Pharmacokinetic study (phase I-II) of a new dobutamine formulation in preterm infants immediately after birth.

BACKGROUND: Dobutamine is particularly suited to treatment of haemodynamic insufficiency caused by increased peripheral vascular resistance and myocardial dysfunction in the preterm infant. Knowledge of the elimination half-life is essential to estimate the steady state when its efficacy/safety can be evaluated. METHODS: Analysis of pharmacokinetic data in ten preterm newborns treated with a new neonatal formulation of dobutamine (IMP) after screening for haemodynamic insufficiency within the first 72 h from birth. Blood samples were withdrawn at the end of IMP infusion and at a random time after the end of infusion (5 min, 15 min, 45 min, 2 h and 6 h). IMP concentration in each sample was measured by ultra-high performance liquid chromatography with electrochemical detection. RESULTS: Median duration of IMP infusion was 37.7 h (IQR 21.2). Calculated IMP half-life ranged between 3.06 and 36.1 min (median 10.6 min), leading to a time to reach the steady-state concentration between 15 min and >2 h. Adverse events were not related to IMP. CONCLUSIONS: The wide variability in dobutamine metabolism in preterm infants requires awareness about the risk of under- or overtreatment. A delay of up to 3 h might be required before drawing blood samples to evaluate the effective dose. IMPACT: Small trials suggest dobutamine as the optimal drug in the preterm infant with haemodynamic insufficiency after birth. Age-related differences in drug pharmacokinetics may result in suboptimal treatments. The lack of formal studies in preterms results in inadequate data on efficacy and safety. This study provides data on the variability of the elimination half-life of dobutamine in the very preterm infant during transitional circulation. There is a wide variation in the time to reach the plasma concentration corresponding to steady state, the moment when its efficacy/safety can be reliably evaluated. This information is crucial for planning future trials on cardiovascular support.

Pharmacodynamic and pharmacokinetic behavior of landiolol during dobutamine challenge in healthy adults.

BACKGROUND: To study the pharmacokinetic and -dynamic behavior of landiolol in the presence of dobutamine in healthy subjects of European ancestry. METHODS: We conducted a single-center, prospective randomized study in 16 healthy subjects each receiving an infusion of dobutamine sufficient to increase heart rate by 30 bpm followed by a 60 min infusion of 10 µg/kg/min landiolol. RESULTS: Dobutamine-induced increases in heart rate were stable for at least 20 min before a 60 min landiolol- infusion was started. The dobutamine effects were rapidly antagonized by landiolol within 16 min. A further slight decrease in heart rate during 20-60 min of the landiolol infusion occurred as well. Upon termination of landiolol infusion, heart rate and blood pressure recovered rapidly in response to the persisting dobutamine infusion but did not return to the maximum values before landiolol infusion. The pharmacokinetic parameters of landiolol in presence of dobutamine showed a short half-life (3.5 min) and a low distribution volume (0.3 l/kg). No serious adverse events were observed. CONCLUSION: Landiolol can antagonize the dobutamine-induced increases in heart rate and blood pressure in a fast way. A rapid bradycardic effect until steady-state plasma levels is followed by a slow heart rate reduction. The latter can be attributed to an early desensitization to dobutamine. Consequently, after termination of landiolol, the heart rate did not achieve maximum pre-landiolol values. The pharmacokinetics of landiolol during dobutamine infusion are similar when compared to short- and long-term data in Caucasian subjects. Landiolol in the given dose can thus serve as an antagonist of dobutamine-induced cardiac effects. TRIAL REGISTRATION: Registration number 2010-023311-34 at the EU Clinical Trials Register, registration date 2010-12-21.

Cardiac Dysfunction in the Sigma 1 Receptor Knockout Mouse Associated With Impaired Mitochondrial Dynamics and Bioenergetics.

Background The Sigma 1 receptor (Sigmar1) functions as an interorganelle signaling molecule and elicits cytoprotective functions. The presence of Sigmar1 in the heart was first reported on the basis of a ligand-binding assay, and all studies to date have been limited to pharmacological approaches using less-selective ligands for Sigmar1. However, the physiological function of cardiac Sigmar1 remains unknown. We investigated the physiological function of Sigmar1 in regulating cardiac hemodynamics using the Sigmar1 knockout mouse (Sigmar1-/-). Methods and Results Sigmar1-/- hearts at 3 to 4 months of age showed significantly increased contractility as assessed by left ventricular catheterization with stimulation by increasing doses of a ß1-adrenoceptor agonist. Noninvasive echocardiographic measurements were also used to measure cardiac function over time, and the data showed the development of cardiac contractile dysfunction in Sigmar1 -/- hearts as the animals aged. Histochemistry demonstrated significant cardiac fibrosis, collagen deposition, and increased periostin in the Sigmar1 -/- hearts compared with wild-type hearts. Ultrastructural analysis of Sigmar1-/- cardiomyocytes revealed an irregularly shaped, highly fused mitochondrial network with abnormal cristae. Mitochondrial size was larger in Sigmar1-/- hearts, resulting in decreased numbers of mitochondria per microscopic field. In addition, Sigmar1-/- hearts showed altered expression of mitochondrial dynamics regulatory proteins. Real-time oxygen consumption rates in isolated mitochondria showed reduced respiratory function in Sigmar1-/- hearts compared with wild-type hearts. Conclusions We demonstrate a potential function of Sigmar1 in regulating normal mitochondrial organization and size in the heart. Sigmar1 loss of function led to mitochondrial dysfunction, abnormal mitochondrial architecture, and adverse cardiac remodeling, culminating in cardiac contractile dysfunction.

A Literature Review of the Pharmacokinetics and Pharmacodynamics of Dobutamine in Neonates.

Since its discovery in 1975 dobutamine has been used off-label for treating hemodynamic insufficiency in newborns and children. We present a structured literature review of pharmacokinetic and pharmacodynamic data for dobutamine in the pediatric population. Structured searches were conducted to identify relevant articles according to pre-defined inclusion criteria. Where possible, results for the pharmacodynamic and pharmacokinetic effect of dobutamine were reported as pooled data. Forty-six papers met the inclusion criteria. With regard to pharmacodynamic data a number of studies reported significant increases in a number of clinical parameters such as heart rate, blood pressure, cardiac output across a wide range of pediatric populations. With regard to pharmacokinetic data studies reported that the infusion rate was positively correlated to plasma dobutamine concentration. There was great variability with regard to dobutamine clearance between individuals and as to whether it followed first- or zero-order elimination kinetics. While the pharmacodynamic effects of dobutamine appear to reflect the pharmacological profile of the drug, the pharmacokinetic data are difficult to interpret due to inhomogeneity between study populations ages, comorbidities, dobutamine dosages and methodologies. High-quality prospective pharmacokinetic and pharmacodynamic data especially in newborns are urgently required prior to a large randomized study.

Actualización en el manejo de fármacos vasoactivos en insuficiencia cardiaca aguda y shock cardiogénico y mixto / Update on the use of vasoactive drugs for acute heart failure and cardiogenic and undifferentiated shock

Los fármacos vasoactivos poseen propiedades inotrópicas y vasomotoras. La variabilidad de su respuesta se explica por múltiples factores relacionados con la dosis empleada, la densidad, la afinidad y la selectividad de sus receptores, así como por las complejas vías de señalización. Su indicación no solo debería recaer en un umbral de presión arterial recomendado, sino también en parámetros objetivos de microcirculación. Hasta el momento no se ha demostrado que ningún fármaco vasoactivo aumente la supervivencia, y la crítica más importante es por los graves efectos adversos. Las líneas de investigación se han centrado en la búsqueda de fármacos más selectivos intentando evitar estos efectos adversos y no solo buscando la mejoría sintomática y hemodinámica a corto plazo (AU)

Vasoactive drugs can have inotropic or vasomotor properties or both. Variability in responses to these drugs can be explained by factors related to the dose used, the drugs’ affinity for specific receptors, the density and selectivity of these receptors, and the operation of complex signaling pathways. Indications for their use should not be based solely on recommended blood pressure thresholds but should also take into account objective microcirculatory parameters. To date, no vasoactive drug has been shown to increase survival, and the main criticism of their use is that they produce serious adverse effects. Research has focused on finding more selective compounds that will avoid these adverse effects and has not only sought to achieve short-term improvements in symptoms and hemodynamics (AU)

Local epicardial inotropic drug delivery allows targeted pharmacologic intervention with preservation of myocardial loading conditions.

Local myocardial application of inotropes may allow the study of pharmacologically augmented central myocardial contraction in the absence of confounding peripheral vasodilating effects and alterations in heart loading conditions. Novel alginate epicardial (EC) drug releasing platforms were used to deliver dobutamine to the left ventricle of rats. Pressure-volume analyses indicated that although both local and systemic intravenous (i.v.) use of inotropic drugs increase stroke volume and contractility, systemic infusion does so through heart unloading. Conversely, EC application preserves heart load and systemic blood pressure. EC dobutamine increased indices of contractility with minimal rise in heart rate and lower reduction in systemic vascular resistance than i.v. infusion. Drug sampling showed that dobutamine concentration was 650-fold higher in the anterior wall than in the inferior wall. The plasma dobutamine concentration with local delivery was about half as much as with systemic infusion. These data suggest that inotropic EC delivery has a localized effect and augments myocardial contraction by different mechanisms than systemic infusion, with far fewer side effects. These studies demonstrate a pharmacologic paradigm that may improve heart function without interference from effects on the vasculature, alterations in heart loading, and may ultimately improve the health of heart failure patients.

Vascular and extravascular volume expansion of dobutamine and norepinephrine in normovolemic sheep.

In low-flow states, such as circulatory shock, both fluids and catecholamines are often coadministered. We have previously found that adrenergic agents alter volume expansion after a fluid bolus. The present study tested the volume expansion properties of dobutamine and norepinephrine in sheep treated with (series 1) and without (series 2) a fluid bolus. Series 1 (n = 6 per group): no drug (control), dobutamine (10 µg x kg(-1) x min), or norepinephrine (1.0 µg x kg(-1) x min(-1)) was begun 30 min before a 24-mL x kg(-1), 20-min, 0.9% NaCl bolus. The effect of drug and fluid on plasma volume (ΔPV), urinary output (UOP), and extravascular volume (ΔEVV) was determined. Series 2: Identical protocol but no fluid bolus. Series 1: the fluid bolus resulted in a peak and sustained ΔPV expansion. Norepinephrine (7.5 ± 0.9 mL x kg(-1)) and dobutamine (9.5 ± 1.1 mL x kg(-1)) significantly increased ΔPV compared with control (3.8 ± 1.1 mL x kg(-1)). Cumulative UOP was reduced by dobutamine (3.8 ± 1.4 mL x kg) compared with norepinephrine (25.1 ± 3.9 mL x kg(-1)) and control (16.9 ± 4.0 mL x kg(-1)). Norepinephrine increased ΔPV, while reducing ΔEVV after bolus. Series 2: ΔPV was unchanged in the control group. Dobutamine and norepinephrine increased ΔPV over time, 5.1 ± 0.5 and 4.0 ± 0.5 mL x kg(-1), respectively. At study end, UOP was lowest in dobutamine. Norepinephrine resulted in loss of ΔEVV fluid. data suggest a novel role for adrenergic receptors in regulating vascular and EVV expansion. ß-Adrenergic agonists enhance vascular volume expansion, whereas α-adrenergic agonists eliminate extravascular fluid.

Decreased [99mTc]Sestamibi uptake with dobutamine versus dipyridamole stress.

AIM: Animal studies suggest an interference of dobutamine on [99mTc]sestamibi uptake. In this study dobutamine was compared to dipyridamole rest-stress [99mTc]sestamibi uptake ratio (UR). METHODS: Twenty-five patients with suspect coronary artery disease (CAD) underwent rest, dobutamine, and dipyridamole [99mTc]sestamibi SPECT at 24-h intervals and coronary angiography. UR was calculated separately for each coronary territory considering injected dose and acquisition delay. RESULTS: There were 38 CAD territories in 20 patients. On a patient basis, dipyridamole SPECT sensitivity was 85%, versus 70% for dobutamine. On a territory basis, sensitivity was 66% versus 42% (P<0.05), and specificity 92% versus 86%, respectively for dipyridamole versus dobutamine. In the 38 CAD territories, dipyridamole UR was -4.1+/-29.4%, and dobutamine UR was -13.1+/-19.9% (P<0.05). In the 37 no-CAD territories, UR was 34+/-23.6% for dipyridamole and -0.4+/-17.8% for dobutamine (P<0.0001). UR difference between CAD versus no-CAD territories was larger using dipyridamole (P<0.0001) than dobutamine (P<0.005). CONCLUSIONS: The UR comparison confirms that [99mTc]sestamibi uptake underestimates the blood flow heterogeneity induced by dobutamine more than that produced by dipyridamole.

Comparison of the prognostic value of dipyridamole and dobutamine myocardial perfusion scintigraphy in hemodialysis patients.

Screening for coronary artery disease (CAD) in hemodialysis patients is hampered by contraindications and/or limitations of the available techniques in this population. Myocardial perfusion scintigraphy (MPS) using dipyridamole has been considered inaccurate due to abnormally high basal levels of adenosine in uremia that could blunt the vasodilatory response. Since dobutamine may be more reliable, we directly compared the two in patients on hemodialysis. We performed MPS at rest and after separate dipyridamole or dobutamine stress in 121 chronic hemodialysis patients. More numerous, larger, and more intense reversible lesions were induced with dobutamine than with dipyridamole, mainly in the anteroseptal segments. Reversibility with dipyridamole but not dobutamine MPS was independently and strongly related with mortality associated with CAD and with fatal and non-fatal CAD. We hypothesize that the chronotropic action of dobutamine induced alterations of wall motion, leading to spurious perfusion defects, not unlike artifacts seen with left bundle branch block. Our study shows that even though dobutamine induced more pronounced myocardial ischemia than dipyridamole in chronic hemodialysis patients, dipyridamole MPS more accurately identifies patients at high risk for subsequent cardiac death or non-fatal CAD than dobutamine.

Pharmacokinetic-pharmacodynamic relationship of dobutamine and heart rate, stroke volume and cardiac output in healthy volunteers.

BACKGROUND AND OBJECTIVE: Dobutamine causes an increase in cardiac output (CO) by augmenting stroke volume (SV) through enhanced left ventricular contractility and by decreasing systemic vascular resistance. However, in some patients, the dominant mechanism by which dobutamine improves left ventricular performance is an increase in the subject's heart rate (HR). We therefore decided to evaluate the pharmacokinetic-pharmacodynamic relationship of dobutamine plasma concentrations and heart rate, SV and CO in healthy volunteers. METHODS: We enrolled 23 subjects who received dobutamine at a dose of 2.5, 5 and 10 microg/kg/min for three consecutive periods of 60 minutes each. Dobutamine plasma concentrations were determined from 22 blood samples drawn during each study session. Echocardiography was used to measure CO before administration of dobutamine and once during each infusion period. RESULTS: There was a clear linear relationship between dobutamine plasma concentrations and CO (r(2) = 0.628; p < 0.001). In most subjects, HR remained stable at dobutamine plasma concentrations produced by the lowest infusion rate but increased markedly thereafter so that overall there was a linear relationship between dobutamine plasma concentrations and HR (r(2) = 0.540; p < 0.001). However, SV increased significantly at the dobutamine plasma concentrations produced by the lowest infusion rate but remained mostly stable or even decreased thereafter. Although clinically slight, the overall increase in SV was statistically significant (r(2) = 0.062; p < 0.05). CONCLUSION: Low plasma concentrations of dobutamine resulted in an increase in CO almost solely due to improved left ventricular contractility. However, at higher plasma concentrations of dobutamine, SV remained stable or even decreased, and the linear increase in CO was entirely based on increased HR.

Modeling sequence-sequence interactions for drug response.

MOTIVATION: Genetic interactions or epistasis may play an important role in the genetic etiology of drug response. With the availability of large-scale, high-density single nucleotide polymorphism markers, a great challenge is how to associate haplotype structures and complex drug response through its underlying pharmacodynamic mechanisms. RESULTS: We have derived a general statistical model for detecting an interactive network of DNA sequence variants that encode pharmacodynamic processes based on the haplotype map constructed by single nucleotide polymorphisms. The model was validated by a pharmacogenetic study for two predominant beta-adrenergic receptor (betaAR) subtypes expressed in the heart, beta1AR and beta2AR. Haplotypes from these two receptors trigger significant interaction effects on the response of heart rate to different dose levels of dobutamine. This model will have implications for pharmacogenetic and pharmacogenomic research and drug discovery. AVAILABILITY: A computer program written in Matlab can be downloaded from the webpage of statistical genetics group at the University of Florida. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Heterogeneity and prediction of hemodynamic responses to dobutamine in patients with septic shock.

OBJECTIVE: To establish the heterogeneity of hemodynamic responses to dobutamine in patients with septic shock and to identify the predictive factors of these hemodynamic responses. DESIGN: Prospective study. SETTING AND PATIENTS: A total of 12 patients with septic shock in a tertiary medical intensive care unit. INTERVENTIONS: A 20-min dobutamine infusion at 5 microg.kg(-1).min(-1) with subsequent increments to 8, 12.6, and 20 microg.kg(-1).min(-1), on two consecutive days. Responses were dichotomized into changes in heart rate (HR) or stroke volume index (SVI) of >10% and < or =10% at the maximal dobutamine infusion. MEASUREMENTS AND MAIN RESULTS: No differences were found in survival, Acute Physiology and Chronic Health Evaluation II score, maximal dobutamine doses, or pharmacokinetics of dobutamine between HR and SVI groups. In DeltaHR > 10% vs. DeltaHR < or = 10%, baseline HR was lower, and baseline mixed venous oxygen tension and saturation were higher. During dobutamine infusion, mean arterial pressure decreased in DeltaHR > 10%. Cardiac index and the systemic oxygen delivery index increased and the systemic vascular resistance index decreased at unchanged SVI. Pressure work index increased and the ratio of the diastolic to systolic aortic pressure time indices decreased but not to <0.6. In DeltaHR < or = 10%, systemic vascular resistance index and the ratio of the diastolic to systolic aortic pressure time indices decreased (but remained >0.6) without changes in SVI or cardiac index. Baseline hemodynamic and metabolic variables did not differ between SVI groups. In DeltaSVI > 10%, cardiac index increased with dobutamine, but Pao2 and the systemic oxygen delivery index decreased. In DeltaSVI < or = 10%, HR and the systemic oxygen delivery index increased; mean arterial pressure, left ventricular stroke work index, systemic vascular resistance index, and the ratio of the diastolic to systolic aortic pressure time indices decreased. CONCLUSIONS: Patients with a positive chronotropic response to dobutamine had lower baseline HR values, and a chronotropic rather than inotropic response predicted an increase in cardiac index and systemic oxygen delivery index. Incremental dosages of dobutamine did not compromise indirectly measured myocardial oxygen balance.

Comparación de los efectos hemodinámicos del levosimendán con la dobutamina en pacientes con bajo gasto después de cirugía cardiaca / Hemodynamic effects of levosimendan compared with dobutamine in patients with low cardiac output after cardiac surgery

Introducción y objetivos. El levosimendán es un fármaco inotrópico positivo eficaz en la insuficiencia cardiaca. Sin embargo, la experiencia con levosimendán en pacientes con bajo gasto después de una cirugía cardiaca es reducida. El propósito de este estudio es comparar a corto plazo los efectos hemodinámicos del levosimendán frente a la dobutamina después de la cirugía cardiaca. Métodos. Se estudió a 41 pacientes con bajo gasto después de una cirugía cardiaca bajo circulación extracorpórea divididos en 2 grupos. Un grupo (n = 20) recibió una infusión continua de 7,5 μg/kg/min de dobutamina durante 24 h. Otro grupo (n = 21) recibió una dosis de carga de levosimendán de 12 μg/kg seguida de una infusión de 0,2 μg/kg/min durante 24 h. Se determinaron el gasto cardiaco, la frecuencia cardiaca, la presión arterial, la presión venosa central, la presión arterial pulmonar, la presión capilar, la resistencia vascular pulmonar y sistémica, y el volumen sistólico. Resultados. Ambos fármacos aumentaron significativamente el índice cardiaco aunque fue más marcado con el levosimendán (a las 24 h, 2,4 ± 0,2 frente a 2,9 ± 0,3 l/min/m²; p < 0,05). El levosimendán redujo significativamente la resistencia vascular sistémica y pulmonar y ocasionó un descenso significativo de la presión arterial sistémica, pulmonar, venosa central y capilar pulmonar. Conclusiones. El levosimendán y la dobutamina son eficaces en el tratamiento del bajo gasto después de la cirugía cardiaca. Sin embargo, el levosimendán ejerce un efecto vasodilatador inespecífico capaz de provocar hipotensión arterial. En estos pacientes es recomendable reducir o suprimir la dosis de carga

Introduction and objectives. Levosimendan is an inotropic agent that is effective in the treatment of heart failure. However, experience with levosimendan in patients with reduced cardiac output following cardiopulmonary bypass is limited. The objective of this study was to compare the short-term hemodynamic effects of levosimendan with those of dobutamine in managing low cardiac output after cardiac surgery. Methods. Forty-one patients who had low cardiac output after cardiopulmonary bypass were randomly assigned to dobutamine (n=20), 24-hour infusion of 7.5 μg/kg per min, or levosimendan (n=21), at a loading dose of 12 μg/kg followed by 24-hour infusion of 0.2 μg/kg per min. The following parameters were determined during a 48-hour observation period: arterial, central venous, pulmonary arterial and pulmonary capillary wedge pressure, cardiac index, heart rate, stroke volume, and systemic and pulmonary vascular resistance. Results. Although both dobutamine and levosimendan improved the cardiac index, the increase was significantly greater with levosimendan (2.4 [0.2] l/min per m² vs 2.9 [0.3] l/min per m2, respectively, at 24 h; P<.05). Moreover, levosimendan significantly reduced systemic and pulmonary vascular resistance, and significantly decreased systemic arterial, pulmonary arterial, pulmonary capillary wedge, and central venous pressure. Conclusions. Both dobutamine and levosimendan are effective in managing postoperative low cardiac output. However, levosimendan induces non-specific systemic, venous and pulmonary vasodilation which can result in hypotension as a adverse event. In these patients, it is advisable to omit or reduce the loading dose

Influence of exposure to electromagnetic field on the cardiovascular system.

1 We examined whether extremely low frequency electromagnetic fields (ELF-EMF) affect the basal level of cardiovascular parameters and influence of drugs acting on the sympathetic nervous system. 2 Male rats were exposed to sham control and EMF (60 Hz, 20 G) for 1 (MF-1) or 5 days (MF-5). We evaluated the alterations of blood pressure (BP), pulse pressure (PP), heart rate (HR), and the PR interval, QRS interval and QT interval on the electrocardiogram and dysrhythmic ratio in basal level and dysrhythmia induced by beta-adrenoceptor agonists. 3 In terms of the basal levels, there were no statistically significant differences among control, MF-1 and MF-5 in PR interval, QRS interval, mean BP, HR and PP. However, the QT interval, representing ventricular repolarization, was significantly reduced by MF-1 (P < 0.05). 4 (-)-Dobutamine (beta1-adrenoceptor-selective agonist)-induced tachycardia was significantly suppressed by ELF-EMF exposure in MF-1 for the increase in HR (DeltaHR), the decrease in QRS interval (DeltaQRS) and the decrease in QT (DeltaQT) interval. Adrenaline (nonselective beta-receptor agonist)-induced dysrhythmia was also significantly suppressed by ELF-EMF in MF-1 for the number of missing beats, the dysrhythmic ratio, and the increase in BP and PP. 5 These results indicated that 1-day exposure to ELF-EMF (60 Hz, 20 G) could suppress the increase in HR by affecting ventricular repolarization and may have a down-regulatory effect on responses of the cardiovascular system induced by sympathetic agonists.

Myocardial metabolism of 123I-BMIPP under low-dose dobutamine infusion: implications for clinical SPECT imaging of ischemic heart disease.

PURPOSE: 123I-(p-iodophenyl)-3-(R,S)-methylpentadecanoic acid (123I-BMIPP) is a fatty acid analog for single-photon emission computed tomography (SPECT) imaging that is mainly stored in the triglyceride pool. Low-dose dobutamine infusion has been reported to improve BMIPP uptake in the stunned myocardium, but the mechanism underlying this effect remains unclear. The purpose of this study was therefore to investigate the myocardial metabolism of 123I-BMIPP in the stunned myocardium under low-dose dobutamine infusion, and to elucidate the mechanism by which dobutamine improves BMIPP uptake. METHODS: Using open-chest dogs, stunned myocardium was induced by occlusion of the left anterior descending artery (LAD) for 30 min, with subsequent reperfusion (ischemia group, n=6). After direct injection of BMIPP into the LAD, myocardial extraction and retention were examined and metabolites evaluated (using high-performance liquid chromatography) during dobutamine infusion. The results in the ischemia group were compared with findings obtained in a control group under dobutamine infusion (n=6). RESULTS: Dobutamine infusion significantly increased both the rapid extraction (within 30 s) of BMIPP into the myocardium (control vs ischemia group: 48+/-19% vs 66+/-14%, p<0.05) and its subsequent retention (73+/-13% vs 85+/-8%, p<0.05). The metabolites from the myocardium consisted of back diffusion of nonmetabolized BMIPP, the alpha-oxidation metabolite, intermediate metabolites, and the full-oxidation metabolite. Among these metabolites, the full-oxidation metabolite decreased significantly (from 34.0+/-20.0% to 15.8+/-9.3%, p<0.05) in the stunned regions, though back diffusion of nonmetabolized BMIPP increased (from 51.3+/-21.9% to 71.3+/-10.1%, p<0.05). CONCLUSION: These results indicate that increased uptake of BMIPP in stunned myocardium is mainly due to decreased beta-oxidation in tissue and increased shunt retention of BMIPP in the triglyceride pool, and thereby provide further insight into the pathophysiology of stunned myocardium.

Chronic beta-adrenoreceptor stimulation in vivo decreased Bcl-2 and increased Bax expression but did not activate apoptotic pathways in mouse heart.

Prolonged activation of the sympathetic nervous system is deleterious to heart function. In vitro beta1-adrenergic activation promotes apoptosis, whereas beta2-adrenergic activation reduces apoptosis in cultured adult cardiomyocytes. To determine the effect of chronic catecholamine infusion in vivo, we measured apoptosis marker expression in C57Bl/6 and catecholamine-sensitive Egr-1 deficient mice after treatment with the nonspecific beta-adrenergic agonist, isoproterenol, the beta1-specific agonist, dobutamine, or the beta2-specific agonist, metaproterenol. Antiapoptotic and proapoptotic protein expression, cytochrome c release and caspases 3, 9, and 12 activation products were measured on immunoblots. Catecholamine-treated mice had decreased Bcl-2 and increased Bax and BNIP1 expression, suggesting mitochondria-dependent apoptosis pathway activation. However, cytosolic cytochrome c or caspase 3 or 9 activation products were not detected. In mice, increased molecular chaperone expression and caspase 12 activation characterize endoplasmic-reticulum-driven apoptosis. Clusterin expression was increased in catecholamine-treated mice, but GRP78 expression was not increased, and caspase 12 activation products were not detected. Thus, neither the mitochondrial nor the endoplasmic apoptotic pathway was fully activated. Further, Egr-1 deficiency did not increase cardiac apoptosis. We conclude that although chronic in vivo infusion of beta1- or beta2-adrenergic receptor agonists partially activates the apoptosis program, full activation of the caspase cascade requires more, or other, cardiac insults.

Negative chronotropic effects of fentanyl attenuate beneficial effects of dobutamine on oxygen metabolism: hemodynamic and pharmacokinetic interactions.

Opioids are well known to cause cardiovascular depression. The aim of the present investigation was to determine whether an interaction of opioid derivatives with catecholamines might be involved in these hemodynamic alterations. Six comatose patients were enrolled into a prospective, nonrandomized pilot trial. All patients first received a continuous i.v. infusion of dobutamine (10 microgram. kg-1. min-1) paralleled by continuous administration of midazolam (0.4 mg. kg-1. h-1); thereafter, fentanyl was added i.v. (4 microgram. kg-1. h-1). Hemodynamic parameters as well as dobutamine and endogenous catecholamines plasma levels were determined. The mean arterial blood pressure did not change significantly during the whole study period. The continuous administration of dobutamine (steady-state plasma concentrations: 217 +/- 118 ng. ml-1) increased the beta1-adrenergic receptor-mediated hemodynamic parameters such as heart rate, stroke volume index, cardiac index, and oxygen delivery index (p <.05). The concomitant administration of fentanyl decreased the heart rate-dependent hemodynamic parameters (p <.05), suggesting that fentanyl antagonizes the chronotropic effects of dobutamine. In parallel, dobutamine plasma levels increased significantly (275 +/- 165 ng. ml-1; p <.05). Noteworthy, after administration of fentanyl, oxygen delivery and consumption index returned to baseline values. Radioligand binding experiments on rat cardiac ventricular microsomes ruled out a direct interaction of fentanyl with beta-adrenergic receptors and, more importantly, a fentanyl-induced inhibition of beta-adrenergic receptor G protein coupling. Our observations suggest that fentanyl inhibits the frequency-related hemodynamic changes induced by dobutamine. The underlying mechanism is independent of beta-adrenergic receptors, but is powerful enough to abolish the salutary effect of dobutamine on oxygen delivery and consumption.

A model for the design and evaluation of algorithms for closed-loop cardiovascular therapy.

Developing a clinically useful closed-loop drug delivery system can be extremely time consuming and costly. One approach to reducing the time and cost associated with developing closed-loop systems is to reduce the number of animal experiments and perform an extensive set of simulation studies. Through simulations, a closed-loop controller's performance can be evaluated over a complete spectrum of the patient population, including boundary conditions. Simulation studies are repeatable, offering significant advantages in comparing modifications in control algorithms. Finally, simulation studies can be performed in a fraction of the time required for animal studies, at a fraction of the cost. We have developed a simulator, that included a nonlinear pulsatile-flow cardiovascular model, a physiological regulatory mechanism, and the pharmacology of four frequently titrated cardiovascular drugs. This simulator has already been used in the design and evaluation of two closed-loop algorithms-a self-tuning regulator (STR) and a multiple model adaptive controller (MMAC)-for blood pressure control during and after cardiac surgery.

Sulfoconjugation and renal excretion contribute to the interpatient variation of exogenous catecholamine clearance in critically ill children.

OBJECTIVE: To delineate the contributions of sulfoconjugation, renal excretion, and patient age to the wide interpatient variability in exogenous dobutamine and dopamine plasma clearance. DESIGN: Simultaneous plasma free and sulfoconjugated dobutamine and/or dopamine, respective urine free catecholamine, and serum creatinine were determined on stable critically ill children receiving unchanged continuous infusions of dobutamine and/or dopamine for at least 1 hr. Free dobutamine and dopamine clearance rates were calculated. SETTING: Pediatric and neonatal intensive care units in university settings. PATIENTS: Forty-seven stable critically ill neonates and children. INTERVENTIONS: Continuous infusions of dobutamine and/or dopamine: nine patients received dopamine only, 27 patients received dobutamine only, and 11 patients received both simultaneously. MEASUREMENTS AND MAIN RESULTS: Fractions of plasma dobutamine and dopamine sulfoconjugated were 0.73 +/- 0.05 and 0.76 +/- 0.05, respectively. Free plasma dobutamine and dopamine clearances were 102 +/- 15 mL/kg/min and 250 +/- 38 mL/kg/min, respectively. Linear regression analyses demonstrated relationships of the fraction of plasma dobutamine and dopamine sulfoconjugated to the respective free plasma clearances (r2 = .30, p < .01, and r2 = 0.29, p < .01, respectively), and, more impressively, to the natural logarithm of the respective free plasma clearances (r2 = 0.58, p < .001, and r2 = 0.39, p < .01). Patients with serum creatinine concentrations >2 mg/dL had lower free plasma dobutamine and dopamine clearance rates than those patients with serum creatinine of <2 mg/dL (6 +/- 1 vs. 107 +/- 15 mL/kg/min for dobutamine and 40 +/- 38 vs. 270 +/- 39 mL/kg/min for dopamine, respectively, p < .05 for both by Mann-Whitney U test). No relationship was noted between free catecholamine clearance and age. CONCLUSION: Sulfoconjugation and renal excretion are important determinants of the wide interpatient variability in plasma free dobutamine and dopamine clearance rates.