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1.
BMC Pulm Med ; 21(1): 23, 2021 Jan 12.
Article in English | MEDLINE | ID: mdl-33435939

ABSTRACT

BACKGROUND: Salbutamol-induced lactic acidosis is a rare presentation that could manifest in specific clinical context as acute asthmatic attack treatment. An increase of glycolysis pathway leading to pyruvate escalation is the mechanism of hyperlactatemia in ß2-adrenergic agonist drug. CASE PRESENTATION: A 40-year-old man who had poor-controlled asthma, presented with progressive dyspnea with coryza symptom for 6 days. He was intubated and admitted into medical intensive care unit due to deteriorated respiratory symptom. Severe asthmatic attack was diagnosed and approximate 1.5 canisters of salbutamol inhaler was administrated within 24 h of admission. Initial severe acidosis consisted of acute respiratory acidosis from ventilation-perfusion mismatch and acute metabolic acidosis resulting from bronchospasm and hypoxia-related lactic acidosis, respectively. The lactate level was normalized in 6 h after hypoxemia and ventilation correction. Given the lactate level re-elevated into a peak of 4.6 mmol/L without signs of tissue hypoxia nor other possible etiologies, the salbutamol toxicity was suspected and the inhaler was discontinued that contributed to rapid lactate clearance. The patient was safely discharged on the 6th day of admission. CONCLUSION: The re-elevation of serum lactate in status asthmaticus patient who had been administrated with the vast amount of ß2-adrenergic agonist should be considered for salbutamol-induced lactic acidosis and promptly discontinued especially when there were no common potentials.


Subject(s)
Acidosis, Lactic/chemically induced , Adrenergic beta-2 Receptor Agonists/adverse effects , Albuterol/adverse effects , Lactic Acid/blood , Status Asthmaticus/drug therapy , Acidosis/metabolism , Acidosis/therapy , Acidosis, Lactic/blood , Acidosis, Respiratory/metabolism , Acidosis, Respiratory/therapy , Adult , Bronchial Spasm/drug therapy , Bronchial Spasm/metabolism , Humans , Hypoxia/metabolism , Hypoxia/therapy , Male , Status Asthmaticus/metabolism , Ventilation-Perfusion Ratio
2.
Clin Pharmacokinet ; 59(2): 257-264, 2020 02.
Article in English | MEDLINE | ID: mdl-31432470

ABSTRACT

BACKGROUND: Intravenous salbutamol is used to treat children with refractory status asthmaticus, however insufficient pharmacokinetic data are available to guide initial and subsequent dosing recommendations for its intravenous use. The pharmacologic activity of salbutamol resides predominantly in the (R)-enantiomer, with little or no activity and even concerns of adverse reactions attributed to the (S)-enantiomer. OBJECTIVE: Our aim was to develop a population pharmacokinetic model to characterize the pharmacokinetic profile for intravenous salbutamol in children with status asthmaticus admitted to the pediatric intensive care unit (PICU), and to use this model to study the effect of different dosing schemes with and without a loading dose. METHODS: From 19 children (median age 4.9 years [range 9 months-15.3 years], median weight 18 kg [range 7.8-70 kg]) treated with continuous intravenous salbutamol at the PICU, plasma samples for R- and S-salbutamol concentrations (111 samples), as well as asthma scores, were collected prospectively at the same time points. Possible adverse reactions and patients' clinical data (age, sex, weight, drug doses, liver and kidney function) were recorded. With these data, a population pharmacokinetic model was developed using NONMEM 7.2. After validation, the model was used for simulations to evaluate the effect of different dosing regimens with or without a loading dose. RESULTS: A two-compartment model with separate clearance for R- and S-salbutamol (16.3 L/h and 8.8 L/h, respectively) best described the data. Weight was found to be a significant covariate for clearance and volume of distribution. No other covariates were identified. Simulations showed that a loading dose can result in higher R-salbutamol concentrations in the early phase after the start of infusion therapy, preventing accumulation of S-salbutamol. CONCLUSIONS: The pharmacokinetic model of intravenous R- and S-salbutamol described the data well and showed that a loading dose should be considered in children. This model can be used to evaluate the pharmacokinetic-pharmacodynamic relationship of intravenous salbutamol in children, and, as a next step, the effectiveness and tolerability of intravenous salbutamol in children with severe asthma.


Subject(s)
Adrenergic beta-2 Receptor Agonists/pharmacokinetics , Albuterol/pharmacokinetics , Status Asthmaticus/drug therapy , Administration, Intravenous , Adolescent , Adrenergic beta-2 Receptor Agonists/administration & dosage , Adrenergic beta-2 Receptor Agonists/blood , Adrenergic beta-2 Receptor Agonists/pharmacology , Albuterol/administration & dosage , Albuterol/blood , Albuterol/pharmacology , Child , Child, Preschool , Female , Hospitalization/statistics & numerical data , Humans , Infant , Intensive Care Units, Pediatric/statistics & numerical data , Male , Models, Theoretical , Prospective Studies , Status Asthmaticus/metabolism
3.
BMJ Case Rep ; 20172017 Jul 27.
Article in English | MEDLINE | ID: mdl-28754757

ABSTRACT

Status asthmaticus (SA) is a life-threatening disorder. Severe respiratory failure may require extracorporeal membrane oxygenation (ECMO). Previous reports have demonstrated utility of ECMO in SA in various patients with varying success. A 25-year-old man was admitted with status asthmatics and severe hypercapnic respiratory failure. Despite tailored ventilator therapies, such as pressure control ventilation and maximal pharmacological therapy, including general anaesthesia, the patient’s condition deteriorated rapidly. Veno-venous ECMO (VV-ECMO) was provided for respiratory support. The patient’s clinical condition improved over the following 72 hours and was discharged from the intensive care unit on day 3. This case report demonstrates the successful use of VV-ECMO in a patient with severe respiratory failure due to SA, who failed to respond to maximal therapy. This case adds support to a growing body of literature that shows that ECMO can be used with success for refractory status asthmaticus.


Subject(s)
Carbon Dioxide/metabolism , Critical Care , Extracorporeal Membrane Oxygenation , Hypercapnia/therapy , Respiratory Insufficiency/therapy , Status Asthmaticus/therapy , Adult , Chest Tubes , Extracorporeal Circulation , Humans , Hypercapnia/physiopathology , Male , Respiratory Insufficiency/metabolism , Status Asthmaticus/metabolism , Status Asthmaticus/physiopathology , Treatment Outcome
4.
Clin Respir J ; 10(5): 653-6, 2016 Sep.
Article in English | MEDLINE | ID: mdl-25515844

ABSTRACT

Status asthmaticus is a life-threatening condition that requires intensive care management. Most of these patients have severe hypercapnic acidosis that requires lung protective mechanical ventilation. A small proportion of these patients do not respond to conventional lung protective mechanical ventilation or pharmacotherapy. Such patients have an increased mortality and morbidity. Successful use of extracorporeal membrane oxygenation (ECMO) is reported in such patients. However, the use of ECMO is invasive with its associated morbidity and is limited to specialised centres. In this report, we report the use of a novel, minimally invasive, low-flow extracorporeal carbon dioxide removal device in management of severe hypercapnic acidosis in a patient with life threatening status asthmaticus.


Subject(s)
Extracorporeal Membrane Oxygenation/methods , Status Asthmaticus/therapy , Adult , Carbon Dioxide/metabolism , Critical Care , Extracorporeal Membrane Oxygenation/instrumentation , Humans , Male , Status Asthmaticus/metabolism , Treatment Outcome
6.
Pediatr Crit Care Med ; 13(2): 141-5, 2012 Mar.
Article in English | MEDLINE | ID: mdl-21666533

ABSTRACT

OBJECTIVE: To measure levels of 8-isoprostane and Lipoxin A4 in the exhaled breath condensate of children (7-17 yrs old) recovering from status asthmaticus in a pediatric intensive care unit and to compare their respective levels in the exhaled breath condensate collected from age-matched "healthy" children enrolled from an ambulatory pediatric clinic during well-child visits. DESIGN: Prospective case-controlled study. SETTING: Teaching hospitals and a research laboratory. PATIENTS: Children recovering from status asthmaticus and age-matched controls. INTERVENTIONS: Collection of exhaled breath condensate from patients recovering from status asthmaticus and controls for purpose of measurement of 8-isoprostane and Lipoxin A4. MEASUREMENTS AND MAIN RESULTS: There was no difference in age (11.9 ± 3.0 vs. 12.0 ± 3.3 yrs, p = .9) between patients and control subjects. All participants completed the exhaled breath condensate collection without complications. There was no difference in the pulmonary index (3.3 ± 2.2 vs. 3.1 ± 1.9, p = 1.0) after collection of exhaled breath condensate compared with baseline values in patients with status asthmaticus. The level of 8-isoprostane was significantly higher (63 ± 9 vs. 41 ± 13 pg/mL, p < .001), whereas the level of Lipoxin A4 was significantly lower (5.6 ± 2.9 vs. 10.5 ± 3.1 ng/mL, p < .001) in the exhaled breath condensate from children recovering from status asthmaticus compared with control subjects. CONCLUSIONS: 8-Isoprostane was elevated and Lipoxin A4 is decreased in the exhaled breath condensate of children recovering from status asthmaticus in a pediatric intensive care unit. These data may provide new insight into the pathophysiology of asthma in children in this clinical setting.


Subject(s)
Dinoprost/analogs & derivatives , Exhalation , Lipoxins/metabolism , Status Asthmaticus/metabolism , Adolescent , Biomarkers/metabolism , Breath Tests/methods , Case-Control Studies , Child , Dinoprost/metabolism , Female , Hospitalization/statistics & numerical data , Humans , Male , Pilot Projects , Prospective Studies , Status Asthmaticus/therapy , Time Factors
7.
Pediatr Crit Care Med ; 12(1): e25-8, 2011 Jan.
Article in English | MEDLINE | ID: mdl-20375755

ABSTRACT

OBJECTIVE: To evaluate the safety and feasibility of exhaled breath condensate (EBC) collection in children recovering from status asthmaticus (SA) in a pediatric intensive care unit (PICU); and to investigate whether 8-isoprostane (8-Iso) could be detected in the EBC of these children and to compare its concentration with that in the EBC collected from healthy children. DESIGN: Prospective study. SETTING: Multidisciplinary PICU in a teaching hospital. PATIENTS: Sixteen consecutive patients (7-18 yrs of age) with SA and 16 age- and sex-matched controls. INTERVENTIONS: The Wood clinical asthma score and the pulmonary index were used to assess the clinical severity of patients with SA upon admission to the PICU. EBC samples were collected within 24 hrs of admission to the PICU and were analyzed for the concentration of 8-Iso. MEASUREMENTS AND MAIN RESULTS: Data are presented as mean ± sd values. There were no differences in age (12 ± 3.3 yrs vs.12 ± 2 yrs, p > .05) or sex (n = 10 males and n = 6 females in each group), between SA patients and controls. All patients with SA and the controls completed the EBC collection without complications. There was no statistically significant difference in the pulmonary index (3.2 ± 2.7 vs. 3.1 ± 2.8, p 0.9) post collection of EBC compared with the baseline values. There was a statistically significant correlation between Wood score and pulmonary index at the time of admission to the PICU in children with SA (r = .7, p < .01). The concentration of 8-Iso was significantly higher in the EBC of children with SA compared with controls (14.3 ± 1.8 pg/mL vs. 5.2 ± 0.7 pg/mL, p < .001). The correlation between the concentration 8-Iso and either the pulmonary index or Wood score at the time admission to the PICU was not statistically significant. CONCLUSIONS: EBC collection is well tolerated by children aged 7-18 yrs who are recovering from SA in a PICU. 8-Iso is elevated in the EBC from children with SA and may provide insight into the biochemical changes of oxidative stress in children in this clinical setting.


Subject(s)
Isoprostanes/metabolism , Status Asthmaticus/metabolism , Adolescent , Breath Tests , Case-Control Studies , Child , Exhalation , Female , Hospitals, Teaching , Humans , Intensive Care Units, Pediatric , Male , Prospective Studies , Severity of Illness Index
9.
BMC Immunol ; 9: 73, 2008 Dec 16.
Article in English | MEDLINE | ID: mdl-19087256

ABSTRACT

BACKGROUND: Asthma is a complicated network of inflammatory reactions. It is classified into mild, moderate, and severe persistent asthma. The success of asthma therapy relies much on understanding the underlying mechanisms of inflammation at each stage of asthma severity. The aim of this study was to explore the differences in apoptotic potential, CD4/CD8 ratio, memory compartment, and T- helper (Th) 1 and 2 profile of peripheral blood lymphocytes (PBL) in patients with mild intermittent asthma and severe persistent asthma during exacerbation periods. RESULTS: Four research lines were investigated and compared among mild asthmatics, severe asthmatics, and healthy groups by applying immunocytochemical staining of PBL. Antiapoptotic and proapoptotic proteins with Bcl-2/Bax ratio, CD4, CD8 markers with CD4+/CD8+ ratio, CD45RO+, CD45RA+ markers with memory/naive ratio (CD45RO+/CD45RA+). Th2/Th1 cytokines balance represented by IL-4/IFN-gamma ratio was measured by enzyme-linked immunosorbent assay (ELISA) for in vitro PBL cytokine synthesis. It was found that Bcl-2/Bax ratio was higher in severe than in mild asthmatics which in turn was higher than in healthy group. And memory/naive ratio of PBL was higher in severe than in mild asthmatics. Moreover, memory cells, CD45RO+ and CD45RO+/CD45RA+ ratio were correlated directly with Bcl-2/Bax, in severe and mild asthma patients. In contrast, CD4+/CD8+ ratio was not changed significantly among healthy group, mild and severe asthmatics. However, CD8+ cells were correlated directly with memory cells, CD45RO+, in severe asthmatics only. Interestingly, the dominant profile of cytokines appeared to change from T helper 2 (Th2) in mild asthmatics to T helper 1 (Th1) in severe asthmatics where the lowest in vitro IL-4/IFN-gamma ratio and highest IFN-gamma were found. CONCLUSION: It was concluded that the underlying mechanisms of inflammation might vary greatly with asthma stage of severity. Mild intermittent asthma is mainly Th2 allergen-oriented reaction during exacerbations with good level of apoptosis making the inflammation as self-limiting, while in severe persistent asthma, the inflammatory reaction mediated mainly by Th1 cytokines with progressive loss of apoptosis leading to longer exacerbations, largely expanded memory cells, CD45RO+, leading to persistent baseline inflammation.


Subject(s)
Asthma/immunology , Status Asthmaticus/immunology , Th1 Cells/metabolism , Th2 Cells/metabolism , Adolescent , Adult , Apoptosis/immunology , Asthma/metabolism , Asthma/pathology , Asthma/physiopathology , CD4-CD8 Ratio , Cell Survival/immunology , Disease Progression , Enzyme-Linked Immunosorbent Assay , Female , Humans , Immunohistochemistry , Immunologic Memory , Interferon-gamma/metabolism , Interleukin-4/metabolism , Leukocyte Common Antigens/biosynthesis , Lymphocyte Activation , Male , Middle Aged , Proto-Oncogene Proteins c-bcl-2/biosynthesis , Severity of Illness Index , Status Asthmaticus/metabolism , Status Asthmaticus/pathology , Th1 Cells/immunology , Th1 Cells/pathology , Th2 Cells/immunology , Th2 Cells/pathology
10.
J Pathol ; 207(1): 102-10, 2005 Sep.
Article in English | MEDLINE | ID: mdl-16041692

ABSTRACT

It has been suggested that airway remodelling is responsible for the persistent airway obstruction and decline in lung function observed in some asthmatic patients. The small airways are thought to contribute significantly to this functional impairment. Proteoglycans (PGs) are important components of the extracellular matrix (ECM) in the lungs. Besides controlling biophysical properties of the ECM, they play important roles in the regulation of some cytokines. Increased subepithelial PG deposition in the airways of mild asthmatics has been reported. However, there are no data on the PG content in small airways in asthma. This study has compared the content and distribution of PGs in large and small airways of patients who died of asthma with those in control lungs. Immunohistochemistry and image analysis were used to determine the content of lumican, decorin, biglycan, and versican in large (internal perimeter >6 mm) and small (internal perimeter < or =6 mm) airways of 18 patients who had died of asthma (A) and ten controls (C). The results were expressed as PG area (microm2)/epithelial basement membrane length (microm). The main differences between asthmatics and controls were observed in the small airways. There was a significant decrease in decorin and lumican contents in the external area of small airways in asthmatics (decorin: A = 1.05 +/- 0.27 microm, C = 3.97 +/- 1.17 microm, p = 0.042; lumican: A = 1.97 +/- 0.37 microm, C = 5.66 +/- 0.99 microm, p = 0.002). A significant increase in versican content in the internal area of small and large airways in asthmatics was also observed (small: A = 7.48 +/- 0.84 microm, C = 5.16 +/- 0.61 microm, p = 0.045; large: A = 18.38 +/- 1.94 microm, C = 11.90 +/- 2.86 microm, p = 0.028). The results show that PGs are differentially expressed in the airways of fatal asthma and may contribute to airway remodelling. These data reinforce the importance of the small airways in airway remodelling in asthma.


Subject(s)
Lung/chemistry , Proteoglycans/analysis , Status Asthmaticus/metabolism , Adolescent , Adult , Aged , Autopsy , Chondroitin Sulfate Proteoglycans/analysis , Decorin , Extracellular Matrix Proteins , Female , Humans , Immunoenzyme Techniques , Keratan Sulfate/analysis , Lectins, C-Type , Lumican , Lung/pathology , Male , Middle Aged , Status Asthmaticus/pathology , Versicans
11.
J Immunol ; 166(9): 5763-72, 2001 May 01.
Article in English | MEDLINE | ID: mdl-11313420

ABSTRACT

Eosinophil recruitment and enhanced production of NO are characteristic features of asthma. However, neither the ability of eosinophils to generate NO-derived oxidants nor their role in nitration of targets during asthma is established. Using gas chromatography-mass spectrometry we demonstrate a 10-fold increase in 3-nitrotyrosine (NO(2)Y) content, a global marker of protein modification by reactive nitrogen species, in proteins recovered from bronchoalveolar lavage of severe asthmatic patients (480 +/- 198 micromol/mol tyrosine; n = 11) compared with nonasthmatic subjects (52.5 +/- 40.7 micromol/mol tyrosine; n = 12). Parallel gas chromatography-mass spectrometry analyses of bronchoalveolar lavage proteins for 3-bromotyrosine (BrY) and 3-chlorotyrosine (ClY), selective markers of eosinophil peroxidase (EPO)- and myeloperoxidase-catalyzed oxidation, respectively, demonstrated a dramatic preferential formation of BrY in asthmatic (1093 +/- 457 micromol BrY/mol tyrosine; 161 +/- 88 micromol ClY/mol tyrosine; n = 11 each) compared with nonasthmatic subjects (13 +/- 14.5 micromol BrY/mol tyrosine; 65 +/- 69 micromol ClY/mol tyrosine; n = 12 each). Bronchial tissue from individuals who died of asthma demonstrated the most intense anti-NO(2)Y immunostaining in epitopes that colocalized with eosinophils. Although eosinophils from normal subjects failed to generate detectable levels of NO, NO(2-), NO(3-), or NO(2)Y, tyrosine nitration was promoted by eosinophils activated either in the presence of physiological levels of NO(2-) or an exogenous NO source. At low, but not high (e.g., >2 microM/min), rates of NO flux, EPO inhibitors and catalase markedly attenuated aromatic nitration. These results identify eosinophils as a major source of oxidants during asthma. They also demonstrate that eosinophils use distinct mechanisms for generating NO-derived oxidants and identify EPO as an enzymatic source of nitrating intermediates in eosinophils.


Subject(s)
Eosinophils/metabolism , Nitric Oxide/metabolism , Oxidants/metabolism , Reactive Oxygen Species/metabolism , Status Asthmaticus/metabolism , Tyrosine/analogs & derivatives , Eosinophil Peroxidase , Eosinophils/enzymology , Eosinophils/pathology , Free Radicals/metabolism , Humans , Immunohistochemistry , Nitrates/metabolism , Nitric Oxide Donors/metabolism , Nitrites/metabolism , Oxidation-Reduction , Peroxidases/metabolism , Phenylpropionates/metabolism , Proteins/metabolism , Status Asthmaticus/pathology , Tyrosine/metabolism
12.
J Pediatr ; 138(1): 51-58, 2001 Jan.
Article in English | MEDLINE | ID: mdl-11148512

ABSTRACT

OBJECTIVE: To determine whether the addition of repeated doses of nebulized ipratropium bromide (IB) to a standardized inpatient asthma care algorithm (ACA) for children with status asthmaticus improves clinical outcome. STUDY DESIGN: Children with acute asthma (N = 210) age 1 to 18 years admitted to the ACA were assigned to the intervention or placebo group in randomized double-blind fashion. Both groups received nebulized albuterol, systemic corticosteroids, and oxygen according to the ACA. The intervention group received 250 microg IB combined with 2.5 mg albuterol by jet nebulization in a dosing schedule determined by the ACA phase. The placebo group received isotonic saline solution substituted for IB. Progression through each ACA phase occurred based on assessments of oxygenation, air exchange, wheezing, accessory muscle use, and respiratory rate performed at prescribed intervals. RESULTS: No significant differences were observed between treatment groups in hospital length of stay (P =.46), asthma carepath progression (P =.37), requirement for additional therapy, or adverse effects. Children >6 years (N = 70) treated with IB had shorter mean hospital length of stay (P =.03) and more rapid mean asthma carepath progression (P =.02) than children in the placebo group. However, after adjustment was done for baseline group differences, the observed benefit of IB therapy in older children no longer reached statistical significance. CONCLUSION: The routine addition of repeated doses of nebulized IB to a standardized regimen of systemic corticosteroids and frequently administered beta-2 agonists confers no significant enhancement of clinical outcome for the treatment of hospitalized children with status asthmaticus.


Subject(s)
Adrenergic beta-Agonists/therapeutic use , Albuterol/therapeutic use , Anti-Inflammatory Agents/therapeutic use , Bronchodilator Agents/therapeutic use , Cholinergic Antagonists/therapeutic use , Hospitalization , Ipratropium/therapeutic use , Status Asthmaticus/drug therapy , Acute Disease , Administration, Inhalation , Adolescent , Adrenergic beta-Agonists/pharmacology , Age Factors , Albuterol/pharmacology , Algorithms , Anti-Inflammatory Agents/pharmacology , Bronchodilator Agents/pharmacology , Child , Child, Preschool , Cholinergic Antagonists/pharmacology , Critical Pathways , Double-Blind Method , Drug Therapy, Combination , Female , Hospitalization/statistics & numerical data , Humans , Infant , Ipratropium/pharmacology , Length of Stay/statistics & numerical data , Male , Nebulizers and Vaporizers , Pulmonary Gas Exchange , Status Asthmaticus/diagnosis , Status Asthmaticus/metabolism , Status Asthmaticus/physiopathology , Steroids , Treatment Outcome
13.
Am J Respir Crit Care Med ; 162(2 Pt 1): 586-92, 2000 Aug.
Article in English | MEDLINE | ID: mdl-10934091

ABSTRACT

In status asthmaticus (SA), severe bronchial inflammation is associated with acute respiratory failure. Neutrophils are the prominent cells found in bronchi from SA patients, but eosinophils are also recruited within the first 48 h after the beginning of mechanical ventilation (MV). Interleukin (IL)-5 and CC chemokines have been directly implicated in the pathophysiology of allergic asthma. However, their involvement in SA had not been determined. The aim of this study was to evaluate the production of CC chemokines and of IL-5 in airways from ventilated patients with SA as compared with mild asthma (A), and to assess the role of these mediators in eosinophil recruitment. We measured levels of the chemokines monocyte chemotactic proteins (MCPs)-1 and -3; regulated on activation, normal T-cell expressed and secreted (RANTES); macrophage inflammatory peptide (MIP)-1alpha; and eotaxin; and of the cytokine IL-5 in bronchial lavage fluid (BLF) from 10 SA patients, four patients without respiratory disease but undergoing ventilation (V) who were receiving MV, 11 patients with A, and eight healthy volunteers (C). We further evaluated in vitro eosinophil chemotactic activity of BLF from the various groups. Levels of MCP-1, MIP-1alpha, RANTES, and IL-5 were significantly higher in the SA than in the V, A, and C groups. MCP-3 and eotaxin values were not significantly different in the SA and other groups; however, their levels, as well as those of MIP-1alpha, RANTES, and IL-5 correlated with eosinophil influx. Eosinophil chemotactic activity in BLF was increased in asthmatic subjects (A and SA groups) as compared with the other groups, and in SA patients as compared with A patients. Addition of neutralizing anti-IL-5, anti-MCP-3, anti-eotaxin, and anti-RANTES antibodies significantly inhibited the eosinophil chemotactic activity as compared with that of native BLF. This study shows that the levels of various CC chemokines and IL-5 are increased in airways of SA patients, and are potentially involved in eosinophil recruitment.


Subject(s)
Bronchoalveolar Lavage Fluid/chemistry , Chemokines, CC/biosynthesis , Eosinophils/physiology , Interleukin-5/biosynthesis , Neutrophil Infiltration/physiology , Status Asthmaticus/metabolism , Adult , Asthma/metabolism , Bronchoscopy , Chemokine CCL11 , Chemokine CCL2/analysis , Chemokine CCL3 , Chemokine CCL4 , Chemokine CCL5/analysis , Chemokine CCL7 , Chemokines, CC/physiology , Cytokines/analysis , Female , Humans , Interleukin-5/physiology , Macrophage Inflammatory Proteins/analysis , Male , Middle Aged , Monocyte Chemoattractant Proteins/analysis , Respiration, Artificial
14.
J Allergy Clin Immunol ; 104(4 Pt 1): 747-54, 1999 Oct.
Article in English | MEDLINE | ID: mdl-10518817

ABSTRACT

BACKGROUND: Recent evidence has shown that nitric oxide (NO) levels are increased in asthmatic airways. Although the role of NO in asthma is unknown, reactive metabolites of NO may lead to nitrotyrosine formation and promote airway dysfunction. OBJECTIVE: The aim of this study was to determine whether nitrotyrosine, as a marker of nitrating species, could be found in the airways and lung parenchyma of subjects with asthma who died of status asthmaticus or other nonrespiratory causes. METHODS: Lung tissue specimens were obtained from 5 patients who died of status asthmaticus, 2 asthmatic patients who died of nonrespiratory causes, and 6 nonasthmatic control subjects who died of nonrespiratory causes. Lung sections were stained for immunofluorescence with use of an antinitrotyrosine antibody, followed by a indiocarbocyanine (Cy5, Jackson Immunochemicals, Westgrove, Pa)-conjugated secondary antibody. RESULTS: Nonasthmatic lungs showed little or no nitrotyrosine staining, whereas asthmatic lungs demonstrated significantly more staining of nitrotyrosine residues distributed in both the airways and lung parenchyma. CONCLUSION: This study demonstrates the presence of nitrotyrosine, and hence evidence of formation of nitrating species, in the airways and lung parenchyma of patients with asthma who died of status asthmaticus or other nonrespiratory causes. This finding supports the concept that widespread airway and parenchymal inflammation occurs in asthma, and, more specifically, that NO and its reactive metabolites may play a pathophysiologic role in asthma.


Subject(s)
Asthma/metabolism , Bronchi/metabolism , Lung/metabolism , Nitric Oxide/metabolism , Status Asthmaticus/metabolism , Tyrosine/analogs & derivatives , Adolescent , Adult , Asthma/immunology , Asthma/mortality , Bronchi/immunology , Female , Fluorescent Antibody Technique , Free Radicals , Humans , Lung/immunology , Male , Middle Aged , Models, Immunological , Nitrogen Compounds , Status Asthmaticus/immunology , Status Asthmaticus/mortality , Tyrosine/isolation & purification
15.
Am J Respir Crit Care Med ; 159(4 Pt 1): 1298-307, 1999 Apr.
Article in English | MEDLINE | ID: mdl-10194181

ABSTRACT

In order to assess inflammatory features related to severe asthma as compared with mild asthma, we investigated the secretion of 92 kDa gelatinase matrix metalloproteinase (MMP-9) in bronchial lavages of six patients undergoing mechanical ventilation (MV) for status asthmaticus (SA) and in six patients with mild asthma. Ten healthy nonventilated patients and four patients under MV without preexisting respiratory disease were also investigated. Patients with SA were characterized by prominent neutrophilic inflammation (82 +/- 4% versus 10% in mild asthma). On the basis of enzymatic and immunological analysis, results showed an acute 10- to 160-fold increase of 92 kDa gelatinase (MMP-9) concentration in epithelial lining fluid (ELF) from patients with SA, together with activated forms (46 and 26 kDa) of stromelysin-1 matrix metalloproteinase (MMP-3) and detectable concentration of free metallogelatinolytic activity (1-5 micrograms gelatin hydrolyzed/48 h/ml ELF). Concomitant elevated level of tissue inhibitor of metalloproteinase-1 (TIMP-1) was shown only in patients with SA, thus counterbalancing, at least partially, excess of activated 92 kDa gelatinase. Acutely enhanced albumin levels were only observed in patients with SA; in addition, 92 kDa gelatinase and albumin levels were significantly and positively correlated (r = 0.96, p < 0.0001), suggesting that 92 kDa gelatinase may account for increased bronchial permeability in patients with SA. Several arguments support that 92 kDa gelatinase during SA originates both from numerous activated chemoattracted neutrophils and from activated bronchial epithelial cells in response to in situ lung injury. The fact that no relevant change in ELF, albumin, MMP-9, MMP-3, TIMP-1, or laminin degradation products was observed during mild asthma, strongly supports that the mechanism of airway inflammation in SA is quite distinct from that observed in mild asthma.


Subject(s)
Bronchi/pathology , Collagenases/physiology , Status Asthmaticus/pathology , Adult , Albumins/analysis , Asthma/enzymology , Asthma/pathology , Body Water/metabolism , Bronchoalveolar Lavage Fluid/chemistry , Bronchoalveolar Lavage Fluid/cytology , Bronchoscopy , Collagenases/metabolism , Enzyme Activation , Epithelium/metabolism , Humans , Inflammation , Laminin/metabolism , Matrix Metalloproteinase 3/analysis , Matrix Metalloproteinase 9 , Middle Aged , Peroxidase/analysis , Status Asthmaticus/metabolism , Tissue Inhibitor of Metalloproteinase-1/analysis , Urea/analysis
16.
Am J Respir Crit Care Med ; 159(2): 487-94, 1999 Feb.
Article in English | MEDLINE | ID: mdl-9927362

ABSTRACT

Status asthmaticus (SA) is an acute respiratory failure combining an acute bronchospastic reaction with a severe airway inflammation. We previously reported an important influx of neutrophils and an increased secretion of interleukin-8 (IL-8) in patients with SA. The aim of this prospective study was to evaluate in bronchial lavage (BL) of patients with SA (n = 9) under mechanical ventilation (MV) the concentrations of cytokines and related mediators which have the ability to modulate inflammation, either proinflammatory (interleukin-1beta [IL-1beta], IL-6, tumor necrosis factor-alpha [TNF-alpha]), or anti-inflammatory mediators (IL-10, transforming growth factor-beta1 [TGF-beta1]), interleukin-1 receptor antagonist [IL-1Ra], soluble TNF receptor I and II [sTNFRI and II]). To determine the relative importance of both pro- and anti-inflammatory mediators, the net inflammatory activity was analyzed by the capacity of BL fluids (BLF) to increase intercellular adhesion molecule-1 (ICAM-1) expression in the human lung A549 epithelial cell line. These data were compared with those obtained from patients who required MV without respiratory disease (V, n = 4), controlled asthma (A, n = 11), and nonsmoking healthy volunteers (C, n = 8). Levels of IL-1, IL-6, TNF-alpha, and of the active form of TGF-beta1 were significantly higher in SA compared with the other groups. The concentrations of IL-1Ra, IL-10, the latent form of TGF-beta1, and of the sTNFRI and II were not significantly different between SA and V, albeit higher in SA than in A and C. The ratio between IL-1Ra and IL-1beta was significantly higher in patients with SA compared with the other groups, whereas there was no difference for the ratio between both types of sTNFR and TNF-alpha. Despite a marked increase of anti-inflammatory mediators in BL from patients with SA, the net inflammatory activity was found to be proinflammatory and mainly due to the presence of bioactive IL-1beta (79% inhibition of ICAM-1 expression with anti-IL-1beta antibodies) and to a lesser extent TNF-alpha (32% inhibition with anti-TNF-alpha antibodies).


Subject(s)
Bronchoalveolar Lavage Fluid/chemistry , Cytokines/metabolism , Status Asthmaticus/metabolism , Adult , Antigens, CD/metabolism , Biomarkers , Bronchoalveolar Lavage , Bronchoalveolar Lavage Fluid/cytology , Bronchoscopy , Enzyme-Linked Immunosorbent Assay , Female , Humans , Interleukin 1 Receptor Antagonist Protein , Interleukin-1/metabolism , Interleukin-10/metabolism , Interleukin-6/metabolism , Male , Middle Aged , Receptors, Tumor Necrosis Factor/metabolism , Receptors, Tumor Necrosis Factor, Type I , Respiration, Artificial , Sialoglycoproteins/metabolism , Status Asthmaticus/pathology , Status Asthmaticus/therapy , Transforming Growth Factor beta/metabolism , Tumor Necrosis Factor-alpha/metabolism
17.
Crit Care Med ; 26(10): 1744-8, 1998 Oct.
Article in English | MEDLINE | ID: mdl-9781734

ABSTRACT

OBJECTIVES: To determine the clinical effects of intravenous terbutaline at >0.4 microg/kg/min in children with status asthmaticus; to describe the clinical findings associated with such therapy, including creatinine phosphokinase-myocardial band isoenzyme (CPK-MB) concentrations, electrocardiographic alterations, and decreased diastolic blood pressure (DBP) with terbutaline usage; and to assess the requirement for epinephrine to counteract the decrease in diastolic blood pressure. DESIGN: A retrospective review of children admitted with status asthmaticus who failed emergency room therapy and required intravenous terbutaline. SETTING: San Diego Children's Hospital Pediatric Intensive Care Unit. PATIENTS: Eighteen children with status asthmaticus, based on clinical and laboratory criteria, between September 1994 and July 1996. INTERVENTIONS: Epinephrine was added for below-normal decreases in diastolic blood pressure. MEASUREMENTS AND MAIN RESULTS: Continuous monitoring for arrhythmias, ST-segment changes, and DBP values during variations in the dose of intravenous terbutaline, with or without epinephrine. CPK-MB concentrations were determined in 15 of 18 patients. CONCLUSIONS: Intravenous terbutaline was well tolerated in asthmatic children for < or =305 continuous hours and at varying doses up to a maximum of 10 microg/kg/min. There was no relationship between the magnitude of CPK-MB concentrations and the terbutaline or epinephrine doses used. Arrhythmias were rare and not related to either terbutaline or epinephrine doses. However, ST-segment depression did occur in two patients requiring high-dose epinephrine. Terbutaline significantly lowered DBP when used between 0.4 and 1.0 microg/kg/min, which required epinephrine to be initiated. Epinephrine was not required at terbutaline doses of >2 microg/kg/min. There was no mortality.


Subject(s)
Bronchodilator Agents/therapeutic use , Status Asthmaticus/drug therapy , Terbutaline/therapeutic use , Adolescent , Arrhythmias, Cardiac/chemically induced , Blood Pressure/drug effects , Child , Child, Preschool , Creatine Kinase/blood , Drug Monitoring , Drug Therapy, Combination , Electrocardiography , Epinephrine/therapeutic use , Female , Humans , Infusions, Intravenous/methods , Isoenzymes , Male , Retrospective Studies , Status Asthmaticus/metabolism , Status Asthmaticus/physiopathology , Time Factors
18.
J Allergy Clin Immunol ; 100(6 Pt 2): S52-5, 1997 Dec.
Article in English | MEDLINE | ID: mdl-9440545

ABSTRACT

BACKGROUND: RANTES is considered to play an important role in various immune and allergic disorders since it is a potent chemoattractant for inflammatory cells such as eosinophils, memory T cells, and monocytes. OBJECTIVE: To investigate the possible role of RANTES in the pathogenesis of bronchial asthma. METHODS: The plasma level of RANTES was measured in 12 asthma patients and 15 normal controls by a sandwich enzyme-linked immunosorbent assay. RESULTS: In the patients with asthma, the plasma RANTES level was significantly elevated during acute attacks compared to that in the controls. In addition, it was higher than that during the asymptomatic state in the same patients. Plasma beta-thromboglobulin levels were also elevated in asthma patients during acute attacks and showed a correlation with the RANTES level. CONCLUSION: These findings suggest a role for RANTES in the pathogenesis of asthma and a possible role for platelets in RANTES release in asthma.


Subject(s)
Asthma/blood , Chemokine CCL5/blood , Adult , Female , Humans , Male , Middle Aged , Status Asthmaticus/metabolism , beta-Thromboglobulin/metabolism
19.
Rev. cuba. med ; 29(2): 196-203, mar.-abr. 1990. ilus, tab
Article in Spanish | LILACS | ID: lil-88305

ABSTRACT

Se realiza un estudio en quince pacientes con estado de mal asmático, hospitalizados en la unidad de cuidados intensivos del Hospital Docente Clinicoqurúrgico 10 de Octubre en Ciudad de La Habana. Se les aplicó una dosis inicial de 5,6 mg x kg de peso de teofilina, o la mitad de la dosis en caso de administración previa del medicamento, hepatopatías crónicas, enfermedad pulmonar obstructiva crónica o insuficiencia cardíaca congestiva, por bomba de infusión en viente minutos. Se continúa posteriormente con una solución de teofilina 0,9 mg por kilo de peso por hora. Se comprobó mediante monitorización sérica concentraciones estables ligeramente por encima del nivel terapéutico máximo recomenmdado, sin aparecer manifestaciones de toxicidad


Subject(s)
Adolescent , Middle Aged , Humans , Male , Female , Status Asthmaticus/metabolism , Theophylline/pharmacokinetics
20.
Rev. cuba. med ; 29(2): 196-203, mar.-abr. 1990. Ilus, tab
Article in Spanish | CUMED | ID: cum-3270

ABSTRACT

Se realiza un estudio en quince pacientes con estado de mal asmático, hospitalizados en la unidad de cuidados intensivos del Hospital Docente Clinicoqurúrgico 10 de Octubre en Ciudad de La Habana. Se les aplicó una dosis inicial de 5,6 mg x kg de peso de teofilina, o la mitad de la dosis en caso de administración previa del medicamento, hepatopatías crónicas, enfermedad pulmonar obstructiva crónica o insuficiencia cardíaca congestiva, por bomba de infusión en viente minutos. Se continúa posteriormente con una solución de teofilina 0,9 mg por kilo de peso por hora. Se comprobó mediante monitorización sérica concentraciones estables ligeramente por encima del nivel terapéutico máximo recomenmdado, sin aparecer manifestaciones de toxicidad


Subject(s)
Adolescent , Middle Aged , Aged , Humans , Male , Female , Status Asthmaticus/metabolism , Theophylline/pharmacokinetics
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