RESUMEN
OBJECTIVE: Topical hemostats are important adjuncts for stopping surgical bleeding. The safety and efficacy of Fibrocaps, a dry-powder, fibrin sealant containing human plasma-derived thrombin and fibrinogen, was evaluated in patients undergoing vascular surgical procedures. METHODS: In this single-blind trial (clinicaltrials.gov: NCT01527357), adult patients were randomized 2:1 to Fibrocaps plus gelatin sponge (Fibrocaps) vs gelatin sponge alone. Results are presented for the patient subset undergoing vascular procedures with suture hole bleeding. The primary efficacy endpoint compared time to hemostasis (TTH) over 5 minutes. Safety follow-up continued to day 29. RESULTS: A total of 175 patients were randomized and treated (Fibrocaps, 117; gelatin sponge, 58). Patients were predominately male (69%) and underwent arterial bypass (81%), arteriovenous graft formation (9%), or carotid endarterectomy (9%). Fibrocaps significantly reduced TTH compared with gelatin sponge (hazard ratio [HR], 2.1; 95% confidence interval [CI], 1.5-3.1; median TTH, 2 minutes; 95% CI, 1.5-2.5 vs 4 minutes; 95% CI, 3.0-5.0; P < .002). Significant reductions were also observed in patients receiving concomitant antiplatelet agents alone (HR, 2.8; 95% CI, 1.0-7.4; P = .03; n = 33), anticoagulants alone (HR, 2.0; 95% CI, 1.0-4.0; P = .04; n = 43), or both antiplatelet agents and anticoagulants (Fibrocaps vs gelatin sponge, HR, 2.3; 95% CI, 1.2-4.3; P = .008; n = 65). Incidences of common adverse events (procedural pain, nausea, constipation) were generally comparable between treatment arms. Anti-thrombin antibodies developed in 2% of Fibrocaps-treated patients and no-gelatin-sponge patients. CONCLUSIONS: Fibrocaps, a ready-to-use, dry-powder fibrin sealant, was well-tolerated and reduced TTH in patients undergoing vascular procedures, including those receiving antiplatelet agents and/or anticoagulants, demonstrating its safety and usefulness as an adjunct to hemostasis.
Asunto(s)
Adhesivo de Tejido de Fibrina/administración & dosificación , Técnicas Hemostáticas , Hemostáticos/administración & dosificación , Hemorragia Posoperatoria/prevención & control , Procedimientos Quirúrgicos Vasculares/efectos adversos , Administración Tópica , Anciano , Anticoagulantes/uso terapéutico , Femenino , Adhesivo de Tejido de Fibrina/efectos adversos , Esponja de Gelatina Absorbible , Hemostáticos/efectos adversos , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Países Bajos , Inhibidores de Agregación Plaquetaria/uso terapéutico , Hemorragia Posoperatoria/etiología , Polvos , Factores de Riesgo , Método Simple Ciego , Factores de Tiempo , Resultado del Tratamiento , Reino Unido , Estados UnidosRESUMEN
STUDY OBJECTIVE: To evaluate the safety and immunogenicity of recombinant human thrombin (rThrombin), an active topical stand-alone hemostatic agent. DESIGN: Analysis of pooled data from 10 rThrombin clinical trials. PATIENTS: A total of 644 adult and pediatric patients treated with rThrombin; 609 patients were included in the immunogenicity analysis. MEASUREMENTS AND MAIN RESULTS: In all studies, rThrombin was applied during a single surgical procedure (day 1); the procedures consisted of spinal procedures, major hepatic resection, peripheral arterial bypass, arteriovenous graft formation for hemodialysis access, and synchronous burn wound excision and skin grafting. A dosage of 1000 IU/ml of rThrombin was administered for more than 99% of patients. Adverse events and clinical laboratory values were monitored through day 29. Blood samples were obtained for immunogenicity analyses before the procedure and on day 29. Adverse events were mild or moderate in severity for the majority of patients; no patients discontinued from an rThrombin study due to adverse events. The most commonly reported adverse events in the 644 patients were incision site pain (305 patients [47.4%]), procedural pain (215 patients [33.4%]), and nausea (170 patients [26.4%]). Five patients (0.8%) died during the studies; all deaths were considered unrelated to rThrombin treatment. Antibodies to the rThrombin product developed in 5 (0.8%, 95% confidence interval 0.4-2.8%) of 609 patients by day 29, approximately 1 month after treatment; these antibodies did not neutralize the activity of native human thrombin. The development of antibodies did not appear to differ substantively by type of surgical procedure, amount of rThrombin administered, or patient age. CONCLUSION: Recombinant human thrombin was well tolerated, and adverse events were consistent with those reported in the postoperative setting in the surgical populations studied. Approximately 1 month after treatment, less than 1% of the patients had developed antibodies to the rThrombin product, and these antibodies did not neutralize the activity of native human thrombin. These results support the safety of rThrombin when used as a topical aid to hemostasis in numerous surgical settings and for patients of differing ages.
Asunto(s)
Hipersensibilidad a las Drogas/epidemiología , Hemostáticos/efectos adversos , Hemorragia Posoperatoria/tratamiento farmacológico , Proteínas Recombinantes/efectos adversos , Trombina/efectos adversos , Adulto , Niño , Ensayos Clínicos como Asunto , Relación Dosis-Respuesta a Droga , Relación Dosis-Respuesta Inmunológica , Hipersensibilidad a las Drogas/inmunología , Femenino , Hemostáticos/administración & dosificación , Hemostáticos/uso terapéutico , Humanos , Incidencia , Masculino , Hemorragia Posoperatoria/prevención & control , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/uso terapéutico , Trombina/administración & dosificación , Trombina/uso terapéutico , Estados Unidos/epidemiologíaRESUMEN
BACKGROUND: This Phase 4, open-label study evaluated the immunogenicity and safety of a second exposure to recombinant human thrombin (rThrombin) in adult patients with previous exposure to rThrombin. STUDY DESIGN: Topical rThrombin was applied as a hemostatic aid during a surgical procedure (day 1). Adverse events and clinical laboratory abnormalities were monitored to day 29 (study end). Immunogenicity samples were collected on days 1 and 29. Thirty-one patients were treated at 9 study sites; 30 patients completed the study. RESULTS: Mean age was 59.5 years; 61.3% of patients were male. Study operations types included spinal (n = 23 of 31; 74.2%), arterial reconstruction or peripheral arterial bypass (n = 4; 12.9%), arteriovenous vascular access procedure (n = 3; 9.7%), and other (n = 1; 3.2%). A median of 10 mL rThrombin (1,000 IU/mL; range 5 to 60 mL) was prepared per patient. Median elapsed time since previous rThrombin exposure was 1.3 years (range 19 days to 3.3 years). Recombinant human thrombin was not observed to be immunogenic; no patients (n = 0 of 30, 0%; 95% CI 0.0%, 11.6%) became positive for anti-rThrombin product antibodies at day 29, approximately 1 month after the second exposure to rThrombin. The most commonly reported adverse events were procedural pain (n = 23 of 31, 74.2%), constipation (n = 8, 25.8%), and nausea (n = 8, 25.8%) All adverse events and clinical laboratory abnormalities were considered unrelated to treatment. For the majority of patients, maximal severity of any adverse event was mild or moderate. CONCLUSIONS: The immunogenicity and safety results of this Phase 4 rThrombin trial suggest that patients with known previous exposure may be safely re-exposed to topical rThrombin.
Asunto(s)
Hemostasis Quirúrgica , Hemostáticos/efectos adversos , Hemostáticos/inmunología , Complicaciones Posoperatorias , Proteínas Recombinantes/efectos adversos , Proteínas Recombinantes/inmunología , Trombina/efectos adversos , Trombina/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos/sangre , Estudios de Cohortes , Esquema de Medicación , Femenino , Hemostáticos/administración & dosificación , Humanos , Masculino , Persona de Mediana Edad , Proteínas Recombinantes/administración & dosificación , Retratamiento , Trombina/administración & dosificación , Factores de Tiempo , Adulto JovenRESUMEN
BACKGROUND: Immunoassays that detect antibovine thrombin product antibodies are not widely available. However, knowing whether these antibodies are present preoperatively would be useful because re-exposure to bovine thrombin-containing products is contraindicated in patients with pre-existing antiproduct antibodies due to the risk of developing immune-mediated coagulopathies. In these exploratory analyses, we characterized one aspect of immune sensitization, the persistence of circulating antibodies after exposure to bovine thrombin product. STUDY DESIGN: Elapsed time since a historical surgical procedure with documented or highly likely use of bovine thrombin product was determined for 204 patients enrolled in a recently completed trial. After study completion, baseline samples were assayed for antibovine thrombin product antibodies using validated immunoassays. Antibody data were sorted by time elapsed since the historical procedure. The proportion of patients with antibovine thrombin product antibodies and 95% confidence interval (CI) were determined for each 1-year period, providing an estimate for antibody persistence. RESULTS: Antibovine thrombin product antibodies were detected in 20.7% of patients (23 of 111; 95% CI 14.2%, 29.2%) with ≤1 year since the historical surgical procedure; 6.8% of patients (3 of 44; 95% CI 1.68%, 18.9%) with 1 to <2 years; 16.1% of patients (5 of 31; 95% CI 6.62%, 33.1%) with 2 to <3 years; and 5.6% of patients (1 of 18; 95% CI 0.00%, 27.6%) with ≥3 years since the historical procedure. CONCLUSIONS: The proportion of patients with antibovine thrombin product antibodies ranged from 5.6% to 20.7% across the multiyear postoperative window. Clinicians should be aware that antibodies to bovine thrombin products may persist for years after exposure.
Asunto(s)
Anticuerpos/sangre , Hemostasis Quirúrgica/métodos , Hemostáticos/administración & dosificación , Hemostáticos/inmunología , Trombina/administración & dosificación , Trombina/inmunología , Administración Tópica , Adulto , Anciano , Animales , Bovinos , Ensayos Clínicos como Asunto , Intervalos de Confianza , Femenino , Humanos , Inmunización , Inmunoensayo , Masculino , Persona de Mediana Edad , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/inmunología , Factores de TiempoRESUMEN
OBJECTIVE: To determine the clinical relevance and prognostic significance of serial measurement of inter-alpha inhibitor proteins (IalphaIp) in severely septic patients. DESIGN: A laboratory-based study of serial plasma samples over the first 5 days of severe sepsis from a prospective clinical trial. SETTING: Small business and academic medical center research laboratories. PATIENTS: Two hundred sixty-six patients with severe sepsis from a multiple-center phase III clinical trial. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Inter-alpha inhibitor proteins serve as endogenous serine protease inhibitors in human plasma. The levels of IalphaIp were markedly reduced to a mean value of 290+/-15 microg/mL at the onset of severe sepsis compared with normal plasma levels (617+/-197 microg/mL). Failure of IalphaIp levels to recover over the first 5 days of sepsis was associated with an unfavorable outcome (p<.001). IalphaIp levels were inversely correlated with interleukin-6 levels at study entry and over the first 5 days of management of severe sepsis. IalphaIp levels were significantly lower in women, with increased age, in the presence of multiple organ failure and in patients with intra-abdominal sources of sepsis. CONCLUSIONS: Inter-alpha inhibitor proteins are markedly reduced in severe sepsis, and failure of recovery of IalphaIp levels over the course of sepsis is associated with an unfavorable outcome.
Asunto(s)
alfa-Globulinas/análisis , Sepsis/sangre , Adulto , Biomarcadores/sangre , Femenino , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Factores de TiempoRESUMEN
Despite recent advances in the prospective identification of the patient with sepsis who may benefit from anti-inflammatory or antithrombotic therapies, successful treatment regimens have been fairly modest. We have explored whether determination of several proinflammatory cytokine or mediator concentrations can complement physiologic scoring systems to identify patients with severe sepsis who will survive or expire within 28 days. The design of the study included an exploratory analysis performed in conjunction with a prospective, randomized, double-blind, placebo-controlled, multicenter, clinical trial and involved 33 academic institutions in the United States. One hundred twenty-four patients with severe sepsis with or without septic shock were included in this analysis. Blood samples were obtained at baseline and on days 1 through 4, and were evaluated for proinflammatory and anti-inflammatory cytokine concentrations, as well as for procalcitonin and total protein C levels. Baseline concentrations and changes in the concentrations of these mediators were evaluated in relationship to the Acute Physiology and Chronic Health Evaluation (APACHE) II and multiple organ dysfunction (MOD) scores, and 28-day all-cause mortality. Using univariate logistic regression analyses, APACHE II and MOD scores, age (but not gender), and baseline plasma interleukin (IL)-6 and soluble tumor necrosis factor receptor (sTNFR) 1 (log transformed) concentrations were all predictive of increased 28-day all-cause mortality (P < 0.01). Baseline total protein C, IL-8, IL-10, TNF-alpha, and procalcitonin concentrations, and the change in plasma cytokine concentrations from baseline over the initial 4 days were not useful in predicting outcome. Selected baseline proinflammatory cytokine concentrations and APACHE II score were correlated (P < 0.01). IL-6 concentration is a strong candidate for predicting clinical outcome in patients with severe sepsis alone, or when combined with the APACHE II or MOD scores. The potential usefulness of the combination of cytokine measurements and prognostic scores to identify patients who may benefit from treatment with anti-inflammatory or antithrombotic therapies should be further evaluated.
Asunto(s)
Citocinas/sangre , Sepsis/sangre , Sepsis/mortalidad , Anciano , Calcitonina/sangre , Calcitonina/metabolismo , Péptido Relacionado con Gen de Calcitonina , Citocinas/metabolismo , Método Doble Ciego , Femenino , Humanos , Inflamación , Interleucina-10/metabolismo , Interleucina-6/sangre , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Masculino , Persona de Mediana Edad , Placebos , Pronóstico , Proteína C/metabolismo , Precursores de Proteínas/sangre , Precursores de Proteínas/metabolismo , Receptores del Factor de Necrosis Tumoral/metabolismo , Análisis de Regresión , Síndrome de Dificultad Respiratoria/diagnóstico , Riesgo , Sepsis/diagnóstico , Factores de Tiempo , Resultado del Tratamiento , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
To determine the role of CD14 in lipopolysaccharide (LPS)-induced release of chemokines, 16 humans were injected with LPS (4 ng/kg) preceded (-2 h) by intravenous IC14, an anti-human CD14 monoclonal antibody, or placebo. LPS elicited increases in interleukin (IL)-8 concentrations in plasma and in lysates of red blood cell (RBC), polymorphonuclear cell and mononuclear cell fractions, which were all reduced by IC14. LPS also induced rises in the plasma and RBC levels of monocyte chemoattractant protein (MCP)-1, which were diminished by IC14. Macrophage inflammatory protein (MIP)-1alpha and MIP-1beta, chemokines that in contrast to IL-8 and MCP-1 can not bind to the Duffy antigen receptor for chemokines on RBCs, were only detected in plasma. IC14 attenuated the LPS-induced release of MIP-1beta, but not of MIP-1alpha. IL-8 and MCP-1, but not MIP-1alpha and MIP-1b, circulate in RBC-associated form during endotoxemia. LPS-induced chemokine release is, in part, mediated by an interaction with CD14.
Asunto(s)
Antígenos/administración & dosificación , Quimiocinas/sangre , Endotoxemia/sangre , Receptores de Lipopolisacáridos/inmunología , Adulto , Antígenos/inmunología , Método Doble Ciego , Ensayo de Inmunoadsorción Enzimática , Humanos , Lipopolisacáridos/administración & dosificación , Masculino , Placebos , Valores de ReferenciaRESUMEN
CD14 is a receptor important for activation of cells by lipopolysaccharide (LPS). Treatment with the CD14 antibody IC14 was previously found to attenuate the release of proinflammatory cytokines and some chemokines into the circulation of healthy humans intravenously injected with LPS. To determine the role of circulating leukocytes in CD14-dependent gene expression, 16 healthy volunteers received LPS preceded by either IC14 or placebo. At different time points, mRNA was isolated from whole blood and gene expression was determined by multiplex ligation-dependent probe amplification (MLPA). LPS induced MIP-1alpha, MIP-1beta, IL-8, IL-1beta, and IL-1Ra mRNA production, which was delayed by 1 hr and reduced twofold by IC14 treatment. TNFR1 was unresponsive, whereas other investigated cytokines remained undetectable. Further, LPS showed differential effects on NFkappaB gene expression. LPS induced IkappaBalpha production, whereas p50 was unresponsive and p65 and p49/p100 remained undetectable. LPS induced IkappaBalpha expression was delayed (1 hr) and reduced by IC14. Gene expression profiles in blood cells corresponded poorly with observed changes in plasma levels. These data suggest that peripheral blood cells are of negligible importance in LPS-induced production of inflammatory mediators in vivo and that LPS may activate genes via a CD14-independent pathway that is slower and less efficient.
Asunto(s)
Anticuerpos Monoclonales/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Receptores de Lipopolisacáridos/fisiología , Adulto , Citocinas/genética , Perfilación de la Expresión Génica/métodos , Humanos , Leucocitos/fisiología , Receptores de Lipopolisacáridos/inmunología , Lipopolisacáridos/farmacología , FN-kappa B/genética , Técnicas de Amplificación de Ácido Nucleico/métodos , ARN Mensajero/análisisRESUMEN
To determine the role of CD14 in lipopolysaccharide (LPS)-induced effects on coagulation and fibrinolysis in humans, 16 healthy subjects received an intravenous injection of LPS preceded by intravenous IC14, a recombinant chimeric monoclonal antibody against human CD14, or placebo. LPS-induced coagulation activation (tissue-factor mRNA in whole blood cells and plasma concentrations of F1+2) was not influenced by IC14, whereas the antibody reduced the increase in thrombin-antithrombin complexes and soluble fibrin. LPS injection also was associated with an early activation of fibrinolysis (plasma concentrations of tissue-type plasminogen activator and plasmin-alpha(2)-antiplasmin complexes), followed by an inhibitory response (plasminogen activator inhibitor type 1), which were attenuated by IC14. Furthermore, LPS reduced thrombin-activatable fibrinolysis-inhibitor antigen levels and increased soluble thrombomodulin levels, which were not influenced by IC14. These results suggest that different hemostatic responses during endotoxemia may proceed via CD14-dependent and -independent pathways.