RESUMEN
PURPOSE: Hypoxic pulmonary vasoconstriction (HPV) regulates regional pulmonary blood flow in order to match regional ventilation to preserve arterial oxygenation. HPV is impaired in patients with sepsis or acute respiratory distress syndrome (ARDS). Endotoxemic mice show reduced HPV and recent evidence suggests a central role of voltage gated potassium channel 7 (Kv7) in regulating HPV. Therefore, we tested the hypothesis if Kv7 is induced and inhibition of Kv7 increases HPV in endotoxemia. MATERIALS AND METHODS: Isolated lungs of LPS-pretreated and untreated animals were perfused with and without specific inhibitors of Kv7 (linopirdine (LI) 0, 0.1, 1 and 10 µM) or Kv7.1 (HMR1556 100 nM). Pulmonary artery pressure (PAP) during normoxic (FiO2 0.21) as well as hypoxic (FiO2 0.01) ventilation were obtained. Expressions of Kv7 composing (KCNQ1-5) as well as auxiliary subunits (KCNE1-5) were measured in mouse lungs with and without endotoxemia. RESULTS: HPV was impaired in lungs from LPS mice (16 ± 7% vs 105 ± 13% control, p < 0.05). Perfusion of control lungs with 10 µM LI or 100 nM HMR1556 did not affect HPV (LI 105 ± 12% vs 105 ± 13% vehicle, HMR1556 100 ± 6% vs 98 ± 26%, P = NS). In LPS mice perfusion with 10 µM LI (74.2 ± 7% vs. 16 ± 7% vehicle, P < 0.05) or HMR1556 100 nM augmented HPV (74 ± 28% vs. 15 ± 17% vehicle, P < 0.05). KCNQ1, 4 and 5 gene- and protein expressions as well as KCNE1, 2 and 4 gene expressions were unaltered in endotoxemic lungs. KCNE3 gene and protein expressions were increased in lungs of LPS treated mice (3.1 ± 1.3-fold and 1.8 ± 0.3-fold, respectively, P < 0.05 for both). CONCLUSIONS: Endotoxemia does not alter KCNQ1, 4 and 5 gene and protein expressions but increases pulmonary KCNE3 gene and protein expression. In isolated perfused endotoxemic mouse lungs, perfusion with 10 µM LI or 100 nM HMR1556 augments HPV.
Asunto(s)
Endotoxemia , Canales de Potasio con Entrada de Voltaje , Animales , Humanos , Hipoxia , Lipopolisacáridos/farmacología , Pulmón , Ratones , Arteria Pulmonar , Circulación Pulmonar , VasoconstricciónRESUMEN
BACKGROUND: Atrial fibrillation (AF) represents the most frequent arrhythmic disorder after thoracoabdominal esophageal resection and is associated with a significant increase in perioperative morbidity and mortality. METHODS: In this retrospective cohort study, 167 patients who underwent thoracoabdominal esophagectomy at a large university hospital were assessed. We compared patients who received a 14-day postoperative course of diltiazem with a control group of patients who did not undergo diltiazem prophylaxis. Diltiazem therapy started immediately upon admission to the intensive care unit (ICU) with a loading dose of 0.25 mg/kg bodyweight (i.v.) followed by continuous infusion (0.1 mg/kg bodyweight/h) for 40-48 h. Oral administration (Dilzem® 180 mg uno retard, once a day) was started on postoperative day 3. RESULTS: A total of 117 patients were assessed. Twelve (10.3%) of all patients developed postoperative new-onset atrial fibrillation in the first 30 days after surgical intervention. Prevalence of new-onset AF showed no significant differences between the diltiazem group and control group (p = 0.74). The prevalence of bradycardia (14.7% vs. 3.6%; p = 0.03) and dose of norepinephrine required (0.09 vs. 0.04 µg/kg bodyweight/min; p = 0.04) were higher in the diltiazem group. There were no significant differences between the groups for the median postoperative duration of hospital/ICU stay or mortality. CONCLUSIONS: A prophylactic 14-day postoperative course of diltiazem was not associated with a reduction in new-onset AF or 30-day mortality following thoracoabdominal esophagectomy. Prophylactic diltiazem therapy was associated with drug-related adverse effects such as bradycardia and increased requirement of norepinephrine. German Clinical Trial Registration Number: DKRS00016631.
Asunto(s)
Fibrilación Atrial/prevención & control , Fármacos Cardiovasculares/uso terapéutico , Diltiazem/uso terapéutico , Esofagectomía , Cuidados Posoperatorios/métodos , Complicaciones Posoperatorias/prevención & control , Administración Oral , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Fibrilación Atrial/epidemiología , Fibrilación Atrial/etiología , Esquema de Medicación , Esofagectomía/métodos , Femenino , Estudios de Seguimiento , Humanos , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Complicaciones Posoperatorias/epidemiología , Estudios Retrospectivos , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Hypoxic pulmonary vasoconstriction (HPV) is a reaction of the pulmonary vasculature upon hypoxia, diverting blood flow into ventilated areas to preserve oxygenation. It is impaired in endotoxemia or ARDS. Voltage gated potassium channels have been shown to play a key role in the regulation of HPV. The aim of the study was to identify a voltage gated potassium channel involved in dysregulated HPV during endotoxemia. METHODS: Lungs of male C57BL/6 mice with and without endotoxemia (n = 6 ea. group) were analyzed for Kv3.4 gene and protein expression. HPV was examined in isolated perfused lungs of mice with and without endotoxemia and with and without selective Kv3.4 blocker BDS-I (n = 7 ea. group). Pulmonary artery pressure (PAP) and pressure-flow curves were measured during normoxic (FiO2 0.21) and hypoxic (FiO2 0.01) ventilation. HPV was quantified as the increase in perfusion pressure in response to hypoxia in percent of baseline perfusion pressure (ΔPAP) in the presence and absence of BDS-I. RESULTS: Kv3.4 gene (3.2 ± 0.5-fold, p < 0.05) and protein (1.5 ± 0.1-fold p < 0.05) expression levels were increased in endotoxemic mouse lungs. Endotoxemia reduced HPV (∆PAP control: 121.2 ± 8.7% vs. LPS 19.5 ± 8.0%, means ± SEM) while inhibition of Kv3.4 with 50 nM BDS-I augmented HPV in endotoxemic but not in control lungs (∆PAP control BDS-I: 116.6 ± 16.0% vs. LPS BDS-I 84.4 ± 18.2%, means ± SEM). CONCLUSIONS: Kv3.4 gene and protein expressions are increased in endotoxemic mouse lungs. Selective inhibition of Kv3.4 augments HPV in lungs of endotoxemic mice, but not in lungs of control mice.
Asunto(s)
Endotoxemia/metabolismo , Hipoxia/metabolismo , Pulmón/metabolismo , Canales de Potasio Shaw/biosíntesis , Vasoconstricción/fisiología , Animales , Endotoxemia/patología , Hipoxia/patología , Lipopolisacáridos/antagonistas & inhibidores , Lipopolisacáridos/farmacología , Pulmón/irrigación sanguínea , Pulmón/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Técnicas de Cultivo de Órganos , Perfusión , Arteria Pulmonar/efectos de los fármacos , Arteria Pulmonar/fisiopatología , Circulación Pulmonar/efectos de los fármacos , Canales de Potasio Shaw/antagonistas & inhibidores , Vasoconstricción/efectos de los fármacosRESUMEN
BACKGROUND: Hypoxic pulmonary vasoconstriction (HPV) optimizes the match between ventilation and perfusion in the lung by reducing blood flow to poorly ventilated regions. Sepsis and endotoxemia impair HPV. We previously showed that nitric oxide synthase 2 (NOS2) is required, but not sufficient, for the effect of endotoxin on HPV. The aim of the current study was to identify additional factors that might contribute to the impairment of HPV during endotoxemia. METHODS: Gene expression profiling was determined using pulmonary tissues from NOS2-deficient (NOS2-/-) and wild-type mice subjected to endotoxin or saline challenge (control). HPV was accessed as the percentage increase in left pulmonary vascular resistance (LPVR) in response to left main bronchus occlusion (LMBO) in wild-type mice. RESULTS: Among the 22,690 genes analyzed, endotoxin induced a greater than three-fold increase in 59 and 154 genes in the lungs of wild-type and NOS2-/- mice, respectively. Of all the genes induced by endotoxin in wild-type mice, arginase 1 (Arg1) showed the greatest increase (16.3-fold compared to saline treated wild-type mice). In contrast, endotoxin did not increase expression of Arg1 in NOS2-/- mice. There was no difference in the endotoxin-induced expression of Arg2 between wild-type and NOS2-deficient mice. We investigated the role of arginase in HPV by treating the mice with normal saline or the arginase inhibitor Nω-hydroxy-nor-L-arginine (norNOHA). In control mice (in the absence of endotoxin) treated with normal saline, HPV was intact as determined by profound LMBO-induced increase in LPVR (121 ± 22% from baseline). During endotoxemia and treatment with normal saline, HPV was impaired compared to normal saline treated control mice (33 ± 9% vs. 121 ± 22%, P < 0.05). HPV was restored in endotoxin-exposed mice after treatment with the arginase inhibitor norNOHA as shown by the comparison to endotoxemic mice treated with normal saline (113 ± 29% vs, 33 ± 9%, P < 0.05) and to control mice treated with normal saline (113 ± 29% vs, 121 ± 22%, P = 0.97). CONCLUSIONS: The results of this study suggest that endotoxemia induces Arg1 and that arginase contributes to the endotoxin-induced impairment of HPV in mice.
Asunto(s)
Arginasa/metabolismo , Endotoxemia/enzimología , Circulación Pulmonar/fisiología , Resistencia Vascular/fisiología , Vasoconstricción/fisiología , Animales , Endotoxemia/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones NoqueadosRESUMEN
BACKGROUND: ATP-regulated potassium channels (KATP) regulate pulmonary vascular tone and are involved in hypoxic pulmonary vasoconstriction (HPV). In patients with inflammation like sepsis or ARDS, HPV is impaired, resulting in a ventilation-perfusion mismatch and hypoxia. Since increase of vascular KATP channel Kir6.1 has been reported in animal models of endotoxemia, we studied the expression and physiological effects of Kir6.1 in murine endotoxemic lungs. We hypothesized that inhibition of overexpressed Kir6.1 increases HPV in endotoxemia. METHODS: Mice (C57BL/6; n = 55) with (n = 27) and without (n = 28) endotoxemia (35 mg/kg LPS i.p. for 18 h) were analyzed for Kir6.1 gene as well as protein expression and HPV was examined in isolated perfused mouse lungs with and without selective inhibition of Kir6.1 with PNU-37883A. Pulmonary artery pressure (PAP) and pressure-flow curves during normoxic (FiO2 0.21) and hypoxic (FiO2 0.01) ventilation were obtained. HPV was quantified as the increase in perfusion pressure in response to hypoxic ventilation in mmHg of baseline perfusion pressure (ΔPAP) in the presence and absence of PNU-37883A. RESULTS: Endotoxemia increases pulmonary Kir6.1 gene (+ 2.8 ± 0.3-fold) and protein expression (+ 2.1 ± 0.3-fold). Hypoxia increases HPV in lungs of control animals, while endotoxemia decreases HPV (∆PAP control: 9.2 ± 0.9 mmHg vs. LPS: 3.0 ± 0.7 mmHg, p < 0.05, means ± SEM). Inhibition of Kir6.1 with 1 µM PNU-37883A increases HPV in endotoxemia, while not increasing HPV in controls (∆PAP PNU control: 9.3 ± 0.7 mmHg vs. PNU LPS: 8.3 ± 0.9 mmHg, p < 0.05, means ± SEM). CONCLUSION: Endotoxemia increases pulmonary Kir6.1 gene and protein expression. Inhibition of Kir6.1 augments HPV in murine endotoxemic lungs.
Asunto(s)
Endotoxemia/metabolismo , Hipoxia/metabolismo , Canales KATP/biosíntesis , Pulmón/metabolismo , Vasoconstricción/fisiología , Adamantano/análogos & derivados , Adamantano/farmacología , Animales , Endotoxemia/patología , Hipoxia/patología , Canales KATP/antagonistas & inhibidores , Pulmón/irrigación sanguínea , Pulmón/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Morfolinas/farmacología , Técnicas de Cultivo de Órganos , Vasoconstricción/efectos de los fármacosRESUMEN
BACKGROUND: Inhaled carbon monoxide (CO) appears to have beneficial effects on endotoxemia-induced impairment of hypoxic pulmonary vasoconstriction (HPV). This study aims to specify correct timing of CO application, it's biochemical mechanisms and effects on inflammatory reactions. METHODS: Mice (C57BL/6; n = 86) received lipopolysaccharide (LPS, 30 mg/kg) intraperitoneally and subsequently breathed 50 ppm CO continuously during defined intervals of 3, 6, 12 or 18 h. Two control groups received saline intraperitoneally and additionally either air or CO, and one control group received LPS but breathed air only. In an isolated lung perfusion model vasoconstrictor response to hypoxia (FiO2 = 0.01) was quantified by measurements of pulmonary artery pressure. Pulmonary capillary pressure was estimated by double occlusion technique. Further, inflammatory plasma cytokines and lung tissue mRNA of nitric-oxide-synthase-2 (NOS-2) and heme oxygenase-1 (HO-1) were measured. RESULTS: HPV was impaired after LPS-challenge (p < 0.01). CO exposure restored HPV-responsiveness if administered continuously for full 18 h, for the first 6 h and if given in the interval between the 3(rd) and 6(th) hour after LPS-challenge (p < 0.05). Preserved HPV was attributable to recovered arterial resistance and associated with significant reduction in NOS-2 mRNA when compared to controls (p < 0.05). We found no effects on inflammatory plasma cytokines. CONCLUSION: Low-dose CO prevented LPS-induced impairment of HPV in a time-dependent manner, associated with a decreased NOS-2 expression.
Asunto(s)
Monóxido de Carbono/administración & dosificación , Endotoxemia/tratamiento farmacológico , Hipoxia/fisiopatología , Arteria Pulmonar/efectos de los fármacos , Vasoconstricción/efectos de los fármacos , Administración por Inhalación , Animales , Presión Arterial/efectos de los fármacos , Citocinas/sangre , Modelos Animales de Enfermedad , Esquema de Medicación , Endotoxemia/inducido químicamente , Endotoxemia/genética , Endotoxemia/metabolismo , Endotoxemia/fisiopatología , Hemo-Oxigenasa 1/genética , Hemo-Oxigenasa 1/metabolismo , Hipoxia/genética , Hipoxia/metabolismo , Mediadores de Inflamación/sangre , Lipopolisacáridos , Masculino , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Ratones Endogámicos C57BL , Óxido Nítrico Sintasa de Tipo II/genética , Óxido Nítrico Sintasa de Tipo II/metabolismo , Arteria Pulmonar/metabolismo , Arteria Pulmonar/fisiopatología , ARN Mensajero/metabolismo , Factores de TiempoRESUMEN
RATIONALE: Mice lacking the EF-hand Ca2+ sensor S100A1 display endothelial dysfunction because of distorted Ca2+ -activated nitric oxide (NO) generation. OBJECTIVE: To determine the pathophysiological role of S100A1 in endothelial cell (EC) function in experimental ischemic revascularization. METHODS AND RESULTS: Patients with chronic critical limb ischemia showed almost complete loss of S100A1 expression in hypoxic tissue. Ensuing studies in S100A1 knockout (SKO) mice subjected to femoral artery resection unveiled insufficient perfusion recovery and high rates of autoamputation. Defective in vivo angiogenesis prompted cellular studies in SKO ECs and human ECs, with small interfering RNA-mediated S100A1 knockdown demonstrating impaired in vitro and in vivo proangiogenic properties (proliferation, migration, tube formation) and attenuated vascular endothelial growth factor (VEGF)-stimulated and hypoxia-stimulated endothelial NO synthase (eNOS) activity. Mechanistically, S100A1 deficiency compromised eNOS activity in ECs by interrupted stimulatory S100A1/eNOS interaction and protein kinase C hyperactivation that resulted in inhibitory eNOS phosphorylation and enhanced VEGF receptor-2 degradation with attenuated VEGF signaling. Ischemic SKO tissue recapitulated the same molecular abnormalities with insufficient in vivo NO generation. Unresolved ischemia entailed excessive VEGF accumulation in SKO mice with aggravated VEGF receptor-2 degradation and blunted in vivo signaling through the proangiogenic phosphoinositide-3-kinase/Akt/eNOS cascade. The NO supplementation strategies rescued defective angiogenesis and salvaged limbs in SKO mice after femoral artery resection. CONCLUSIONS: Our study shows for the first time downregulation of S100A1 expression in patients with critical limb ischemia and identifies S100A1 as critical for EC function in postnatal ischemic angiogenesis. These findings link its pathological plasticity in critical limb ischemia to impaired neovascularization, prompting further studies to probe the microvascular therapeutic potential of S100A1.
Asunto(s)
Células Endoteliales/enzimología , Isquemia/enzimología , Músculo Esquelético/irrigación sanguínea , Neovascularización Fisiológica , Óxido Nítrico Sintasa de Tipo III/metabolismo , Proteínas S100/deficiencia , Anciano , Anciano de 80 o más Años , Animales , Calcio/metabolismo , Células Cultivadas , Modelos Animales de Enfermedad , Células Endoteliales/efectos de los fármacos , Femenino , Miembro Posterior , Células Endoteliales de la Vena Umbilical Humana/enzimología , Humanos , Isquemia/tratamiento farmacológico , Isquemia/genética , Isquemia/fisiopatología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Persona de Mediana Edad , Músculo Esquelético/patología , Neovascularización Fisiológica/efectos de los fármacos , Óxido Nítrico/metabolismo , Donantes de Óxido Nítrico/farmacología , Fosfatidilinositol 3-Quinasa/metabolismo , Fosforilación , Proteína Quinasa C/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Interferencia de ARN , Flujo Sanguíneo Regional , Proteínas S100/genética , Transducción de Señal , Factores de Tiempo , Transfección , Factor A de Crecimiento Endotelial Vascular/metabolismo , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismoRESUMEN
This single-centre retrospective cohort study evaluated the incidence and outcome of mycoses in critical ill patients (n = 283) with sepsis due to peritonitis. Overall mortality was 41.3%, and the 28-day mortality was 29.3%. Fungal pathogens were found in 51.9%. The common first location was the respiratory tract (66.6%), followed by the abdominal site (19.7%). Candida colonisation was found in 64.6%, and invasive Candida infection in 34.0%. Identified fungi were Candida spp. in 98.6% and Aspergillus spp. in 6.1%. Patients with fungal pathogens showed a higher rate of postoperative peritonitis, APACHE II and tracheotomy. In comparison to patients without fungal pathogens, these patients showed a longer duration on mechanical ventilation, and a higher overall mortality. Patients with Candida-positive swabs from abdominal sites had more fascia dehiscence and anastomosis leakage. Seventy-two patients (48.9%) received antifungal therapy, 26 patients were treated empirically. Antifungal therapy was not associated with a decrease in mortality. Age and renal replacement therapy were associated with mortality. In conclusion, fungi are common pathogens in critically ill patients with peritonitis, and detection of fungi is associated with an increase in overall mortality. Particularly, Candida-positive abdominal swabs are associated with an increase in morbidity. However, we were not able to demonstrate a survival benefit for antifungal therapy in peritonitis patients.
Asunto(s)
Aspergilosis/mortalidad , Candidiasis Invasiva/mortalidad , Peritonitis/microbiología , Sepsis/microbiología , Sepsis/mortalidad , Choque Séptico/microbiología , Choque Séptico/mortalidad , APACHE , Factores de Edad , Anciano , Antifúngicos/uso terapéutico , Aspergilosis/tratamiento farmacológico , Aspergilosis/microbiología , Aspergillus/aislamiento & purificación , Candida/aislamiento & purificación , Candidiasis Invasiva/tratamiento farmacológico , Candidiasis Invasiva/microbiología , Estudios de Cohortes , Enfermedad Crítica/mortalidad , Enfermedad Crítica/terapia , Femenino , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Peritonitis/complicaciones , Peritonitis/mortalidad , Terapia de Reemplazo Renal , Estudios Retrospectivos , TraqueotomíaRESUMEN
Liver transplant recipients are at a significant risk for invasive fungal infections (IFI). This retrospective study evaluated the impact of the pretransplant model for end stage liver disease (MELD) on the incidence of posttransplant IFI in a single centre. From 2004 to 2008, 385 liver transplantations were included, from which 210 transplantations were conducted allocated by Child Turcotte Pugh and 175 were allocated by MELD score. Both groups differed regarding the age of transplant recipients (50.1 ± 10.7 vs. 52.5 ± 9.9, P = 0.036), pretransplant MELD score (16.43 ± 8.33 vs. 18.29 ± 9.05), rate of re-transplantations, duration of surgery, demand in blood transfusions and rates of renal impairments. In the MELD era, higher incidences of IFI (pre-MELD 11.9%, MELD 24.0%, P < 0.05) and Candida infections (9% vs. 18.9%, P < 0.05) were observed. There was no difference in the incidence of probable or possible aspergillosis. Mortality, length of stay in intensive care or hospital, and duration of mechanical ventilation did not differ between the pre-MELD and MELD era. Regardless the date of transplantation, patients with fungi-positive samples showed higher mortality rates than patients without. MELD score was analysed as independent predictors for posttransplant IFI. Higher MELD scores predispose to a more problematic postoperative course and are associated with an increase in fungal infections.
Asunto(s)
Aspergilosis/mortalidad , Candidiasis Invasiva/mortalidad , Enfermedad Hepática en Estado Terminal/cirugía , Trasplante de Hígado/mortalidad , APACHE , Adulto , Antifúngicos/uso terapéutico , Aspergilosis/diagnóstico , Aspergilosis/tratamiento farmacológico , Aspergillus/aislamiento & purificación , Candida/aislamiento & purificación , Candidiasis Invasiva/tratamiento farmacológico , Femenino , Mortalidad Hospitalaria , Humanos , Incidencia , Estimación de Kaplan-Meier , Tiempo de Internación , Masculino , Persona de Mediana Edad , Tempo Operativo , Estudios Retrospectivos , Índice de Severidad de la EnfermedadRESUMEN
In recent decades, infusion solutions such as NaCl 0.9% and lactate Ringer's solution have been replaced in clinical practice. Since 2017, the national guidelines for perioperative infusion therapy in children recommend balanced isotonic solutions to maintain fluid balance. The composition of balanced infusion solutions varies with respect to their electrolyte content. Hyperchloremia may be mistaken for hypovolemia and may interfere with volume therapy in pediatric patients. Sterofundin ISO® balanced solution contains 127 mmol/L chloride and may cause hyperchloremic acidosis if administered in large volumes. OBJECTIVES: The purpose of this study was to compare the effects of Sterofundin ISO® (SF) therapy with the balanced isochloremic solution Deltajonin® (DJ) (106 mmol/L chloride) on the acid-base status in infants undergoing craniofacial surgery. METHODS: This retrospective, non-blinded study included 100 infants undergoing craniectomy due to isolated nonsyndromic sagittal craniosynostosis. The first 50 infants received Sterofundin ISO®. Due to changes in national guidelines, the infusion was changed to the isoionic Deltajonin® in an additional 50 infants in 2017. Pre- and postoperative values of chloride, pH, base excess, bicarbonate, and albumin and phosphate were determined, and the strong-ion difference, strong-ion gap, anion gap, and weak acids were calculated. RESULTS: Both groups were comparable in terms of their age, sex, underlying disease, preoperative electrolytes (except K at 3.9 ± 0.3 mmol/L (SF) vs. 4.1 ± 0.3 mmol/L (DJ) and lactate 8.7 ± 2.1 (SF) vs. 9.6 ± 2.6 mmol/L (DJ)). In the Sterofundin ISO® group, hyperchloremic metabolic acidosis was observed in 19 patients, whereas only 2 infants in the Deltajonin® group had hyperchloremic metabolic acidosis. The postoperative chloride level was 111 ± 2.7 mmol/L (SF) vs. 108 ± 2.4 mmol/L (DJ). The difference in anion gap was 12.5 ± 3.0 mmol/L (SF) vs. 14.6 ± 2.8 mmol/L (DJ), and the difference in SIDa (apparent strong-ion difference) was 30.9 mmol/L (SF) vs. 33.8 mmol/L (DJ). CONCLUSIONS: Hyperchloremic acidosis can be induced by the volume replacement with high-chloride-concentration crystalloids such as Sterofundin ISO®. This can be detected using the Stewart model.
RESUMEN
Abdominal surgery may affect intestinal absorption and the resulting levels of posaconazole in the blood. We measured plasma posaconazole levels in surgical intensive care unit (SICU) patients and tried to develop a predictive population pharmacokinetics model. A total of 270 samples from 15 patients receiving posaconazole via nasogastric tube were measured by high-performance liquid chromatography (HPLC). SICU patients showed lower plasma drug concentrations, a higher apparent clearance, and a higher volume of distribution than those in hematology patients, possibly due to poor absorption.
Asunto(s)
Antifúngicos/administración & dosificación , Antifúngicos/sangre , Intubación Gastrointestinal , Triazoles/administración & dosificación , Triazoles/sangre , Adulto , Anciano , Antifúngicos/farmacocinética , Disponibilidad Biológica , Cromatografía Líquida de Alta Presión , Cuidados Críticos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Triazoles/farmacocinéticaRESUMEN
Automation of plate streaking is ongoing in clinical microbiological laboratories, but evaluation for routine use is mostly open. In the present study, the recovery of microorganisms from the Previ Isola system plated polyurethane (PU) swab samples is compared to manually plated control viscose swab samples from wounds according to the CLSI procedure M40-A (quality control of microbiological transport systems). One hundred twelve paired samples (224 swabs) were analyzed. In 80/112 samples (71%), concordant culture results were obtained with the two methods. In 32/112 samples (29%), CFU recovery of microorganisms from the two methods was discordant. In 24 (75%) of the 32 paired samples with a discordant result, Previ Isola plated PU swabs were superior. In 8 (25%) of the 32 paired samples with a discordant result, control viscose swabs were superior. The quality of colony growth on culture media for further investigations was superior with Previ Isola inoculated plates compared to manual plating techniques. Gram stain results were concordant between the two methods in 62/112 samples (55%). In 50/112 samples (45%), the results of Gram staining were discordant between the two methods. In 34 (68%) of the 50 paired samples with discordant results, Gram staining of PU swabs was superior to that of control viscose swabs. In 16 (32%) of the 50 paired samples, Gram staining of control viscose swabs was superior to that of PU swabs. We report the first clinical evaluation of Previ Isola automated specimen inoculation for wound swab samples. This study suggests that use of an automated specimen inoculation system has good results with regard to CFU recovery, quality of Gram staining, and accuracy of diagnosis.
Asunto(s)
Automatización/métodos , Técnicas Microbiológicas/métodos , Manejo de Especímenes/métodos , Infección de Heridas/diagnóstico , Automatización/economía , Costos y Análisis de Costo , Humanos , Técnicas Microbiológicas/economía , Manejo de Especímenes/economíaRESUMEN
Nitric oxide (NO) regulates vascular smooth muscle cell (VSMC) structure and function, in part by activating soluble guanylate cyclase (sGC) to synthesize cGMP. The objective of this study was to further characterize the signaling mechanisms by which NO regulates VSMC gene expression using transcription profiling. DNA microarrays were hybridized with RNA extracted from rat pulmonary artery smooth muscle cells (RPaSMC) exposed to the NO donor compound, S-nitroso-glutathione (GSNO). Many of the genes, whose expression was induced by GSNO, contain a cAMP-response element (CRE), of which one encoded the inducible cAMP early repressor (ICER). sGC and cAMP-dependent protein kinase, but not cGMP-dependent protein kinase, were required for NO-mediated phosphorylation of CRE-binding protein (CREB) and induction of ICER gene expression. Expression of a dominant-negative CREB in RPaSMC prevented the NO-mediated induction of CRE-dependent gene transcription and ICER gene expression. Pre-treatment of RPaSMC with the intracellular calcium (Ca(2+)) chelator, BAPTA-AM, blocked the induction of ICER gene expression by GSNO. The store-operated Ca(2+) channel inhibitors, 2-ABP, and SKF-96365, reduced the GSNO-mediated increase in ICER mRNA levels, while 2-ABP did not inhibit GSNO-induced CREB phosphorylation. Our results suggest that induction of ICER gene expression by NO requires both CREB phosphorylation and Ca(2+) signaling. Transcription profiling of RPaSMC exposed to GSNO revealed important roles for sGC, PKA, CREB, and Ca(2+) in the regulation of gene expression by NO. The induction of ICER in GSNO-treated RPaSMC highlights a novel cross-talk mechanism between cGMP and cAMP signaling pathways.
Asunto(s)
Modulador del Elemento de Respuesta al AMP Cíclico/genética , Músculo Liso Vascular/metabolismo , Óxido Nítrico/metabolismo , Arteria Pulmonar/metabolismo , Animales , Células Cultivadas , Masculino , Ratones , Ratones Endogámicos C57BL , Músculo Liso Vascular/citología , Hibridación de Ácido Nucleico , Arteria Pulmonar/citología , ARN Mensajero/genética , Ratas , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
BACKGROUND AND OBJECTIVE: During sepsis and endotoxaemia, hypoxic pulmonary vasoconstriction (HPV) is impaired. Sedation of septic patients in ICUs is performed with various anaesthetics, most of which have pulmonary dilatory properties. Ketamine is a sympathetic nervous system-activating anaesthetic that preserves cardiovascular stability. The effects of ketamine on the pulmonary vasculature and HPV during sepsis have not been characterized yet. METHODS: Therefore, isolated lungs of mice were perfused with ketamine (0, 0.1, 1.0, and 10 mg kg(-1) body weight min) 18 h following intraperitoneal injection of lipopolysaccharide (LPS); untreated mouse groups served as controls (n = 7 per group, respectively). Pulmonary artery pressure (PAP) and pressure-flow curves during normoxic (FiO(2) = 0.21) and hypoxic (FiO(2) = 0.01) ventilation were obtained. RESULTS: HPV was reduced in endotoxaemic animals when compared with controls (means +/- SD; DeltaPAP control 103 +/- 28% vs. LPS 23 +/- 25%, P < 0.05). Ketamine caused a dose-dependent reduction of HPV in the lungs of control (DeltaPAP 0 mg kg(-1) min(-1) ketamine 103 +/- 28% vs. 10 mg kg(-1) min(-1) ketamine 28 +/- 21%, P < 0.05) and septic animals (DeltaPAP 0 mg kg(-1) min(-1) ketamine 23 +/- 25% vs. 10 mg kg(-1) min(-1) ketamine 0 +/- 4%, P < 0.05). Analysis of pressure-flow curves revealed that ketamine partly reversed the endotoxin-induced changes in basal pulmonary vascular wall properties rather than interfering with the HPV response itself. CONCLUSION: Ketamine modified baseline pulmonary vascular properties, resulting in a reduced HPV responsiveness in untreated mice. Further, ketamine counteracted the LPS-induced changes in pulmonary vascular pressure-flow relationships, but did not affect impaired HPV in this murine endotoxaemia model.
Asunto(s)
Anestésicos Disociativos/uso terapéutico , Endotoxemia/tratamiento farmacológico , Hipoxia/patología , Ketamina/uso terapéutico , Arteria Pulmonar/efectos de los fármacos , Circulación Pulmonar/efectos de los fármacos , Vasoconstricción/efectos de los fármacos , Animales , Presión Sanguínea , Modelos Animales de Enfermedad , Lipopolisacáridos/metabolismo , Ratones , Oxígeno/metabolismo , Factores de TiempoRESUMEN
Pain therapy is one of the basic tasks of a clinician. Good knowledge of the active profile of prescribed analgesics as well as their side effects will facilitate their use and decrease undesired effects. This article discusses currently used analgesics, their indication and practical application with special consideration of dose requirements at the beginning and end of treatment.
Asunto(s)
Analgésicos/administración & dosificación , Dolor/tratamiento farmacológico , Síndrome de Abstinencia a Sustancias/prevención & control , Enfermedad Aguda , Analgésicos/efectos adversos , Analgésicos Opioides/administración & dosificación , Analgésicos Opioides/efectos adversos , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Humanos , Dolor/diagnóstico , Dimensión del Dolor/efectos de los fármacosRESUMEN
Craniofacial surgery in infants still harbors the risk of significant blood loss and the need for red blood cell (RBC) transfusion. Hence, the aim of the present study was to investigate the antifibrinolytic effect of tranexamic acid (TXA) on intraoperative blood loss and RBC transfusion rates during fronto-orbital advancement (FOA) in isolated metopic synostosis. A total of 33 children with metopic synostosis were operated on using standardized FOA, of which 16 patients (48.5%) were treated without intraoperative TXA (non-TXA group) and 17 patients (51.5%) received TXA intraoperatively (TXA group). To accurately evaluate the calculated blood loss (CBL) we analyzed the values for pre- and postoperative hematocrit and the volume of the RBC transfusion. The mean CBL and the mean weight-adjusted CBL was significantly lower for patients receiving TXA compared with the non-TXA group (158.8 ml vs. 198.5 ml, p = 0.0001; and 19.1 ml/kg vs. 22.3 ml/kg, p = 0.0293, respectively). In addition, the mean RBC transfusion and the mean weight-adjusted RBC transfusion was significantly lower for the TXA group (252.2 ml vs. 280.0 ml, p = 0.0001; and 27.9 ml/kg vs. 31.3 ml/kg, p = 0.0345, respectively). The mean duration of the surgical procedure did not differ statistically between the groups (132 min vs. 136 min, p = 0.4081), hence the lower CBL in the TXA-group was not related to a shorter cutting-suture time. As the use of intraoperative TXA minimizes blood transfusion volumes in children who undergo FOA, antifibrinolytics, such as TXA, should be considered for routine use in pediatric craniofacial surgery.
Asunto(s)
Antifibrinolíticos/uso terapéutico , Pérdida de Sangre Quirúrgica/prevención & control , Transfusión Sanguínea/métodos , Craneosinostosis/complicaciones , Craneosinostosis/cirugía , Ácido Tranexámico/uso terapéutico , Femenino , Humanos , Lactante , Masculino , Resultado del TratamientoRESUMEN
INTRODUCTION: Echocardiography is a useful tool in patients suffering from shock of unknown origin to evaluate cardiac function and volume status in order to decide on further treatment. The aim of the study was to evaluate how well participants could identify function, preload and regional wall motion abnormalities after attending a 4-day transoesophageal echocardiography (TOE) seminar. METHODS: In this prospective educational trial, participants of six TOE seminars from 2005 to 2006 were evaluated. On the basis of seven echocardiographic studies, evaluations by participants concerning cardiac function, preload and regional wall motion were analyzed. Moreover, specific causes of undifferentiated hypotension were to be judged in three cases by the participants. RESULTS: A total of 115 participants of the TOE seminars from 2005 to 2006 were evaluated. Correct sectional plane was recognized by more than 76% of the participants. Left ventricular function, preload, and regional wall abnormalities were assessed correctly by the participants in 98%, 96%, and 84%, respectively. Moreover, more than 70% of the participants recognized the correct cause of hemodynamic instability. CONCLUSION: The results of the investigation show that participants of a 4-day TOE seminar can interpret left ventricular function, preload and regional wall motion abnormalities correctly at a very high rate. TOE seminars seem to be effective in teaching basic theoretical knowledge of TOE.
Asunto(s)
Competencia Clínica , Ecocardiografía Transesofágica/métodos , Educación Médica Continua/métodos , Cardiopatías/diagnóstico por imagen , Choque/diagnóstico , Adulto , Femenino , Cardiopatías/etiología , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Reproducibilidad de los Resultados , Choque/complicaciones , Adulto JovenRESUMEN
BACKGROUND: Hypoxic pulmonary vasoconstriction (HPV) is impaired during inflammatory lung processes such as pneumonia or the acute respiratory distress syndrome. Voltage-gated potassium channels play a central role in mediating HPV. The aim of this study was to determine whether 4-aminopyridine (4-AP), a known voltage-gated potassium channel inhibitor, may restore HPV in sepsis. METHODS: The effects of 0.01, 0.1, and 1.0 mm 4-AP on HPV responsiveness were assessed in isolated lungs of untreated mice and of mice 18 h after lipopolysaccharide injection (20 mg/kg intraperitoneal Escherichia coli 0111:B4 lipopolysaccharide). HPV was quantified as the increase in perfusion pressure in response to hypoxic ventilation in percent of baseline perfusion pressure. Intrinsic pulmonary vascular resistance (R0) and pulmonary vascular distensibility (alpha) were determined by nonlinear regression analysis of pulmonary vascular pressure-flow curves generated during normoxic and hypoxic ventilation, respectively. RESULTS: HPV was impaired in lungs isolated from lipopolysaccharide-challenged mice. Addition of 4-AP to the perfusate did not alter HPV responsiveness in untreated mice but dose dependently restored HPV in endotoxemic mice. Analysis of pulmonary vascular pressure-flow curves revealed that 4-AP (1) counteracted the observed lipopolysaccharide-induced changes in alpha and R0 under normoxic conditions and (2) augmented the hypoxia-induced increase in R0 in lungs of endotoxemic mice. CONCLUSIONS: This study demonstrates that lipopolysaccharide-induced pulmonary vascular hyporesponsiveness to hypoxia can be restored by 4-AP in murine endotoxemia and, thus, may be a new therapeutic approach to treat patients with hypoxemia due to impaired HPV.
Asunto(s)
4-Aminopiridina/uso terapéutico , Endotoxemia/tratamiento farmacológico , Endotoxemia/fisiopatología , Hipoxia/fisiopatología , Bloqueadores de los Canales de Potasio/uso terapéutico , Circulación Pulmonar/efectos de los fármacos , Vasoconstricción/efectos de los fármacos , Algoritmos , Angiotensina II/farmacología , Animales , Peso Corporal/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Técnicas In Vitro , Lipopolisacáridos/antagonistas & inhibidores , Lipopolisacáridos/farmacología , Masculino , Ratones , Tamaño de los Órganos/efectos de los fármacos , Perfusión , Canales de Potasio/biosíntesis , Arteria Pulmonar/efectos de los fármacos , Arteria Pulmonar/fisiopatología , ARN Mensajero/biosíntesisRESUMEN
Phosphodiesterases (PDE) metabolize cyclic nucleotides limiting the effects of vasodilators such as prostacyclin and nitric oxide (NO). In this study, DNA microarray techniques were used to assess the impact of NO on expression of PDE genes in rat pulmonary arterial smooth muscle cells (rPASMC). Incubation of rPASMC with S-nitroso-l-glutathione (GSNO) increased expression of a PDE isoform that specifically metabolizes cAMP (PDE4B) in a dose- and time-dependent manner. GSNO increased PDE4B protein levels, and rolipram-inhibitable PDE activity was 2.3 +/- 1.0-fold greater in GSNO-treated rPASMC than in untreated cells. The soluble guanylate cyclase (sGC) inhibitor, 1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one, and the cAMP-dependent protein kinase inhibitor, H89, prevented induction of PDE4B gene expression by GSNO, but the protein kinase G (PKG) inhibitors, Rp-8-pCPT-cGMPs and KT-5823, did not. Incubation of rPASMC with IL-1beta and tumor necrosis factor-alpha induced PDE4B gene expression, an effect that was inhibited by l-N(6)-(1-iminoethyl)lysine, an antagonist of NO synthase 2 (NOS2). The GSNO-induced increase in PDE4B mRNA levels was blocked by actinomycin D but augmented by cycloheximide. Infection of rPASMC with an adenovirus specifying a dominant negative cAMP response element binding protein (CREB) mutant inhibited the GSNO-induced increase of PDE4B gene expression. These results suggest that exposure of rPASMC to NO induces expression of PDE4B via a mechanism that requires cGMP synthesis by sGC but not PKG. The GSNO-induced increase of PDE4B gene expression is CREB dependent. These findings demonstrate that NO increases expression of a cAMP-specific PDE and provide evidence for a novel "cross talk" mechanism between cGMP and cAMP signaling pathways.
Asunto(s)
3',5'-AMP Cíclico Fosfodiesterasas/biosíntesis , Miocitos del Músculo Liso/enzimología , Óxido Nítrico/farmacología , Arteria Pulmonar/enzimología , 3',5'-AMP Cíclico Fosfodiesterasas/genética , Animales , Células Cultivadas , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Proteínas Quinasas Dependientes de GMP Cíclico/metabolismo , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4 , Inducción Enzimática/efectos de los fármacos , Expresión Génica/efectos de los fármacos , Guanilato Ciclasa/metabolismo , Miocitos del Músculo Liso/citología , Miocitos del Músculo Liso/efectos de los fármacos , Óxido Nítrico/biosíntesis , Donantes de Óxido Nítrico/farmacología , Óxido Nítrico Sintasa de Tipo II/metabolismo , Inhibidores de Fosfodiesterasa/farmacología , Arteria Pulmonar/citología , Arteria Pulmonar/efectos de los fármacos , Ratas , Rolipram/farmacología , S-Nitrosoglutatión/farmacología , Transcripción GenéticaRESUMEN
Phosphodiesterase 1 (PDE1) modulates vascular tone and the development of tolerance to nitric oxide (NO)-releasing drugs in the systemic circulation. Any role of PDE1 in the pulmonary circulation remains largely uncertain. We measured the expression of genes encoding PDE1 isozymes in the pulmonary vasculature and examined whether or not selective inhibition of PDE1 by vinpocetine attenuates pulmonary hypertension and augments the pulmonary vasodilator response to inhaled NO in lambs. Using RT-PCR, we detected PDE1A, PDE1B, and PDE1C mRNAs in pulmonary arteries and veins isolated from healthy lambs. In 13 lambs, the thromboxane A(2) analog U-46619 was infused intravenously to increase mean pulmonary arterial pressure to 35 mmHg. Four animals received an intravenous infusion of vinpocetine at incremental doses of 0.3, 1, and 3 mg.kg(-1).h(-1). In nine lambs, inhaled NO was administered in a random order at 2, 5, 10, and 20 ppm before and after an intravenous infusion of 1 mg.kg(-1).h(-1) vinpocetine. Administration of vinpocetine did not alter pulmonary and systemic hemodynamics or transpulmonary cGMP or cAMP release. Inhaled NO selectively reduced mean pulmonary arterial pressure, pulmonary capillary pressure, and pulmonary vascular resistance index, while increasing transpulmonary cGMP release. The addition of vinpocetine enhanced pulmonary vasodilation and transpulmonary cGMP release induced by NO breathing without causing systemic vasodilation but did not prolong the duration of pulmonary vasodilation after NO inhalation was discontinued. Our findings demonstrate that selective inhibition of PDE1 augments the therapeutic efficacy of inhaled NO in an ovine model of acute chemically induced pulmonary hypertension.