RESUMO
A highly concentrated (20%) immunoglobulin (Ig)G preparation for subcutaneous administration (IGSC 20%), would offer a new option for antibody replacement therapy in patients with primary immunodeficiency diseases (PIDD). The efficacy, safety, tolerability and pharmacokinetics of IGSC 20% were evaluated in a prospective trial in Europe in 49 patients with PIDD aged 2-67 years. Over a median of 358 days, patients received 2349 IGSC 20% infusions at monthly doses equivalent to those administered for previous intravenous or subcutaneous IgG treatment. The rate of validated acute bacterial infections (VASBIs) was significantly lower than 1 per year (0·022/patient-year, P < 0·0001); the rate of all infections was 4·38/patient-year. Median trough IgG concentrations were ≥ 8 g/l. There was no serious adverse event (AE) deemed related to IGSC 20% treatment; related non-serious AEs occurred at a rate of 0·101 event/infusion. The incidence of local related AEs was 0·069 event/infusion (0·036 event/infusion, when excluding a 13-year-old patient who reported 79 of 162 total related local AEs). The incidence of related systemic AEs was 0·032 event/infusion. Most related AEs were mild, none were severe. For 64·6% of patients and in 94·8% of IGSC 20% infusions, no local related AE occurred. The median infusion duration was 0·95 (range = 0·3-4·1) h using mainly one to two administration sites [median = 2 sites (range = 1-5)]. Almost all infusions (99·8%) were administered without interruption/stopping or rate reduction. These results demonstrate that IGSC 20% provides an effective and well-tolerated therapy for patients previously on intravenous or subcutaneous treatment, without the need for dose adjustment.
Assuntos
Imunoglobulinas Intravenosas/uso terapêutico , Síndromes de Imunodeficiência/tratamento farmacológico , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Europa (Continente) , Feminino , Seguimentos , Humanos , Imunoglobulinas Intravenosas/administração & dosagem , Imunoglobulinas Intravenosas/farmacocinética , Infusões Subcutâneas , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Adulto JovemRESUMO
Since parenteral beta 2-adrenergic stimulation can induce hypokalemia, we postulated that administration of beta 2 adrenoreceptor agonists by inhalation could induce the same. We administered the usual clinical doses of three commonly used bronchodilators to each of six subjects receiving assisted mechanical ventilation in line with the ventilator: two beta 2-adrenoreceptor agonists, metaproterenol, 5 percent solution, and isoetharine, 1 percent solution; and the anticholinergic agent atropine as a control. Each bronchodilator was nebulized over 10 to 15 minutes in random order, four hours apart, and given to every subject. Plasma potassium was measured at five-minute intervals and arterial blood gases at 15-minute intervals, for a total of 50 minutes after administration of each bronchodilator. Following administration of each drug, plasma potassium showed an average decline. The mean decline in plasma potassium from baseline was statistically significant for metaproterenol (p = 0.04) and atropine (p = 0.001) but not for isoetharine (p = 0.09). Although there were no statistically significant differences among the declines in plasma potassium induced by the three drugs, metaproterenol caused the greatest decline (-0.6 mEq/L).
Assuntos
Broncodilatadores/efeitos adversos , Hipopotassemia/induzido quimicamente , Administração por Inalação , Adulto , Idoso , Atropina/administração & dosagem , Atropina/efeitos adversos , Broncodilatadores/administração & dosagem , Humanos , Hipopotassemia/sangue , Isoetarina/administração & dosagem , Isoetarina/efeitos adversos , Metaproterenol/administração & dosagem , Metaproterenol/efeitos adversos , Pessoa de Meia-Idade , Potássio/sangueRESUMO
A patient is presented in whom direct current counter-shock was applied for primary ventricular fibrillation. He recovered uneventfully and no evidence was found of a myocardial infarction; however, a positive 99m technetium stannous diphosphate scan obtained four days after the defibrillation showed positive findings. This positive scintigram was most probably due to myocardial or skeletal muscular damage consequent to counter-schock, but myocardial necrosis induced by ventricular fibrillation may be another cause. This case demonstrates again that a transmural or subendocardial infarction is not the only circumstance under which an abnormal scintigram can be obtained.
Assuntos
Cardioversão Elétrica/efeitos adversos , Infarto do Miocárdio/etiologia , Fibrilação Ventricular/complicações , Eletrocardiografia , Humanos , Masculino , Pessoa de Meia-Idade , Cintilografia , Fibrilação Ventricular/terapiaRESUMO
BACKGROUND: In the treatment of lung cancer, the best outcome is achieved when the lesion is discovered in the intraepithelial (preinvasive) stage. However, intraepithelial neoplastic lesions are difficult to localize by conventional white-light bronchoscopy (WLB). OBJECTIVE: To determine if autofluorescence bronchoscopy, when used as an adjunct to WLB, could improve the bronchoscopist's ability to locate and remove biopsy specimens from areas suspicious of intraepithelial neoplasia as compared with WLB alone. METHOD: A multicenter clinical trial was conducted in seven institutions in the United States and Canada. WLB followed by fluorescence examination with the light-induced fluorescence endoscopy (LIFE) device was performed in 173 subjects known or suspected to have lung cancer. Biopsy specimens were taken from all areas suspicious of moderate dysplasia or worse on WLB and/or LIFE examination. In addition, random biopsy specimens were also taken from other parts of the bronchial tree. RESULTS: The relative sensitivity of WLB + LIFE vs WLB alone was 6.3 for intraepithelial neoplastic lesions and 2.71 when invasive carcinomas were also included. The positive predictive value was 0.33 and 0.39 and the negative predictive value was 0.89 and 0.83, respectively, for WLB+LIFE and WLB alone. CONCLUSION: Autofluorescence bronchoscopy, when used as an adjunct to standard WLB, enhances the bronchoscopist's ability to localize small neoplastic lesions, especially intraepithelial lesions that may have significant implication in the management of lung cancer in the future.
Assuntos
Brônquios/patologia , Broncoscopia , Neoplasias Pulmonares/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia , Broncoscópios , Broncoscopia/métodos , Carcinoma Broncogênico/diagnóstico , Carcinoma Broncogênico/patologia , Epitélio/patologia , Feminino , Fluorescência , Humanos , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Sensibilidade e EspecificidadeRESUMO
OBJECTIVE: To evaluate changes in serum and urinary zinc, cobalt, copper, iron, and calcium concentrations in critically ill patients receiving propofol containing disodium edetate (disodium ethylenediaminetetraacetic acid [EDTA]) versus sedative agents without EDTA. DESIGN: This was a randomised, open-label, parallel-group study with randomisation stratified by baseline Acute Physiology and Chronic Health Evaluation (APACHE II) scores. SETTING: Intensive care units (ICU) in 23 medical centres. PATIENTS: Medical, surgical, or trauma ICU patients 17 years of age or older who required mechanical ventilator support and sedation. INTERVENTIONS: A total of 106 patients received propofol containing 0.005 % EDTA (propofol EDTA), and 104 received other sedative agents without EDTA (non-EDTA). Only the first 108 patients were assessed for urinary trace metal excretion. Twenty-four-hour urine samples were collected on days 2, 3, and 7 and every 7 days thereafter for determination of zinc, cobalt, copper, iron, and calcium excretion; EDTA levels; urine osmolality; albumin levels; and glucose levels. The first 143 patients were assessed for serum concentration of zinc, cobalt, copper, iron, and calcium; creatinine; blood urea nitrogen; and albumin at baseline and once during each 24-hour urine collection. MEASUREMENTS AND RESULTS: For the assessment of trace metals, patients receiving propofol EDTA demonstrated increased mean urinary excretion of zinc, copper, and iron compared with the normal range. All patients receiving sedatives demonstrated increased urinary excretion of zinc and copper above normal reference values. Compared with the non-EDTA sedative group, the propofol EDTA group demonstrated increased urinary excretion of zinc and iron. Mean serum concentrations of zinc and total calcium were decreased in both patient groups. Serum zinc concentrations increased from baseline to day 3 in the non-EDTA sedative group but not in the propofol EDTA group. Renal function, measured by blood urea nitrogen, serum creatinine, and creatinine clearance, did not deteriorate during ICU sedation with either regimen. CONCLUSION: This study showed that critical illness is associated with increased urinary losses of zinc, copper, and iron. Propofol EDTA-treated patients had greater urinary losses of zinc and iron and lower serum zinc concentrations compared with the non-EDTA sedative group. No adverse events indicative of trace metal deficiency were observed in either group. The clinical significance of trace metal losses during critical illness is unclear and requires further study.
Assuntos
Anestésicos Intravenosos/farmacocinética , Cálcio/metabolismo , Quelantes/farmacocinética , Ácido Edético/farmacocinética , Conservantes Farmacêuticos/farmacocinética , Propofol/farmacocinética , Oligoelementos/metabolismo , APACHE , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anestésicos Intravenosos/farmacologia , Quelantes/farmacologia , Distribuição de Qui-Quadrado , Estado Terminal , Ácido Edético/farmacologia , Feminino , Hemodinâmica/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Conservantes Farmacêuticos/farmacologia , Propofol/farmacologia , Estudos Prospectivos , Estatísticas não ParamétricasRESUMO
We examined mechanisms of ventilator asynchrony and noncapture in a typical ventilator-dependent patient who failed numerous attempts at weaning. As trigger sensitivity was decreased within its usual range, a marked and progressive ventilator response delay occurred which was associated with erratic changes in functional residual capacity as well as dyspnea and tachypnea. This phenomenon varies among ventilators and underscores the importance of understanding technical differences between them. Appropriate ventilator selection is as important as mode selection when attempting to wean patients with advanced chronic obstructive pulmonary disease.
Assuntos
Pneumopatias Obstrutivas/fisiopatologia , Insuficiência Respiratória/fisiopatologia , Desmame do Respirador , Idoso , Estudos de Avaliação como Assunto , Feminino , Humanos , Pneumopatias Obstrutivas/terapia , Respiração , Insuficiência Respiratória/terapiaRESUMO
The microcirculatory disturbances in sepsis have prompted micropore bulk-filtration studies of red blood cell (RBC) mechanical behavior (i.e., deformability). However, these prior reports may not solely reflect RBC behavior because of possible white blood cell (WBC) occlusion of the filter pores. The present study was designed to examine RBC mechanical alterations in human and experimental sepsis using techniques that are not affected by WBC artifacts. RBC were obtained from adult patients with sepsis and from healthy control donors. RBC were also obtained from Swiss-albino rats in which experimental sepsis was induced via cecal ligation-puncture. Red cell mechanical behavior was tested using a computerized micropore filtration system (CTA) and a laser-diffraction shearing device (LORCA); the latter provides the extent of RBC deformation at various stresses and the time constant for RBC shape recovery. Salient findings include: (1) for human RBC, significantly decreased deformability at fluid shear stresses < 5 Pa (LORCA) yet no differences from control with the CTA; (2) for rat RBC in experimental sepsis, significant decreases of deformability and shape-recovery time constant (LORCA) but no differences with the CTA. We conclude that RBC deformability is reduced in sepsis but that micropore bulk-filtration methods may not be appropriate for detecting these changes.
Assuntos
Deformação Eritrocítica/fisiologia , Infecções/sangue , Adulto , Animais , Contagem de Células Sanguíneas , Eritrócitos/citologia , Eritrócitos/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Ratos , Ratos Endogâmicos , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismoRESUMO
We studied the spontaneous breathing patterns of 10 normal adult volunteers during high-frequency chest wall oscillation (HFCWO), accomplished by inflating and deflating a vest worn around each subject's thorax at 2.5 Hz. Tidal volumes generated by HFCWO averaged 100 ml. Mean vest pressure was maintained at approximately 35 cm H2O throughout each experiment, even when HFCWO was not applied. During HFCWO, subjects were instructed occasionally to exhale deeply to obtain end-tidal samples representative of PACO2. HFCWO increased the breath-to-breath variability of spontaneous respiration in all subjects, prolonging expiratory pauses and producing short apneas in some cases. PACO2 decreased significantly (p less than 0.05). The effects on minute ventilation, tidal volume, and inspiratory and expiratory durations remained variable across subjects, even when differences in PACO2 between control and HFCWO states were reduced through inhalation of a low CO2 mixture. None of the changes were statistically significant, although average expiratory duration increased by 29%. Ventilatory responses to CO2 with and without HFCWO were also measured. Normocapnic (PACO2 = 40 mm Hg) ventilatory drive increased significantly (p less than 0.05) in six subjects (Type 1 response) and decreased substantially in the others (Type 2 response); with hypercapnia, the changes in drive were attenuated in both groups. Consequently, CO2 sensitivity decreased in Type 1 subjects and increased in Type 2 subjects. A simple analysis based on this result shows that with HFCWO, Type 2 subjects breathing air will tend to have a lower spontaneous minute ventilation and become hypercapnic. Type 1 subjects will become hypocapnic, but minute ventilation may be higher or lower than control.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Ventilação de Alta Frequência , Respiração , Adulto , Volume de Reserva Expiratória , Feminino , Ventilação de Alta Frequência/instrumentação , Ventilação de Alta Frequência/métodos , Humanos , Hipercapnia/fisiopatologia , Volume de Reserva Inspiratória , Masculino , Valores de Referência , Volume de Ventilação PulmonarRESUMO
It has been proposed that abnormal mechanical properties may contribute to capillary retention of polymorphonuclear leukocytes (PMN) in sepsis, leading to the development of organ dysfunction. The present study was designed to determine whether PMN rigidity is increased in severe sepsis, and whether changes in the rheologic behavior of PMN correlate with the clinical course in sepsis. Eighteen adults with severe sepsis were studied over a period of 14 d; 11 survived and seven died. PMN deformation behavior was investigated via micropore filtration, using the cell transit analyzer. On Day 0, PMN rigidity was 2.5-fold greater for sepsis patients than for five normal controls (p < 0.001). PMN rigidity progressively improved over the 14 d study period for patients who recovered, but not for those who died; clinical indicators correlated with PMN rigidity. Patient PMN also exhibited a 5-fold greater increase in rigidity in response to formyl-methionylleucylphenylalanine (fMLP) than did control PMN. Both the increased rigidity and enhanced response to fMLP could be simulated in vitro by incubation of normal PMN with tumor necrosis factor-alpha (TNF-alpha). We conclude that circulating PMN are more rigid in severe sepsis, and are "primed" for an augmented response to chemotactic stimuli. These findings support the hypothesis that cytokine-mediated increases of PMN rigidity may lead to sequestration of these cells in capillaries and to the consequent impairment of microvascular perfusion in sepsis.
Assuntos
Infecções/fisiopatologia , Neutrófilos/fisiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Elasticidade , Feminino , Humanos , Infecções/patologia , Masculino , Pessoa de Meia-Idade , N-Formilmetionina Leucil-Fenilalanina/farmacologia , Neutrófilos/efeitos dos fármacos , Fator de Necrose Tumoral alfa/farmacologiaRESUMO
OBJECTIVE: To evaluate the safety and efficacy of p55 tumor necrosis factor receptor fusion protein, a recombinant chimeric protein of human p55 (type I) tumor necrosis factor receptor (CD120a) extracellular domain and IgG1 sequences (referred to as p55-IgG), in the treatment of patients with severe sepsis or septic shock. DESIGN: Randomized, prospective, multicenter, double-blind, placebo-controlled clinical trial. SETTING: Forty-four community and university-affiliated hospitals in the United States and Europe. PATIENTS: There were 498 patients enrolled in this clinical trial. INTERVENTION: Patients prospectively stratified within each site into refractory shock or severe sepsis groups were randomized to receive a single infusion of p55-IgG, 0.083 mg/kg, 0.042 mg/kg, or 0.008 mg/kg, or placebo. Patients received standard aggressive medical/surgical care during the 28-day postinfusion period. OUTCOME MEASURE: Twenty-eight-day all-cause mortality. RESULTS: The distribution of variables describing demographics, organ system dysfunction or failure, infecting microorganisms, predicted mortality, plasma interleukin 6 levels, and plasma tumor necrosis factor alpha (TNF-alpha) levels were similar among patients in the p55-IgG and placebo treatment arms. A planned interim analysis was performed after 201 patients were enrolled. Because a statistically nonsignificant trend toward increased mortality was present in patients who had received 0.008 mg/kg, this treatment arm was discontinued, and the study continued with 3 arms. Among all infused patients, there was a statistically nonsignificant trend toward reduced 28-day all-cause mortality in those who received p55-IgG compared with placebo-treated patients (5% reduction, 0.042 mg/kg vs placebo; 15% reduction, 0.083 mg/kg vs placebo; P=.30). However, in patients with severe sepsis and early septic shock (n=247), therapy with p55-IgG, 0.083 mg/kg, was associated with a 36% reduction in 28-day all-cause mortality compared with placebo (P=.07): 20 (23%) of 87 patients died among those treated with p55-IgG, 0.083 mg/kg; 30 (37%) of 82 among those treated with p55-IgG, 0.042 mg/kg; and 28 (36%) of 78 in the placebo group. A prospectively planned logistic regression analysis to assess treatment effect on 28-day all-cause mortality by means of predicted mortality and serum interleukin 6 levels as continuous covariates demonstrated a significant improvement in outcome for the patients with severe sepsis treated with p55-IgG, 0.083 mg/kg, compared with placebo (P=.01). Serious adverse events, including death and the development of new organ system dysfunction, were reported in 65% of patients infused with placebo, with no increased frequency (56%) present in the 2 p55-IgG treatment arms. There were no reports of immediate hypersensitivity reactions caused by p55-IgG. CONCLUSIONS: In this dose-finding study, there was no decrease in mortality between placebo and p55-IgG in all infused patients. In the prospectively defined population of patients with severe sepsis who received p55-IgG, 0.083 mg/kg, there was a trend toward reduced mortality at day 28 that became significant when predicted mortality and plasma interleukin 6 levels were included in a logistic regression analysis.