endothelin-1 and Heart-Arrest

Outcomes of victims of cardiac arrest or acute myocardial ischemic events have improved with advances in medical therapy. Heart failure, however, remains a leading cause of morbidity and mortality after these conditions have occurred. Clinical features may be useful for predicting patients who are at risk of developing such complications, but they lack of sensitivity and specificity. Biomarkers have been therefore suggested as means to provide relevant prognostic information. The more commonly used biomarkers after cardiovascular ischemic events, including cardiac arrest, are creatin kinases and troponins. In addition, natriuretic peptides and C-reactive protein have gained great interest and now sufficient data has been collected such to justify their clinical applicability. Finally, several other novel biomarkers, to be used after resuscitation from cardiac arrest or more generally after a myocardial ischemic event, have been anticipated. Nevertheless, the "perfect" biomarker, able to provide diagnosis and prognosis with high sensitivity and specificity does not exit. A multimarker strategy that categorizes patients based on the number of elevated biomarkers at presentation is therefore suggested.

Topics: Adrenomedullin; Arginine Vasopressin; Biomarkers; C-Reactive Protein; Cardiopulmonary Resuscitation; Creatine Kinase; Endothelin-1; Heart Arrest; Heart Failure; Humans; Immunity, Innate; Myocardial Ischemia; Natriuretic Peptides; Serum Amyloid P-Component; Troponin

Vital organ blood flow during cardiopulmonary resuscitation (CPR) and neurologic recovery after CPR were significantly better in pigs treated with vasopressin compared with epinephrine. Furthermore, two clinical studies evaluating both out-of-hospital and inhospital cardiac arrest patients found higher 24-hr survival rates in patients who were resuscitated with vasopressin compared with epinephrine. Scientists at the Leopold Franzens University in Innsbruck, Austria, are currently coordinating a multicenter, randomized clinical trial under the aegis of the European Resuscitation Council to study the effects of vasopressin vs. epinephrine in out-of-hospital cardiac arrest patients. Results of anticipated 1,500 enrolled patients may be available in 2001 and may help to determine the role of vasopressin during CPR. Another new, recently studied vasopressor for CPR is endothelin-1. To date, this vasopressor has only been studied as an intervention in animal CPR models, although plasma levels have been investigated in cardiac arrest patients. Initial reports found improved coronary perfusion pressure when combined with epinephrine. However, the CPR research group of the University of Arizona Sarver Heart Center found excessive vasoconstriction and worse survival than with epinephrine alone.

Topics: Advanced Cardiac Life Support; Animals; Endothelin-1; Heart Arrest; Humans; Survival Rate; Swine; Vasoconstrictor Agents; Vasopressins

The survival rate of patients undergoing cardiopulmonary resuscitation (CPR) is 5% to 15%. New treatment approaches under investigation for CPR include the use of vasopressin as a vasopressor, amiodarone for the treatment of ventricular tachyarrhythmia, and adenosine antagonists (i.e., theophylline) for bradyasystolic rhythms. More innovative approaches include the use of thyroid hormone and endothelin.

Topics: Amiodarone; Animals; Anti-Arrhythmia Agents; Antihypertensive Agents; Cardiopulmonary Resuscitation; Endothelin-1; Heart Arrest; Humans; Vasoconstrictor Agents; Vasopressins

Our previous study found that mild hypothermia (MH) after resuscitation reduced cerebral microcirculation, but the mechanism was not elucidated. The aim of this study was to clarify changes of endothelin-1 (ET-1) and nitric oxide (NO) systems in brain tissue during hypothermia after resuscitation.. Twenty-six domestic male Beijing Landrace pigs were used in this study. MH was intravascularly induced 1 h after resuscitation from 8-min ventricular fibrillation. Core temperature was reduced to 33 °C and maintained until 8 h after resuscitation, and then animals were euthanized. ET-1 and NO levels in brain tissue and peripheral plasma were measured. Expression of endothelin-converting enzyme-1 (ECE-1), endothelin A receptor (ET-AR), endothelin-B receptor, and nitric oxide synthase (NOS) in brain tissue was determined by Western blot analysis.. Compared with non-hypothermia (NH) treatment, MH after resuscitation significantly increased the level of endothelin-1 and reduced the level of NO in peripheral blood and brain tissue. Cerebral expression of ECE-1 and ET-AR was significantly increased during MH after resuscitation. Moreover, MH significantly decreased inducible NOS expression compared with the NH group.. The ET-1 system is activated, while inducible NOS is inhibited in brain tissue during MH after resuscitation.

Topics: Animals; Brain; Disease Models, Animal; Endothelin-1; Endothelin-Converting Enzymes; Heart Arrest; Hypothermia, Induced; Male; Nitric Oxide; Nitric Oxide Synthase; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin; Sus scrofa; Swine

The aim of this paper was to describe differences between levels of endothelial nitric oxide synthase (NOS-3) and endothelin-1 (ET-1) in swine kidneys removed from living donors (group I) and after inducing brain death by brain herniation (group II) and cardiac arrest (group III).. Each group consisted of 3 animals who underwent dual renal removal procedure; kidneys were further rinsed according to standardized procedure with Biolasol perfusion liquid, stored for 24 hours (4°C), and rinsed again. Renal specimens of 4 g mass, including renal cortex and medulla, were collected before and after perfusion (times 0 and 1), after 12 hours (time 2), and after reperfusion (time 3). Enzyme-linked immunosorbent assay was used to describe levels of NOS-3 and ET-1 in collected tissues homogenates. Mann-Whitney U test was used to compare results in groups in relation to total protein content (ng/mg), and the correlation between the 2 substances was measured with the use of Spearman rho.. Group I presented low and stable levels of NOS-3 in all time intervals (averages, 0.73, 0.99, 0.52, and 0.89, respectively). Level sof ET-1 were similar (0.87, 0.63, 0.69, and 0.86, respectively), and significant correlation between levels of the 2 substances was observed. Increased levels of NOS-3 (1.89 and 1.86) and ET-1 (1.38 and 1.49) were observed directly after removal in groups II and III and further maintained during organ storage. No correlation in group I was observed, and after perfusion significantly lower level of NOS-3 was observed in kidneys removed after brain death in relation to group III (1.77 vs 2.60).. The lowest and stable levels of NOS-3 and ET1 during storage were observed in kidneys removed from living donors. Levels of analyzed substances in this group showed correlation in subsequent time intervals.

Topics: Animals; Brain Death; Endothelin-1; Heart Arrest; Kidney; Kidney Transplantation; Living Donors; Nitric Oxide; Nitric Oxide Synthase Type III; Organ Preservation; Swine

Post-cardiac arrest myocardial dysfunction is a major cause of mortality in patients receiving successful cardiopulmonary resuscitation (CPR). Mild therapeutic hypothermia (MTH) is the recommended treatment after resuscitation from cardiac arrest (CA) and is known to exert neuroprotective effects and improve short-term survival. Yet its cytoprotective mechanisms are not fully understood. In this study, our aim was to determine the possible effect of MTH on vasoactive mediators belonging to the endothelin/nitric oxide axis in our porcine model of CA and CPR. Pigs underwent either untreated CA or CA with subsequent CPR. After state-of-the-art resuscitation, the animals were either left untreated, cooled between 32-34 °C after ROSC or treated with a bolus injection of S-PBN (sodium 4-[(tert-butylimino) methyl]benzene-3-sulfonate N-oxide) until 180 min after ROSC, respectively. The expression of endothelin 1 (ET-1), endothelin converting enzyme 1 (ECE-1), and endothelin A and B receptors (ETAR and ETBR) transcripts were measured using quantitative real-time PCR while protein levels for the ETAR, ETBR and nitric oxide synthases (NOS) were assessed using immunohistochemistry and Western Blot. Our results indicated that the endothelin system was not upregulated at 30, 60 and 180 min after ROSC in untreated postcardiac arrest syndrome. Post-resuscitative 3 hour-long treatments either with MTH or S-PBN stimulated ET-1, ECE-1, ETAR and ETBR as well as neuronal NOS and endothelial NOS in left ventricular cardiomyocytes. Our data suggests that the endothelin and nitric oxide pathways are activated by MTH in the heart.

Topics: Animals; Aspartic Acid Endopeptidases; Benzenesulfonates; Cardiopulmonary Resuscitation; Cardiovascular Agents; Endothelin-1; Gene Expression; Gene Expression Regulation; Heart Arrest; Hypothermia, Induced; Myocardial Reperfusion Injury; Myocardium; Nitric Oxide; Nitric Oxide Synthase; Receptors, Endothelin; Sus scrofa

Endothelin-1 (ET-1) increases in the ischemically induced ventricular fibrillation (VF) swine model of cardiac arrest and affects outcome by potentially attenuating the hemodynamic response to epinephrine. Fifty-one swine underwent percutaneous left anterior descending occlusion. Seven minutes postonset of ischemic VF, cardiopulmonary resuscitation (CPR) was initiated. If VF persisted after 3 shocks, 1 mg of epinephrine was given. ET-1 (collected at baseline and every 5 min until VF onset) was assayed with ELISA. Bayesian multivariate logistic regression analysis compared peak ET-1 levels with the binary outcome of a positive coronary perfusion pressure response of >20 mmHg following epinephrine. Sixteen animals (31%) failed to achieve a positive response. Restoration of spontaneous circulation (ROSC) was observed in 1/16 (6.3%) of epinephrine nonresponders and 20/35 (57.1%) of epinephrine responders (P = 0.0006). The median peak ET-1 level was 2.71 pg/mL [interquartile range (IQR) 1.06-4.40] in nonresponders and 1.69 pg/mL (IQR 0.99-2.35) in responders. ET-1 levels were inversely associated with epinephrine response with a median posterior odds ratio (OR) of a coronary perfusion pressure response of 0.72 (95% confidence interval [CI] 0.48-1.06) for each one-unit increase in ET-1 and a probability that the associated OR is <1 of 0.95. Peak ET-1 levels predict a lack of a hemodynamic response to epinephrine during treatment of cardiac arrest during ischemic VF.

Topics: Animals; Disease Models, Animal; Endothelin-1; Epinephrine; Heart Arrest; Hemodynamics; Male; Myocardial Ischemia; Swine; Ventricular Fibrillation

The assessment of myocardial viability after global warm ischemia (WI) but before reperfusion is challenging. We hypothesized that fractional anisotropy (FA), a magnetic resonance imaging (MRI) parameter of water diffusion that characterizes cellular integrity within tissues, provides a rapid and useful method for evaluating the viability of hearts after WI.. Dog hearts were exposed to 60 minutes of WI after exanguination, explanted and preserved in a cold, non-beating state for 6 hours, using continuous perfusion (CP) or static cold storage (CS). Toward the end of preservation, a global FA assessment, acquired using MRI, was compared with analyses obtained from myocardial biopsies that included adenosine triphosphate (ATP), endothelin-1 (ET-1) and caspase-3 levels, light microscopy and tetrazolium staining. Functional recovery was analyzed after restoration of blood flow on a non-working Langendorff preparation.. FA measured at the end of CP showed strong correlations with all parameters of functional recovery (developed pressure, R = 0.60; dP/dt, R = 0.96; -dP/dt, R = 0.96). Although FA also correlated with tissue levels of ATP, ET-1 and caspase-3 (R = 0.77, -0.84, -0.64), recovery of myocardial function did not correlate with these markers or any other conventional analyses of myocardial injury (troponin I, changes on light microscopy or tetrazolium staining).. FA, an MRI-based parameter that indicates cellular integrity, was found to reflect better myocardial ATP stores, less induction of ET-1 and caspase-3 and improved functional recovery of hearts after global WI. As a clinically applicable tool capable of rapidly differentiating reversible from lethal injury, diffusion tensor imaging may prove useful in the eventual adoption of non-beating donor hearts for transplantation.

Topics: Adenosine Triphosphate; Animals; Anisotropy; Biomarkers; Biopsy; Caspase 3; Diffusion Magnetic Resonance Imaging; Dogs; Endothelin-1; Heart; Heart Arrest; Myocardium; Organ Preservation; Predictive Value of Tests; Recovery of Function; Tissue Donors; Tissue Survival; Warm Ischemia

Lung retrieval from non-heart-beating donors (NHBD) has been introduced into clinical practice successfully. However, because of potentially deleterious effects of warm ischemia on microvascular integrity, use of NHBD lungs is limited by short tolerable time periods before preservation. Recently, improvement of NHBD graft function was demonstrated by donor pre-treatment using aerosolized Ventavis (Schering Inc., Berlin, Germany). Currently, there is no information whether additional application of this approach in reperfusion can further optimize immediate graft function.. Asystolic pigs (n = 5/group) were ventilated for 180-min of warm ischemia (groups 1-3). In groups 2 and 3, 100 microg Ventavis were aerosolized over 30-min using an ultrasonic nebulizer (Optineb). Lungs were then retrogradely preserved with Perfadex and stored for 3-h. After left lung transplantation and contralateral lung exclusion, grafts were reperfused for 6-h. Only in group 3, another dose of 100 microg Ventavis was aerosolized during the first 30-min of reperfusion. Hemodynamics, pO2/FiO2 and dynamic compliance were monitored continuously and compared to controls. Intraalveolar edema was quantified stereologically, and extravascular-lung-water-index (EVLWI) was measured. Statistics comprised ANOVA analysis with repeated measurements.. Dynamic compliance was significantly lower in both Ventavis groups, but additional administration did not result in further improvement. Oxygenation, pulmonary hemodynamics, EVLWI and intraalveolar edema formation were comparable between groups.. Alveolar deposition of Ventavis in NHBD lungs before preservation significantly improves dynamic lung compliance and represents an important strategy for improvement of preservation quality and expansion of warm ischemic intervals. However, additional application of this method in early reperfusion is of no benefit.

Topics: Administration, Inhalation; Animals; Endothelin-1; Extravascular Lung Water; Female; Graft Survival; Heart Arrest; Iloprost; Lung Compliance; Lung Transplantation; Reperfusion Injury; Sus scrofa; Transplantation Conditioning; Vascular Resistance; Vasodilator Agents

The effects of pretreatment with cariporide (HOE 642 Aventis Pharma, Strasbourg-Cedex, France), a Na+-H+ exchanger (NHE) blocker, were studied in a cerebral ischemia-reperfusion model of hypothermic arrest.. Fifteen Yorkshire-Duroc pigs (37.1 +/- 4.2 kg) underwent femoral-jugular bypass and 90 minutes of deep hypothermic circulatory arrest at 19 degrees C. Ten animals were untreated, whereas 5 received 5 mg/kg of intravenous cariporide before cooling. After rewarming and off cardiopulmonary bypass, the pigs were weaned from anesthesia and followed for 24 hours. A standardized neurologic scoring system assessed brain functional recovery. Biochemical markers were used to analyze cellular injury. Control studies without circulatory arrest were done in 2 animals that underwent similar cooling and rewarming.. Neurologic recovery was rapid and complete in the nonischemic controls and in all pretreated animals. Conversely, at 24 hours, all untreated pigs exhibited a cloudy or stuporous level of consciousness, abnormal positioning, and with only one exception, could not sit or stand. The gradation of neurologic score (evaluating central nervous system, motor and sensory functions, respiration condition, level of consciousness, and behavior) was 0 +/- 0 (0 = normal, 500 = brain death) in the treated group, compared with 124 +/- 59 in the untreated animals. Biochemical analysis showed every variable of whole-body injury (including conjugated dienes (p < 0.05), serum aspartate amino transferase (p < 0.01), creatine kinase p < 0.001) and endothelin-1 (p < 0.001) to be higher in the untreated group.. NHE function alters experimental brain ischemia-reperfusion damage. These observations imply that NHE inhibition therapy before ischemia may improve neurologic protection in adult and infant patients undergoing cerebral ischemia during procedures that use hypothermic circulatory arrest.

Topics: Animals; Biomarkers; Creatine Kinase; Endothelin-1; Glutamyl Aminopeptidase; Guanidines; Heart Arrest; Heart Arrest, Induced; Hypothermia, Induced; Ischemic Attack, Transient; Reperfusion Injury; Sodium-Hydrogen Exchangers; Sulfones; Swine

In this study, we evaluated whether median fibrillation frequency (MF) and mean fibrillation amplitude (AMP) reflect coronary perfusion pressure (CoPP) and predict successful defibrillation. MF, AMP, and CoPP were measured during prolonged ventricular fibrillation (VF) cardiac arrest and resuscitation in pigs. After 5 min of VF, cardiopulmonary resuscitation was started. At 10 min, the pigs received randomly a single dose of endothelin-1 50 mug (n = 7), 100 mug (n = 7), or 200 mug (n = 5), or repeated doses of epinephrine 0.04 mg/kg (n = 6), or saline (n = 6) every 3 min. At 25 min, the pigs were defibrillated to achieve restoration of spontaneous circulation (ROSC). In a nonparametric spectral analysis of the individual MF versus CoPP and AMP versus CoPP curves, we found no link between the different curves in different animals or therapies. No difference was found in MF in pigs with ROSC (n = 8) compared with animals not achieving ROSC (n = 23) immediately before defibrillation (P = 0.85). Our data suggest that, in prolonged VF cardiac arrest, MF and AMP might not be useful tools to reflect myocardial perfusion.

Topics: Adrenergic alpha-Agonists; Animals; Cardiopulmonary Resuscitation; Coronary Circulation; Electric Countershock; Electrocardiography; Endothelin-1; Epinephrine; Female; Heart Arrest; Male; Monitoring, Physiologic; Respiration, Artificial; Swine; Ventricular Fibrillation

Topics: Animals; Brain; Cardiopulmonary Resuscitation; Cerebrovascular Circulation; Combined Modality Therapy; Disease Models, Animal; Endothelin-1; Epinephrine; Heart Arrest; Infusions, Intravenous; Reference Values; Sensitivity and Specificity; Swine; Ventricular Fibrillation

Topics: Animals; Calcitonin Gene-Related Peptide; Electric Stimulation; Endothelin-1; Female; Heart Arrest; Male; Rabbits; Resuscitation

Since adrenaline (epinephrine) also has negative effects during and after cardiopulmonary resuscitation (CPR) a non-adrenergic vasoconstrictor like endothelin might be an alternative to increase vital organ blood flow. We studied the effect of different doses of endothelin-1 compared with adrenaline on the ability to resuscitate, cerebral and myocardial blood flow (MBF) in a closed chest cardiac arrest pig model. After 5 min of ventricular fibrillation, CPR with a ventilator and a mechanical compression device was started. At 10 min, 31 pigs were randomized to receive a single dose of endothelin-1 50, 100 or 200 microg or repeated doses of adrenaline 0.04 mg kg(-1) or saline every 3 min. After 25 min, the pigs were defibrillated to achieve restoration of spontaneous circulation. Blood flow was measured with the fluorescent microsphere method. In animals receiving endothelin-1 50, 100 and 200 microg the cerebral blood flow (CBF) increased from median 28 (25th; 75th quartile: 16; 40), 32 (15; 48) and 17 (4; 65) to 36 (31; 54), 47 (39; 57) and 63 (35; 83) ml min(-1) per 100 g, respectively, 6 min after drug administration (P<0.05 endothelin-1 50 microg vs. Control, P<0.01 endothelin-1 100 and 200 microg vs. Control). At the same time CBF decreased in the control and adrenaline group from 36 (21; 41) and 39 (15; 50) to 12 (2; 25) and 24 (15; 26) ml min(-1) per 100 g, respectively, (P<0.05 adrenaline vs. endothelin-1 200 microg). There was no difference in MBF between the treatment groups despite a higher coronary perfusion pressure (CoPP) in the endothelin-1 groups. Restoration of spontaneous circulation could be only achieved in the endothelin-1 50 microg (3 of 7; 43%) and 100 microg (5 of 7; 71%) group. This study suggests that endothelin-1 enhances CBF during CPR better than adrenaline and increases resuscitation success.

Topics: Animals; Blood Pressure; Brain; Cardiopulmonary Resuscitation; Coronary Circulation; Double Bind Interaction; Endothelin-1; Epinephrine; Heart Arrest; Prospective Studies; Random Allocation; Regional Blood Flow; Swine; Vasoconstrictor Agents; Ventricular Fibrillation

The optimal method for preserving livers from non-heart-beating donors (NHBD) is still unknown. We compared the Celsior solution, a new extracellular-type, low-potassium, low-viscosity preservation solution, with the University of Wisconsin (UW) solution in a canine orthotopic liver transplantation from NHBD.. Fourteen adult mongrel dogs, weighing 9 to 17 kg, were divided into two groups: the Celsior or the UW group (n = 7 each). The thoracic descending aorta and supradiaphragmatic inferior vena cava were cross-clamped for 20 min to induce warm ischemia as a NHBD model. The liver was flushed with the respective cold preservation solution and then stored at 4 degrees C for 4 h. The grafts were transplanted using the piggy-back technique under portal decompression by leaving the native right lobe as a temporary shunt.. The duration of liver flushing out (min) was shorter (P < 0.05), and the serum glutamic oxaloacetic transaminase, glutamic pyruvic transaminase, lactate dehydrogenase, lactate, and alpha-glutathione S-transferase concentrations 2 and 6 h after reperfusion of the graft (RPF) were lower (P < 0.05) in the Celsior group than in the UW group. Hepatic tissue blood flow (HTBF) did not deteriorate as much (P < 0.05) in the Celsior group. The serum endothelin-1 level was lower (P < 0.05) in the Celsior group 2 h after RPF. Histopathology of liver specimens revealed portal congestion and hepatocyte necrosis with neutrophil infiltration in the UW group, while these findings were mild in the Celsior group.. The Celsior solution improves vascular endothelial injury in livers from NHBDs and may have advantages in graft flush and preservation of grafts from NHBDs.

Topics: Adenosine; Alanine Transaminase; Allopurinol; Animals; Aspartate Aminotransferases; Disaccharides; Dogs; Electrolytes; Endothelin-1; Female; Glutamates; Glutathione; Glutathione Transferase; Graft Survival; Heart Arrest; Histidine; Insulin; L-Lactate Dehydrogenase; Lactic Acid; Liver; Liver Circulation; Liver Transplantation; Male; Mannitol; Neutrophils; Organ Preservation Solutions; Raffinose

Topics: Cardiac Surgical Procedures; Endothelin Receptor Antagonists; Endothelin-1; Heart Arrest; Heart Arrest, Induced; Humans; Myocardium; Vasoconstriction

Topics: Animals; Endothelin-1; Epoprostenol; Heart Arrest; Kidney Transplantation; Renal Artery; Reperfusion; Swine; Thromboxane B2; Transplantation, Homologous; Vasoconstrictor Agents

Topics: Animals; Endothelin-1; Graft Survival; Heart Arrest; Liver Transplantation; Peptides, Cyclic; Piperidines; Platelet Activating Factor; Pyridinium Compounds; Swine; Tacrolimus; Time Factors; Tissue and Organ Harvesting; Transplantation, Homologous

Endothelin-1 (ET-1) is a potent vasoconstrictor and has been shown to improve coronary perfusion pressure (CPP) during arrest. The effects of ET-1 on organ blood flow during arrest have not been extensively studied.. To investigate the effects of ET-1 on myocardial and cerebral blood flow during cardiac arrest.. Sixty immature swine were anesthetized and instrumented. The animals were randomized to receive one of three doses of ET-1 (50, 150, or 300 microg) or placebo with/without standard-dose epinephrine (SDE) during cardiac arrest. After a 10-minute period of no-flow ventricular fibrillation (VF), cardiopulmonary resuscitation (CPR) was performed for 3 minutes, followed by drug administration. Placebo or SDE was given every 3 minutes. Myocardial and cerebral blood flow was measured using a fluorescent microsphere technique.. Prearrest and CPR variables were not different between groups. Beginning 4 minutes after giving 300 microg ET-1 with or without SDE, CPP was significantly increased compared with SDE alone. Total myocardial blood flow following ET-1 administration was no different than myocardial blood flow following SDE alone. Cerebral blood flow increased 3.5 minutes after administration of 300 microg ET-1 with SDE and reached significance 9.5 minutes after drug administration when compared with SDE alone [92.5 (48.8-117.9) vs 15.6 (7.7-23) mL/min/100 g].. Three hundred microg ET-1 with SDE increases CPP and improves cerebral blood flow but does not improve myocardial blood flow during cardiac arrest. The peripheral effects of ET-1 significantly improve CPP and cerebral blood flow, but myocardial blood flow is not increased due to coronary vasoconstriction.

Topics: Animals; Brain; Coronary Circulation; Endothelin-1; Evaluation Studies as Topic; Heart Arrest; Prospective Studies; Random Allocation; Regional Blood Flow; Swine

Vasoconstriction during cardiopulmonary resuscitation (CPR) improves coronary perfusion pressure (CPP) and thereby outcome. The combination of endothelin-1 (ET-1) plus epinephrine improved CPP during CPR compared with epinephrine alone in a canine cardiac arrest model. The effect of the combination on outcome variables, such as successful resuscitation and survival, has not been investigated.. Twenty-seven swine were randomly provided with 1 mg epinephrine (Epi group) or 1 mg epinephrine plus 0.1 mg ET-1 (ET-1 group) during a prolonged ventricular fibrillatory cardiac arrest. ET-1 resulted in substantially superior aortic relaxation pressure and CPP during CPR. These hemodynamic improvements tended to increase initial rates of restoration of spontaneous circulation (8 of 10 versus 8 of 17, P=0.12). However, continued intense vasoconstriction from ET-1 led to higher aortic diastolic pressure and very narrow pulse pressure after resuscitation. The mean pulse pressure 1 hour after resuscitation was 7+/-8 mm Hg with ET-1 versus 24+/-1 mm Hg with Epi, P<0.01. Most importantly, the postresuscitation mortality was dramatically higher in the ET-1 group (6 of 8 versus 0 of 8 in the Epi group, P<0.01).. These data establish that administration of ET-1 during CPR can result in worse postresuscitation outcome. The intense vasoconstriction from ET-1 improved CPP during CPR but had detrimental effects in the postresuscitation period.

Topics: Animals; Cardiopulmonary Resuscitation; Endothelin-1; Epinephrine; Heart Arrest; Hemodynamics; Swine; Treatment Failure; Vasoconstrictor Agents; Ventricular Fibrillation

Endothelin-1 (ET-1) is a potent peripheral and coronary artery vasoconstrictor and has been shown to improve coronary perfusion pressure (CPP) during cardiac arrest. The effect of ET-1 on return of spontaneous circulation (ROSC) following cardiac arrest has not been studied. Our hypothesis was that ET-1 does not improve ROSC from cardiac arrest when compared to placebo.. A total of 11 immature swine were used in this laboratory study. Animals were randomized to receive 300 microg ET-1 and standard dose epinephrine (SDE) or placebo and SDE during arrest. After a 10-min period of no-flow ventricular fibrillation (VF), CPR was performed for 3 min followed by ET-1/SDE or placebo/SDE administration. Following drug administration, standard ACLS was followed with SDE given every 3 min. Aortic pressure was monitored during resuscitation. ROSC was defined as any perfusing rhythm with a systolic pressure greater than 60 mmHg for 60 s. Animals received post-ROSC care as needed for 2 h post-ROSC. CPP and ROSC were analyzed using repeated measures ANOVA and Fischer's exact test respectively. P<0.05 was considered significant.. Pre-arrest variables and CPP prior to ET-1 administration were not different between groups. Following ET-1 administration, CPP was significantly increased at all time points in ET-1/SDE versus placebo/SDE animals. ROSC was achieved in 1/5 (20%) ET-1/SDE versus 1/6 (16.7%) placebo/SDE animals (P>0.05). The resuscitated ET-1/SDE animal survived 6.5 min compared to 120 min for the resuscitated placebo/SDE animal.. In our study, ET-1 administration during cardiac arrest increases CPP but does not improve ROSC.

Topics: Animals; Cardiopulmonary Resuscitation; Coronary Circulation; Endothelin-1; Epinephrine; Heart Arrest; Myocardial Reperfusion; Random Allocation; Swine; Vasoconstrictor Agents

Vasopressin is a possible stimulus for both adrenocorticotropin (ACTH) and endothelin-1 release. The aim of this study was to compare plasma concentrations of ACTH, cortisol, and endothelin-1 after epinephrine or vasopressin administration in an experimental animal model of cardiopulmonary resuscitation (CPR).. Prospective, randomized, controlled animal study.. A university research laboratory.. Fourteen 12- to 14-wk-old domestic pigs.. After 4 mins of cardiac arrest and 3 mins of external chest compression, the pigs were randomly assigned to receive either 0.045 mg/kg epinephrine (n = 7) or 0.4 units/kg vasopressin (n = 7). At 5 mins after drug administration, defibrillation was attempted.. Coronary perfusion pressure, ACTH, cortisol, and endothelin-1 were measured before cardiocirculatory arrest, during CPR before drug administration, and at 90 secs and 5 mins after drug administration. Coronary perfusion pressure was comparable between groups. All seven animals in the vasopressin group survived, but only one pig in the epinephrine group survived (p = .005). ACTH and cortisol concentrations remained unchanged in epinephrine-treated animals, but increased significantly after vasopressin administration and were significantly higher than in epinephrine-treated animals 5 mins after drug administration. Endothelin-1 concentrations remained unchanged during the study period and were comparable between both groups.. Vasopressin is a potent stimulus for ACTH secretion, but does not trigger endothelin-1 release from vascular cells during cardiac arrest and CPR. The increased plasma cortisol concentrations caused by the enhanced ACTH release after vasopressin may be one factor contributing to the improved outcome repeatedly observed with vasopressin in animal models of CPR.

Topics: Adrenocorticotropic Hormone; Animals; Cardiopulmonary Resuscitation; Disease Models, Animal; Drug Evaluation, Preclinical; Electric Countershock; Endothelin-1; Epinephrine; Heart Arrest; Hemodynamics; Hydrocortisone; Random Allocation; Survival Analysis; Swine; Time Factors; Vasoconstrictor Agents; Vasopressins

Topics: Animals; Aspartate Aminotransferases; Blood Pressure; Endothelin Receptor Antagonists; Endothelin-1; Endothelins; Heart Arrest; Intraoperative Period; Liver Transplantation; Peptides, Cyclic; Portal Vein; Postoperative Period; Protein Precursors; Reperfusion; Swine; Time Factors

Topics: Adenosine; Allopurinol; Animals; Aspartate Aminotransferases; Biomarkers; Endothelin-1; Female; Glutathione; Heart Arrest; Hyaluronic Acid; Insulin; Liver; Liver Transplantation; Organ Preservation; Organ Preservation Solutions; Potassium Chloride; Raffinose; Swine; Tissue and Organ Harvesting

With the shortage of cadaveric donors, non-heart-beating donors (NHBDs) are a potential source of liver allografts. However, warm ischemic injury in NHBDs seriously affects the viability of graft liver. Endothelin (ET)-1 has been reported to be involved in the hepatic microcirculatory disturbances after ischemia-reperfusion.. In a porcine orthotopic liver transplantation model, changes in the serum and liver tissue ET-1 concentration were measured and the effects of an ET receptor antagonist, TAK-044, were evaluated. After cardiac arrest of the donors, liver allografts were subjected to 90 min of warm ischemia, flushed, and preserved for 4 hr at 4 degrees C. The pigs were divided into two groups: a control group (no drug treatment) and a drug-treated group, in which donors and recipients were treated with TAK-044 (10 mg/kg body, drip intravenous injection). Both groups had six donor/recipient pairs.. -The ET-1 concentration in the hepatic venous blood increased after reperfusion of the graft in the control group recipients. ET-1 in the graft liver significantly increased during the cold preservation period. TAK-044 treatment significantly increased recipient 7-day survival rate. After reperfusion of the graft, the concentrations of serum liver enzymes and arterial lactate in the drug-treated group were significantly lower than in the control group. The postoperative increase in portal venous pressure was significantly reduced in the drug-treated group. Measurements of liver enzymes in the washed-out preservation fluid at the time of graft rinsing indicated that TAK-044 treatment of the donors significantly suppressed liver enzyme release during ischemia.. These findings indicate TAK-044 treatment has protective effects on postoperative function of hepatic allografts procured from NHBDs.

Topics: Alanine Transaminase; Animals; Aspartate Aminotransferases; Blood Pressure; Endothelin-1; Heart Arrest; Humans; Lactates; Liver; Liver Transplantation; Male; Organ Preservation; Peptides, Cyclic; Portal Vein; Swine; Tissue Donors

To study the hemodynamic effects of exogenously administered endothelin-1 (ET-1), a peptide produced by endothelial cells with potent non-adrenergically mediated vasoconstrictor properties.. A prospective drug intervention study was carried out in a resuscitation research laboratory. Fifteen mixed-breed dogs were anesthetized and instrumented for hemodynamic monitoring. Asphyxia arrest was produced by clamping the endotracheal tube. Hemodynamic data were collected continuously. Following loss of aortic fluctuations monitored by thoracic aortic catheter, the animals remained in pulseless electrical activity (PEA) for 10 minutes. After 10 minutes of no-flow PEA, closed-chest CPR was begun and the animals were randomized to one of three treatment groups (EPI, 0.02 mg/kg epinephrine IV every 3 minutes; ENDO, 100 micrograms ET-1 IV at 0 minutes; and EPI/ENDO, a combination of the EPI and ENDO treatments).. ENDO and EPI alone produced similar coronary perfusion pressures (CPPs). The EPI/ENDO combination produced significantly improved CPP compared with that of either EPI or ENDO alone. In the EPI group, the best mean CPP was 16 +/- 14 mm Hg and occurred 7 minutes after drug administration. In the ENDO group, the best mean CPP was 28 +/- 7 mm Hg and occurred 13 minutes after drug administration. In the EPI/ENDO combination group, the best mean CPP was 61 +/- 37 mm Hg and occurred 7 minutes after drug administration (p < 0.05 compared with the EPI and ENDO groups alone).. ET-1 is a potent vasoconstrictor. The combination of EPI and ENDO significantly improved CPP compared with that for either agent alone. ET-1 should be investigated further as a vasoconstrictor in cardiac arrest.

Topics: Animals; Cardiopulmonary Resuscitation; Coronary Circulation; Disease Models, Animal; Dogs; Drug Therapy, Combination; Endothelin-1; Epinephrine; Evaluation Studies as Topic; Female; Heart Arrest; Male; Prospective Studies; Vasoconstrictor Agents

To determine the role of cerebral vasoconstriction in the delayed hypoperfusion phase in comatose patients after cardiac arrest.. Prospective study.. Medical intensive care unit in a university hospital.. 10 comatose patients (Glasgow Coma Score +/- 6)successfully resuscitated from a cardiac arrest occurring outside the hospital.. We measured the pulsatility index (PI) and mean blood flow velocity (MFV) of the middle cerebral artery, the cerebral oxygen extraction ratio and jugular bulb levels of endothelin, nitrate, and cGMP during the first 24 h after cardiac arrest.. The PI decreased significantly from 1.86 +/- 1.02 to 1.05 +/- 0.22 (p = 0.03). The MFV increased significantly from 29 +/- 10 to 62 +/- 25 cm/s (p = 0.003). Cerebral oxygen extraction ratio decreased also from 0.39 +/- 0.13 to 0.24 +/- 0.11 (p = 0.015). Endothelin levels were high but did not change during the study period. Nitrate levels varied widely and showed a slight but significant decrease from 37.1 mumol/l (median; 25th-75th percentiles: 26.8-61.6) to 31.3 mumol/l (22.1-39.6) (p = 0.04). Cyclic guanosine monophosphate levels increased significantly from 2.95 mumol/l (median; 25th-75th percentiles: 2.48-5.43) to 7.5 mumol/l (6.20-14.0) (p = 0.02).. We found evidence of increased cerebrovascular resistance during the first 24 h after cardiac arrest with persistent high endothelin levels, gradually decreasing nitrate levels, and gradually increasing cGMP levels, This suggests that active cerebral vasoconstriction due to an imbalance between local vasodilators and vasoconstrictors plays a role in the delayed hypoperfusion phase.

Topics: Adult; Aged; Aged, 80 and over; Brain Ischemia; Cardiopulmonary Resuscitation; Cerebrovascular Circulation; Coma; Critical Care; Cyclic GMP; Endothelin-1; Female; Heart Arrest; Humans; Male; Middle Aged; Nitrates; Prospective Studies; Vascular Resistance