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BACKGROUND: Body composition parameters provide relevant prognostic significance in critical care cohorts and cancer populations. Published results regarding polytrauma patients are inconclusive to date. The goal of this study was to analyse the role of body composition parameters in severely injured trauma patients. METHODS: All consecutive patients requiring emergency tracheal intubation and mechanical ventilation before initial computed tomography (CT) at a level-1 trauma centre over a 12-year period (2008-2019) were reanalysed. The analysis included CT-derived body composition parameters based upon whole-body trauma CT as prognostic variables for 30-day mortality, intensive care unit length of stay (ICU LOS) and mechanical ventilation duration. RESULTS: Four hundred seventy-two patients (75% male) with a median age of 49 years, median injury severity score of 26 and 30-day mortality rate of 22% (104 patients) met the inclusion criteria and were analysed. Regarding body composition parameters, 231 patients (49%) had visceral obesity, 75 patients had sarcopenia (16%) and 35 patients had sarcopenic obesity (7.4%). After adjustment for statistically significant univariable predictors age, body mass index, sarcopenic obesity, visceral obesity, American Society of Anesthesiologists classification ≥3, injury severity score and Glasgow Coma Scale ≤ 8 points, the Cox proportional hazard model identified sarcopenia as significant prognostic factor of 30-day mortality (hazard ratio 2.84; 95% confidence interval 1.38-5.85; P = 0.004), which was confirmed in Kaplan-Meier survival analysis (log-rank P = 0.006). In a subanalysis of 363 survivors, linear multivariable regression analysis revealed no significant associations of body composition parameters with ICU LOS and duration of mechanical ventilation. CONCLUSIONS: In a multivariable analysis of mechanically ventilated trauma patients, CT-defined sarcopenia was significantly associated with 30-day mortality whereas no associations of body composition parameters with ICU LOS and duration of mechanical ventilation were observed.
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OBJECTIVES: Coronary artery calcifications detected by computed tomography (CT) provide prognostic relevance for vascular disorders and coronary heart disease, whereas their prognostic relevance in severely injured trauma patients remains unclear. MATERIAL AND METHODS: All consecutive trauma patients requiring emergency tracheal intubation before initial CT at a level-1 trauma center and admission to the intensive care unit (ICU) over a 12-year period (2008-2019) were reanalyzed. The Weston score, a semiquantitative method to quantify coronary calcifications, was evaluated as a prognostic variable based upon whole-body trauma CT analysis. RESULTS: Four hundred fifty-eight patients (74.6% male) with a median age of 49 years, median injury severity score of 26 points, 24-h mortality rate of 7.6%, and 30-day mortality rate of 22.1% met the inclusion criteria and were analyzed. Coronary artery calcification was present in 214 patients (46.7%). After adjustment for confounding factors, the Weston score was an independent predictor for 24-h mortality (hazard ratio, HR 1.19, 95% confidence interval, CI 1.06-1.32, p = .002) and 30-day mortality (HR 1.09, 95% CI 1.01-1.17, p = .027). In a subanalysis of 357 survivors, the Weston score was significantly associated with ICU length of stay (LOS) (beta weight 0.89, 95% CI 0.3-1.47, p = .003) but not with mechanical ventilation duration (beta weight 0.05, 95% CI -0.2-0.63, p = .304). CONCLUSION: CT-detected coronary calcification was a significant prognostic factor for 24-h- and 30-day-mortality in severely injured trauma patients requiring tracheal intubation, and influenced ICU LOS in survivors.
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Percutaneous hepatic melphalan perfusion (chemosaturation) in patients with liver metastases is known to be associated with procedure-related hemodynamic depression and coagulation impairment, which may cause bleeding complications and/or a prolonged intensive care unit length of stay (ICU LOS). We retrospectively analyzed possible predictive factors for bleeding complications and an ICU LOS > 1 d in a cohort of 31 patients undergoing 90 chemosaturation procedures. Using a multivariable mixed-model approach, we identified the amount of perioperative fluid volume (OR 12.0, 95% CI 2.3-60.0, p = 0.003) and protamine (OR 0.065, 95% CI 0.007-0.55, p = 0.012) to be associated with bleeding complications. Furthermore, the amount of perioperative fluid volume was associated with an ICU LOS > 1 d (OR 5.2, 95% CI 1.4-19.0, p = 0.011). Heparin dosage, melphalan dosage, extracorporeal circulation time, and noradrenaline dosage had no significant effects on outcomes. Protamine use was not associated with anaphylactic or thromboembolic complications. Despite the limited sample size, these results suggest a restrictive perioperative fluid regime to be beneficial, and support the use of protamine for heparin reversal after chemosaturation procedures. Further prospective randomized trials are needed to confirm these findings.
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Percutaneous hepatic melphalan perfusion (PHMP) is a last-line treatment of inoperable primary or secondary liver tumors. Selective perfusion and saturation (chemosaturation) of the liver with the chemotherapeutic agent melphalan is performed via catheterization of the hepatic artery without affecting the rest of the body with its cytotoxic properties. Using an extracorporeal circulation and balloon occlusion of the inferior vena cava, the venous hepatic blood is filtered and returned using a bypass procedure. During the procedure, considerable circulatory depression and coagulopathy are frequent. The purpose of this article is to review the anesthesiological and postprocedural management of patients undergoing PHMP with consideration of the pitfalls and special circumstances.
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Antineoplásicos , Melfalan , Humanos , Melfalan/efeitos adversos , Quimioterapia do Câncer por Perfusão Regional/efeitos adversos , Antineoplásicos/uso terapêutico , Circulação Extracorpórea , PerfusãoRESUMO
Endoprosthetic surgery can lead to relevant blood loss resulting in red blood cell (RBC) transfusions. This study aimed to identify risk factors for blood loss and RBC transfusion that enable the prediction of an individualized transfusion probability to guide preoperative RBC provision and blood saving programs. A retrospective analysis of patients who underwent primary hip or knee arthroplasty was performed. Risk factors for blood loss and transfusions were identified and transfusion probabilities computed. The number needed to treat (NNT) of a potential correction of preoperative anemia with iron substitution for the prevention of RBC transfusion was calculated. A total of 308 patients were included, of whom 12 (3.9%) received RBC transfusions. Factors influencing the maximum hemoglobin drop were the use of drain, tranexamic acid, duration of surgery, anticoagulation, BMI, ASA status and mechanical heart valves. In multivariate analysis, the use of a drain, low preoperative Hb and mechanical heart valves were predictors for RBC transfusions. The transfusion probability of patients with a hemoglobin of 9.0-10.0 g/dL, 10.0-11.0 g/dL, 11.0-12.0 g/dL and 12.0-13.0 g/dL was 100%, 33.3%, 10% and 5.6%, and the NNT 1.5, 4.3, 22.7 and 17.3, while it was 100%, 50%, 25% and 14.3% with a NNT of 2.0, 4.0, 9.3 and 7.0 in patients with a drain, respectively. Preoperative anemia and the insertion of drains are more predictive for RBC transfusions than the use of tranexamic acid. Based on this, a personalized transfusion probability can be computed, that may help to identify patients who could benefit from blood saving programs.
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Artroplastia de Quadril/efeitos adversos , Artroplastia do Joelho/efeitos adversos , Perda Sanguínea Cirúrgica/estatística & dados numéricos , Transfusão de Eritrócitos/estatística & dados numéricos , Idoso , Anemia/epidemiologia , Anticoagulantes/administração & dosagem , Artroplastia de Quadril/métodos , Artroplastia do Joelho/métodos , Biomarcadores/sangue , Feminino , Hemoglobinas/análise , Humanos , Masculino , Pessoa de Meia-Idade , Ácido Tranexâmico/administração & dosagemRESUMO
BACKGROUND: Alterations of the expression of microRNAs (miRNAs) in chronic pain models seem to play a crucial role in the development of neuropathic pain, with microRNA-1 (miR-1) being of particular interest. Recently, we were able to show that decreased miR-1 levels were associated with increased expression of brain-derived neurotrophic factor (BDNF) and Connexin 43 (Cx43). We hypothesized that miR-1 mimetic nucleotides could alleviate neuropathic pain caused by chronic constriction injury in rats. METHODS: MiR-1 mimetic nucleotides were evaluated for effectiveness, functionality, and intracellular stability by transfecting human glioblastoma cells (U-87 MG). In vivo transfection with miR-1 mimics and corresponding scrambled miRNAs serving as control was performed by repetitive injection (days 0, 3, and 7) into the sciatic nerve following chronic constriction injury (CCI) in rats. Quantitative PCR was used to measure miR-1 content. Cx43 expression was determined by Western blot analysis. Effects on neuropathic pain were assessed by detecting paw withdrawal thresholds using an automated filament application. RESULTS: Transfection of miR-1 mimics was confirmed in U-87 MG cells, with miR-1 content being increased significantly after 48 h and after 96 h (p<0.05). Effective downregulation of Cx43 expression was observed 48 and 96 h after transfection (-44 ± 0.07% and -40 ± 0.11%; p<0.05). In vivo, repetitive transfection with miR-1 mimetic nucleotides led to a 17.9-fold (± 14.2) increase of miR-1 in the sciatic nerve. However, the protein expression of Cx43 in sciatic nerves as well as paw withdrawal thresholds for mechanical stimulation was not significantly increased 10 days after chronic constriction injury. CONCLUSION: While transfection with miR-1 mimics effective reduces Cx43 expression in vitro and restores miR-1 after CCI, we did neither observe altered levels of Cx43 protein level in nerves nor a beneficial effect on mechanical allodynia in vivo, most likely caused by insufficient Cx43 suppression.
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BACKGROUND: Photodynamic inactivation (PDI) is a promising approach to treat multidrug-resistant infections. However, effectiveness of PDI is limited, particularly in Gram-negative bacteria. The use of photosensitizer (PS) 3,3',3'',3'''-(7,8,17,18-tetrahydro-21H,23H-porphyrine-5,10,15,20-tetrayl)tetrakis[1-methyl-pyridinium]tetratosylate (THPTS) and laser light has led to very promising results. This study focuses on the effects of THPTS in various critical multidrug-resistant bacterial strains and explores the possibility of light-emitting diode (LED)-based activation as a clinically more feasible alternative to laser light. METHODS: THPTS was further chemically characterized and in vitro testing of PDI of different multidrug-resistant bacterial strains was performed under various experimental conditions, including varying drug concentration, incubation time, light source (laser and LED) and light intensity, by determination of viable bacteria after treatment. The effect of hyaluronic acid as an adjuvant for medical applications was also evaluated. RESULTS: Bacterial density of all investigated bacterial strains was reduced by several orders of magnitude, irrespective of multidrug-resistance or hyaluronic acid addition. The effect was less intense in Gram-negative strains (disinfection), and more pronounced in Gram-positive strains (sterilization), even at reduced THPTS concentrations or decreased light treatment intensity. Controls without THPTS or without light treatment did not indicate reduced bacterial density. CONCLUSIONS: PDI with THPTS and laser light was effective in all investigated bacterial strains. Gram-negative strains were less, but sufficiently, susceptible to PDI. Adding hyaluronic acid did not reduce the antibacterial treatment effect. LED-based PDI is equally effective when illumination duration is increased to compensate for reduced light intensity.
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Bactérias/efeitos dos fármacos , Bactérias/efeitos da radiação , Infecções Bacterianas/tratamento farmacológico , Fármacos Fotossensibilizantes/farmacologia , Porfirinas/farmacologia , Antibacterianos/farmacologia , Farmacorresistência Bacteriana Múltipla , Humanos , Lasers , Luz , Testes de Sensibilidade Microbiana , Viabilidade Microbiana , Fotoquimioterapia/métodos , SemicondutoresRESUMO
BACKGROUND: Iatrogenic tracheal ruptures are rare but life-threatening airway complications that often require surgical repair. Data on perioperative vital functions and anesthetic regimes are scarce. The goal of this study was to explore comorbidity, perioperative management, complications and outcomes of patients undergoing thoracotomy for surgical repair. METHODS: We retrospectively evaluated adult patients who required right thoracotomy for emergency surgical repair of iatrogenic posterior tracheal ruptures and were admitted to a university hospital over a 15-year period (2004-2018). The analyses included demographic, diagnostic, management and outcome data on preinjury morbidity and perioperative complications. RESULTS: Thirty-five patients who met the inclusion criteria were analyzed. All but two patients (96%) presented with critical underlying diseases and/or emergency tracheal intubations. The median time (interquartile range) from diagnosis to surgery was 0.3 (0.2-1.0) days. The durations of anesthesia, surgery and one-lung ventilation (OLV) were 172 (128-261) min, 100 (68-162) min, and 52 (40-99) min, respectively. The primary airway management approach to OLV was successful in only 12 patients (34%). Major complications during surgery were observed in 10 patients (29%). Four patients (11%) required cardiopulmonary resuscitation, one of whom received extracorporeal membrane oxygenation, and another one of these patients died during surgery. Major complications were associated with significantly higher all-cause 30-day mortality (p = 0.002) and adjusted mortality (p = 0.001) compared to patients with minor or no complications. CONCLUSIONS: Surgical repair of iatrogenic tracheal ruptures requires advanced perioperative care in a specialized center due to high morbidity and potential complications. Airway management should include early anticipation of alternative OLV approaches to provide acceptable conditions for surgery.
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Manuseio das Vias Aéreas/métodos , Toracotomia/métodos , Traqueia/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Reanimação Cardiopulmonar/estatística & dados numéricos , Emergências , Oxigenação por Membrana Extracorpórea , Feminino , Humanos , Doença Iatrogênica , Intubação Intratraqueal , Masculino , Pessoa de Meia-Idade , Ventilação Monopulmonar/estatística & dados numéricos , Assistência Perioperatória/métodos , Estudos Retrospectivos , Ruptura/cirurgia , Traqueia/lesõesRESUMO
This review summarizes current knowledge concerning incidence, risk factors, and mechanisms of perioperative nerve injury, with focus on local anesthetic-induced neurotoxicity. Perioperative nerve injury is a complex phenomenon and can be caused by a number of clinical factors. Anesthetic risk factors for perioperative nerve injury include regional block technique, patient risk factors, and local anesthetic-induced neurotoxicity. Surgery can lead to nerve damage by use of tourniquets or by direct mechanical stress on nerves, such as traction, transection, compression, contusion, ischemia, and stretching. Current literature suggests that the majority of perioperative nerve injuries are unrelated to regional anesthesia. Besides the blockade of sodium channels which is responsible for the anesthetic effect, systemic local anesthetics can have a positive influence on the inflammatory response and the hemostatic system in the perioperative period. However, next to these beneficial effects, local anesthetics exhibit time and dose-dependent toxicity to a variety of tissues, including nerves. There is equivocal experimental evidence that the toxicity varies among local anesthetics. Even though the precise order of events during local anesthetic-induced neurotoxicity is not clear, possible cellular mechanisms have been identified. These include the intrinsic caspase-pathway, PI3K-pathway, and MAPK-pathways. Further research will need to determine whether these pathways are non-specifically activated by local anesthetics, or whether there is a single common precipitating factor.
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Anestésicos Locais/toxicidade , Síndromes Neurotóxicas/etiologia , Anestesia por Condução/efeitos adversos , Anestesia por Condução/instrumentação , Caspases/metabolismo , Relação Dose-Resposta a Droga , Período Perioperatório , Transdução de Sinais/efeitos dos fármacos , Fatores de TempoRESUMO
BACKGROUND: Temozolomide (TMZ) induces a G2/M cell cycle arrest and is used for treatment of paediatric tumours, especially neuroblastomas. Patients treated with TMZ frequently receive midazolam for sedation prior to surgery and other interventions. Previous studies suggested both cytoprotective and apoptosis-inducing properties of midazolam. Therefore, the impact of midazolam on TMZ-induced cytotoxicity was investigated in vitro. METHODS: Human neuroblastoma cells were incubated with midazolam alone, as a pretreatment prior to incubation with TMZ or a coincubation of both. Cell viability and proliferation was analysed (XTT and BrdU assay) after 24 h and flowcytometric cell cycle analysis was performed after 24 and 48 h. RESULTS: Midazolam alone increased cell viability at lower concentrations (2, 4, 8, 16 µM), whereas higher concentrations (128, 256, 512 µM) reduced cell viability. Pretreatment with midazolam 6 h prior to TMZ incubation reduced cytotoxic effects (IC25 1005 ± 197 µM; IC50 1676 ± 557 µM; P < 0.05) compared to incubation with TMZ alone (IC25 449 ± 304 µM; IC50 925 ± 196 µM) and reduced the antiproliferative effect of TMZ (1000 µM) by 43.9 % (P < 0.05). In contrast, cytotoxic effects of TMZ were increased (IC75 1175 ± 221 µM vs. 2764 ± 307 µM; P < 0.05) when midazolam pretreatment was followed by coincubation of midazolam and TMZ. Cell cycle analysis revealed increased fractions of cells in G2/M phase after TMZ treatment (100 µM; 48 h), irrespective of midazolam pretreatment. CONCLUSION: Midazolam causes a hormetic dose-response relationship in human neuroblastoma cells. Pretreatment with midazolam reduces the cytotoxic and antiproliferative effects of TMZ without interfering with G2/M cell cycle arrest. In contrast, subsequent midazolam coincubation increases overall cytotoxicity.
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Antineoplásicos Alquilantes/farmacologia , Dacarbazina/análogos & derivados , Midazolam/farmacologia , Neuroblastoma/tratamento farmacológico , Antineoplásicos Alquilantes/administração & dosagem , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Dacarbazina/administração & dosagem , Dacarbazina/farmacologia , Relação Dose-Resposta a Droga , Interações Medicamentosas , Citometria de Fluxo/métodos , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Humanos , Hipnóticos e Sedativos/administração & dosagem , Hipnóticos e Sedativos/farmacologia , Concentração Inibidora 50 , Pontos de Checagem da Fase M do Ciclo Celular/efeitos dos fármacos , Midazolam/administração & dosagem , Neuroblastoma/patologia , Temozolomida , Fatores de TempoRESUMO
BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSION: Xenon monoanesthesia in healthy volunteers and xenon/remifentanil anesthesia in patients without clinically relevant cardiovascular disease do not increase QTc interval.
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Anestésicos Inalatórios/administração & dosagem , Doenças Cardiovasculares , Frequência Cardíaca/efeitos dos fármacos , Xenônio/administração & dosagem , Adulto , Estudos de Coortes , Feminino , Voluntários Saudáveis , Frequência Cardíaca/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Monitorização Intraoperatória/métodos , Adulto JovemRESUMO
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 locus, such as Inherited Primary Erythromelalgia, Paroxysmal Extreme Pain Disorder and Painful Small Fibre Neuropathy, but who do not contain mutations in the sense gene. Our results strongly suggest the SCN9A NAT as a prime candidate for new therapies based upon augmentation of existing antisense RNAs in the treatment of chronic pain conditions in man.
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Gânglios Espinais/metabolismo , Canal de Sódio Disparado por Voltagem NAV1.7/genética , RNA Antissenso/metabolismo , Animais , Clonagem Molecular , Simulação por Computador , Sequência Conservada , Regulação da Expressão Gênica , Células HEK293 , Humanos , Camundongos , Canal de Sódio Disparado por Voltagem NAV1.7/química , Canal de Sódio Disparado por Voltagem NAV1.7/metabolismo , Dor/genética , Dor/metabolismo , RNA Antissenso/química , RNA Mensageiro/metabolismoRESUMO
The activity of voltage-gated sodium channels has long been linked to disorders of neuronal excitability such as epilepsy and chronic pain. Recent genetic studies have now expanded the role of sodium channels in health and disease, to include autism, migraine, multiple sclerosis, cancer as well as muscle and immune system disorders. Transgenic mouse models have proved useful in understanding the physiological role of individual sodium channels, and there has been significant progress in the development of subtype selective inhibitors of sodium channels. This review will outline the functions and roles of specific sodium channels in electrical signalling and disease, focusing on neurological aspects. We also discuss recent advances in the development of selective sodium channel inhibitors.
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Ativação do Canal Iônico , Canais de Sódio/fisiologia , Animais , Epilepsia/tratamento farmacológico , Ativação do Canal Iônico/efeitos dos fármacos , Ativação do Canal Iônico/fisiologia , Camundongos , Camundongos Transgênicos , Transtornos de Enxaqueca/tratamento farmacológico , Dor/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Bloqueadores dos Canais de Sódio/farmacologia , Bloqueadores dos Canais de Sódio/uso terapêutico , Canais de Sódio/genéticaRESUMO
BACKGROUND AND OBJECTIVES: Local neurotoxicity of local anaesthetics is a well known phenomenon which is determined by lipophilicity. Recent reports have indicated the relevance of local anaesthetic-induced cytotoxicity also in nonneuronal tissues. This study re-evaluates the role of lipophilicity in local anaesthetic cytotoxicity in nonneuronal cells. In addition, the toxicities of pipecoloxylidine S(-) enantiomers were investigated. METHODS: Local anaesthetic-induced cytotoxicity was investigated in vitro in T-lymphoma cells (Jurkat). Cells were incubated with each of eight different local anaesthetics, two esters and six amides. Annexin V-fluorescein isothiocyanate and 7-aminoactinomycin D double staining followed by flow cytometry were used to investigate the fraction of early apoptotic cells as well as the overall cell death. The concentrations leading to 50% cell death (LC50) were calculated and compared. In a second step, we compared the toxicities of S(-) bupivacaine and the racemate as well as R(+) and S(-) ropivacaine. RESULTS: Concentration-dependent cytotoxicity was observed for all investigated local anaesthetics. Apoptosis was seen at low concentrations, whereas necrosis was observed at higher concentrations. LC50 values of the different local anaesthetics yielded the following decreasing order of toxicity: tetracaine, bupivacaine, ropivacaine, prilocaine, procaine, lidocaine, articaine and mepivacaine. Toxicity correlated with octanol/buffer partition coefficients, but was independent of the ester or amide linkage. There was no effect of stereoisomerism on apoptosis and necrosis. CONCLUSION: Moderate correlations for cytotoxicity with lipophilicity and clinical potency of local anaesthetics can be found in nonneuronal cells that are less than those reported previously with neuronal cells. Structural factors such as ester or amide linkage or stereospecificity do not have any influence on cytotoxicity. Although S(-) enantiomers may be advantageous with regard to systemic toxicity, they have no advantage in respect of local cytotoxicity in vitro.
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Anestésicos Locais/toxicidade , Apoptose/efeitos dos fármacos , Linfoma de Células T/patologia , Amidas/toxicidade , Anestésicos Locais/química , Bupivacaína/análogos & derivados , Bupivacaína/toxicidade , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Citometria de Fluxo , Humanos , Concentração Inibidora 50 , Células Jurkat , Microscopia de Fluorescência , Necrose , Ropivacaina , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
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 lidocaine-induced apoptosis is unclear. Therefore, we investigated the influence of different adjuvants on the neurotoxicity of lidocaine. METHODS: Human neuroblastoma cells and primary rat astrocytes were incubated for 24 hrs with lidocaine at a toxic concentration alone and in combination with morphine, sufentanil, clonidine, epinephrine, neostigmine, ketamine, and midazolam. Subsequently, the rates of cell death and early apoptosis were measured by flow cytometry in neuroblastoma cells, whereas astrocyte viability was analyzed by mitochondrial activity assay. In addition, isobolograms were calculated to describe the additive effects of lidocaine with ketamine or midazolam, respectively. RESULTS: Coadministration of lidocaine with sufentanil, clonidine, epinephrine, and neostigmine did not alter the rates of cell death compared with cells treated with lidocaine alone. Morphine improved the viability of astrocytes only at concentrations beyond those occurring clinically. In contrast, coincubation of lidocaine with ketamine or midazolam led to significantly increased rates of cell death. The combined toxicity of ketamine and lidocaine was additive, whereas the combined toxicity of midazolam and lidocaine was subadditive. CONCLUSIONS: Sufentanil, clonidine, epinephrine, and neostigmine do not influence the neurotoxicity of lidocaine in vitro. Morphine may have some cytoprotective effect at concentrations greater than those seen intrathecally in humans. In contrast, ketamine and midazolam increase the neurotoxicity of lidocaine in vitro, presumably by additive induction of mitochondrial apoptosis.
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Adjuvantes Anestésicos/toxicidade , Anestésicos Locais/toxicidade , Astrócitos/efeitos dos fármacos , Lidocaína/toxicidade , Adjuvantes Anestésicos/administração & dosagem , Anestesia por Condução/efeitos adversos , Anestésicos Locais/administração & dosagem , Animais , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Astrócitos/patologia , Linhagem Celular Tumoral , Células Cultivadas , Quimioterapia Combinada , Humanos , Lidocaína/administração & dosagem , Neuroblastoma/patologia , Ratos , Ratos WistarRESUMO
STUDY OBJECTIVE: To test the feasibility and efficacy of a new approach to paravertebral catheter placement in patients undergoing major surgery of the breast. DESIGN: Single-group, single-center observational study. SETTING: Operating room, postoperative recovery area, and normal ward of a university hospital. PATIENTS: 25 ASA physical status 1, 2, 3, and 4 patients undergoing major unilateral surgery of the breast. INTERVENTIONS: Paravertebral catheters for intraoperative and postoperative anesthesia and analgesia were applied using the recently described lamina technique. This technique is performed at a more medial puncture site, avoiding the pleura. MEASUREMENTS: Additional opioid requirements were recorded to assess effectiveness of regional anesthesia. At the time of catheter withdrawal, patients, staff nurses, and anesthesiologists who provided postoperative pain management were asked to rate their satisfaction with paravertebral catheter effectiveness. MAIN RESULTS: All patients successfully received a paravertebral catheter using the lamina technique. During the surgical procedure, 84% of patients received no additional opioids after intubation. No patient required opioids as rescue medication postoperatively (visual analog scale rating > 30 mm) or during the rest of the hospital stay. Postoperative analgesia provided with paravertebral catheters was rated very high by patients, staff nurses, and anesthesiologists involved in postoperative care. CONCLUSIONS: The lamina technique for placement of a paravertebral catheter is a feasible and effective technique for intraoperative and postoperative analgesia in patients scheduled for major breast surgery with or without axillary lymph node resection.
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Raquianestesia/métodos , Mama/cirurgia , Coluna Vertebral , Adulto , Idoso , Idoso de 80 Anos ou mais , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/uso terapêutico , Período de Recuperação da Anestesia , Anestesia Geral , Neoplasias da Mama/cirurgia , Cateterismo , Feminino , Humanos , Injeções Espinhais , Pessoa de Meia-Idade , Dor Pós-Operatória/tratamento farmacológico , Projetos Piloto , Complicações Pós-Operatórias/epidemiologiaRESUMO
BACKGROUND AND OBJECTIVES: Midazolam has neurotoxic properties when administered neuraxially in vivo. Furthermore, midazolam induces neurodegeneration in neonatal animal models in combination with other general anesthetics. Therefore, this study focuses on the mechanism of neurotoxicity by midazolam in neuronal and nonneuronal cells. The study aims to evaluate the apoptotic pathway and to investigate the protective effects of the benzodiazepine antagonist flumazenil and the caspase inhibitor N-(2-quinolyl)valyl-aspartyl-(2,6-difluorophenoxy)-methylketone. METHODS: The apoptosis-inducing effect of preservative-free midazolam on human lymphoma and neuroblastoma cell lines was evaluated using flow cytometric analysis of early apoptotic stages (annexin V/7AAD) and caspase 3 activation. B-cell lymphoma (Bcl2) protein overexpressing and caspase 9-deficient lymphoma cells were used to determine the role of the mitochondrial (intrinsic) pathway. Caspase 8-deficient and Fas-associated protein with death domain (FADD)-deficient cells were used to evaluate the death receptor (extrinsic) pathway. The protective effects of flumazenil and the caspase inhibitor N-(2-quinolyl)valyl-aspartyl-(2,6-difluorophenoxy)-methylketone were investigated in neuroblastoma cells and primary rat neurons using metabolic activity assays (2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide) and immunofluorescence microscopy. RESULTS: Midazolam induced apoptosis in all investigated cell types in a concentration-dependent manner, indicated by flow cytometry. Bcl2-overexpression and caspase 9 deficiency protected against toxicity, whereas caspase 8 or FADD deficiency had no effect. Pancaspase inhibition had a strong protective effect, whereas flumazenil did not inhibit midazolam-induced apoptosis. CONCLUSIONS: Midazolam induces apoptosis via activation of the mitochondrial pathway in a concentration-dependent manner. The mechanism of midazolam toxicity switches from caspase-dependent apoptosis to necrosis with increasing concentrations. The induction of apoptosis and necrosis by midazolam is presumably unrelated to GABAA receptor pathway signaling.
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Apoptose/efeitos dos fármacos , Benzodiazepinas/farmacologia , Midazolam/farmacologia , Receptores de Morte Celular/fisiologia , Transdução de Sinais/efeitos dos fármacos , Animais , Apoptose/fisiologia , Morte Celular/efeitos dos fármacos , Morte Celular/fisiologia , Células Cultivadas , Relação Dose-Resposta a Droga , Feminino , Humanos , Células Jurkat , Gravidez , Ratos , Ratos Wistar , Transdução de Sinais/fisiologiaRESUMO
INTRODUCTION: Ketamine has been demonstrated to be neurotoxic in animals as well as in patients. Preservatives added to ketamine have been accused to induce this neurotoxicity. Therefore, we investigated whether the most widely used preservative of ketamine-benzethonium chloride-enhances the toxicity of S(+)-ketamine in vitro in lymphoma, neuroblastoma cells and primary astrocytes. METHODS: Human Jurkat T-lymphoma- and neuroblastoma cells (SHEP) were incubated for 24 hours with commercially available S-ketamine containing benzethonium, pure S-ketamine and pure benzethonium chloride. The rate of early- and late-apoptotic cells was evaluated by flowcytometry. In a second step the combined toxicity of benzethonium and ketamine was investigated in neuroblastoma cells and primary rat astrocytes in a mitochondrial activity assay (XTT). The additivity of the toxicities was evaluated by employing isobolographic analysis. RESULTS: In Jurkat T-lymphoma and neuroblastoma cells benzethonium increased the toxicity of ketamine from 32% to 80% and from 64% to 84% cell deaths, respectively. In neuroblastoma cells as well as in primary rat astrocytes the measured combined toxicity was within the confidence interval of the calculated pure additive toxicity as seen in the isobolograms. CONCLUSIONS: We conclude that benzethonium increases the local toxicity of ketamine in cells of hematopoietic, neuronal and glial origin in an additive manner. Therefore, caution is recommended especially when using preservative containing S-ketamine as an additive for long-term neuraxial analgesia.
Assuntos
Analgésicos/toxicidade , Apoptose/efeitos dos fármacos , Benzetônio/toxicidade , Ketamina/toxicidade , Linfoma/patologia , Neuroglia/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Conservantes Farmacêuticos/toxicidade , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/patologia , Química Farmacêutica , Relação Dose-Resposta a Droga , Citometria de Fluxo , Humanos , Concentração Inibidora 50 , Células Jurkat , Linfoma/metabolismo , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Necrose , Neuroglia/metabolismo , Neuroglia/patologia , Neurônios/metabolismo , Neurônios/patologia , Ratos , Fatores de TempoRESUMO
OBJECTIVE: 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. CASE REPORT: 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 the foot was observed. At the end of the operation, the patient was free of pain, a good capillary pulse of the leg was observed, and the patient was able to move the foot and toes of the rotated leg. CONCLUSIONS: The use of epidural stimulating catheters as a tool to monitor nerve function is a novel and simple procedure to monitor nerve function intraoperatively and to enable good postoperative pain control.
Assuntos
Artroplastia , Quadril/cirurgia , Bloqueio Nervoso , Nervos Periféricos/fisiologia , Cateterismo , Criança , Neoplasias Femorais/cirurgia , Humanos , Perna (Membro)/irrigação sanguínea , Masculino , Contração Muscular/fisiologia , Osteossarcoma/cirurgia , Estimulação Física , Fluxo Sanguíneo Regional/fisiologia , Reperfusão , Nervo Isquiático/efeitos dos fármacos , Nervo Isquiático/fisiologia , TermografiaRESUMO
BACKGROUND AND OBJECTIVES: In neuraxial anesthesia, increase of skin temperature is an early sign of successful block. Yet, during peripheral nerve block of the lower extremity, increase in skin temperature is a highly sensitive, but late sign of a successful block. We hypothesized that after interscalene brachial plexus block, a rise in skin temperature follows impairment of sensation during successful nerve block and occurs only distally, as observed in the lower extremity. METHODS: In the present study, we prospectively evaluated the changes in skin temperature after interscalene brachial plexus blockade in 45 patients scheduled for elective shoulder surgery. We assessed pinprick and cold sensation as well as skin temperature at sites of the skin innervated by the median, ulnar, radial, axillary and musculocutaneous nerve. RESULTS: At the skin areas innervated by the axillary and musculocutaneous nerve, skin temperature did not increase after successful block. At the distal sites, innervated by the median, ulnar, and radial nerve, skin temperature increased significantly (1.9-2.1 degrees C within 30 min) after successful block while it did not after failed nerve block or on the contralateral side. In these areas attenuation of skin sensation preceded a measurable rise in skin temperature (> or =1 degrees C) in 56.3% of nerve blocks, occurred at the same time in 35.2%, and in 8.5% the temperature rise occurred first. CONCLUSIONS: Assessment of skin temperature cannot predict the success of an interscalene brachial plexus block of the axillary and musculocutaneous nerve. Distally, the increase of skin temperature has a high sensitivity and specificity but occurs later than the loss of sensory and motor functions. Therefore, the measurement of skin temperature during interscalene blockade is of limited clinical value.