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BACKGROUND: Remimazolam, a novel intravenous benzodiazepine recently approved by both the European Medicines Agency and the Food and Drug Agency, shows considerable promise in clinical practice. Its pharmacodynamic profile closely resembles that of midazolam, while its pharmacokinetic properties are similar to those of remifentanil. While research in adult populations continues to accumulate, the pace of pediatric studies is not as significant. This scoping review aims to systematically examine published studies, clinical trials, observational research, case reports, and relevant literature to provide a comprehensive understanding of remimazolam in pediatric sedation and anesthesia. By synthesizing the gathered evidence, we aim to identify gaps in the literature, guide future research endeavors, and inform clinical practices. METHODS: The review follows the guidelines outlined by the Preferred Reporting Items for Systematic Review and Meta-Analysis for Scoping Review. A thorough search strategy was implemented across prominent peer-reviewed databases, with focused efforts to identify relevant grey literature. All primary studies involving the use of remimazolam in pediatric populations were included in this review. RESULTS: Eighteen studies were included in this analysis, comprising 2 randomized controlled trials, 4 prospective cohort trials, 12 case reports, and 692 children in total. CONCLUSION: This scoping review highlights the increasing interest in using remimazolam as a sedative or anesthetic for children. Although initial evidence indicates its effectiveness and safety, more research is necessary to fill knowledge gaps, establish standard protocols, and optimize its use in pediatric anesthesia and sedation. Addressing these challenges will enable clinicians to improve the quality of care and outcomes for pediatric patients undergoing sedation and anesthesia.
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Benzodiazepinas , Hipnóticos y Sedantes , Humanos , Niño , Benzodiazepinas/farmacocinética , Benzodiazepinas/administración & dosificación , Hipnóticos y Sedantes/farmacocinética , Hipnóticos y Sedantes/administración & dosificación , Anestesia/métodos , Preescolar , Lactante , AdolescenteRESUMEN
INTRODUCTION: The impact of therapeutic plasma exchange (TPE) on short-term mortality in adult patients with sepsis-induced organ dysfunction remains uncertain. The objective of the study is to assess the effect of adjunct TPE in this setting through a comprehensive literature review. METHODS: The National Library of Medicine's Medline, Ovid (Embase), the Cochrane Library database and clinicaltrial.gov from January 01, 1966, until October 01, 2022, were searched for terms: therapeutic plasma exchange, plasmapheresis, sepsis, and septic shock. We reviewed, selected and extracted data from relevant randomized clinical trials (RCTs) and matched cohort studies (MCSs) comparing short-term mortality in critically ill adult septic patients treated with standard therapy versus those receiving adjunct TPE. Risk of bias was assessed in the RCTs using Cochrane Collaboration tool and in MCSs using ROBINS-I tool. Summary statistics, risk ratios (RRs), and confidence intervals (CIs) were calculated using random effects model. RESULTS: This systematic review included 937 adult critically ill septic patients from five RCTs (n = 367) and fifteen MCSs (n = 570). Of these total, 543 received treatment with TPE in addition to standard care. The meta-analysis includes all five RCTs and only six MCSs (n = 627). The adjunct TPE treatment (n = 300) showed a significant reduction in short-term mortality (RR 0.59, 95% CI 0.47-0.74, I2 3%) compared to standard therapy alone (n = 327). The systematic review of all 20 trials revealed that adding TPE to the standard therapy of critically ill septic patients resulted in faster clinical and/or laboratory recovery. CONCLUSIONS: Our comprehensive and up-to-date review demonstrates that adjunct TPE may provide potential survival benefits when compared to standard care for critically ill adult patients with sepsis-induced organ dysfunction. While results of this meta-analysis are encouraging, large well-designed randomized trials are required to identify the optimal patient population and TPE procedure characteristics prior to widespread adoption into practice.
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Sepsis , Choque Séptico , Adulto , Humanos , Intercambio Plasmático/métodos , Enfermedad Crítica/terapia , Insuficiencia Multiorgánica/etiología , Insuficiencia Multiorgánica/terapia , Sepsis/terapia , Sepsis/tratamiento farmacológico , Choque Séptico/tratamiento farmacológicoRESUMEN
Agglomeration of distributed particles is the main problem in polymer composites reinforced with such particles. It leads to a decrease in mechanical performance and its poor reproducibility. Thus, development of methods to address the agglomeration of particles is relevant. Evaluation of the size and concentration of agglomerates is required to select a method to address agglomeration. The paper analyzes aluminum oxide particles agglomeration in particles-reinforced polymethyl methacrylate (PMMA) composites. Quantitative parameters of polystyrene-coated aluminum oxide particles agglomerates are obtained for the first time in this article. Unlike uncoated aluminum oxide particles, when coated aluminum oxide particles are used, agglomerates concentration in polymer composites decreases approx. 10 times. It demonstrates that modification of submicron particles by a polymer coating decreases the number of agglomerates in the polymer composite. The use of transmittance and opacity values to estimate particles agglomerates is reasonable in this article. It is shown that the difference in optical performance of specimens reinforced with coated and the original particles is related to the number and average size of agglomerates in the specimens. For example, when the concentration exceeds 0.2%, transmittance values for the specimens reinforced with coated particles are greater than the ones for the specimens reinforced with the original particles.
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Aluminio , Polimetil Metacrilato , Óxido de Aluminio , Reproducibilidad de los Resultados , PolímerosRESUMEN
Objects and structures made of organic glass require protection from damage caused by external factors. Light, humidity, temperature, dust pollution and, undoubtedly, microorganisms lead to the deterioration of optical and mechanical properties. Polysiloxane-based protective coatings, consisting of silicon-oxygen backbones linked together with organic side groups attached to the silicon atoms, are widely used. However, the polysiloxane coatings themselves also cannot avoid deterioration during operation that implies the constant development of new protective materials. Here, we created a new cross-linked polysiloxane that covers organic glasses to enhance their resistance to aggressive external factors, and investigated its own resistance to damage induced by micromycetes in natural tropical conditions and in the laboratory. It has been established that the surface of coatings in the tropics is prone to fouling with micromycetes, mainly of the genera Aspergillus and Penicillium, which produce oxalic, malic, lactic, and citric acids contributing to the biodeterioration of polysiloxane. The testing of monolithic polycarbonate, polymethyl methacrylate, and triplex coated with polysiloxane showed that they retained significant resistance to abrasion and transparency at a level of more than 90% under aggressive natural conditions. Under artificial laboratory conditions, the infection of samples with micromycete spores also revealed their growth on surfaces and a similar trend of damage.
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BACKGROUND: In different models of hypoxia, blockade of opioid or N-methyl-D-aspartate (NMDA) receptors shows cardio- and neuroprotective effects with a consequent increase in animal survival. The aim of the study was to investigate effects of pre-treatment with Morphine or Ketamine on hemodynamic, acid-base status, early survival, and biochemical markers of brain damage in a rat model of asphyxial cardiac arrest (ACA). METHODS: Under anaesthesia with Thiopental Sodium 60 mg/kg, i.p., Wistar rats (n = 42) were tracheostomized and catheters were inserted in a femoral vein and artery. After randomization, the rats were pre-treated with: Morphine 5 mg/kg i.v. (n = 14); Ketamine 40 mg/kg i.v. (n = 14); or equal volume of i.v. NaCl 0.9% as a Control (n = 14). ACA was induced by corking of the tracheal tube for 8 min, and defined as a mean arterial pressure (MAP) < 20 mmHg. Resuscitation was started at 5 min after cardiac arrest (CA). Invasive MAP was recorded during experiments. Arterial pH and blood gases were sampled at baseline (BL) and 10 min after CA. At the end of experiments, all surviving rats were euthanised, brain and blood samples for measurement of Neuron Specific Enolase (NSE), s100 calcium binding protein B (s100B) and Caspase-3 (CS-3) were retrieved. RESULTS: At BL no differences between groups were found in hemodynamic or acid-base status. After 3 min of asphyxia, all animals had cardiac arrest (CA). Return of spontaneous circulation (MAP > 60 mmHg) was achieved in all animals within 3 min after CA. At the end of the experiment, the Ketamine pre-treated group had increased survival (13 of 14; 93%) compared to the Control (7 of 14; 50%) and Morphine (10 of 14; 72%) groups (p = 0.035). Biochemical analysis of plasma concentration of NSE and s100B as well as an analysis of CS-3 levels in the brain tissue did not reveal any differences between the study groups. CONCLUSION: In rats after ACA, pre-treatment with Morphine or Ketamine did not have any significant influence on hemodynamic and biochemical markers of brain damage. However, significantly better pH level and increased early survival were found in the Ketamine pre-treated group.
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Lesiones Encefálicas/etiología , Paro Cardíaco/terapia , Ketamina/farmacología , Morfina/farmacología , Analgésicos Opioides/administración & dosificación , Analgésicos Opioides/farmacología , Animales , Asfixia/complicaciones , Análisis de los Gases de la Sangre , Lesiones Encefálicas/fisiopatología , Reanimación Cardiopulmonar , Modelos Animales de Enfermedad , Antagonistas de Aminoácidos Excitadores/administración & dosificación , Antagonistas de Aminoácidos Excitadores/farmacología , Paro Cardíaco/complicaciones , Paro Cardíaco/fisiopatología , Hemodinámica/efectos de los fármacos , Concentración de Iones de Hidrógeno , Ketamina/administración & dosificación , Masculino , Morfina/administración & dosificación , Ratas , Ratas Wistar , SobrevidaRESUMEN
BACKGROUND: We recently introduced the efficacy safety score (ESS) as a new "call-out algorithm" for management of postoperative pain and side effects. In this study, we report the influence of ESS recorded hourly during the first 8 hours after surgery on the mobility degree, postoperative nonsurgical complications, and length of hospital stay (LOS). METHODS: We randomized 1152 surgical patients into three groups for postoperative observation: (1) ESS group (n = 409), (2) Verbal Numeric Rate Scale (VNRS) for pain group (n = 417), and (3) an ordinary qualitative observation (Control) group (n = 326). An ESS > 10 or VNRS > 4 at rest or a nurse's observation of pain or adverse reaction to analgesic treatment in the Control group served as a "call-out alarm" for an anaesthesiologist. RESULTS: We found no significant differences in the mobility degree and number of postoperative nonsurgical complications between the groups. LOS was significantly shorter with 12.7 ± 6.3 days (mean ± SD) in the ESS group versus 14.2 ± 6.2 days in the Control group (P < 0.001). CONCLUSION: Postoperative ESS recording in combination with the possibility to call upon an anaesthesiologist when exceeding the threshold score might have contributed to the reductions of LOS in this two-centre study. This trial is registered with NCT02143128.
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Algoritmos , Tiempo de Internación , Dimensión del Dolor , Dolor Postoperatorio/diagnóstico , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Dolor Postoperatorio/tratamiento farmacológico , Complicaciones Posoperatorias/epidemiología , Estudios ProspectivosRESUMEN
BACKGROUND: Several reports have shown that postoperative monitoring of general safety and quality issues, including pain treatment, after discharge from recovery is often non-systematic and inadequate. We suggest a new score with assessment of key recovery parameters, as a supportive tool for postoperative care and a call-out algorithm for need of extra help. The aim of this investigation was to validate the score. METHODS: After suggesting a prototype score from a pilot study in 182 postoperative patients, we performed a Delphi process by using international experts to create consensus on the final score contents and called the revised tool the Efficacy Safety Score (ESS). Then, we performed a prospective observational study with the ESS throughout the first 24 h postoperatively in 207 surgical in-patients. We compared ESS with Modified Early Warning Systems (MEWS), and postoperative journal information. We subsequently validated ESS by addressing recognized quality criteria for measurement of health status questionnaires. RESULTS: A call-out value of ESS ≥10 correlated with MEWS > 0 values and journal information about postoperative concerns with a sensitivity of 94% and 92%, respectively. All serious safety issues were identified with the ESS ≥ 10, and a higher number of quality issues were identified than with routine care or MEWS. We obtained positive ratings for six out of seven tested criteria of questionnaire quality; one criterion had an indeterminate rating. CONCLUSION: ESS fulfils suggested criteria for score quality validation and reflects the patient's postoperative status adequately and with high sensitivity. Further clinical trials are warranted to evaluate the usefulness of ESS as a simple tool for assessment of the postoperative safety and quality of patients.
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Indicadores de Salud , Atención al Paciente/instrumentación , Seguridad del Paciente , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Lista de Verificación/instrumentación , Femenino , Humanos , Masculino , Persona de Mediana Edad , Periodo Posoperatorio , Estudios Prospectivos , Adulto JovenRESUMEN
BACKGROUND: Experimental studies both in vivo and in vitro show significantly increased survival rate in animals and in cortical neurons respectively exposed to acute hypoxia and pre-treated with opioids compared to non-treated counterparts. Thus, the main aim of the study was to examine survival rates in patients after sudden cardiac arrest (SCA) in the hospital who were or were not treated with opioids before and/or during cardiac pulmonary resuscitation (CPR). METHODS: The registry SCA database at the University Hospital of Northern Norway (UNN) for the period of January 2006-December 2009 was used to obtain data for the evaluation. Inclusion criteria were observed SCA at UNN for patients with American Society of Anesthesiologists (ASA) 1-3. Exclusion criteria included ASA four to five patients and unobserved SCA. Study patients were divided into two groups: Those not treated with opioids and those treated with opioids not more then 3 h before and/or during CPR. Survival rate 1, 2, 3 and 28 days post CPR were compared for the two groups. RESULTS: A total of 117 patients were registered in the SCA database at UNN for the period from January 2006 to December 2009. Sixty seven patients were excluded from the study: 17 patients had an unknown time of SCA dιbut, two patients had only syncope and 48 were ASA four to five patients. A total of 50 ASA one to three patients were included in the study, 33 and 17 patients respectively in the control and opioid-treated groups. The patients who were treated with opioids before or during CPR had a significantly higher 1, 2, 3 and 28 days survival rate as compared to those receiving only conventional CPR. The model was adjusted for duration of CPR (P=0.047) and treatment with adrenaline (P=0.779) in the groups. Adjusted Odds ratio was 0.075 (95% confidence interval (CI): 0.015-0.387). Relative risk of fatal outcome in the opioids group was 0.2944 (95% CI: 0.1549-0.5594). CONCLUSION: Significantly higher 1, 2, 3 and 28 days survival rate and reduced duration of CPR were found in the patients additionally treated with opioids compared to ordinary resuscitation. Further prospective, randomized, controlled trials are needed to investigate the effects of early administration of opioids during CPR on survival and brain function in patients with witnessed in-hospital SCA.
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INTRODUCTION: We recently demonstrated that intravenously infused recombinant human activated protein C (APC) attenuates ovine lipopolysaccharide (LPS)-induced lung injury. In this study, our aim was to find out whether treatment with inhaled aerosolised APC (inhAPC) prevents formation of increased lung densities and oedema and derangement of oxygenation during exposure to LPS. METHODS: Sheep were anaesthetised during placement of intravascular introducers. After one to four days of recovery from instrumentation, the animals were re-anaesthetised, endotracheally intubated and mechanically ventilated throughout a six-hour experiment where the sheep underwent quantitative lung computed tomography. Sheep were randomly assigned to one of three groups: a sham-operated group (n = 8) receiving inhaled aerosolised saline from two hours after the start of the experiment; a LPS group (n = 8) receiving an intravenous infusion of LPS 20 ng/kg per hour and, after two hours, inhaled aerosolised saline over the next four hours; a LPS+inhAPC group (n = 8) receiving an intravenous infusion of LPS 20 ng/kg per hour and, after two hours, aerosolised APC 48 microg/kg per hour inhaled throughout the experiment. Data were analysed with analysis of variance; P less than 0.05 was regarded as significant. RESULTS: An infusion of LPS was associated with a reduction of well-aerated lung volume and a rapid fall in arterial oxygenation that were both significantly antagonised by inhaled APC. Pulmonary vascular pressures and extravascular lung water index increased significantly during exposure to LPS, but inhaled APC had no effect on these changes. CONCLUSIONS: Inhalation of aerosolised APC attenuates LPS-induced lung injury in sheep by preventing a decline in the volume of aerated lung tissue and improving oxygenation.
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Lesión Pulmonar Aguda/prevención & control , Aerosoles , Modelos Animales de Enfermedad , Lipopolisacáridos/toxicidad , Proteína C/uso terapéutico , Lesión Pulmonar Aguda/inducido químicamente , Lesión Pulmonar Aguda/fisiopatología , Administración por Inhalación , Animales , Consumo de Oxígeno/efectos de los fármacos , Proteína C/administración & dosificación , Proteína C/farmacología , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/farmacología , Proteínas Recombinantes/uso terapéutico , OvinosRESUMEN
INTRODUCTION: Acute lung injury (ALI) may arise both after sepsis and non-septic inflammatory conditions and is often associated with the release of fatty acids, including oleic acid (OA). Infusion of OA has been used extensively to mimic ALI. Recent research has revealed that intravenously administered recombinant human activated protein C (rhAPC) is able to counteract ALI. Our aim was to find out whether rhAPC dampens OA-induced ALI in sheep. METHODS: Twenty-two yearling sheep underwent instrumentation. After 2 days of recovery, animals were randomly assigned to one of three groups: (a) an OA+rhAPC group (n = 8) receiving OA 0.06 mL/kg infused over the course of 30 minutes in parallel with an intravenous infusion of rhAPC 24 mg/kg per hour over the course of 2 hours, (b) an OA group (n = 8) receiving OA as above, or (c) a sham-operated group (n = 6). After 2 hours, sheep were sacrificed. Hemodynamics was assessed by catheters in the pulmonary artery and the aorta, and extravascular lung water index (EVLWI) was determined with the single transpulmonary thermodilution technique. Gas exchange was evaluated at baseline and at cessation of the experiment. Data were analyzed by analysis of variance; a P value of less than 0.05 was regarded as statistically significant. RESULTS: OA induced profound hypoxemia, increased right atrial and pulmonary artery pressures and EVLWI markedly, and decreased cardiac index. rhAPC counteracted the OA-induced changes in EVLWI and arterial oxygenation and reduced the OA-induced increments in right atrial and pulmonary artery pressures. CONCLUSIONS: In ovine OA-induced lung injury, rhAPC dampens the increase in pulmonary artery pressure and counteracts the development of lung edema and the derangement of arterial oxygenation.
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Fibrinolíticos/farmacología , Lesión Pulmonar/tratamiento farmacológico , Proteína C/farmacología , Proteínas Recombinantes/farmacología , Animales , Modelos Animales de Enfermedad , Fibrinolíticos/administración & dosificación , Fibrinolíticos/uso terapéutico , Lesión Pulmonar/inducido químicamente , Noruega , Ácido Oléico , Proteína C/administración & dosificación , Proteína C/uso terapéutico , Distribución Aleatoria , OvinosRESUMEN
INTRODUCTION: Acute lung injury often complicates severe sepsis. In gram-negative sepsis, bacterial endotoxin activates both coagulation and inflammation. Enhanced lung vascular pressures and permeability, increased extravascular lung water content and deteriorated gas exchange characterize ovine endotoxin-induced lung injury, a frequently used model of acute lung injury. Recombinant human activated protein C (rhAPC), with its anticoagulant, anti-inflammatory, fibrinolytic and antiapoptotic effects, reportedly reduces the respirator-dependent days and the mortality of patients with severe sepsis. We speculate whether rhAPC antagonizes endotoxin-induced lung injury in sheep. METHODS: Two groups of sheep were exposed to Escherichia coli endotoxin (lipopolysaccharide) 15 ng/kg/minute intravenously from 0 to 24 hours; one group received only lipopolysaccharide throughout (n = 8), and the other group received lipopolysaccharide in combination with rhAPC 24 microg/kg/hour from 4 to 24 hours (n = 9). In addition, one group received rhAPC as above as the only intervention (n = 4), and four sham-operated sheep were used for determination of the alpha and epsilon isoforms of protein kinase C in pulmonary tissue. Data were assessed by one-way analysis of variance for repeated measurements. Biochemical data were analyzed using Student's t test, or using the Mann-Whitney U test when appropriate. RESULTS: Infusion of endotoxin caused lung injury, manifested by increments in pulmonary artery pressure, in pulmonary micro-occlusion pressure, in pulmonary vascular downstream resistance, in pulmonary vascular permeability index, in extravascular lung water index and in deterioration of oxygenation that were all attenuated by infusion of rhAPC. Endotoxemia led to changes in inflammation and coagulation, including pulmonary neutrophil accumulation paralleled by increased TNFalpha and decreased protein C and fibrinogen in animal plasma, which all improved following infusion of rhAPC. Moreover, rhAPC prevented the translocation of protein kinase C alpha and epsilon isoforms from the cytosolic fraction of lung tissue extracts. CONCLUSION: In awake sheep, rhAPC alleviates endotoxin-induced lung injury--as characterized by improvements of oxygenation, coagulation and inflammation, as well as by reversal of pulmonary hemodynamic and volumetric changes.
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Endotoxinas/toxicidad , Lesión Pulmonar/inducido químicamente , Lesión Pulmonar/prevención & control , Proteína C/uso terapéutico , Vigilia/fisiología , Animales , Fibrinólisis/fisiología , Humanos , Mediadores de Inflamación/fisiología , Lesión Pulmonar/metabolismo , Lesión Pulmonar/patología , Consumo de Oxígeno/fisiología , Proteína C/farmacología , Proteínas Recombinantes/farmacología , Proteínas Recombinantes/uso terapéutico , Ovinos , Vigilia/efectos de los fármacosRESUMEN
OBJECTIVE: To compare the single thermodilution and the thermal-dye dilution techniques with postmortem gravimetry for assessment of changes in extravascular lung water after pneumonectomy and to explore the evolution of edema after injurious ventilation of the left lung. DESIGN: Experimental study. SETTING: University laboratory. SUBJECTS: A total of 30 sheep weighing 35.6 +/- 4.6 kg. The study included two parts: a pneumonectomy study (n = 18) and an injurious ventilation study (n = 12). METHODS: Sheep were anesthetized and mechanically ventilated with an FiO2 of 0.5, tidal volume of 6 mL/kg, and positive end-expiratory pressure of 2 cm H2O. In the pneumonectomy study, sheep were assigned to right-sided pneumonectomy (n = 7), left-sided pneumonectomy (n = 7), or lateral thoracotomy only (sham operation, n = 4). In the injurious ventilation study, right-sided pneumonectomy was followed by ventilation with a tidal volume of 12 mL/kg and positive end-expiratory pressure of 0 cm H2O (n = 6) or by ventilation with a tidal volume of 6 mL/kg and positive end-expiratory pressure of 2 cm H2O for 4 hrs (n = 6). Volumetric variables, including extravascular lung water index (EVLWI), were measured with single thermodilution (STD; EVLWI(STD)) and thermal-dye dilution (TDD; EVLWI(TDD)) techniques. We monitored pulmonary hemodynamics and respiratory variables. After the sheep were killed, EVLWI was determined for each lung by gravimetry (EVLWI(G)). RESULTS: In total, the study yielded strong correlations of EVLWI(STD) and EVLWI(TDD) with EVLWI(G) (n = 30; r = .83 and .94, respectively; p < .0001). After pneumonectomy, both the left- and the right-sided pneumonectomy groups displayed significant decreases in EVLWI(STD) and EVLWI(TDD). The injuriously ventilated sheep demonstrated significant increases in EVLWI that were detected by both techniques. The mean biases (+/-2 SD) compared with EVLWI(G) were 3.0 +/- 2.6 mL/kg for EVLWI(STD) and 0.4 +/- 1.6 mL/kg for EVLWI(TDD). CONCLUSIONS: After pneumonectomy and injurious ventilation of the left lung, TDD and STD displayed changes in extravascular lung water with acceptable accuracy when compared with postmortem gravimetry. Ventilator-induced lung injury seems to be a crucial mechanism of pulmonary edema after pneumonectomy.
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Agua Pulmonar Extravascular , Neumonectomía/efectos adversos , Edema Pulmonar/fisiopatología , Respiración Artificial/efectos adversos , Animales , Análisis de los Gases de la Sangre , Modelos Animales de Enfermedad , Técnica de Dilución de Colorante , Edema Pulmonar/etiología , Pruebas de Función Respiratoria , Ovinos , Termodilución/métodosRESUMEN
OBJECTIVE: To find out if the extravascular lung water index (EVLWI) and the derived permeability indexes determined by the single transpulmonary thermodilution technique are associated with markers of acute lung injury in human septic shock. DESIGN: Prospective, observational study. SETTING: Mixed intensive care unit of a 900-bed university hospital. PATIENTS: Thirty-eight consecutive adult patients with septic shock and acute lung injury. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The variables were assessed over a 72-hr period and included hemodynamics, EVLWI, and pulmonary vascular permeability indexes determined with the single indicator transpulmonary thermodilution technique, lung compliance, oxygenation ratio (Pao2/Fio2), lung injury score, cell counts, and the plasma concentration of endothelin-1. At day 1, EVLWI was elevated (>or=7 mL/kg) in 28 (74%) patients and correlated with lung compliance (r=-.48, p=.002), Pao2/Fio2 (r=-.50, p=.001), lung injury score (r=.46, p=.004), roentgenogram quadrants (r=.39, p=.02), and platelet count (r=-.43, p=.007). At day 3, EVLWI correlated with compliance (r=-.51, p=.002), Pao2/Fio2 (r=-.49, p = .006), and lung injury score (r=.53, p=.003). At day 3, EVLWI and pulmonary vascular permeability indexes were higher in nonsurvivors (p<.05). The plasma concentration of endothelin-1 (mean+/-sd) was significantly higher in patients with elevated EVLWI (>or=7 mL/kg) (3.85+/-1.40 vs. 2.07+/-0.38 pg/mL, respectively). Twenty-two (59%) patients died before day 28. CONCLUSIONS: In human septic shock, EVLWI demonstrated moderate correlation with markers of acute lung injury, such as lung compliance, oxygenation ratio, roentgenogram quadrants, and lung injury score. In nonsurvivors, EVLWI and permeability indexes were significantly increased at day 3. Thus, EVLWI might be of value as an indicator of prognosis and severity of sepsis-induced acute lung injury.
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Agua Pulmonar Extravascular/fisiología , Síndrome de Dificultad Respiratoria/fisiopatología , Choque Séptico/complicaciones , Biomarcadores/sangre , Endotelina-1/sangre , Femenino , Estudios de Seguimiento , Humanos , Rendimiento Pulmonar/fisiología , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Prospectivos , Síndrome de Dificultad Respiratoria/sangre , Síndrome de Dificultad Respiratoria/etiología , Índice de Severidad de la Enfermedad , Choque Séptico/sangre , Choque Séptico/fisiopatología , Termodilución/métodosRESUMEN
INTRODUCTION: We recently demonstrated that the non-selective endothelin-1 (ET-1) receptor blocker tezosentan antagonizes ovine acute lung injury (ALI) following infusion of endotoxin or ET-1 by reducing the enhanced lung microvascular pressure, although we could not exclude the possibility of a simultaneous decline in microvascular permeability. In the present study, our aim was to find out if tezosentan reverses the rise in microvascular filtration coefficient (Kfc) in rat lungs that have been isolated and perfused 12 h after cecum ligation and puncture (CLP) or infusion of ET-1. METHODS: Wistar rats (n = 42) were subjected to CLP. Postoperatively, rats were randomized to a CLP group (n = 7) and a CLP + tezosentan group (n = 7); the latter received tezosentan 30 mg/kg. A sham-operated group (n = 5) underwent laparotomy without CLP. Twelve hours postoperatively, the lungs were isolated and perfused with blood from similarly treated rats that also were used to assess plasma concentration of ET-1 and protein kinase Calpha (PKCalpha) in lung tissue. Additionally, isolated blood perfused lungs from healthy rats were randomized to a control group (n = 8), an ET-1 group (n = 7) subjected to pulmonary arterial injection of ET-1 10 nM, and an ET-1 + tezosentan group (n = 7) that received tezosentan 30 mg/kg. All lung preparations received papaverine 0.1 microg/kg added to the perfusate for vasoplegia. Pulmonary hemodynamic variables, Kfc and lung compliance (CL) were assessed. RESULTS: After CLP, the plasma concentration of ET-1 increased. Papaverine abolished the vasoconstrictor response to ET-1 and the pulmonary vascular pressures remained close to baseline throughout the experiments. Both CLP and injection of ET-1 caused significant changes in Kfc and CL that were prevented in tezosentan-treated rats. Compared to sham-operated animals, CLP increased the content of PKCalpha by 50% and 70% in the cytosolic and the membrane fractions of lung tissue homogenates, respectively. Tezosentan prevented the upregulation of PKCalpha in the membrane fraction. CONCLUSION: In rat lungs isolated and perfused after CLP, tezosentan precludes both the increase in Kfc and the upregulation of PKCalpha in the membrane fraction of lung tissue.
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Permeabilidad Capilar/efectos de los fármacos , Pulmón/irrigación sanguínea , Piridinas/farmacología , Tetrazoles/farmacología , Vasodilatadores/farmacología , Animales , Ciego/lesiones , Modelos Animales de Enfermedad , Antagonistas de los Receptores de la Endotelina A , Técnicas In Vitro , Ligadura , Pulmón/metabolismo , Proteína Quinasa C-alfa/metabolismo , Edema Pulmonar/metabolismo , Punciones , Ratas , Ratas Wistar , Receptor de Endotelina A/sangre , Valores de ReferenciaRESUMEN
INTRODUCTION: Studies in vitro reveal that endothelin-1 (ET-1) activates the alpha isoform of protein kinase C (PKC-alpha) in cultures of endothelial cells, thereby deranging cellular integrity. Sepsis and endotoxemia are associated with increased plasma concentrations of ET-1 that induce acute lung injury (ALI). We recently reported that non-selective ET-1 receptor blockade attenuates ALI in sheep by reducing the endotoxin-induced increase in extravascular lung water index (EVLWI). The aim of this study was to find out whether this attenuation is associated with reduced translocation of PKC-alpha from the cytosolic to the membrane fraction of lung tissue homogenate. METHODS: Seventeen awake, instrumented sheep were randomly assigned to a sham-operated group (n = 3), a lipopolysaccharide (LPS) group (n = 7) receiving an intravenous infusion of Escherichia coli 15 ng/kg per min for 24 hours, and a tezosentan group (n = 7) subjected to LPS and, from 4 hours, an intravenous injection of tezosentan 3 mg/kg followed by infusion at 1 mg/kg per hour for the reminder of the experiment. Pulmonary micro-occlusion pressure (Pmo), EVLWI, plasma concentrations of ET-1, tumor necrosis factor-a (TNF-a), and interleukin-8 (IL-8) were determined every 4 hours. Western blotting was used to assess PKC-alpha. RESULTS: In non-treated sheep a positive correlation was found between the plasma concentration of ET-1 and Pmo in the late phase of endotoxemia (12 to 24 hours). A positive correlation was also noticed between Pmo and EVLWI in the LPS and the LPS plus tezosentan groups, although the latter was significantly reduced in comparison with LPS alone. In both endotoxemic groups, plasma concentrations of ET-1, TNF-alpha, and IL-8 increased. In the LPS group, the cytosolic fraction of PKC-alpha decreased by 75% whereas the membrane fraction increased by 40% in comparison with the sham-operated animals. Tezosentan completely prevented the changes in PKC-alpha in both the cytosolic and the membrane fractions, concomitantly causing a further increase in the plasma concentrations of ET-1, TNF-alpha, and IL-8. CONCLUSION: In endotoxemic sheep, ET-1 receptor blockade alleviates lung injury as assessed by a decrease in EVLWI paralleled by a reduction in Pmo and the prevention of activation of PKC-alpha.
Asunto(s)
Antagonistas de los Receptores de la Endotelina A , Endotoxemia/tratamiento farmacológico , Infecciones por Escherichia coli/tratamiento farmacológico , Proteína Quinasa C/metabolismo , Piridinas/uso terapéutico , Síndrome de Dificultad Respiratoria/tratamiento farmacológico , Tetrazoles/uso terapéutico , Vasodilatadores/uso terapéutico , Animales , Endotelina-1/sangre , Endotelina-1/fisiología , Endotoxemia/enzimología , Activación Enzimática/efectos de los fármacos , Infecciones por Escherichia coli/enzimología , Interleucina-8/sangre , Síndrome de Dificultad Respiratoria/enzimología , Ovinos , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
INTRODUCTION: Acute lung injury is associated with accumulation of extravascular lung water (EVLW). The aim of the present study was to compare two methods for quantification of EVLW: transpulmonary single thermodilution (EVLWST) and postmortem gravimetric (EVLWG). METHODS: Eighteen instrumented and awake sheep were randomly assigned to one of three groups. All groups received Ringer's lactate (5 ml/kg per hour intravenously). To induce lung injury of different severities, sheep received Escherichia coli lipopolysaccharide 15 ng/kg per min intravenously for 6 hours (n = 7) or oleic acid 0.06 ml/kg intravenously over 30 min (n = 7). A third group (n = 4) was subjected to sham operation. Haemodynamic variables, including EVLWST, were measured using a PiCCOplus monitor (Pulsion Medical Systems, Munich, Germany), and the last measurement of EVLWST was compared with EVLWG. RESULTS: At the end of experiment, values for EVLWST (mean +/- standard error) were 8.9 +/- 0.6, 11.8 +/- 1.0 and 18.2 +/- 0.9 ml/kg in the sham-operated, lipopolysaccharide and oleic acid groups, respectively (P < 0.05). The corresponding values for EVLWIG were 6.2 +/- 0.3, 7.1 +/- 0.6 and 11.8 +/- 0.7 ml/kg (P < 0.05). Ranges of EVLWIST and EVLWIG values were 7.5-21.0 and 4.9-14.5 ml/kg. Regression analysis between in vivo EVLWST and postmortem EVLWG yielded the following relation: EVLWST = 1.30 x EVLWG + 2.32 (n = 18, r = 0.85, P < 0.0001). The mean bias +/- 2 standard deviations between EVLWST and EVLWG was 4.9 +/- 5.1 ml/kg (P < 0.001). CONCLUSION: In sheep, EVLW determined using transpulmonary single thermodilution correlates closely with gravimetric measurements over a wide range of changes. However, transpulmonary single thermodilution overestimates EVLW as compared with postmortem gravimetry.
Asunto(s)
Agua Pulmonar Extravascular , Pulmón/irrigación sanguínea , Edema Pulmonar/diagnóstico , Síndrome de Dificultad Respiratoria/fisiopatología , Termodilución/métodos , Animales , Análisis de los Gases de la Sangre , Modelos Animales de Enfermedad , Humanos , Inflamación , Lipopolisacáridos/administración & dosificación , Pulmón/patología , Ácido Oléico/administración & dosificación , Arteria Pulmonar , Edema Pulmonar/etiología , Distribución Aleatoria , Reproducibilidad de los Resultados , OvinosRESUMEN
OBJECTIVE: To evaluate the cardiopulmonary effects of the novel endothelin receptor antagonist tezosentan in endotoxin-induced lung injury in sheep and to assess the dose response to tezosentan and endothelin-1 in healthy sheep. DESIGN: Prospective, randomized, controlled experimental study. SETTING: University animal laboratory. SUBJECTS: Twenty-one yearling sheep. INTERVENTIONS: Seventeen awake, chronically instrumented sheep were subjected to intravenous infusion of Ringer's lactate for 24 hrs. The animals were randomly assigned to a sham-operated group (n = 3), a lipopolysaccharide group (n = 7) receiving an intravenous infusion of Escherichia coli lipopolysaccharide 15 ng x kg x min, and a tezosentan group (n = 7) subjected to lipopolysaccharide and, from 4 hrs, an intravenous injection of tezosentan 3 mg/kg followed by infusion of 1 mg x kg x hr. In addition, four healthy sheep, exposed to an intravenous infusion of endothelin-1 at 20 ng x kg x min, after 1 hr received tezosentan in stepwise increasing doses of 0.5, 1, and 2 mg x kg x hr that were maintained for 1 hr each. After a 4-hr recovery, the sheep received infusions of tezosentan at the same dose rates as a pretreatment to endothelin-1. MEASUREMENTS AND MAIN RESULTS: In the sham-operated sheep, all cardiopulmonary variables remained unchanged. Lipopolysaccharide caused pulmonary hypertension, increased extravascular lung water index, and induced arterial hypoxemia. Tezosentan decreased the increments in pulmonary vascular resistance and extravascular lung water index by as much as 60% and 70%, respectively. In parallel, tezosentan ameliorated arterial hypoxemia, increased cardiac index, attenuated the decrease in stroke volume index, and reduced systemic vascular resistance. Compared with the lipopolysaccharide group, tezosentan further increased plasma concentrations of endothelin-1. In healthy animals, the administration of endothelin-1 induced systemic and pulmonary hypertension, increased extravascular lung water index, and evoked bradycardia and a decrease in cardiac index. These changes were attenuated by tezosentan infused at 1 and 2 mg x kg x hr. CONCLUSIONS: In an ovine model of endotoxin-induced lung injury, tezosentan ameliorates pulmonary hypertension, lung edema, cardiac dysfunction, and arterial hypoxemia. Tezosentan counteracts the hemodynamic effects of endothelin-1 in a dose-dependent manner.
Asunto(s)
Antagonistas de los Receptores de Endotelina , Piridinas/uso terapéutico , Síndrome de Dificultad Respiratoria/tratamiento farmacológico , Tetrazoles/uso terapéutico , Vasodilatadores/uso terapéutico , Análisis de Varianza , Animales , Relación Dosis-Respuesta a Droga , Agua Pulmonar Extravascular/efectos de los fármacos , Agua Pulmonar Extravascular/metabolismo , Hemodinámica/efectos de los fármacos , Lipopolisacáridos , Estudios Prospectivos , Piridinas/farmacología , Distribución Aleatoria , Ovinos , Tetrazoles/farmacología , Vasodilatadores/farmacologíaRESUMEN
Pulmonary hypertension and edema are mainstays of acute lung injury (ALI). We synthesized linear polyethylenimine-nitric oxide/nucleophile adduct (DS-1), a water-soluble nitric oxide donor, and demonstrated that it is a potent relaxant of precontracted rat aortic rings without inducing desensitization. Moreover, DS-1 does not suppress the viability of human pulmonary epithelial cells in vitro. We also tested whether DS-1 counteracts ALI in endotoxemic sheep. Animals were instrumented for a chronic study. In 16 awake, spontaneously breathing sheep, Escherichia coli endotoxin (10 ng/kg/minute) was infused for 8 hours. From 2 hours of endotoxemia, sheep received either nebulized DS-1 (1 mg/kg/hour) or isotonic saline. DS-1 reduced endotoxin-induced rises in pulmonary arterial and microwedge pressures and vascular resistance index by 40-70%. In parallel, DS-1 decreased the accumulation of extravascular lung water by 60-70% and reduced the increment in right ventricle stroke work index and the falls in right ventricle ejection fraction, stroke volume, and left ventricle stroke work indices. Furthermore, DS-1 reduced venous admixture and improved arterial oxygen saturation. In four healthy animals, DS-1 alone slightly increased arterial oxygenation but had no other effects. Thus, aerosolized DS-1 attenuates endotoxin-induced ALI in sheep by reducing pulmonary hypertension and edema and improving myocardial function and gas exchange.