RESUMO
BACKGROUND: Progressive familial intrahepatic cholestasis (PFIC) is a group of autosomal recessive disorders, the most prevalent being BSEP deficiency, resulting in disrupted bile formation, cholestasis, and pruritus. Building on a previous phase 2 study, we aimed to evaluate the efficacy and safety of maralixibat-an ileal bile acid transporter inhibitor-in participants with all types of PFIC. METHODS: MARCH-PFIC was a multicentre, randomised, double-blind, placebo-controlled, phase 3 study conducted in 29 community and hospital centres across 16 countries in Europe, the Americas, and Asia. We recruited participants aged 1-17 years with PFIC with persistent pruritus (>6 months; average of ≥1·5 on morning Itch-Reported Outcome [Observer; ItchRO(Obs)] during the last 4 weeks of screening) and biochemical abnormalities or pathological evidence of progressive liver disease, or both. We defined three analysis cohorts. The BSEP (or primary) cohort included only those with biallelic, non-truncated BSEP deficiency without low or fluctuating serum bile acids or previous biliary surgery. The all-PFIC cohort combined the BSEP cohort with participants with biallelic FIC1, MDR3, TJP2, or MYO5B deficiencies without previous surgery but regardless of bile acids. The full cohort had no exclusions. Participants were randomly assigned (1:1) to receive oral maralixibat (starting dose 142·5 µg/kg, then escalated to 570 µg/kg) or placebo twice daily for 26 weeks. The primary endpoint was the mean change in average morning ItchRO(Obs) severity score between baseline and weeks 15-26 in the BSEP cohort. The key secondary efficacy endpoint was the mean change in total serum bile acids between baseline and the average of weeks 18, 22, and 26 in the BSEP cohort. Efficacy analyses were done in the intention-to-treat population (all those randomly assigned) and safety analyses were done in all participants who received at least one dose of study drug. This completed trial is registered with ClinicalTrials.gov, NCT03905330, and EudraCT, 2019-001211-22. FINDINGS: Between July 9, 2019, and March 4, 2022, 125 patients were screened, of whom 93 were randomly assigned to maralixibat (n=47; 14 in the BSEP cohort and 33 in the all-PFIC cohort) or placebo (n=46; 17 in the BSEP cohort and 31 in the all-PFIC cohort), received at least one dose of study drug, and were included in the intention-to-treat and safety populations. The median age was 3·0 years (IQR 2·0-7·0) and 51 (55%) of 93 participants were female and 42 (45%) were male. In the BSEP cohort, least-squares mean change from baseline in morning ItchRO(Obs) was -1·7 (95% CI -2·3 to -1·2) with maralixibat versus -0·6 (-1·1 to -0·1) with placebo, with a significant between-group difference of -1·1 (95% CI -1·8 to -0·3; p=0·0063). Least-squares mean change from baseline in total serum bile acids was -176 µmol/L (95% CI -257 to -94) for maralixibat versus 11 µmol/L (-58 to 80) for placebo, also representing a significant difference of -187 µmol/L (95% CI -293 to -80; p=0·0013). The most common adverse event was diarrhoea (27 [57%] of 47 patients on maralixibat vs nine [20%] of 46 patients on placebo; all mild or moderate and mostly transient). There were five (11%) participants with serious treatment-emergent adverse events in the maralixibat group versus three (7%) in the placebo group. No treatment-related deaths occurred. INTERPRETATION: Maralixibat improved pruritus and predictors of native liver survival in PFIC (eg, serum bile acids). Maralixibat represents a non-surgical, pharmacological option to interrupt the enterohepatic circulation and improve the standard of care in patients with PFIC. FUNDING: Mirum Pharmaceuticals.
Assuntos
Colestase Intra-Hepática , Prurido , Humanos , Método Duplo-Cego , Masculino , Feminino , Colestase Intra-Hepática/tratamento farmacológico , Colestase Intra-Hepática/sangue , Criança , Adolescente , Pré-Escolar , Lactente , Prurido/etiologia , Prurido/tratamento farmacológico , Resultado do Tratamento , Membro 11 da Subfamília B de Transportadores de Cassetes de Ligação de ATP/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/deficiênciaRESUMO
BACKGROUND: Primary sclerosing cholangitis (PSC) is frequently associated with pruritus, which significantly impairs quality of life. Maralixibat is a selective ileal bile acid transporter (IBAT) inhibitor that lowers circulating bile acid (BA) levels and reduces pruritus in cholestatic liver diseases. This is the first proof-of-concept study of IBAT inhibition in PSC. METHODS: This open-label study evaluated the safety and tolerability of maralixibat ≤10 mg/d for 14 weeks in adults with PSC. Measures of pruritus, biomarkers of BA synthesis, cholestasis, and liver function were also assessed. RESULTS: Of 27 enrolled participants, 85.2% completed treatment. Gastrointestinal treatment-emergent adverse events (TEAEs) occurred in 81.5%, with diarrhea in 51.9%. TEAEs were mostly mild or moderate (63.0%); 1 serious TEAE (cholangitis) was considered treatment related. Mean serum BA (sBA) levels decreased by 16.7% (-14.84 µmol/L; 95% CI, -27.25 to -2.43; p = 0.0043) by week 14/early termination (ET). In participants with baseline sBA levels above normal (n = 18), mean sBA decreased by 40.0% (-22.3 µmol/L, 95% CI, -40.38 to -4.3; p = 0.004) by week 14/ET. Liver enzyme elevations were not significant; however, increases of unknown clinical significance in conjugated bilirubin levels were observed. ItchRO weekly sum scores decreased from baseline to week 14/ET by 8.4% (p = 0.0495), by 12.6% (p = 0.0275) in 18 participants with pruritus at baseline, and by 70% (p = 0.0078) in 8 participants with ItchRO daily average score ≥3 at baseline. CONCLUSIONS: Maralixibat was associated with reduced sBA levels in adults with PSC. In participants with more severe baseline pruritus, pruritus improved significantly from baseline. TEAEs were mostly gastrointestinal related. These results support further investigation of IBAT inhibitors for adults with PSC-associated pruritus. ClinicalTrials.gov: NCT02061540.
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Colangite Esclerosante , Colestase , Humanos , Adulto , Projetos Piloto , Colangite Esclerosante/complicações , Colangite Esclerosante/tratamento farmacológico , Qualidade de Vida , Ácidos e Sais Biliares , Colestase/complicações , Colestase/tratamento farmacológico , Prurido/tratamento farmacológicoRESUMO
Children with progressive familial intrahepatic cholestasis, including bile salt export pump (BSEP) and familial intrahepatic cholestasis-associated protein 1 (FIC1) deficiencies, suffer debilitating cholestatic pruritus that adversely affects growth and quality of life (QoL). Reliance on surgical interventions, including liver transplantation, highlights the unmet therapeutic need. INDIGO was an open-label, Phase 2, international, long-term study to assess the efficacy and safety of maralixibat in children with FIC1 or BSEP deficiencies. Thirty-three patients, ranging from 12 months to 18 years of age, were enrolled. Eight had FIC1 deficiency and 25 had BSEP deficiency. Of the latter, 6 had biallelic, protein truncating mutations (t)-BSEP, and 19 had ≥ 1 nontruncating mutation (nt)-BSEP. Patients received maralixibat 266 µg/kg orally, once daily, from baseline to Week 72, with twice-daily dosing permitted from Week 72. Long-term efficacy was determined at Week 240. Serum bile acid (sBA) response (reduction in sBAs of > 75% from baseline or concentrations <102.0 µmol/L) was achieved in 7 patients with nt-BSEP, 6 during once-daily dosing, and 1 after switching to twice-daily dosing. sBA responders also demonstrated marked reductions in sBAs and pruritus, and increases in height, weight, and QoL. All sBA responders remained liver transplant-free after > 5 years. No patients with FIC1 deficiency or t-BSEP deficiency met the sBA responder criteria during the study. Maralixibat was generally well-tolerated throughout the study. Conclusion: Response to maralixibat was dependent on progressive familial intrahepatic cholestasis subtype, and 6 of 19 patients with nt-BSEP experienced rapid and sustained reductions in sBA levels. The 7 responders survived with native liver and experienced clinically significant reductions in pruritus and meaningful improvements in growth and QoL. Maralixibat may represent a well-tolerated alternative to surgical intervention.
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Colestase Intra-Hepática , Colestase , Transportadores de Cassetes de Ligação de ATP , Ácidos e Sais Biliares , Criança , Colestase/genética , Colestase Intra-Hepática/tratamento farmacológico , Humanos , Prurido/tratamento farmacológico , Qualidade de VidaRESUMO
BACKGROUND: Alagille syndrome is a rare genetic disease that often presents with severe cholestasis and pruritus. There are no approved drugs for management. Maralixibat, an apical, sodium-dependent, bile acid transport inhibitor, prevents enterohepatic bile acid recirculation. We evaluated the safety and efficacy of maralixibat for children with cholestasis in Alagille syndrome. METHODS: ICONIC was a placebo-controlled, randomised withdrawal period (RWD), phase 2b study with open-label extension in children (aged 1-18 years) with Alagille syndrome (NCT02160782). Eligible participants had more than three times the normal serum bile acid (sBA) levels and intractable pruritus. After 18 weeks of maralixibat 380 µg/kg once per day, participants were randomly assigned (1:1) to continue maralixibat or receive placebo for 4 weeks. Subsequently, all participants received open-label maralixibat until week 48. During the long-term extension (204 weeks reported), doses were increased up to 380 µg/kg twice per day. The primary endpoint was the mean sBA change during the RWD in participants with at least 50% sBA reduction by week 18. Cholestastic pruritus was assessed using observer-rated, patient-rated, and clinician-rated 0-4 scales. The safety population was defined as all participants who had received at least one dose of maralixibat. This trial was registered with ClinicalTrials.gov, NCT02160782, and is closed to recruitment. FINDINGS: Between Oct 28, 2014, and Aug 14, 2015, 31 participants (mean age 5·4 years [SD 4·25]) were enrolled and 28 analysed at week 48. Of the 29 participants who entered the randomised drug withdrawal period, ten (34%) were female and 19 (66%) were male. In the RWD, participants switched to placebo had significant increases in sBA (94 µmol/L, 95% CI 23 to 164) and pruritus (1·7 points, 95% CI 1·2 to 2·2), whereas participants who continued maralixibat maintained treatment effect. This study met the primary endpoint (least square mean difference -117 µmol/L, 95% CI -232 to -2). From baseline to week 48, sBA (-96 µmol/L, -162 to -31) and pruritus (-1·6 pts, -2·1 to -1·1) improved. In participants who continued to week 204 (n=15) all improvements were maintained. Maralixibat was generally safe and well tolerated throughout. The most frequent adverse events were gastrointestinal related. Most adverse events were self-limiting in nature and mild-to-moderate in severity. INTERPRETATION: In children with Alagille syndrome, maralixibat is, to our knowledge, the first agent to show durable and clinically meaningful improvements in cholestasis. Maralixibat might represent a new treatment paradigm for chronic cholestasis in Alagille syndrome. FUNDING: Mirum Pharmaceuticals.
Assuntos
Síndrome de Alagille/tratamento farmacológico , Proteínas de Transporte/antagonistas & inibidores , Proteínas de Transporte/uso terapêutico , Glicoproteínas de Membrana/antagonistas & inibidores , Glicoproteínas de Membrana/uso terapêutico , Prurido/tratamento farmacológico , Adolescente , Proteínas de Transporte/efeitos adversos , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Glicoproteínas de Membrana/efeitos adversos , Resultado do TratamentoRESUMO
INTRODUCTION: Unlike the adult heart failure (HF) patient population, there is scarce information on the overall burden of HF in the pediatric population across geographies and within different age groups. AREAS COVERED: A systematic review aims to describe and quantify the economic, humanistic, and societal burden of pediatric (age <18 years) HF on patients and caregivers. Eighteen published studies over a period of 10 years (1 January 2006-20 May 2016) were identified through Embase, Medline, Cochrane Library and selected congresses. Studies from the US reported higher HF-related hospitalization-rates in infants aged <1 year (49.3%-63.9%) versus children aged 1-12 years (18.7%-30.9%) in HF diagnosed patients. Across the studies, the average length of hospital stay was 15 days, increasing to 26 days for infants. Average annual hospital charges were higher for infants (US$176,000) versus children aged 1-10 years (US$132,000) in the US. In Germany, diagnosis-related group (DRG)-based hospital-allowances per HF-case increased from 3,498 in 1995 to 4,250 in 2009. EXPERT OPINION: To our knowledge, this is the first systematic review, which provides valuable insights into the burden of HF in children and adolescents, and strengthens current knowledge of pediatric HF. However, there is a need for larger population-based studies with wider geographical coverage.
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Efeitos Psicossociais da Doença , Insuficiência Cardíaca/epidemiologia , Hospitalização/estatística & dados numéricos , Adolescente , Fatores Etários , Cuidadores/estatística & dados numéricos , Criança , Pré-Escolar , Insuficiência Cardíaca/economia , Custos Hospitalares/estatística & dados numéricos , Hospitalização/economia , Humanos , Lactente , Recém-Nascido , Tempo de Internação/estatística & dados numéricosRESUMO
While the epidemiology of adult heart failure has been extensively researched, this systematic review addresses the less well characterized incidence and prevalence of pediatric HF. The search strategy used Cochrane methodology and identified 83 unique studies for inclusion. Studies were categorized according to whether the HF diagnosis was reported as primary (n = 10); associated with other cardiovascular diseases (CVDs) (n = 49); or associated with non-CVDs (n = 24). A narrative synthesis of the evidence is presented. For primary HF, the incidence ranged from 0.87/100,000 (UK and Ireland) to 7.4/100,000 (Taiwan). A prevalence of 83.3/100,000 was reported in one large population-based study from Spain. HF etiology varied across regions with lower respiratory tract infections and severe anemia predominating in lower income countries, and cardiomyopathies and congenital heart disease major causes in higher income countries. Key findings for the other categories included a prevalence of HF associated with cardiomyopathies ranging from 36.1% (Japan) to 79% (US); associated with congenital heart disease from 8% (Norway) to 82.2% (Nigeria); associated with rheumatic heart diseases from 1.5% (Turkey) to 74% (Zimbabwe); associated with renal disorders from 3.8% (India) to 24.1% (Nigeria); and associated with HIV from 1% (US) to 29.3% (Brazil). To our knowledge, this is the first systematic review of the topic and strengthens current knowledge of pediatric HF epidemiology. Although a large body of research was identified, heterogeneity in study design and diagnostic criteria limited the ability to compare regional data. Standardized definitions of pediatric HF are required to facilitate cross-regional comparisons of epidemiological data.
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Insuficiência Cardíaca/epidemiologia , Adolescente , Criança , Pré-Escolar , Insuficiência Cardíaca/etiologia , Humanos , Incidência , Lactente , Prevalência , Fatores de RiscoRESUMO
Fragile X syndrome (FXS), the most common cause of inherited intellectual disability and autistic spectrum disorder, is typically caused by transcriptional silencing of the X-linked FMR1 gene. Work in animal models has described altered synaptic plasticity, a result of the up-regulation of metabotropic glutamate receptor 5 (mGluR5)-mediated signaling, as a putative downstream effect. Post hoc analysis of a randomized, placebo-controlled, crossover phase 2 trial suggested that the selective mGluR5 antagonist mavoglurant improved behavioral symptoms in FXS patients with completely methylated FMR1 genes. We present the results of two phase 2b, multicenter, randomized, double-blind, placebo-controlled, parallel-group studies of mavoglurant in FXS, designed to confirm this result in adults (n = 175, aged 18 to 45 years) and adolescents (n = 139, aged 12 to 17 years). In both trials, participants were stratified by methylation status and randomized to receive mavoglurant (25, 50, or 100 mg twice daily) or placebo over 12 weeks. Neither of the studies achieved the primary efficacy end point of improvement on behavioral symptoms measured by the Aberrant Behavior Checklist-Community Edition using the FXS-specific algorithm (ABC-C(FX)) after 12 weeks of treatment with mavoglurant. The safety and tolerability profile of mavoglurant was as previously described, with few adverse events. Therefore, under the conditions of our study, we could not confirm the mGluR theory of FXS nor the ability of the methylation state of the FMR1 promoter to predict mavoglurant efficacy. Preclinical results suggest that future clinical trials might profitably explore initiating treatment in a younger population with longer treatment duration and longer placebo run-ins and identifying new markers to better assess behavioral and cognitive benefits.
Assuntos
Síndrome do Cromossomo X Frágil/tratamento farmacológico , Indóis/uso terapêutico , Adolescente , Adulto , Fatores Etários , Comportamento , Cognição , Metilação de DNA/efeitos dos fármacos , Demografia , Método Duplo-Cego , Feminino , Síndrome do Cromossomo X Frágil/genética , Humanos , Indóis/farmacologia , Análise dos Mínimos Quadrados , Masculino , Placebos , Resultado do TratamentoRESUMO
Cystic fibrosis airways are deficient for L-arginine, a substrate for nitric oxide synthases (NOSs) and arginases. The rationale for this study was to quantify NOS and arginase activity in the mouse lung. Anesthetized unventilated mice received a primed constant stable isotope intravenous infusion containing labeled L-arginine, ornithine, and citrulline. The isotopic enrichment of each of the infused isotopomers and its product amino acids were measured in plasma and organ homogenates using liquid chromatography-tandem mass spectrometry. The effect of infection was studied three days after direct tracheal instillation of Pseudomonas-coated agar beads. In the infusion model, lung infection resulted in a significant (28-fold) increase in NOS activity in lung but not in trachea, kidney, liver, or plasma. Absolute rates of arginase activity in solid tissues could not be calculated in this model. In an isolated lung perfusion model used for comparison increased NOS activity in infected lungs was confirmed (28.5-fold) and lung arginase activity was increased 9.7-fold. The activity of L-arginine metabolizing enzymes can be measured using stable isotope conversion in the mouse. Accumulation of L-ornithine in the whole mouse model hindered the exact quantification of arginase activity in the lung, a problem that was overcome utilizing an isolated lung perfusion model.
Assuntos
Arginase/metabolismo , Pulmão/microbiologia , Óxido Nítrico Sintase/metabolismo , Pseudomonas/patogenicidade , Animais , Modelos Animais de Doenças , Feminino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
The activity of arginase is increased in airway secretions of patients with cystic fibrosis (CF). Downstream products of arginase activity may contribute to CF lung disease. We hypothesized that pulmonary arginase expression and activity would be increased in mouse models of CF and disproportionally increased in CF mice with Pseudomonas aeruginosa pneumonia. Expression of arginase isoforms in lung tissue was quantified with reverse transcriptase-PCR in naive cystic fibrosis transmembrane conductance regulator (Cftr)-deficient mice and ß-epithelial sodium channel-overexpressing [ß-ENaC-transgenic (Tg)] mice. An isolated lung stable isotope perfusion model was used to measure arginase activity in Cftr-deficient mice before and after intratracheal instillation of Pseudomonas aeruginosa. The expression of arginase-2 in lung was increased in adult Cftr-deficient animals and in newborn ß-ENaC-Tg. Arginase-1 lung expression was normal in Cftr-deficient and in newborn ß-ENaC-Tg mice, but was increased in ß-ENaC-Tg mice at age 1, 3, and 6 wk. Arginase activity was significantly higher in lung (5.0 ± 0.7 vs. 3.2 ± 0.3 nmol·(-1)·h(-1), P = 0.016) and airways (204.6 ± 49.8 vs. 79.3 ± 17.2 nmol·(-1)·h(-1), P = 0.045) of naive Cftr-deficient mice compared with sex-matched wild-type littermate controls. Infection with Pseudomonas aeruginosa resulted in a far greater increase in lung arginase activity in Cftr-deficient mice (10-fold) than in wild-type controls (6-fold) (P = 0.01). This is the first ex vivo characterization of arginase expression and activity in CF mouse lung and airways. Our data show that pulmonary arginase expression and activity is increased in CF mice, especially with Pseudomonas aeruginosa infections.
Assuntos
Arginase/metabolismo , Fibrose Cística/metabolismo , Pneumopatias/metabolismo , Pulmão/metabolismo , Pneumonia/metabolismo , Animais , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Modelos Animais de Doenças , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Infecções por Pseudomonas/metabolismo , Pseudomonas aeruginosaRESUMO
OBJECTIVES: To document the prevalence of asynchrony events during noninvasive ventilation in pressure support in infants and in children and to compare the results with neurally adjusted ventilatory assist. DESIGN: Prospective randomized cross-over study in children undergoing noninvasive ventilation. SETTING: The study was performed in a PICU. PATIENTS: From 4 weeks to 5 years. INTERVENTIONS: Two consecutive ventilation periods (pressure support and neurally adjusted ventilatory assist) were applied in random order. During pressure support (PS), three levels of expiratory trigger (ETS) setting were compared: initial ETS (PSinit), and ETS value decreased and increased by 15%. Of the three sessions, the period allowing for the lowest number of asynchrony events was defined as PSbest. Neurally adjusted ventilator assist level was adjusted to match the maximum airway pressure during PSinit. Positive end-expiratory pressure was the same during pressure support and neurally adjusted ventilator assist. Asynchrony events, trigger delay, and cycling-off delay were quantified for each period. RESULTS: Six infants and children were studied. Trigger delay was lower with neurally adjusted ventilator assist versus PSinit and PSbest (61 ms [56-79] vs 149 ms [134-180] and 146 ms [101-162]; p = 0.001 and 0.02, respectively). Inspiratory time in excess showed a trend to be shorter during pressure support versus neurally adjusted ventilator assist. Main asynchrony events during PSinit were autotriggering (4.8/min [1.7-12]), ineffective efforts (9.9/min [1.7-18]), and premature cycling (6.3/min [3.2-18.7]). Premature cycling (3.4/min [1.1-7.7]) was less frequent during PSbest versus PSinit (p = 0.059). The asynchrony index was significantly lower during PSbest versus PSinit (40% [28-65] vs 65.5% [42-76], p < 0.001). With neurally adjusted ventilator assist, all types of asynchronies except double triggering were reduced. The asynchrony index was lower with neurally adjusted ventilator assist (2.3% [0.7-5] vs PSinit and PSbest, p < 0.05 for both comparisons). CONCLUSION: Asynchrony events are frequent during noninvasive ventilation with pressure support in infants and in children despite adjusting the cycling-off criterion. Compared with pressure support, neurally adjusted ventilator assist allows improving patient-ventilator synchrony by reducing trigger delay and the number of asynchrony events. Further studies should determine the clinical impact of these findings.
Assuntos
Unidades de Terapia Intensiva Pediátrica , Suporte Ventilatório Interativo/métodos , Respiração com Pressão Positiva/métodos , Criança , Pré-Escolar , Estudos Cross-Over , Feminino , Humanos , Lactente , Suporte Ventilatório Interativo/efeitos adversos , Masculino , Pacientes , Respiração com Pressão Positiva/efeitos adversos , Prevalência , Estudos Prospectivos , Respiração , SuíçaRESUMO
OBJECTIVES: To document and compare the prevalence of asynchrony events during invasive-assisted mechanical ventilation in pressure support mode and in neurally adjusted ventilatory assist in children. DESIGN: Prospective, randomized, and crossover study. SETTING: Pediatric and Neonatal Intensive Care Unit, University Hospital of Geneva, Switzerland. PATIENTS: Intubated and mechanically ventilated children, between 4 weeks and 5 years old. INTERVENTIONS: Two consecutive ventilation periods (pressure support and neurally adjusted ventilatory assist) were applied in random order. During pressure support, three levels of expiratory trigger setting were compared: expiratory trigger setting as set by the clinician in charge (PSinit), followed by a 10% (in absolute values) increase and decrease of the clinician's expiratory trigger setting. The pressure support session with the least number of asynchrony events was defined as PSbest. Therefore, three periods were compared: PSinit, PSbest, and neurally adjusted ventilatory assist. Asynchrony events, trigger delay, and inspiratory time in excess were quantified for each of them. MEASUREMENTS AND MAIN RESULTS: Data from 19 children were analyzed. Main asynchrony events during PSinit were autotriggering (3.6 events/min [0.7-8.2]), ineffective efforts (1.2/min [0.6-5]), and premature cycling (3.5/min [1.3-4.9]). Their number was significantly reduced with PSbest: autotriggering 1.6/min (0.2-4.9), ineffective efforts 0.7/min (0-2.6), and premature cycling 2/min (0.1-3.1), p < 0.005 for each comparison. The median asynchrony index (total number of asynchronies/triggered and not triggered breaths ×100) was significantly different between PSinit and PSbest: 37.3% [19-47%] and 29% [24-43%], respectively, p < 0.005). With neurally adjusted ventilatory assist, all types of asynchrony events except double-triggering and inspiratory time in excess were significantly reduced resulting in an asynchrony index of 3.8% (2.4-15%) (p < 0.005 compared to PSbest). CONCLUSIONS: Asynchrony events are frequent during pressure support in children despite adjusting the cycling off criteria. Neurally adjusted ventilatory assist allowed for an almost ten-fold reduction in asynchrony events. Further studies should determine the clinical impact of these findings.
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Unidades de Terapia Intensiva Pediátrica , Respiração Artificial/efeitos adversos , Respiração Artificial/métodos , Pré-Escolar , Estudos Cross-Over , Feminino , Humanos , Lactente , Intubação Intratraqueal , Masculino , Estudos ProspectivosRESUMO
Ventilator-induced lung injury (VILI) due to high tidal volume (V(T)) is associated with increased levels of circulating factors that may contribute to, or be markers of, injury. This study investigated if exclusively lung-derived circulating factors produced during high V(T) ventilation can cause or worsen VILI. In isolated perfused mouse lungs, recirculation of perfusate worsened injury (compliance impairment, microvascular permeability, edema) induced by high V(T). Perfusate collected from lungs ventilated with high V(T) and used to perfuse lungs ventilated with low V(T) caused similar compliance impairment and permeability and caused a dose-dependent decrease in transepithelial electrical resistance (TER) across rat distal lung epithelial monolayers. Circulating soluble factors derived from the isolated lung thus contributed to VILI and had deleterious effects on the lung epithelial barrier. These data demonstrate transferability of an injury initially caused exclusively by mechanical ventilation and provides novel evidence for the biotrauma hypothesis in VILI. Mediators of the TER decrease were heat-sensitive, transferable via Folch extraction, and (following ultrafiltration, 3 kDa) comprised both smaller and larger molecules. Although several classes of candidate mediators, including protein cytokines (e.g., tumor necrosis factor-α, interleukin-6, macrophage inflammation protein-1α) and lipids (e.g., eicosanoids, ceramides, sphingolipids), have been implicated in VILI, only prostanoids accumulated in the perfusate in a pattern consistent with a pathogenic role, yet cyclooxygenase inhibition did not protect against injury. Although no single class of factor appears solely responsible for the decrease in barrier function, the current data implicate lipid-soluble protein-bound molecules as not just markers but pathogenic mediators in VILI.
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Pulmão/metabolismo , Pulmão/patologia , Lesão Pulmonar Induzida por Ventilação Mecânica/patologia , Animais , Citocinas/metabolismo , Impedância Elétrica , Epitélio/patologia , Técnicas In Vitro , Lipídeos/isolamento & purificação , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Perfusão , Prostaglandina-Endoperóxido Sintases/metabolismo , Prostaglandinas/metabolismo , Desnaturação Proteica , Ratos , Solubilidade , Temperatura , UltrafiltraçãoRESUMO
BACKGROUND: Significant advances in the management of patients with acute respiratory distress syndrome have been few in the recent past despite considerable efforts in clinical testing and experimental work. The biotrauma hypothesis of ventilator-associated lung injury (VALI), suggesting that mechanical ventilation induces the release of injurious mediators from the lung, implies that pharmaceutical interventions targeting these circulating pathogenic mediators would be clinically beneficial. Among the commonly reported classes of ventilation-associated mediators are cytokines, coagulation factors, hormones (e.g., angiotensin-II), lipid-derived mediators and oxidants, yet proof of their pathogenicity is lacking. DISCUSSION: This review discusses evidence surrounding the roles of these mediators in VALI and describes how definitive proof could be provided based on Koch's postulates, using an isolated perfused lung model. According to this experimental concept, candidate mediators would fulfill certain criteria, including increased accumulation in perfusate during injurious ventilation and induction of injury during non-injurious ventilation. Accumulation of mediators in the perfusate would facilitate isolation and characterization by standard biochemical means, from broad determination of physical and chemical properties to precise identification of individual molecules (e.g., by modern "omic" approaches such as mass spectrometry). Finally, confirmation by exogenous administration of mediators or antagonists can assess effects on injury and its mechanisms such as cell permeability or cytotoxicity. CONCLUSIONS: Adaptation of Koch's postulates to the biotrauma hypothesis of VALI could provide important insights. Translation of the acquired knowledge into clinical testing is challenged by the heterogeneity of the patient population (e.g., etiology, co-morbidity, genetics or concomitant therapy) and the specificity and efficacy of the therapeutic intervention on the cellular/molecular level.
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Mediadores da Inflamação/efeitos adversos , Insuficiência de Múltiplos Órgãos/etiologia , Síndrome do Desconforto Respiratório/terapia , Lesão Pulmonar Induzida por Ventilação Mecânica , Ventiladores Mecânicos/efeitos adversos , HumanosRESUMO
OBJECTIVE: To systematically review the existing literature on third branchial arch anomalies and suggest guidelines for their management. DATA SOURCES: We searched PubMed, Medline, and Embase using Scopus, and collected additional publications cited in bibliographies. We included all English-language articles and all foreign-language articles with an English abstract. REVIEW METHODS: Two investigators reviewed all cases explicitly identified as third arch anomalies or meeting anatomical criteria for third arch anomalies; they assessed presentation, diagnostic methods, intervention, and outcome. RESULTS: We found 202 cases of third arch anomalies; they presented primarily on the left side (89%), usually as neck abscess (39%) or acute suppurative thyroiditis (33%). Barium swallow, direct laryngoscopy, and magnetic resonance imaging were the most useful diagnostic tools. The recurrence rate varied among the treatment options: incision and drainage, 94 percent; endoscopic cauterization of the sinus tract opening, 18 percent; open-neck surgery and tract excision, 15 percent; and partial thyroidectomy during open-neck surgery, 14 percent. Complications after surgery appeared somewhat more frequently in children eight years of age or younger. CONCLUSION: Third arch anomalies are more common than previously reported. They appear to be best treated by complete excision of the cyst, sinus, or fistula during a quiescent period. Repeated incision and drainage yields high rates of recurrence and should be avoided. Complications might be minimized by first initiating antibiotic treatment, delaying surgical treatment until the inflammatory process is maximally resolved, and by using endoscopic cauterization.
Assuntos
Região Branquial/anormalidades , Algoritmos , Anormalidades Congênitas/diagnóstico , Anormalidades Congênitas/terapia , HumanosRESUMO
BACKGROUND/PURPOSE: Congenital fourth branchial arch anomalies are uncommon entities, heretofore described only in case reports, affecting primarily children, and typically presenting as a cervical inflammatory process. The aim of the study was to collect appropriate data on the diagnosis, treatment, and outcome of this condition and to suggest guidelines for its management. METHODS: We conducted a structured review of the literature for cases explicitly identified as congenital fourth branchial arch anomalies or meeting anatomical criteria for this condition. We computed descriptive statistics and performed several post hoc 2-way comparisons of subgroups of cases. RESULTS: We located and critically evaluated 526 cases. Fourth arch anomalies were usually located on the left (94%) and generally presented as acute suppurative thyroiditis (45%) or recurrent neck abscess (42%). Barium swallow and direct laryngoscopy were the most useful diagnostic tools. Treatment options differed mainly in recurrence rates: incision and drainage, 89%; open neck surgery and tract excision, 15%; endoscopic cauterization of the sinus tract opening, 15%; and open neck surgery with partial thyroidectomy, 8%. Complications after surgery occurred primarily in children 8 years or younger. CONCLUSION: Fourth arch anomalies are more common than once thought. Treatment of these disorders with repeated incision and drainage yields high rates of recurrence; thus, complete excision of the entire fistula tract during a quiescent period appears preferable. Combining this surgery with partial thyroidectomy may further decrease recurrence rates. Complications can likely be minimized by using antibiotic treatment of acute infections or endoscopic cauterization in children 8 years or younger, and delaying open neck surgery.
Assuntos
Abscesso/etiologia , Região Branquial/anormalidades , Branquioma/complicações , Neoplasias de Cabeça e Pescoço/complicações , Laringoscopia/métodos , Procedimentos Cirúrgicos Otorrinolaringológicos/métodos , Tireoidite/etiologia , Abscesso/diagnóstico , Abscesso/cirurgia , Branquioma/diagnóstico , Branquioma/cirurgia , Criança , Diagnóstico Diferencial , Neoplasias de Cabeça e Pescoço/diagnóstico , Neoplasias de Cabeça e Pescoço/cirurgia , Humanos , Imageamento por Ressonância Magnética , Pescoço , Tireoidectomia/métodos , Tireoidite/diagnóstico , Tireoidite/cirurgia , Tomografia Computadorizada por Raios X , Resultado do TratamentoRESUMO
OBJECTIVE: Volume-targeted modes are designed to deliver a constant tidal volume (V(t)) at lowest possible pressure independently of changes in compliance, resistance, and leak of the respiratory system. We examined whether these volume-targeted modes respond rapidly enough to sudden changes in respiratory mechanics (e.g., selective intubation, surfactant administration, endotracheal tube kinking, de-kinking, obstruction), resulting in insufficient or excessive V(t) delivery. DESIGN AND SETTING: Bench study of six neonatal ventilators in the volume-targeted mode simulating preterm and full-term infant settings on a test lung. MEASUREMENTS AND RESULTS: Breath-to-breath expiratory V(t) were measured after rapid compliance, resistance, and leak changes. Under our test settings all ventilators showed important volume overshooting following rapid increase in compliance or decrease in resistance. Between one and 16 inflations were required to return to the set V(t). Some ventilators delivered inaccurate V(t) under steady state condition while others showed considerable breath-to-breath V(t) variability. CONCLUSIONS: We observed inaccurate V(t) delivery under specific conditions as well as immediate and sometimes prolonged volume overshooting after a rapid respiratory system compliance increase or resistance decrease in volume-targeted modes of modern neonatal ventilators. Similar discrepancies between the set V(t) and the delivered inflations can be harmful in clinical situations, especially in newborns. Their clinical relevance needs to be clarified with safety studies in the neonatal population and we encourage manufacturers to further improve the ventilators algorithms.
Assuntos
Pediatria/instrumentação , Respiração Artificial/instrumentação , Desenho de Equipamento , Falha de Equipamento , Humanos , Recém-Nascido , Respiração Artificial/efeitos adversos , Volume de Ventilação PulmonarRESUMO
UNLABELLED: Bacteria increasingly resistant to antibiotics are a major treatment concern of respiratory tract pathogens in children. The aim of this study was to assess the trends of resistance of Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis to several classes of antibiotics in children<16 years of age and to compare its prevalence with surrounding countries. We studied retrospectively the susceptibility of respiratory tract pathogens isolated from specimens collected from patients at the Geneva Children's Hospital between 1989 and 2004. The susceptibility of S. pneumoniae to penicillin decreased from 98% to 58% (P<0.001) within 16 years, mainly due to strains intermediately resistant (MICs 0.12-1.0 microg/ml). Also erythromycin-susceptible pneumococci decreased from 97% to 63% (P<0.001). The susceptibility of H. influenzae to amoxicillin also significantly declined (87% vs. 82%, P<0.001), and the susceptibility of M. catarrhalis to this drug almost disappeared (29% vs. 5%, P<0.001). However, in 2004 these two bacteria remained 100% susceptible to amoxicillin-clavulanic acid, second and third generation cephalosporins. Invasive H. influenzae strains were significantly more resistant to ampicillin than non-invasive strains, but no susceptibility difference between invasive and non-invasive S. pneumoniae was determined. CONCLUSION: During the 16 years studied, the antibiotic resistance of respiratory tract pathogens steadily and significantly increased in children, especially S. pneumoniae. This situation in Geneva is similar to neighbouring France rather than to the rest of Switzerland. A permanent surveillance of microbial susceptibility to antibiotics is essential and a limitation of antibiotic prescription together with information of the judicious use may impede the actual resistance trend.