, cardiopulmonary resuscitation (n = 427, 87%) was 60 years or older. In 306 (62%) of 489 patients, at least one life-sustaining measure was withheld or withdrawn. In 297 (61%) of 489 patients dying in ICU/IMC, any type of therapy was withheld, and in 139 patients (28%), any type of therapy was withdrawn. Mostly, cardiopulmonary resuscitation (n = 427, 87%) was 60 years or older. In 306 (62%) of 489 patients, at least one life-sustaining measure was withheld or withdrawn. In 297 (61%) of 489 patients dying in ICU/IMC, any type of therapy was withheld, and in 139 patients (28%), any type of therapy was withdrawn. Mostly, cardiopulmonary resuscitation (n = 427, 87%) was 60 years or older. In 306 (62%) of 489 patients, at least one life-sustaining measure was withheld or withdrawn. In 297 (61%) of 489 patients dying in ICU/IMC, any type of therapy was withheld, and in 139 patients (28%), any type of therapy was withdrawn. Mostly, cardiopulmonary resuscitation (. CONCLUSIONS: About one-third of patients dying in the hospital died in ICU/IMC. At least one life-sustaining therapy was limited/withdrawn in more than 60% of those patients. Withholding of a therapy was more common than active therapy withdrawal. Ventilation and renal replacement therapy were withdrawn in less than 5% of patients, respectively.
RESUMO
Hypoxia alters neuronal function and can lead to neuronal injury or death especially in the central nervous system. But little is known about the effects of hypoxia in neurones of the peripheral nervous system (PNS), which survive longer hypoxic periods. Additionally, people have experienced unpleasant sensations during ischemia which are dedicated to changes in conduction properties or changes in excitability in the PNS. However, the underlying ionic conductances in dorsal root ganglion (DRG) neurones have not been investigated in detail. Therefore we investigated the influence of moderate hypoxia (27.0 +/- 1.5 mmHg) on action potentials, excitability and ionic conductances of small neurones in a slice preparation of DRGs of young rats. The neurones responded within a few minutes non-uniformly to moderate hypoxia: changes of excitability could be assigned to decreased outward currents in most of the neurones (77%) whereas a smaller group (23%) displayed increased outward currents in Ringer solution. We were able to attribute most of the reduction in outward-current to a voltage-gated K+ current which activated at potentials positive to -50 mV and was sensitive to 50 nM alpha-dendrotoxin (DTX). Other toxins that inhibit subtypes of voltage gated K+ channels, such as margatoxin (MgTX), dendrotoxin-K (DTX-K), r-tityustoxin Kalpha (TsTX-K) and r-agitoxin (AgTX-2) failed to prevent the hypoxia induced reduction. Therefore we could not assign the hypoxia sensitive K+ current to one homomeric KV channel type in sensory neurones. Functionally this K+ current blockade might underlie the increased action potential (AP) duration in these neurones. Altogether these results, might explain the functional impairment of peripheral neurones under moderate hypoxia.
Assuntos
Gânglios Espinais/metabolismo , Hipóxia/metabolismo , Neurônios Aferentes/metabolismo , Sistema Nervoso Periférico/metabolismo , Canais de Potássio/metabolismo , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/fisiologia , Animais , Venenos Elapídicos/farmacologia , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/fisiopatologia , Hipóxia/fisiopatologia , Potenciais da Membrana/efeitos dos fármacos , Potenciais da Membrana/fisiologia , Neurônios Aferentes/efeitos dos fármacos , Técnicas de Cultura de Órgãos , Parestesia/etiologia , Parestesia/fisiopatologia , Sistema Nervoso Periférico/fisiopatologia , Bloqueadores dos Canais de Potássio/farmacologia , Canais de Potássio/efeitos dos fármacos , Ratos , Ratos WistarRESUMO
We investigated the effects of 2,2,2-trichloroethanol (TCE), the active metabolite of chloral hydrate, on large-conductance calcium-activated K+ channels (BKCa channels) of dorsal root ganglion (DRG) neurones. In outside-out patches, 2 and 5 mM TCE increased the open probability of BKCa channels to 1.7-fold and 2.8-fold of control, respectively. In 50% of the cells investigated (group A) the action potential (AP) was shortened reversibly by TCE by 20% and the whole-cell outward-current was increased by 44%. Both effects could be antagonized by iberiotoxin. In a second group of neurone (group B), TCE prolonged the AP duration. The effects of TCE in group A, which was 20-fold more potent than ethanol on BKCa channels and AP might contribute to the described analgesic effect of chloral hydrate.
Assuntos
Potenciais de Ação/efeitos dos fármacos , Anestésicos Intravenosos/farmacologia , Hidrato de Cloral/farmacologia , Etilenocloroidrina/análogos & derivados , Etilenocloroidrina/farmacologia , Gânglios Espinais/efeitos dos fármacos , Neurônios Aferentes/efeitos dos fármacos , Canais de Potássio Cálcio-Ativados/efeitos dos fármacos , Potenciais de Ação/fisiologia , Animais , Feminino , Gânglios Espinais/metabolismo , Lectinas , Masculino , Fibras Nervosas/efeitos dos fármacos , Fibras Nervosas/metabolismo , Neurônios Aferentes/metabolismo , Nociceptores/efeitos dos fármacos , Nociceptores/metabolismo , Técnicas de Cultura de Órgãos , Dor/tratamento farmacológico , Dor/metabolismo , Dor/fisiopatologia , Peptídeos/farmacologia , Canais de Potássio Cálcio-Ativados/metabolismo , Ratos , Ratos WistarAssuntos
Gânglios Espinais/metabolismo , Hipóxia/metabolismo , Neurônios Aferentes/metabolismo , Óxido Nítrico/biossíntese , Animais , Canais de Cálcio/metabolismo , Endotélio/enzimologia , Técnicas In Vitro , Isoenzimas/metabolismo , Camundongos , Mitocôndrias/metabolismo , Óxido Nítrico Sintase/metabolismo , Ratos , Frações Subcelulares/enzimologiaRESUMO
We have synthesized a novel analog of the general anesthetic etomidate in which the ethoxy group has been replaced by an azide group, and which can be used as a photolabel to identify etomidate binding sites. This acyl azide analog is a potent general anesthetic in both rats and tadpoles and, as with etomidate, is stereoselective in its actions, with the R(+) enantiomer being significantly more potent than the S(-) enantiomer. Its effects on alpha1beta2gamma2s GABA(A) receptors expressed in HEK-293 cells are virtually indistinguishable from the parent compound etomidate, showing stereoselective potentiation of GABA-induced currents, as well as direct mimetic effects at higher concentrations. In addition, a point mutation (beta2 N265M), which is known to attenuate the potentiating actions of etomidate, also blocks the effects of the acyl azide analog. We have investigated the utility of the analog to identify etomidate binding sites by using it to photolabel human serum albumin, a protein that binds approximately 75% of etomidate in human plasma and which is thought to play a major role in its pharmacokinetics. Using HPLC/mass spectrometry we have identified two anesthetic binding sites on HSA. One site is the well-characterized drug binding site I, located in HSA subdomain IIA, and the second site is also an established drug binding site located in subdomain IIIB, which also binds propofol. The acyl azide etomidate may prove to be a useful new photolabel to identify anesthetic binding sites on the GABA(A) receptor or other putative targets.
Assuntos
Anestésicos/farmacologia , Etomidato/análogos & derivados , Etomidato/farmacologia , Albumina Sérica/química , Animais , Azidas/farmacologia , Sítios de Ligação , Relação Dose-Resposta a Droga , Etomidato/química , Humanos , Masculino , Modelos Químicos , Ligação Proteica , Rana temporaria , Ratos , Ratos Sprague-Dawley , EstereoisomerismoRESUMO
Two-pore-domain potassium channels are a family of ion channels that are widely believed to play an important role in maintaining and regulating neuronal excitability. It has been shown that they can be modulated by an extraordinarily diverse range of endogenous and exogenous factors. One particular member of the family, TREK-1 (also known as KCNK2), is activated by increasing temperature, membrane stretch and internal acidosis, but is also sensitive to the presence of certain polyunsaturated fatty acids (such as arachidonic acid), neuroprotectants (such as riluzole) and volatile and gaseous general anaesthetics (such as halothane and nitrous oxide). It has recently been reported that TREK-1 channels are also affected by oxygen concentrations, and that at the levels of hypoxia that occur in the normal human brain, the channels greatly change their properties and, for example, lose their ability to be modulated by arachidonic acid and internal acidosis. These reports seriously challenge the idea that TREK-1 is a target for general anaesthetics and neuroprotectants. However, in this report we show that TREK-1 is not oxygen sensitive, and its ability to be activated by anaesthetics, arachidonic acid and internal acidosis remains unaltered under conditions of hypoxia. We further show that the protocol used by previous workers to prepare hypoxic solutions of arachidonic acid results in the removal of the compound from solution.
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Hipóxia/fisiopatologia , Canais de Potássio de Domínios Poros em Tandem/fisiologia , Acidose/fisiopatologia , Anestésicos Inalatórios/farmacologia , Ácido Araquidônico/farmacologia , Linhagem Celular , Eletrofisiologia , Halotano/farmacologia , Humanos , Concentração de Íons de Hidrogênio , Potenciais da Membrana/efeitos dos fármacos , Oxigênio/farmacologiaRESUMO
The "trace" elements copper and zinc are essential for life, and their role in the function of metalloproteins is well known. However, mounting evidence shows that these metals are also capable of modulating neuronal excitability under normal physiological conditions. They are present at high levels in the brain, are concentrated at nerve terminals, and are released at micromolar concentrations into the synaptic cleft after depolarization. They have been shown to affect the function of a number of different voltage- and ligand-gated ion channels, but their most important targets in the nervous system remain uncertain. In this study, we show that the two-pore-domain potassium channels TREK-1 and TASK-3 are potently modulated by both copper and zinc. Copper activates TREK-1 channels by 83 +/- 11% with an EC(50) of 3.0 +/- 1.0 microM, whereas TASK-3 channels are potently inhibited, with an IC(50) of 2.7 +/- 0.4 microM. Zinc inhibits both channels but with very different affinities. The IC(50) for inhibition of TREK-1 channels is 659 +/- 94 microM whereas the IC(50) for inhibition of TASK-3 is 12.7 +/- 1.0 microM. Using site-directed mutagenesis, we show that Asp128 plays a critical role in the copper activation of TREK-1. These observations provide a novel explanation for how copper and zinc might affect neuronal excitability under both normal physiological conditions, as well as during diseases in which copper or zinc homeostasis has been disrupted.
Assuntos
Cobre/farmacologia , Bloqueadores dos Canais de Potássio/farmacologia , Canais de Potássio de Domínios Poros em Tandem , Canais de Potássio/metabolismo , Zinco/farmacologia , Células Cultivadas , Humanos , Neurônios/efeitos dos fármacos , Neurônios/fisiologiaRESUMO
Nitrous oxide, xenon, and cyclopropane are anesthetic gases that have a distinct pharmacological profile. Whereas the molecular basis for their anesthetic actions remains unclear, they behave very differently to most other general anesthetics in that they have little or no effect on GABAA receptors, yet strongly inhibit the N-methyl-d-aspartate subtype of glutamate receptors. Here we show that certain members of the two-pore-domain K+ channel superfamily may represent an important new target for these gaseous anesthetics. TREK-1 is markedly activated by clinically relevant concentrations of nitrous oxide, xenon, and cyclopropane. In contrast, TASK-3, a member of this family that is very sensitive to volatile anesthetics, such as halothane, is insensitive to the anesthetic gases. We demonstrate that the C-terminal cytoplasmic domain is not an absolute requirement for the actions of the gases, although it clearly plays an important modulatory role. Finally, we show that Glu306, an amino acid that has previously been found to be important in the modulation of TREK-1 by arachidonic acid, membrane stretch and internal pH, is critical for the activating effects of the anesthetic gases.
Assuntos
Ciclopropanos/farmacologia , Sistemas de Liberação de Medicamentos/métodos , Óxido Nitroso/farmacologia , Canais de Potássio de Domínios Poros em Tandem , Canais de Potássio/metabolismo , Xenônio/farmacologia , Anestésicos Inalatórios/farmacologia , Relação Dose-Resposta a Droga , Humanos , Potenciais da Membrana/efeitos dos fármacos , Potenciais da Membrana/fisiologia , Canais de Potássio/agonistasRESUMO
Oxygen is pivotal for mammalian cell function, and recent studies suggest an involvement of NO in cellular adaptation to low oxygen supply. Here, we report that endothelial NO-synthase is ubiquitously expressed in rat and mice sensory neurons, and is targeted to juxtamitochondrial compartments of the ER. There it is activated in response to hypoxia while generation of reactive oxygen species remains unaltered. Developing a technique for ultrastructural localization of an NO-sensitive indicator allowed to identify the inner mitochondrial membrane as the target of NO under hypoxia. The demonstrated hypoxic stimulation of endothelial NOS in sensory neurons shall contribute to resistance against hypoxia, since NO promotes cellular survival by interfering with mitochondrial function.