RESUMO
BACKGROUND: Periods of ischemia-reperfusion (I/R) during cardiac surgery are associated with transient left ventricular (LV) dysfunction and an inflammatory response. In this study, we examined the potential dose-dependent effects of aprotinin (APRO) on LV contractility and cytokine release in the setting of I/R. METHODS: An index of LV contractility, LV maximal elastance (E(max)), was measured at baseline, 30 min of ischemia, and 60 min of reperfusion by microtransducer volumetry. Mice were randomized as follows: (a) APRO 20,000 kallikrein-inhibiting units (KIU)/kg (n = 11); (b) APRO 4 x 10(4) KIU/kg (n = 10); (c) APRO 8 x 10(4) KIU/kg (n = 10); and (d) vehicle (saline; n = 10). APRO doses were calculated to reflect half, full, and twice the clinical Hammersmith dosing schedule. After I/R, plasma was collected for cytokine measurements. RESULTS: After I/R, E(max) decreased from the baseline value by more than 40% in the vehicle group as well as in the APRO 4 x 10(4) KIU/kg and APRO 8 x 10(4) KIU/kg groups (P < 0.05). However, E(max) returned to near baseline values in the APRO 2 x 10(4) KIU/kg group. Tumor necrosis factor (TNF) increased 10-fold after I/R, but it was reduced with higher APRO doses. CONCLUSIONS: This study demonstrated that a low dose of APRO provided protective effects on LV contractility, whereas higher doses suppressed TNF release. These unique findings suggest that there are distinct and independent mechanisms of action of APRO in the context of I/R.
Assuntos
Aprotinina/farmacologia , Citocinas/metabolismo , Hemostáticos/farmacologia , Contração Miocárdica/efeitos dos fármacos , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Função Ventricular Esquerda/efeitos dos fármacos , Animais , Aprotinina/sangue , Arritmias Cardíacas/etiologia , Arritmias Cardíacas/fisiopatologia , Relação Dose-Resposta a Droga , Elasticidade , Hemodinâmica/fisiologia , Hemostáticos/sangue , Cinética , Camundongos , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Aprotinin is a serine protease inhibitor with diverse biological effects; until recently, it was utilized in the context of ischemia/reperfusion (I/R). It has been hypothesized that a signaling pathway modulated by aprotinin in the context of I/R is the tumor necrosis factor-alpha receptor (TNFR) pathway. An intact mouse model of I/R (30 min ischemia and 60 min reperfusion) was used and left ventricular (LV) peak + maximal rate of left ventricular (LV) peak pressure (dP/dt) was measured in wild-type mice (WT, C57BL/6; n = 10), WT mice with aprotinin (4 mL/kg; n = 10), transgenic mice devoid of the TNFRI (TNFRI-null; n = 10), and TNFRI-null with aprotinin (n=10). Following I/R, LV peak + dP/dt decreased in both WT groups, but remained similar to baseline values in the TNFRI-null group. In contrast, aprotinin caused a marked reduction in LV peak + dP/dt in the TNFRI-null group following I/R. Soluble plasma TNF levels increased in the WT and TNFRI-null mice with I/R and was reduced with aprotinin. Soluble TNFRI and TNFRII levels, indicative of TNF activation, increased in the WT mice following I/R and remained elevated with aprotinin. Soluble TNFRII levels were increased in the TNFRI-null mice following I/R and remained elevated with aprotinin. The new and unique findings of this study were twofold. First, aprotinin failed to improve LV function after I/R despite a reduction in circulating TNF levels. Second, genetic ablation of TNFRI uncovered a negative inotropic effect of aprotinin. These findings demonstrate that complex biological pathways and interactions are affected with broad spectrum serine protease inhibition, which are relevant to myocardial function in the context of I/R.
Assuntos
Aprotinina/administração & dosagem , Receptores Tipo I de Fatores de Necrose Tumoral/genética , Traumatismo por Reperfusão/metabolismo , Inibidores de Serina Proteinase/administração & dosagem , Disfunção Ventricular Esquerda/metabolismo , Animais , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Modelos Animais , Miocárdio/metabolismo , Distribuição Aleatória , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/metabolismoRESUMO
BACKGROUND AND AIMS: In Victoria, maternity services are under significant strain due to increased numbers of women giving birth and critical workforce shortages. Hospitals have experienced challenges in adequately staffing maternity units, particularly on postnatal wards. In 2008, a tertiary maternity hospital in Melbourne introduced a model where undergraduate midwifery students were employed as Division 2 nurses (SMW_Div2) (enrolled nurses), to work in the postnatal area only. This study explored the pilot employment model from the perspective of the SMW_Div2 and hospital midwives. METHODS: A web-based survey was administered to hospital midwives and the SMW_Div2s in the employment model in January 2010. The survey explored the views of midwives and SMW_Div2s regarding the perceived impact of the model on workforce readiness, recruitment and retention, and clinical competence and confidence. FINDINGS: Forty-seven of 158 midwives (30%) and five of nine SMW_Div2s employed in the model responded to the survey. Both groups considered the model to have benefits for the organisation, including increased: student workforce readiness; clinical confidence and competence; and organisational loyalty. Both groups also considered that the model would facilitate: workforce recruitment; a teaching and learning culture within the organisation; and enhanced partnerships between students, hospitals and universities. Caution was expressed regarding workload and the need for ongoing support for SMW_Div2s working in the model. DISCUSSION AND CONCLUSION: SMW_Div2s and midwives were positive about the introduction of the paid employment model at the Women's. The findings are consistent with evaluations of similar programs in the nursing setting. The employment model has potential short and long term individual and organisational advantages, which is important in the context of increasing births and workforce shortages. Progression of such models will be contingent on the collaboration and cooperation of the various stakeholders involved in maternity workforce and education.
Assuntos
Atitude do Pessoal de Saúde , Emprego/organização & administração , Maternidades , Serviços de Saúde Materna , Enfermeiros Obstétricos/educação , Estudantes de Enfermagem , Austrália , Competência Clínica , Educação em Enfermagem , Feminino , Pesquisas sobre Atenção à Saúde , Maternidades/organização & administração , Humanos , Serviços de Saúde Materna/organização & administração , Tocologia , Enfermeiros Obstétricos/provisão & distribuição , Cuidado Pós-Natal , Gravidez , Autoeficácia , Recursos Humanos , Carga de TrabalhoRESUMO
BACKGROUND: Basic studies have suggested that cross-talk exists between the endothelin-A receptor (ET-AR) and tumor necrosis factor signaling pathway. This study tested the hypothesis that administration of an ET-AR antagonist at the separation from cardiopulmonary bypass would alter the tumor necrosis factor activation in the early postoperative period. METHODS: Patients (n = 44) were randomly allocated to receive bolus infusion of vehicle, 0.1, 0.5, 1, or 2 mg/kg of the ET-AR antagonist (sitaxsentan), at the separation from cardiopulmonary bypass (n = 9, 9, 9, 9, and 8, respectively). Plasma levels of tumor necrosis factor-alpha and soluble tumor necrosis factor receptor 1 and 2 were measured. RESULTS: Compared with the vehicle group at 24 hours, plasma levels of tumor necrosis factor-alpha and tumor necrosis factor receptor 2 (indicative of receptor activation) were reduced in the 1 mg/kg ET-AR antagonist group (by approximately 13 pg/mL and approximately 0.5 ng/mL, respectively; p < 0.05). Plasma tumor necrosis factor receptor I levels also decreased (by approximately 1 ng/mL) after infusion of the higher doses of the ET-AR antagonist and remained lower (by approximately 3 ng/mL) at 24 hours after infusion (p < 0.05). In addition, a dose effect was observed between the ET-AR antagonist and these indices of tumor necrosis factor activation (p < 0.01). CONCLUSIONS: This study demonstrated a mechanistic relationship between the ET-AR and tumor necrosis factor receptor activation in the post-cardiac surgery period. Thus, in addition to the potential cardiovascular effects, a selective ET-AR antagonist can modify other biological processes relevant to the post-cardiac surgery setting.
Assuntos
Ponte Cardiopulmonar , Antagonistas do Receptor de Endotelina A , Fator de Necrose Tumoral alfa/sangue , Citocinas/sangue , Relação Dose-Resposta a Droga , Endotelinas/sangue , Humanos , Isoxazóis/farmacologia , Masculino , Pessoa de Meia-Idade , Tiofenos/farmacologiaRESUMO
BACKGROUND: Cardiac surgery can result in left ventricular ischemia and reperfusion (I/R), the release of cytokines such as tumor necrosis factor, and oxidative stress with release of myeloperoxidase. Although aprotinin has been used in cardiac surgery, the likely multiple effects of this serine protease inhibitor limit clinical utility. This study tested the hypothesis that different aprotinin doses cause divergent effects on left ventricular contractility, cytokine release, and oxidative stress in the context of I/R. METHODS: Left ventricular I/R (30 minutes I, 60 minutes R) was induced in mice, and left ventricular contractility (maximal end-systolic elastance) determined. Mice were randomly allocated to 2 x 10(4) kallikrein inhibitory units (KIU)/kg aprotinin (n = 11), 4 x 10(4) KIU/kg aprotinin (n = 10), and vehicle (saline, n = 10). Based upon a fluorogenic assay, aprotinin doses of 2 and 4 x 10(4) KIU/kg resulted in plasma concentrations similar to those of the half and full Hammersmith doses, respectively. RESULTS: After I/R, maximal end-systolic elastance fell by more than 40% from baseline (p < 0.05), and this effect was attenuated by 2 x 10(4) KIU/kg but not 4 x 10(4) KIU/kg aprotinin. Tumor necrosis factor increased by more than 60% from control (p < 0.05) with I/R, but was reduced with 4 x 10(4) KIU/kg aprotinin. Myeloperoxidase increased with I/R, and was reduced to the greatest degree by 2 x 10(4) KIU/kg aprotinin. CONCLUSIONS: Aprotinin influences left ventricular contractility, cytokine release, and oxidative stress, which are dose dependent. These results provide mechanistic evidence that multiple pathways are differentially affected by aprotinin in a context relevant to cardiac surgery.