RESUMO
Mesenchymal stromal cells (MSCs) have a multimodal, immunomodulatory mechanism of action and are now in clinical trials for single organ and systemic sepsis. However, a number of practicalities around source, homogeneity and therapeutic window remain to be determined. Here, we utilised conditioned medium from CD362+-sorted umbilical cord-human MSCs (UC-hMSCs) for a series of in vitro anti-inflammatory assays and the cryopreserved MSCs themselves in a severe (Series 1) or moderate (Series 2+3) caecal ligation and puncture (CLP) rodent model. Surviving animals were assessed at 48 h post injury induction. MSCs improved human lung, colonic and kidney epithelial cell survival following cytokine activation. In severe systemic sepsis, MSCs administered at 30 min enhanced survival (Series 1), and reduced organ bacterial load. In moderate systemic sepsis (Series 2), MSCs were ineffective when delivered immediately or 24 h later. Of importance, MSCs delivered 4 h post induction of moderate sepsis (Series 3) were effective, improving serum lactate, enhancing bacterial clearance from tissues, reducing pro-inflammatory cytokine concentrations and increasing antimicrobial peptides in serum. While demonstrating benefit and immunomodulation in systemic sepsis, therapeutic efficacy may be limited to a specific point of disease onset, and repeat dosing, MSC enhancement or other contingencies may be necessary.
Assuntos
Ceco/microbiologia , Coinfecção/terapia , Transplante de Células-Tronco Mesenquimais/métodos , Sepse/terapia , Animais , Antígenos CD/metabolismo , Ceco/patologia , Ceco/cirurgia , Células Cultivadas , Coinfecção/complicações , Coinfecção/etiologia , Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos , Modelos Animais de Doenças , Humanos , Ligadura/efeitos adversos , Masculino , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/fisiologia , Punções/efeitos adversos , Ratos , Ratos Sprague-Dawley , Sepse/etiologia , Sepse/microbiologia , Cordão Umbilical/citologia , Cordão Umbilical/metabolismoRESUMO
Aerosol therapy is a key modality for drug delivery to the lungs of respiratory disease patients. Aerosol therapy improves therapeutic effects by directly targeting diseased lung regions for rapid onset of action, requiring smaller doses than oral or intravenous delivery and minimizing systemic side effects. In order to optimize treatment of critically ill patients, the efficacy of aerosol therapy depends on lung morphology, breathing patterns, aerosol droplet characteristics, disease, mechanical ventilation, pharmacokinetics, and the pharmacodynamics of cell-drug interactions. While aerosol characteristics are influenced by drug formulations and device mechanisms, most other factors are reliant on individual patient variables. This has led to increased efforts towards more personalized therapeutic approaches to optimize pulmonary drug delivery and improve selection of effective drug types for individual patients. Vibrating mesh nebulizers (VMN) are the dominant device in clinical trials involving mechanical ventilation and emerging drugs. In this review, we consider the use of VMN during mechanical ventilation in intensive care units. We aim to link VMN fundamentals to applications in mechanically ventilated patients and look to the future use of VMN in emerging personalized therapeutic drugs.
RESUMO
Inhibition of the proinflammatory transcription factor NF-κB has previously been shown to attenuate the inflammatory response in tissue after injury. However, the feasibility and efficacy of aerosolized adeno-associated viral (AAV) vector-delivered transgenes to inhibit the NF-κB pathway are less clear. Initial studies optimized the AAV vector for delivery of transgenes to the pulmonary epithelium. The effect of repeated nebulization on the integrity and transduction efficacy of the AAV vector was then examined. Subsequent in vivo studies examined the efficacy of aerosolized rAAV2/6 overexpressing the NF-κB inhibitor IκBα in a rodent endotoxin-induced lung injury model. Initial in vitro investigations indicated that rAAV2/6 was the most effective vector to transduce the lung epithelium, and maintained its integrity and transduction efficacy after repeated nebulization. In our in vivo studies, animals that received aerosolized rAAV2/6-IκBα demonstrated a significant increase in total IκBα levels in lung tissue relative to null vector-treated animals. Aerosolized rAAV2/6-IκBα attenuated endotoxin-induced bronchoalveolar lavage-detected neutrophilia, interleukin-6 and cytokine-induced neutrophil chemoattractant-1 levels, as well as total protein content, and decreased histologic indices of injury. These results demonstrate that aerosolized AAV vectors encoding human IκBα significantly attenuate endotoxin-mediated lung injury and may be a potential therapeutic candidate in the treatment of acute lung injury.
Assuntos
Lesão Pulmonar Aguda/etiologia , Lesão Pulmonar Aguda/terapia , Dependovirus/genética , Vetores Genéticos/genética , Proteínas I-kappa B/genética , Administração por Inalação , Animais , Citocinas/metabolismo , Dependovirus/classificação , Modelos Animais de Doenças , Endotoxinas/efeitos adversos , Células Epiteliais/metabolismo , Expressão Gênica , Vetores Genéticos/administração & dosagem , Lipopolissacarídeos/efeitos adversos , Lipopolissacarídeos/imunologia , Pulmão/metabolismo , Pulmão/patologia , Masculino , Ratos , Mucosa Respiratória/metabolismo , Sorogrupo , Transdução Genética , TransgenesRESUMO
OBJECTIVES: Hypercapnic acidosis protects against ventilation-induced lung injury. We wished to determine whether the beneficial effects of hypercapnic acidosis in reducing stretch-induced injury were mediated via inhibition of nuclear factor-κB, a key transcriptional regulator in inflammation, injury, and repair. DESIGN: Prospective randomized animal study. SETTING: University research laboratory. SUBJECTS: Adult male Sprague-Dawley rats. INTERVENTIONS: In separate experimental series, the potential for hypercapnic acidosis to attenuate moderate and severe ventilation-induced lung injury was determined. In each series, following induction of anesthesia and tracheostomy, Sprague-Dawley rats were randomized to (normocapnia; FICO2 0.00) or (hypercapnic acidosis; FICO2 0.05), subjected to high stretch ventilation, and the severity of lung injury and indices of activation of the nuclear factor-κB pathway were assessed. Subsequent in vitro experiments examined the potential for hypercapnic acidosis to reduce pulmonary epithelial inflammation and injury induced by cyclic mechanical stretch. The role of the nuclear factor-κB pathway in hypercapnic acidosis-mediated protection from stretch injury was then determined. MEASUREMENTS AND MAIN RESULTS: Hypercapnic acidosis attenuated moderate and severe ventilation-induced lung injury, as evidenced by improved oxygenation, compliance, and reduced histologic injury compared to normocapnic conditions. Hypercapnic acidosis reduced indices of inflammation such as interleukin-6 and bronchoalveolar lavage neutrophil infiltration. Hypercapnic acidosis reduced the decrement of the nuclear factor-κB inhibitor IκBα and reduced the generation of cytokine-induced neutrophil chemoattractant-1. Hypercapnic acidosis reduced cyclic mechanical stretch-induced nuclear factor-κB activation, reduced interleukin-8 production, and decreased epithelial injury and cell death compared to normocapnia. CONCLUSIONS: Hypercapnic acidosis attenuated ventilation-induced lung injury independent of injury severity and decreased mechanical stretch-induced epithelial injury and death, via a nuclear factor-κB-dependent mechanism.
Assuntos
Acidose Respiratória/metabolismo , NF-kappa B/metabolismo , Troca Gasosa Pulmonar/fisiologia , Lesão Pulmonar Induzida por Ventilação Mecânica/prevenção & controle , Acidose Respiratória/mortalidade , Acidose Respiratória/fisiopatologia , Animais , Biópsia por Agulha , Gasometria , Modelos Animais de Doenças , Hemodinâmica/fisiologia , Hipercapnia/metabolismo , Hipercapnia/fisiopatologia , Imuno-Histoquímica , Escala de Gravidade do Ferimento , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Masculino , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Sensibilidade e Especificidade , Taxa de Sobrevida , Lesão Pulmonar Induzida por Ventilação Mecânica/metabolismo , Lesão Pulmonar Induzida por Ventilação Mecânica/mortalidade , Lesão Pulmonar Induzida por Ventilação Mecânica/patologiaRESUMO
PURPOSE: Superoxide is produced by activated neutrophils during the inflammatory response to stimuli such as endotoxin, can directly or indirectly injure host cells, and has been implicated in the pathogenesis of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). We wished to determine the potential for pulmonary overexpression of the extracellular isoform of superoxide dismutase (EC-SOD) to reduce the severity of endotoxin-induced lung injury. METHODS: Animals were randomly allocated to undergo intratracheal instillation of (1) surfactant alone (vehicle); (2) adeno-associated virus (AAV) vectors containing a null transgene (AAV-null); and (3) adeno-associated virus vectors containing the EC-SOD transgene (AAV-EC-SOD) and endotoxin was subsequently administered intratracheally. Two additional groups were randomized to receive (1) vehicle or (2) AAV-EC-SOD, and to undergo sham (vehicle) injury. The severity of the lung injury was assessed in all animals 24 h later. RESULTS: Endotoxin produced a severe lung injury compared to sham injury. The AAV vector encoding EC-SOD increased lung EC-SOD concentrations, and enhanced the antioxidant capacity of the lung. EC-SOD overexpression decreased the severity of endotoxin-induced ALI, reducing the decrement in systemic oxygenation and lung compliance, decreasing lung permeability and decreasing histologic injury. EC-SOD attenuated pulmonary inflammation, decreased bronchoalveolar lavage neutrophil counts, and reduced interleukin-6 and CINC-1 concentrations. The AAV vector itself did not contribute to inflammation or to lung injury. CONCLUSIONS: Pulmonary overexpression of EC-SOD protects the lung against endotoxin-induced ALI.
Assuntos
Lesão Pulmonar Aguda/enzimologia , Lesão Pulmonar Aguda/etiologia , Endotoxinas/fisiologia , Superóxido Dismutase/biossíntese , Lesão Pulmonar Aguda/prevenção & controle , Animais , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
Acute respiratory distress syndrome is a devastating disease that causes substantial morbidity and mortality. Mechanical ventilation can worsen lung injury, whereas ventilatory strategies that reduce lung stretch, resulting in a "permissive" hypercapnic acidosis (HCA), improve outcome. HCA directly reduces nonsepsis-induced lung injury in preclinical models and, therefore, has therapeutic potential in these patients. These beneficial effects are mediated via inhibition of the host immune response, particularly cytokine signaling, phagocyte function, and the adaptive immune response. Of concern, these immunosuppressive effects of HCA may hinder the host response to microbial infection. Recent studies suggest that HCA is protective in the earlier phases of bacterial pneumonia-induced sepsis but may worsen injury in the setting of prolonged lung sepsis. In contrast, HCA is protective in preclinical models of early and prolonged systemic sepsis. Buffering of the HCA is not beneficial and may worsen pneumonia-induced injury.
Assuntos
Acidose/etiologia , Hipercapnia/etiologia , Sepse/complicações , Acidose/imunologia , Acidose/microbiologia , Estado Terminal , Humanos , Hipercapnia/imunologia , Hipercapnia/microbiologia , Pneumopatias/microbiologia , Pneumopatias/patologia , Pneumonia/microbiologia , Pneumonia/patologia , Sepse/imunologia , Sepse/microbiologiaRESUMO
BACKGROUND: Acute hypercapnic acidosis protects against lung injury caused by nonseptic insults and after both pulmonary and systemic sepsis. The authors wished to dissect the contribution of the acidosis versus hypercapnia per se to the effects of hypercapnic acidosis on the hemodynamic profile and severity of lung injury induced by systemic sepsis. METHODS: In the hypercapnic acidosis series, adult male Sprague-Dawley rats were randomized to normocapnia or hypercapnic acidosis-produced by adding 5% carbon dioxide to the inspired gas-and cecal ligation and puncture performed. In the buffered hypercapnia series, animals were first randomized to housing under conditions of environmental normocapnia or hypercapnia-produced by exposure to 8% carbon dioxide-to allow renal buffering. After 96 h, cecal ligation and puncture was performed. In both series, the animals were ventilated for 6 h, and the severity of the lung injury and hemodynamic deterioration were assessed. RESULTS: Both hypercapnic acidosis and buffered hypercapnia attenuated the development and severity of hypotension and reduced lactate accumulation compared to normocapnia. Hypercapnic acidosis reduced lung injury and inflammation, decreased mean (+ or - SD) bronchoalveolar lavage protein concentration (232 + or - 50 versus 279 + or - 27 microg x ml(-1)) and median neutrophil counts (3,370 versus 9,120 cells x ml(-1)), and reduced histologic lung injury. In contrast, buffered hypercapnia did not reduce the severity of systemic sepsis induced lung injury. CONCLUSIONS: Both hypercapnic acidosis and buffered hypercapnia attenuate the hemodynamic consequences of systemic sepsis. In contrast, hypercapnic acidosis, but not buffered hypercapnia, reduced the severity of sepsis-induced lung injury.
Assuntos
Acidose , Hipercapnia , Pneumopatias/etiologia , Pneumopatias/terapia , Sepse/complicações , Sepse/terapia , Choque/etiologia , Choque/terapia , Equilíbrio Ácido-Base/fisiologia , Animais , Líquido da Lavagem Broncoalveolar/citologia , Soluções Tampão , Dióxido de Carbono/sangue , Ceco/fisiologia , Hemodinâmica/fisiologia , Concentração de Íons de Hidrogênio , Rim/fisiopatologia , Masculino , Pneumonia/microbiologia , Pneumonia/patologia , Ratos , Ratos Sprague-DawleyRESUMO
PURPOSE: Direct laryngoscopic tracheal intubation is a potentially lifesaving procedure, but a difficult skill to acquire and maintain. The consequences of poorly performed intubation attempts are potentially severe. The Pentax AWS and the Glidescope are indirect laryngoscopes that may require less skill to use. We therefore hypothesized that AWS and Glidescope would prove superior to the Macintosh laryngoscope when used by novices in the normal and simulated difficult airway. METHODS: In this prospective randomized crossover trial following standardized didactic instruction, medical students with no prior experience of laryngoscopy performed tracheal intubation using each device. Each student was allowed up to three attempts to intubate in a Laerdal Intubation Trainer in two laryngoscopy scenarios and in a Laerdal SimMan manikin in one scenario. The students then performed tracheal intubation of the normal airway a second time to characterize the learning curve for each device. RESULTS: The Pentax AWS provided better intubation conditions than the Glidescope or the Macintosh, resulting in greater success of intubation, particularly in the difficult laryngoscopy scenarios. The Glidescope demonstrated advantages over the Macintosh, particularly in the more difficult scenarios. Both the AWS and the Glidescope decreased the duration of intubation attempts, reduced the number of maneuvers required, and reduced the potential for dental trauma. In direct comparisons, the AWS provided the best intubation conditions. CONCLUSIONS: The Pentax AWS appears to constitute a better alternative to the Macintosh for novice personnel to acquire the skills of tracheal intubation.
Assuntos
Intubação Intratraqueal/instrumentação , Laringoscópios , Laringoscopia/métodos , Estudos Cross-Over , Desenho de Equipamento , Humanos , Manequins , Estudos Prospectivos , Estudantes de MedicinaRESUMO
BACKGROUND: Sevoflurane has been demonstrated to vasodilate the foeto-placental vasculature. We aimed to determine the contribution of modulation of potassium and calcium channel function to the vasodilatory effect of sevoflurane in isolated human chorionic plate arterial rings. METHODS: Quadruplicate ex vivo human chorionic plate arterial rings were used in all studies. Series 1 and 2 examined the role of the K+ channel in sevoflurane-mediated vasodilation. Separate experiments examined whether tetraethylammonium, which blocks large conductance calcium activated K+ (KCa++) channels (Series 1A+B) or glibenclamide, which blocks the ATP sensitive K+ (KATP) channel (Series 2), modulated sevoflurane-mediated vasodilation. Series 3 - 5 examined the role of the Ca++ channel in sevoflurane induced vasodilation. Separate experiments examined whether verapamil, which blocks the sarcolemmal voltage-operated Ca++ channel (Series 3), SK&F 96365 an inhibitor of sarcolemmal voltage-independent Ca++ channels (Series 4A+B), or ryanodine an inhibitor of the sarcoplasmic reticulum Ca++ channel (Series 5A+B), modulated sevoflurane-mediated vasodilation. RESULTS: Sevoflurane produced dose dependent vasodilatation of chorionic plate arterial rings in all studies. Prior blockade of the KCa++ and KATP channels augmented the vasodilator effects of sevoflurane. Furthermore, exposure of rings to sevoflurane in advance of TEA occluded the effects of TEA. Taken together, these findings suggest that sevoflurane blocks K+ channels. Blockade of the voltage-operated Ca++channels inhibited the vasodilator effects of sevoflurane. In contrast, blockade of the voltage-independent and sarcoplasmic reticulum Ca++channels did not alter sevoflurane vasodilation. CONCLUSION: Sevoflurane appears to block chorionic arterial KCa++ and KATP channels. Sevoflurane also blocks voltage-operated calcium channels, and exerts a net vasodilatory effect in the in vitro foeto-placental circulation.
RESUMO
BACKGROUND: Aerosol delivery through an endotracheal tube during mechanical ventilation of small animals, simulating neonates and small infants, has shown to be influenced by a variety of factors including aerosol generator type, droplet/particle size, ventilator circuitry and ventilation regime. A review of the literature indicates that reported aerosol deposition rates in rodents are quite low, with lung deposition in anesthetized, mechanically ventilated rats reported to be approximately 3.9 and approximately 8% in anesthetized, spontaneously breathing rats. The optimization of aerosol delivery to both in vitro and in vivo models of anesthetized mechanically ventilated rodents is described in this study. METHODS: Characterization and optimization of the in vitro system performance relied on gravimetric analysis, laser diffraction droplet sizing, and spectrophotometric analysis of drug mass on inspiratory filters. The optimized setup was subsequently employed in vivo to determine deposition of a tracer aerosol in the rat lung. RESULTS: In vitro testing confirmed that droplet size, ventilation regimen, breath actuation setting, and the inclusion of a drug recycling step had the greatest effect on inhaled mass. During testing, improvements of up to 41% were seen in inhaled mass values between runs with the addition of a recycling step. The negative effects of the aerosolization process on albuterol sulphate were minimal. In vitro deposition rates of 29.95 +/- 1.54% of the original dose were recorded (n = 3). In vivo deposition rates of Evans blue were highly comparable (30.88 +/- 5.73%) (n = 6). Intratracheal instillation of the tracer dye resulted in deposition of 87.34 +/- 6.23% of the original dose. CONCLUSIONS: This optimized experimental setup allows for greater inhaled mass than previously reported. The addition of a recycling step may prove to be a significant improvement in achieving higher deposition in mechanically ventilated lungs; however, the suitability of the test agent for repeated nebulization needs assessment.
Assuntos
Albuterol/administração & dosagem , Broncodilatadores/administração & dosagem , Sistemas de Liberação de Medicamentos , Respiração Artificial , Administração por Inalação , Aerossóis , Albuterol/farmacocinética , Animais , Broncodilatadores/farmacocinética , Química Farmacêutica/métodos , Azul Evans/administração & dosagem , Intubação Intratraqueal , Pulmão/metabolismo , Masculino , Nebulizadores e Vaporizadores , Tamanho da Partícula , Ratos , Ratos Sprague-Dawley , Distribuição TecidualRESUMO
BACKGROUND: Intubation of the trachea in the pre-hospital setting may be lifesaving in severely ill and injured patients. However, tracheal intubation is frequently difficult to perform in this challenging environment, is associated with a lower success rate, and failed tracheal intubation constitutes an important cause of morbidity. Novel indirect laryngoscopes, such as the Glidescope and the AWS laryngoscopes may reduce this risk. METHODS: We compared the efficacy of these devices to the Macintosh laryngoscope when used by 25 Advanced Paramedics proficient in direct laryngoscopy, in a randomized, controlled, manikin study. Following brief didactic instruction with the Glidescope and the AWS laryngoscopes, each participant took turns performing laryngoscopy and intubation with each device, in an easy intubation scenario and following placement of a hard cervical collar, in a SimMan manikin. RESULTS: Both the Glidescope and the AWS performed better than the Macintosh, and demonstrate considerable promise in this context. The AWS had the least number of dental compressions in all three scenarios, and in the cervical spine immobilization scenario it required fewer maneuvers to optimize the view of the glottis. CONCLUSION: The Glidescope and AWS devices possess advantages over the conventional Macintosh laryngoscope when used by Advanced Paramedics in normal and simulated difficult intubation scenarios in this manikin study. Further studies are required to extend these findings to the clinical setting.
Assuntos
Pessoal Técnico de Saúde/educação , Intubação Intratraqueal , Laringoscópios/normas , Software , Desenho de Equipamento , Humanos , ManequinsRESUMO
OBJECTIVES: Sildenafil citrate, a specific phosphodiesterase-5 inhibitor, is increasingly used for pulmonary hypertension in pregnancy. Sildenafil is also emerging as a potential candidate for the treatment of intra-uterine growth retardation and for premature labor. Its effects in the feto-placental circulation are not known. Our objectives were to determine whether phosphodiesterase-5 is present in the human feto-placental circulation, and to characterize the effects and mechanisms of action of sildenafil citrate in this circulation. STUDY DESIGN: Ex vivo human chorionic plate arterial rings were used in all experiments. The presence of phosphodiesterase-5 in the feto-placental circulation was determined by western blotting and immunohistochemical staining. In a subsequent series of pharmacologic studies, the effects of sildenafil citrate in pre-constricted chorionic plate arterial rings were determined. Additional studies examined the role of cGMP and nitric oxide in mediating the effects of sildenafil. RESULTS: Phosphodiesterase-5 mRNA and protein was demonstrated in human chorionic plate arteries. Immunohistochemistry demonstrated phosphodiesterase-5 within the arterial muscle layer. Sildenafil citrate produced dose dependent vasodilatation at concentrations at and greater than 10 nM. Both the direct cGMP inhibitor methylene blue and the cGMP-dependent protein kinase inhibitor Rp-8-Br-PET-cGMPS significantly attenuated the vasodilation produced by sildenafil citrate. Inhibition of NO production with L-NAME did not attenuate the vasodilator effects of sildenafil. In contrast, sildenafil citrate significantly enhanced the vasodilation produced by the NO donor sodium nitroprusside. CONCLUSION: Phosphodiesterase-5 is present in the feto-placental circulation. Sildenafil citrate vasodilates the feto-placental circulation via a cGMP dependent mechanism involving increased responsiveness to NO.
Assuntos
Córion/irrigação sanguínea , Inibidores de Fosfodiesterase/farmacologia , Piperazinas/farmacologia , Circulação Placentária/efeitos dos fármacos , Sulfonas/farmacologia , Vasodilatadores/farmacologia , Adolescente , Adulto , Artérias/efeitos dos fármacos , Artérias/metabolismo , Córion/efeitos dos fármacos , Córion/metabolismo , GMP Cíclico/antagonistas & inibidores , GMP Cíclico/fisiologia , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5/metabolismo , Feminino , Humanos , Técnicas In Vitro , Óxido Nítrico/biossíntese , Óxido Nítrico/fisiologia , Inibidores da Fosfodiesterase 5 , Inibidores de Fosfodiesterase/farmacocinética , Piperazinas/farmacocinética , Gravidez , Purinas/farmacocinética , Purinas/farmacologia , RNA Mensageiro/metabolismo , Citrato de Sildenafila , Sulfonas/farmacocinética , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacocinéticaRESUMO
BACKGROUND: Paramedics are frequently required to perform tracheal intubation, a potentially life-saving manoeuvre in severely ill patients, in the prehospital setting. However, direct laryngoscopy is often more difficult in this environment, and failed tracheal intubation constitutes an important cause of morbidity. Novel indirect laryngoscopes, such as the Airtraq and Truview laryngoscopes may reduce this risk. METHODS: We compared the efficacy of these devices to the Macintosh laryngoscope when used by 21 Paramedics proficient in direct laryngoscopy, in a randomized, controlled, manikin study. Following brief didactic instruction with the Airtraq and Truview laryngoscopes, each participant took turns performing laryngoscopy and intubation with each device, in an easy intubation scenario and following placement of a hard cervical collar, in a SimMan manikin. RESULTS: The Airtraq reduced the number of optimization manoeuvres and reduced the potential for dental trauma when compared to the Macintosh, in both the normal and simulated difficult intubation scenarios. In contrast, the Truview increased the duration of intubation attempts, and required a greater number of optimization manoeuvres, compared to both the Macintosh and Airtraq devices. CONCLUSION: The Airtraq laryngoscope performed more favourably than the Macintosh and Truview devices when used by Paramedics in this manikin study. Further studies are required to extend these findings to the clinical setting.
Assuntos
Medicina de Emergência/instrumentação , Intubação Intratraqueal/instrumentação , Laringoscópios , Análise de Variância , Estudos Cross-Over , Medicina de Emergência/métodos , Desenho de Equipamento , Humanos , Intubação Intratraqueal/métodos , ManequinsRESUMO
OBJECTIVE: Deliberate induction of hypercapnic acidosis protects against lung injury after nonseptic lung injury. In contrast, concerns exist regarding the effects of hypercapnic acidosis in the setting of severe pulmonary sepsis. The potential for the effects of hypercapnic acidosis to be neutrophil-mediated remains to be determined. We investigated whether hypercapnic acidosis--induced by adding CO2 to inspired gas--would protect against severe acute lung injury induced by pulmonary Escherichia coli instillation and the role of neutrophils in mediating this effect. DESIGN: Prospective randomized animal study. SETTING: University Research Laboratory. SUBJECTS: Adult male Sprague-Dawley rats. INTERVENTIONS: In series 1, after induction of anesthesia and tracheostomy placement, animals were randomized to normocapnia (FICO2 0.00, n = 12) or hypercapnic acidosis (FICO2 0.05, n = 12). E. coli (0.5-3.0 x 10(15) colony-forming units) was instilled intratracheally and the animals were ventilated for 6 hrs to allow a severe acute lung injury to evolve. In series 2, animals were randomized to neutrophil depletion or nondepletion before bacterial instillation, in a three-group design: normocapnia alone (Normo + polymorphonuclear neutrophils [PMN], n = 9), normocapnia with neutrophil depletion (Normo - PMN, n = 9), or hypercapnic acidosis with neutrophil depletion (hypercapnic acidosis - PMN, n = 9). After intratracheal E. coli administration these animals were also ventilated for 6 hrs. RESULTS: Hypercapnic acidosis protected against evolving pneumonia-induced acute lung injury, attenuating the increase in airway pressure, and the decrement in lung compliance and arterial PO2. However, hypercapnic acidosis did not reduce histologic injury. Hypercapnic acidosis also protected against evolving pneumonia-induced acute lung injury in the presence of neutrophil depletion, reducing both physiologic and histologic indices of lung injury. CONCLUSIONS: Hypercapnic acidosis reduces indices of intratracheal E. coli induced lung injury by a mechanism that seems to be neutrophil-independent.
Assuntos
Acidose/fisiopatologia , Lesão Pulmonar Aguda/prevenção & controle , Infecções por Escherichia coli/complicações , Hipercapnia/fisiopatologia , Neutrófilos/fisiologia , Pneumonia Bacteriana/complicações , Lesão Pulmonar Aguda/etiologia , Lesão Pulmonar Aguda/fisiopatologia , Animais , Dióxido de Carbono/sangue , Dióxido de Carbono/uso terapêutico , Modelos Animais de Doenças , Escherichia coli , Infecções por Escherichia coli/microbiologia , Concentração de Íons de Hidrogênio , Pulmão/patologia , Pulmão/fisiopatologia , Masculino , Pneumonia Bacteriana/microbiologia , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Mecânica RespiratóriaRESUMO
BACKGROUND: Hypercapnic acidosis protects against lung injury after ischemia-reperfusion, endotoxin-induced and ventilation-induced lung injury. The effects of hypercapnic acidosis in the setting of established pulmonary sepsis are not known. The authors investigated whether hypercapnic acidosis -- induced by adding carbon dioxide to inspired gas -- would be beneficial or deleterious in established Escherichia coli pneumonia in an in vivo model, in the presence and absence of antibiotic therapy. METHODS: Adult male Sprague-Dawley rats were anesthetized and ventilated. In the first set of experiments, rats were anesthetized, E. coli (5-6.4 x 10(9)/ml colony-forming units) was instilled intratracheally, and the animals were allowed to recover. After 6 h, during which time a severe pneumonia developed, they were reanesthetized and randomly assigned to normocapnia (fraction of inspired carbon dioxide [Fico(2)] = 0.00, n = 10) or hypercapnic acidosis (Fico(2) = 0.05, n = 10). The second set of experiments was performed in a manner identical to that of series 1, but all rats (n = 10 per group) were given intravenous ceftriaxone (30 mg/kg) at randomization. All animals received normocapnia or hypercapnic acidosis for 6 h, and the severity of lung injury was assessed. RESULTS: In the absence of antibiotic therapy, hypercapnic acidosis reduced the pneumonia-induced increase in peak airway pressure and the decrease in static lung compliance compared with control conditions. In the presence of antibiotic therapy, which substantially reduced lung bacterial counts, hypercapnic acidosis significantly attenuated the extent of pneumonia-induced histologic injury. CONCLUSIONS: Hypercapnic acidosis reduced the magnitude of the lung injury induced by established E. coli pneumonia.
Assuntos
Acidose Respiratória/metabolismo , Infecções por Escherichia coli/metabolismo , Infecções por Escherichia coli/prevenção & controle , Hipercapnia/metabolismo , Pneumonia Bacteriana/metabolismo , Pneumonia Bacteriana/prevenção & controle , Acidose Respiratória/microbiologia , Animais , Infecções por Escherichia coli/microbiologia , Hipercapnia/microbiologia , Pulmão/metabolismo , Pulmão/microbiologia , Pneumopatias/metabolismo , Pneumopatias/microbiologia , Pneumopatias/prevenção & controle , Masculino , Pneumonia Bacteriana/microbiologia , Ratos , Ratos Sprague-DawleyRESUMO
BACKGROUND: Hypertonic saline (HTS) reduces the severity of lung injury in ischemia-reperfusion, endotoxin-induced and ventilation-induced lung injury. However, the potential for HTS to modulate the resolution of lung injury is not known. We investigated the potential for hypertonic saline to modulate the evolution and resolution of oleic acid induced lung injury. METHODS: Adult male Sprague Dawley rats were used in all experiments. Series 1 examined the potential for HTS to reduce the severity of evolving oleic acid (OA) induced acute lung injury. Following intravenous OA administration, animals were randomized to receive isotonic (Control, n = 12) or hypertonic saline (HTS, n = 12), and the extent of lung injury assessed after 6 hours. Series 2 examined the potential for HTS to enhance the resolution of oleic acid (OA) induced acute lung injury. Following intravenous OA administration, animals were randomized to receive isotonic (Control, n = 6) or hypertonic saline (HTS, n = 6), and the extent of lung injury assessed after 6 hours. RESULTS: In Series I, HTS significantly reduced bronchoalveolar lavage (BAL) neutrophil count compared to Control [61.5 +/- 9.08 versus 102.6 +/- 11.89 x 10(3) cells.ml-1]. However, there were no between group differences with regard to: A-a O2 gradient [11.9 +/- 0.5 vs. 12.0 +/- 0.5 KPa]; arterial PO2; static lung compliance, or histologic injury. In contrast, in Series 2, hypertonic saline significantly reduced histologic injury and reduced BAL neutrophil count [24.5 +/- 5.9 versus 46.8 +/- 4.4 x 10(3) cells.ml-1], and interleukin-6 levels [681.9 +/- 190.4 versus 1365.7 +/- 246.8 pg.ml-1]. CONCLUSION: These findings demonstrate, for the first time, the potential for HTS to reduce pulmonary inflammation and enhance the resolution of oleic acid induced lung injury.
Assuntos
Pneumopatias/induzido quimicamente , Pneumopatias/tratamento farmacológico , Ácido Oleico , Pneumonia/tratamento farmacológico , Solução Salina Hipertônica/uso terapêutico , Doença Aguda , Animais , Líquido da Lavagem Broncoalveolar/citologia , Interleucina-6/sangue , Contagem de Leucócitos , Pneumopatias/complicações , Pneumopatias/patologia , Masculino , Neutrófilos/patologia , Pneumonia/sangue , Pneumonia/etiologia , Pneumonia/patologia , Ratos , Ratos Sprague-DawleyRESUMO
BACKGROUND: The effects and mechanisms of action of volatile anesthetics on the feto-placental vasculature are not known. We aimed to quantify the vasoactive effects of sevoflurane and determine the role of nitric oxide (NO) and of vasoactive eicosanoids in mediating these effects in isolated human chorionic plate arterial rings. METHODS: Quadruplicate ex vivo human chorionic plate arterial rings were used in all studies. Series 1 quantified the vasodilation produced by sevoflurane in rings preconstricted with the thromboxane analog U46619. Series 2A-C examined the role of NO in sevoflurane-mediated vasodilation. In separate experiments, we examined the potential for the nonspecific NO inhibitors, L-NAME, L-nMMA, and the inactive D-NAME, to modulate the vasodilation produced by sevoflurane. Series 2D determined whether sevoflurane altered vascular smooth muscle sensitivity to exogenous NO. Series 3A-D examined the role of vasoactive eicosanoids in sevoflurane-mediated vasodilation. In separate experimental series, we examined whether the nonspecific cyclooxygenase inhibitor, indomethacin, or the 5-lipoxygenase inhibitor, nordihydroguaiaretic acid, modulated sevoflurane-mediated vasodilation. RESULTS: Sevoflurane produced dose-dependent vasodilation of preconstricted chorionic plate arterial rings, with mean ring vasodilation increasing from 15 +/- 7% at 2% sevoflurane to 67 +/- 17% (mean +/- sd) at 8% sevoflurane. Blockade of NO synthase did not attenuate the vasodilator effects of sevoflurane. Sevoflurane did not alter smooth muscle sensitivity to NO. Indomethacin augmented sevoflurane vasodilation at 10(-5) M, but not at 10(-6) M. Conversely, nordihydroguaiaretic acid attenuated sevoflurane-mediated vasodilation at 3 x 10(-6) M but not at 3 x 10(-7) M. CONCLUSIONS: Sevoflurane was a vasodilator in the feto-placental vasculature in this in vitro model. Sevoflurane-mediated vasodilation is NO and cyclooxygenase-independent and appears to be mediated in part via a lipoxygenase generated vasodilator eicosanoid.
Assuntos
Anestésicos Inalatórios/farmacologia , Eicosanoides/fisiologia , Feto/irrigação sanguínea , Éteres Metílicos/farmacologia , Óxido Nítrico/fisiologia , Placenta/irrigação sanguínea , Relação Dose-Resposta a Droga , Feminino , Humanos , Técnicas In Vitro , Indometacina/farmacologia , Masoprocol/farmacologia , Nitroprussiato/farmacologia , Gravidez , Sevoflurano , Vasodilatação/efeitos dos fármacos , ômega-N-Metilarginina/farmacologiaRESUMO
The Airtraq laryngoscope is a novel intubation device that may possess advantages over conventional direct laryngoscopes for use by personnel that are infrequently required to perform tracheal intubation. We conducted a prospective study in 20 medical residents with little prior airway management experience. After brief didactic instruction, each participant took turns performing laryngoscopy and intubation using the Macintosh (Welch Allyn, Welch Allyn, NY) and Airtraq (Prodol Ltd. Vizcaya, Spain) devices, in 3 laryngoscopy scenarios in a Laerdal Intubation Trainer (Laerdal, Stavanger, Norway) and 1 scenario in a Laerdal SimMan manikin (Laerdal, Kent, UK). They then performed tracheal intubation of the normal airway a second time to characterize the learning curve. In all scenarios tested, the Airtraq decreased the duration of intubation attempts, reduced the number of optimization maneuvers required, and reduced the potential for dental trauma. The residents found the Airtraq easier to use in all scenarios compared with the Macintosh laryngoscope. The Airtraq may constitute a superior device for use by personnel infrequently required to perform tracheal intubation.