Takotsubo syndrome (TS) is an acute cardiac condition, often triggered by critical illness, for w... more Takotsubo syndrome (TS) is an acute cardiac condition, often triggered by critical illness, for which no specific treatment exists. Previously, we showed that isoflurane can prevent experimental TS. The aim of this study was to evaluate the potential treatment effects of isoflurane. Our primary hypothesis was that early treatment with isoflurane attenuates left ventricular akinesia in experimental TS. In propofol-sedated animals, TS was induced by an intraperitoneal bolus of isoprenaline (50 mg/kg). Animals were randomized to one of six groups (n = 15 in each group), and 1% isoflurane was administered for 90 min in all groups. Isoflurane treatment was started at 0, 10, 30 (early treatment) or 120 (late treatment) minutes after isoprenaline injection. One additional late treatment group received isoflurane 0.5% for 180 min. A control group did not receive isoflurane. Left ventricular (LV) echocardiographic examination was performed at 90 min and 48 h after isoprenaline. Mortality was...
Takotsubo syndrome (TS) is an acute cardiac condition with a substantial mortality for which no s... more Takotsubo syndrome (TS) is an acute cardiac condition with a substantial mortality for which no specific treatment is available. We have previously shown that isoflurane attenuates the development of left ventricular (LV) dysfunction in an experimental TS-model. We compared the effects of equi-anaesthetic doses of isoflurane, propofol and ketamine+midazolam on haemodynamics, global and regional LV systolic function and the activation of intracellular metabolic pathways in experimental TS. We hypothesized that cardioprotection in experimental TS is specific for isoflurane. Forty-five rats were randomized to isoflurane (0.6 MAC, n = 15), propofol (bolus 200 mg/kg+360 mg/kg/h, n = 15) or ketamine (100 mg/kg)+midazolam (10 mg/kg, n = 15) anaesthesia. Arterial pressure, heart rate and body temperature were continuously measured and arterial blood gas analysis was performed intermittently. TS was induced by intraperitoneal injection of isoprenaline, 50 mg/kg. LV echocardiography was perfo...
Experimental data indicate large between-organs variations in rates of synthesis of tissue-type p... more Experimental data indicate large between-organs variations in rates of synthesis of tissue-type plasminogen activator (t-PA), which may reflect important differences in the capacity for constitutive and stimulated t-PA release from the vascular endothelium. In this report we describe a new multiple-organ experimental in vivo model for simultaneous determinations of net release/uptake rates of t-PA across the coronary, splanchnic, pulmonary, and hepatic vascular beds. In eleven intact anesthetized pigs, blood samples were obtained simultaneously from the proximal aorta, coronary sinus, pulmonary artery, and portal and hepatic veins. Plasma flows were monitored separately for each vascular region. Total plasma t-PA was determined by ELISA with a porcine t-PA standard. Regional net release/uptake rates were defined as the product of arteriovenous concentration gradients and local plasma flows. The net release of t-PA across the splanchnic vascular bed was very high, with a mean output ...
To investigate beta2 -adrenergic agonist-mediated effects on coronary fluxes of local fibrinolyti... more To investigate beta2 -adrenergic agonist-mediated effects on coronary fluxes of local fibrinolytic factors, healthy anaesthetised and instrumented pigs (n=10) were studied during infusion of isoprenaline (IPR) into the left main coronary artery. Coronary net fluxes of total t-PA antigen, active t-PA and total PAI-1 antigen were determined at baseline and at 3, 5, 7 and 10 minutes of IPR infusion. During IPR, net release of total t-PA increased in a biphasic pattern with transiently high levels at 3 (+440 %) and 7 minutes (+620%) and returned towards baseline at 10 minutes. Net coronary release of active t-PA increased with maximum levels at 3 minutes (+50%). Baseline coronary net flux of total PAI -1 showed a decrease which was most pronounced at 10 minutes. To conclude, a fast beta2 agonist-mediated local release of t-PA into the coronary vasculature was demonstrated. For total t-PA, this response was characterised by a biphasic release profile.
SummaryTo investigate β2-adrenergic agonist-mediated effects on coronary fluxes of local fibrinol... more SummaryTo investigate β2-adrenergic agonist-mediated effects on coronary fluxes of local fibrinolytic factors, healthy anaesthetised and instrumented pigs (n=10) were studied during infusion of isoprenaline (IPR) into the left main coronary artery. Coronary net fluxes of total t-PA antigen, active t-PA and total PAI-1 antigen were determined at baseline and at 3, 5, 7 and 10 minutes of IPR infusion. During IPR, net release of total t-PA increased in a biphasic pattern with transiently high levels at 3 (+440 %) and 7 minutes (+620%) and returned towards baseline at 10 minutes. Net coronary release of active t-PA increased with maximum levels at 3 minutes (+50%). Baseline coronary net flux of total PAI –1 showed a decrease which was most pronounced at 10 minutes. To conclude, a fast β2agonist-mediated local release of t-PA into the coronary vasculature was demonstrated. For total t-PA, this response was characterised by a biphasic release profile.
Tissue-type plasminogen activator (tPA) is a key mediator of fibrinolysis. Matching of pulmonary ... more Tissue-type plasminogen activator (tPA) is a key mediator of fibrinolysis. Matching of pulmonary perfusion and ventilation is a critical denominator of oxygenation in acute lung injury (ALI). This study investigates pulmonary venoarterial plasma tPA gradients in association with acute ALI induced by bronchoalveolar lavage (BAL) and endotoxinemia (ETX). Twenty-one anaesthetized, ventilated pigs were allocated to control (CTRL, n=5), bronchoalveolar saline lavage (BAL, n=8) or infusion of Escherichia coli endotoxin (ETX, n=8). Total tPA was analyzed in plasma (ELISA calibrated for porcine tPA). The inflammatory response was assessed by TNFa levels (ELISA). All variables were assessed at baseline and 2 h following ALI. Bronchoalveolar lavage and ETX induced similar increases in pulmonary shunt whereas pulmonary vascular resistance was significantly more increased in ETX animals. Cardiac output remained stable in BAL animals but decreased in ETX animals. The pulmonary venoarterial tPA plasma gradient increased in ETX animals, yielding a positive pulmonary net flux of tPA, which was absent in BAL animals. TNFalpha levels increased in ETX, but not in BAL, animals. A significant correlation was observed between TNFalpha and tPA plasma levels in ETX animals. All variables remained unchanged in CTRL animals. Plasma changes of tPA levels support a pulmonary release of tPA in early experimental ALI induced by acute ETX but not lavage, and are related to the inflammatory response. Despite increased vascular fibrinolytic capacity in ETX animals, pulmonary dysfunction was not different from BAL animals. The results demonstrate the close relation between inflammation and coagulation in early ALI.
Different pharmacological approaches have been used in the control of cardiovascular responses to... more Different pharmacological approaches have been used in the control of cardiovascular responses to surgical infra-renal aortic occlusion (AXC). The aim of the present study was to explore the modulatory effects of desflurane (DES) on these responses. The study was performed in normoventilated chloralose-anesthetized pigs (n = 14). Measurements included cardiac output (CO), pulmonary vascular pressures, heart rate (HR) and mean arterial pressure proximal to the AXC site (MAPPROX). Renal arterial (QREN) and portal venous (QPORT) blood flows were measured ultrasonically. Systemic (SVR), preportal (RPORT) and renal (RREN) vascular resistances were derived. Sets of measurements were done a) prior to, b) during and c) 5 min after AXC. This was repeated, in a randomized fashion, at control (no DES) and with 4.9% and 9.8% DES, respectively. DES decreased MAPPROX, CO, HR, SVR, RREN and RPORT. At control, AXC increased MAPPROX (+27%), SVR (+27%), QPORT (+14%), RPORT (+12%) and RREN (+43%). DES 4.9% did not change this response pattern. With 9.8% DES, the AXC-induced increases in MAPPROX (+17%) and SVR (+21%) were attenuated. At this stage, AXC caused no demonstrable changes in RREN or RPORT, while both QREN (+16%) and QPORT increased (+9%). DES effectively controlled increases in proximal blood pressure during AXC. The increases in RREN and RPORT that were seen during AXC at control were inhibited by 9.8% DES. Consequently, at this DES dose, both QREN and QPORT increased during AXC.
Pharmacological control of blood pressure is usually indicated during aortic cross-clamping (AXC)... more Pharmacological control of blood pressure is usually indicated during aortic cross-clamping (AXC). The aim of this study was to analyze the modulation by isoflurane (ISO), sodium nitroprusside (SNP) and milrinone (MIL) of the systemic circulatory responses to a standardized infra-renal AXC. Chloralose-anaesthetized pigs were exposed to AXC at control (no vasoactive drugs) and during the administration of each of the drugs. During control, AXC increased mean arterial pressure (MAP, 17 +/- 4%) and systemic vascular resistance (SVR, 27 +/- 7%), but induced no significant changes in cardiac output (CO), heart rate (HR), pulmonary arterial pressures, pulmonary vascular resistance or central venous pressure. Low-dose ISO (0.7%) and investigated doses of SNP and MIL did not significantly alter this response. High-dose ISO (1.4%, attenuated the AXC-induced increase in SVR, but not in MAP. All drugs decreased non-clamp MAP levels. Therefore, with low-dose ISO and with SNP or MIL, peak MAP during AXC was not significantly different from control non-clamp levels (i.e. prior to pharmacological or surgical interventions). High-dose ISO was associated with a MAP during AXC that was below control non-clamp levels. The objective that during AXC MAP should not exceed control non-clamp levels was achieveable by ISO, SNP or MIL. The modulating actions of the drugs on MAP during AXC were exerted mainly through reductions in non-clamp levels. This systemic hypotension was associated with decreased CO and SVR during ISO, and with decreased SVR and increased HR during SNP and MIL. Attenuation of the AXC-induced increase in SVR was produced only by 1.4% ISO.
Takotsubo syndrome (TS) is an acute cardiac condition, often triggered by critical illness, for w... more Takotsubo syndrome (TS) is an acute cardiac condition, often triggered by critical illness, for which no specific treatment exists. Previously, we showed that isoflurane can prevent experimental TS. The aim of this study was to evaluate the potential treatment effects of isoflurane. Our primary hypothesis was that early treatment with isoflurane attenuates left ventricular akinesia in experimental TS. In propofol-sedated animals, TS was induced by an intraperitoneal bolus of isoprenaline (50 mg/kg). Animals were randomized to one of six groups (n = 15 in each group), and 1% isoflurane was administered for 90 min in all groups. Isoflurane treatment was started at 0, 10, 30 (early treatment) or 120 (late treatment) minutes after isoprenaline injection. One additional late treatment group received isoflurane 0.5% for 180 min. A control group did not receive isoflurane. Left ventricular (LV) echocardiographic examination was performed at 90 min and 48 h after isoprenaline. Mortality was...
Takotsubo syndrome (TS) is an acute cardiac condition with a substantial mortality for which no s... more Takotsubo syndrome (TS) is an acute cardiac condition with a substantial mortality for which no specific treatment is available. We have previously shown that isoflurane attenuates the development of left ventricular (LV) dysfunction in an experimental TS-model. We compared the effects of equi-anaesthetic doses of isoflurane, propofol and ketamine+midazolam on haemodynamics, global and regional LV systolic function and the activation of intracellular metabolic pathways in experimental TS. We hypothesized that cardioprotection in experimental TS is specific for isoflurane. Forty-five rats were randomized to isoflurane (0.6 MAC, n = 15), propofol (bolus 200 mg/kg+360 mg/kg/h, n = 15) or ketamine (100 mg/kg)+midazolam (10 mg/kg, n = 15) anaesthesia. Arterial pressure, heart rate and body temperature were continuously measured and arterial blood gas analysis was performed intermittently. TS was induced by intraperitoneal injection of isoprenaline, 50 mg/kg. LV echocardiography was perfo...
Experimental data indicate large between-organs variations in rates of synthesis of tissue-type p... more Experimental data indicate large between-organs variations in rates of synthesis of tissue-type plasminogen activator (t-PA), which may reflect important differences in the capacity for constitutive and stimulated t-PA release from the vascular endothelium. In this report we describe a new multiple-organ experimental in vivo model for simultaneous determinations of net release/uptake rates of t-PA across the coronary, splanchnic, pulmonary, and hepatic vascular beds. In eleven intact anesthetized pigs, blood samples were obtained simultaneously from the proximal aorta, coronary sinus, pulmonary artery, and portal and hepatic veins. Plasma flows were monitored separately for each vascular region. Total plasma t-PA was determined by ELISA with a porcine t-PA standard. Regional net release/uptake rates were defined as the product of arteriovenous concentration gradients and local plasma flows. The net release of t-PA across the splanchnic vascular bed was very high, with a mean output ...
To investigate beta2 -adrenergic agonist-mediated effects on coronary fluxes of local fibrinolyti... more To investigate beta2 -adrenergic agonist-mediated effects on coronary fluxes of local fibrinolytic factors, healthy anaesthetised and instrumented pigs (n=10) were studied during infusion of isoprenaline (IPR) into the left main coronary artery. Coronary net fluxes of total t-PA antigen, active t-PA and total PAI-1 antigen were determined at baseline and at 3, 5, 7 and 10 minutes of IPR infusion. During IPR, net release of total t-PA increased in a biphasic pattern with transiently high levels at 3 (+440 %) and 7 minutes (+620%) and returned towards baseline at 10 minutes. Net coronary release of active t-PA increased with maximum levels at 3 minutes (+50%). Baseline coronary net flux of total PAI -1 showed a decrease which was most pronounced at 10 minutes. To conclude, a fast beta2 agonist-mediated local release of t-PA into the coronary vasculature was demonstrated. For total t-PA, this response was characterised by a biphasic release profile.
SummaryTo investigate β2-adrenergic agonist-mediated effects on coronary fluxes of local fibrinol... more SummaryTo investigate β2-adrenergic agonist-mediated effects on coronary fluxes of local fibrinolytic factors, healthy anaesthetised and instrumented pigs (n=10) were studied during infusion of isoprenaline (IPR) into the left main coronary artery. Coronary net fluxes of total t-PA antigen, active t-PA and total PAI-1 antigen were determined at baseline and at 3, 5, 7 and 10 minutes of IPR infusion. During IPR, net release of total t-PA increased in a biphasic pattern with transiently high levels at 3 (+440 %) and 7 minutes (+620%) and returned towards baseline at 10 minutes. Net coronary release of active t-PA increased with maximum levels at 3 minutes (+50%). Baseline coronary net flux of total PAI –1 showed a decrease which was most pronounced at 10 minutes. To conclude, a fast β2agonist-mediated local release of t-PA into the coronary vasculature was demonstrated. For total t-PA, this response was characterised by a biphasic release profile.
Tissue-type plasminogen activator (tPA) is a key mediator of fibrinolysis. Matching of pulmonary ... more Tissue-type plasminogen activator (tPA) is a key mediator of fibrinolysis. Matching of pulmonary perfusion and ventilation is a critical denominator of oxygenation in acute lung injury (ALI). This study investigates pulmonary venoarterial plasma tPA gradients in association with acute ALI induced by bronchoalveolar lavage (BAL) and endotoxinemia (ETX). Twenty-one anaesthetized, ventilated pigs were allocated to control (CTRL, n=5), bronchoalveolar saline lavage (BAL, n=8) or infusion of Escherichia coli endotoxin (ETX, n=8). Total tPA was analyzed in plasma (ELISA calibrated for porcine tPA). The inflammatory response was assessed by TNFa levels (ELISA). All variables were assessed at baseline and 2 h following ALI. Bronchoalveolar lavage and ETX induced similar increases in pulmonary shunt whereas pulmonary vascular resistance was significantly more increased in ETX animals. Cardiac output remained stable in BAL animals but decreased in ETX animals. The pulmonary venoarterial tPA plasma gradient increased in ETX animals, yielding a positive pulmonary net flux of tPA, which was absent in BAL animals. TNFalpha levels increased in ETX, but not in BAL, animals. A significant correlation was observed between TNFalpha and tPA plasma levels in ETX animals. All variables remained unchanged in CTRL animals. Plasma changes of tPA levels support a pulmonary release of tPA in early experimental ALI induced by acute ETX but not lavage, and are related to the inflammatory response. Despite increased vascular fibrinolytic capacity in ETX animals, pulmonary dysfunction was not different from BAL animals. The results demonstrate the close relation between inflammation and coagulation in early ALI.
Different pharmacological approaches have been used in the control of cardiovascular responses to... more Different pharmacological approaches have been used in the control of cardiovascular responses to surgical infra-renal aortic occlusion (AXC). The aim of the present study was to explore the modulatory effects of desflurane (DES) on these responses. The study was performed in normoventilated chloralose-anesthetized pigs (n = 14). Measurements included cardiac output (CO), pulmonary vascular pressures, heart rate (HR) and mean arterial pressure proximal to the AXC site (MAPPROX). Renal arterial (QREN) and portal venous (QPORT) blood flows were measured ultrasonically. Systemic (SVR), preportal (RPORT) and renal (RREN) vascular resistances were derived. Sets of measurements were done a) prior to, b) during and c) 5 min after AXC. This was repeated, in a randomized fashion, at control (no DES) and with 4.9% and 9.8% DES, respectively. DES decreased MAPPROX, CO, HR, SVR, RREN and RPORT. At control, AXC increased MAPPROX (+27%), SVR (+27%), QPORT (+14%), RPORT (+12%) and RREN (+43%). DES 4.9% did not change this response pattern. With 9.8% DES, the AXC-induced increases in MAPPROX (+17%) and SVR (+21%) were attenuated. At this stage, AXC caused no demonstrable changes in RREN or RPORT, while both QREN (+16%) and QPORT increased (+9%). DES effectively controlled increases in proximal blood pressure during AXC. The increases in RREN and RPORT that were seen during AXC at control were inhibited by 9.8% DES. Consequently, at this DES dose, both QREN and QPORT increased during AXC.
Pharmacological control of blood pressure is usually indicated during aortic cross-clamping (AXC)... more Pharmacological control of blood pressure is usually indicated during aortic cross-clamping (AXC). The aim of this study was to analyze the modulation by isoflurane (ISO), sodium nitroprusside (SNP) and milrinone (MIL) of the systemic circulatory responses to a standardized infra-renal AXC. Chloralose-anaesthetized pigs were exposed to AXC at control (no vasoactive drugs) and during the administration of each of the drugs. During control, AXC increased mean arterial pressure (MAP, 17 +/- 4%) and systemic vascular resistance (SVR, 27 +/- 7%), but induced no significant changes in cardiac output (CO), heart rate (HR), pulmonary arterial pressures, pulmonary vascular resistance or central venous pressure. Low-dose ISO (0.7%) and investigated doses of SNP and MIL did not significantly alter this response. High-dose ISO (1.4%, attenuated the AXC-induced increase in SVR, but not in MAP. All drugs decreased non-clamp MAP levels. Therefore, with low-dose ISO and with SNP or MIL, peak MAP during AXC was not significantly different from control non-clamp levels (i.e. prior to pharmacological or surgical interventions). High-dose ISO was associated with a MAP during AXC that was below control non-clamp levels. The objective that during AXC MAP should not exceed control non-clamp levels was achieveable by ISO, SNP or MIL. The modulating actions of the drugs on MAP during AXC were exerted mainly through reductions in non-clamp levels. This systemic hypotension was associated with decreased CO and SVR during ISO, and with decreased SVR and increased HR during SNP and MIL. Attenuation of the AXC-induced increase in SVR was produced only by 1.4% ISO.
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Papers by H. Seeman-lodding