The cardiopulmonary effects of dobutamine and norepinephrine in isoflurane-anesthetized foals

ArticleinVeterinary Anaesthesia and Analgesia 34(6):377-87 · December 2007with 13 Reads
Abstract
To evaluate the cardiovascular effects of norepinephrine (NE) and dobutamine (DB) in isoflurane-anesthetized foals. Prospective laboratory study. Norepinephrine (0.05, 0.10, 0.20, and 0.40 microg kg(-1) minute(-1)) and dobutamine (2.5, 5.0, and 10 microg kg(-1) minute(-1)) were alternately administered to seven healthy, 1- to 2-week-old isoflurane-anesthetized foals. Arterial and pulmonary arterial blood pressure, right atrial pressure, pulmonary artery occlusion pressure, heart rate, body temperature, cardiac output, arterial and mixed venous blood pH, partial pressure of carbon dioxide, partial pressure of oxygen [arterial partial pressure of oxygen (PaO(2)) and mixed venous partial pressure of oxygen (PvO(2))], and packed cell volume were measured. Standard base excess, bicarbonate concentration, systemic and pulmonary vascular resistance, cardiac index (CI), stroke volume, left and right stroke work indices, oxygen delivery (DO(2)), consumption, and extraction were calculated. Results Norepinephrine infusion resulted in significant increases in arterial and pulmonary arterial pressure, systemic and pulmonary vascular resistance indices, and PaO(2); heart rate was decreased. Dobutamine infusion resulted in significant increases in heart rate, stroke volume index, CI, and arterial and pulmonary arterial blood pressure. Systemic and pulmonary vascular resistance indices were decreased while the ventricular stroke work indices increased. The PaO(2) decreased while DO(2) and oxygen consumption increased. Oxygen extraction decreased and PvO(2) increased. Norepinephrine primarily augments arterial blood pressure while decreasing CI. Dobutamine primarily augments CI with only modest increases in arterial blood pressure. Both NE and DB could be useful in the hemodynamic management of anesthetized foals.
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    The effects of vasoconstrictors and vasodilators were compared in conscious, newborn lambs and adult sheep instrumented with electromagnetic flow probes on the ascending aorta and catheters in the thoracic aorta. Methoxamine, angiotensin II, norepinephrine, nitroglycerin and isoproterenol were administered intravenously to evaluate their effects on arterial pressure, cardiac output and systemic vascular resistance (SVR). The difference in response between adults and newborns was most apparent with methoxamine. Methoxamine, 400 micrograms/kg, i.v., which increased mean arterial pressure by 57 +/- 6% and SVR by 278 +/- 27% in newborn lambs, caused greater increases (p less than 0.01) of 81 +/- 8% and 1418 +/- 141%, respectively, in the adults. Responses also differed significantly between newborn and adult animals to norepinephrine, angiotensin II, nitroglycerin and isoproterenol. In a second group of animals in which smaller amounts of methoxamine and isoproterenol were injected directly into the terminal aorta, changes in terminal aortic flow and resistance were examined. Again, both vasoconstrictor and vasodilator responses were more marked in adults than in newborns. Finally, the sensitivity of the arterial baroreceptor reflex was evaluated by comparing the regression of pulse interval (PI) on systolic arterial pressure (SAP) after an intravenous dose of methoxamine in conscious, adult and newborn animals. The PI/SAP slopes in adult sheep, 45.4 +/- 3.5 msec/mm Hg, were significantly greater (p less than 0.01) than in newborn lambs, 11.7 +/- 2.2 msec/mm Hg.
  • Article
    To compare the hemodynamic effects of isoproterenol, dopamine, and dobutamine in the immature animal, each drug was infused into anesthetized open chest puppies and cardiac output was measured, as were systemic arterial blood pressure, heart rate, and renal artery blood flow. Cardiac output was increased by dopamine and dobutamine. Isoproterenol caused a significantly greater increment of heart rate than either of the other agents to achieve a similar change of cardiac output. Systemic arterial mean blood pressure was increased by dopamine and dobutamine, but decreased by isoproterenol. Dopamine produced a significant increase of renal artery blood flow while renal artery blood flow was unchanged by dobutamine and decreased by isoproterenol.
  • Article
    Changes in resting cardiac output (CO), stroke volume (SV), and systemic vascular resistance (SVR) during neonatal growth were studied in chronically instrumented lambs from the 1st to 5th wk of age; adult nonpregnant sheep values measured simultaneously were used as standard reference. Neonatal responses to autonomic agonists and antagonists were also investigated. Total CO increased linearly with neonatal growth, but decreased strikingly when expressed per weight unit; at 5 wk of age, CO/kg was still significantly higher than the adult value. SV also increased with neonatal growth but did not change when related to body weight; at 5 wk of age, SV/kg values were still higher than those of adult sheep. SVR changed reciprocally to CO. The decrease in CO/kg during neonatal growth paralleled the progressive decline in heart rate (HR). Beta receptor stimulation increased neonatal CO markedly and the increment was the same from the first through the fifth neonatal week. Beta blockade had insignificant effects, but cholinergic blockade produced moderate CO increases.
  • Article
    The minimal alveolar concentration of anesthetic required to prevent gross purposeful movement in response to electrical stimulation of oral mucous membranes was determined in horses for 3 agents. Equipotent concentrations of enflurane were 2.12 volumes %; of halothane, 0.88 volumes %; and of isoflurane, 1.31 volumes +. The alveolar concentration required to produce at least 60 seconds of apnea was also determined for these agents. From these data and the minimal alveolar concentration information, anesthetic indices were determined for each agent. The indices for enflurane, halothane, and isoflurane were 2.26, 2.60, and 2.33, respectively.
  • Article
    We have measured the changes in Vo2 and the Vo2; Do2 relationship duringinfusion of dobutamine in healthy volunteers. Nine healthy, adult, non-obese, male physicians were infused with an incremental infusion of dobutamine starting at 2.5 μg kg−1 min−1 increasing to 5.0 and then 7.5 y.g kg−1 min−1 for 15 min each. Vo 2 and cardiac index were measured every five minutes. Vo2/(VO2 m−2) increased from a baseline of 128 (SEM 6.1) ml min−1 m−2 to 159 (8.0)ml min1 m−2(P < 0.05) at 7.5 fig kg−1 min−1. The corresponding changes for Do2l (Do2m−2) were from 643 (35) ml min−1 m−2 to 1240 (142) ml min−1 m−2 (P<0.05). The coefficient of correlation for pairs of Vo2 and DO2 values, at baseline and each dobutamine infusion in individual subjects, range from 0.89 to 0.99 (mean 0.95, SD 0.03). Dobutamine has potent calorigenic effects; demonstration of a positive correlation between Vo2 and Do2 after infusion of dobutamine does not necessarily imply an underlying tissue oxygen debt.
  • Article
    The purpose of this study was to measure and compare the relationship of cardiovascular depression and dose during equal potent levels of halothane and isoflurane anesthesia in neonates (n = 19) (16.7 +/- 6.9 days) and infants (n = 54) (6.1 +/- 3.1 mo). Seventy-three children had heart rate, arterial blood pressure, and pulsed Doppler pulmonary blood flow velocity as well as two-dimensional echocardiographic assessments of left ventricular area and length recorded just before anesthesia induction. Anesthesia was induced by inhalation of increasing inspired concentrations of halothane or isoflurane in oxygen using a pediatric circle system and mask. During controlled ventilation, halothane and isoflurane concentrations were adjusted to maintain 1.0 MAC and then 1.5 MAC (corrected for age), and echocardiographic and hemodynamic measurements were repeated. A final cardiovascular measurement was recorded after intravenous administration of 0.02 mg/kg of atropine. All measurements were completed before tracheal intubation and the start of elective surgery. In neonates, 1.0 MAC concentrations of halothane and isoflurane decreased cardiac output (74% +/- 16%), stroke volume (75% +/- 15%), and ejection fraction (76% +/- 15%) similarly from awake levels. Decreases in cardiac output, stroke volume, and ejection fraction with halothane and isoflurane were significantly larger at 1.5 MAC (approximately 35% decreases from awake values) than at 1.0 MAC. Heart rate decreased significantly during 1.5 MAC halothane anesthesia (94% +/- 4%) but remained unchanged during isoflurane anesthesia. In infants, 1.0 MAC halothane and isoflurane decreased cardiac output (83% +/- 12%), stroke volume (78% +/- 12%), and ejection fraction (74% +/- 12%) when compared with awake measures.(ABSTRACT TRUNCATED AT 250 WORDS)
  • Article
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    The pharmacokinetics and pharmacodynamics of dobutamine were studied in 13 critically ill neonates requiring inotropic support. Dobutamine was administered as a constant infusion in increasing doses of 2.5, 5, and 7.5 micrograms/kg per minute. During dobutamine infusions, there were significant increases in cardiac output measurements above perinfusion values. There were no statistically significant changes in systolic or diastolic blood pressure or heart rate during the infusions. The mean calculated threshold value, or the minimum plasma concentration necessary for a change in cardiac output, was 39 +/- 8 ng/mL. The mean plasma clearance rate was 90 +/- 38 mL/min per kilogram and was most consistent with first-order kinetics over the range of dosages studied. Plasma catecholamine levels were unchanged during the dobutamine infusions. These data suggest that dobutamine is an effective but limited inotropic agent in the neonate. Dobutamine may be most beneficial when cardiogenic failure is presented.
  • Article
    The influence of different rates of dopamine and dobutamine on the cardiovascular depression during a standard halothane anesthesia was studied in dorsally recumbent ventilated ponies. Haemodynamic and respiratory responses were investigated by means of cardiac output (CO) determination (thermodilution technique), mean systemic (MAP) and pulmonary artery pressure (MPAP) (direct intravascular method) and arterial blood analysis (blood gases and packed cell volume). An important cardiopulmonary depression characterized by decreases (55% of the standing values) in CO, cardiac index (CI), MAP, MPAP and other cardiovascular related parameters occurred in the dorsally recumbent anaesthetized ponies after a stabilization period of 30 minutes. Dopamine at 2 different infusion rates (2.5 and 5.0 micrograms/kg/min) induced few changes of the cardiopulmonary parameters (non-significant increases in MAP, CI, left ventricular work [LVW], stroke volume [SV]; non-significant decrease in total peripheral resistance [TPR]). Several minor time related influences were also observed (increases in MPAP and total pulmonary resistance [TpR]). Arterial blood gases did not change during the different dopamine infusions. Low doses of dobutamine (1.25 micrograms/kg/min) were efficient to counteract the cardiovascular depression. Significant increases in CO, CI, MAP, MPAP and SV were observed. TPR and TpR tended to decrease but non-significantly. Heart rate and blood gases remained constant. The higher doses of dobutamine (2.5 and 5.0 micrograms/kg/min) accentuated these changes but a significant increase in heart rate with even periods of severe tachycardia and an increase of the packed cell volume were also observed. Apparently, low doses of dobutamine were indicated for the management of the cardiovascular depression during anaesthesia in the dorsally recumbent ventilated horse.
  • Article
    The effects of norepinephrine and dobutamine were compared during endotoxin shock in dogs anesthetized either with enflurane (E: 1.5%, N = 12) or with i.v. ketamine (K: 5 mg.kg-1 + 0.2 mg.kg-1.min-1, N = 12). An i.v. bolus of 1.5 mg.kg-1 E. coli endotoxin was followed by saline infusion to restore left-sided filling pressures at baseline. With E, heart rate, mean arterial pressure and stroke index decreased (P less than 0.01). The decrease in oxygen delivery (DO2) and in oxygen consumption (VO2) was associated with an increase in blood lactate. In contrast, K anesthesia was associated with remarkable hemodynamic stability. DO2 was well maintained, VO2 decreased (P less than 0.01) and blood lactate did not change. Under E anesthesia, mean arterial pressure increased more with norepinephrine and heart rate increased more with dobutamine. Under K anesthesia, cardiac index, stroke index and left ventricular stroke work index increased similarly with both agents. In both groups DO2 and VO2 increased markedly. The amount of fluid infused was higher with dobutamine than with norepinephrine. Thus, enflurane but not ketamine had depressant cardiovascular effects at the doses used in this model. With both anesthetics, norepinephrine and dobutamine could effectively improve cardiac function. Dobutamine could therefore represent a valuable alternative to norepinephrine for cardiovascular support during anesthesia in septic shock.
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  • Article
    Increased cardiac index, oxygen delivery (DO2), and oxygen consumption (VO2) patterns were shown to characterize the physiologic status of surviving high-risk surgical patients, and indicate increased metabolic needs; relatively normal DO2 and VO2 values were found to characterize the sequential pattern of nonsurvivors who developed an early oxygen debt followed by lethal organ failure. The cardiac index, DO2, and VO2 values empirically determined from survivors' patterns were shown to improve outcome in prospective randomized trials. The present study considers these criteria to evaluate the tissue perfusion status as well as the effects of therapy on tissue perfusion and oxygenation. To summarize new information on the temporal patterns of DO2, VO2, and oxygen debt on outcome and the effects of fluids and inotropes on these patterns in a wide range of clinical, temporal, and physiologic conditions. Descriptive analysis based on data gathered prospectively using a specified protocol. High-risk patients with accidental or elective surgical trauma, and patients with or without sepsis or septic shock and organ failure. University-run county hospital with a large trauma service. Fluids, dobutamine, and dopamine at various times and at various doses throughout critical illness of postoperative, posttraumatic, septic, and hypovolemic patients with and without lethal and nonlethal organ failure. The pattern of DO2 plotted against the corresponding VO2 values in 437 consecutive critically ill surgical patients showed a wide variability and poor correlation probably because complex clinical conditions may obscure the supply-dependent and supply-independent VO2 relationships observed in normal dogs bled or given bacterial infusions. However, the use of specific therapy by well-defined protocols was shown to provide objective evidence of efficacy. Significant increases in DO2 and VO2 were previously shown after whole blood, packed red cells, and colloid administration, but not after crystalloid administration. Dobutamine administration in 715 circumstances in postoperative, traumatic, septic patients and patients with adult respiratory distress syndrome, renal failure, and multiple organ failure significantly improved DO2 and VO2. Dopamine under comparable conditions produced less improvement in DO2 and VO2 than that of dobutamine; most of the VO2 changes were not significant. The monitored patterns of cardiac index, DO2, and VO2 may be used to evaluate the adequacy of tissue perfusion as well as the relative effectiveness of alternative therapies. Second, these physiologic criteria may be used to titrate therapy in order to achieve optimal outcome. Third, after colloids optimally expand the plasma volume, dobutamine may be used to enhance flow and the distribution of flow in order to improve tissue oxygenation. Vasodilators may be used when hypertensive episodes occur or there is an inadequate response to inotropic agents. Vasopressors are used as a last resort, usually in the terminal or preterminal state.
  • Article
    The authors investigated the cardiovascular effects of low doses of nitroprusside, dobutamine, and phenylephrine and a beta-adrenergic blocking dose of propranolol in conscious, healthy horses with and without prior atropine administration. A parasympathetic blocking dose of atropine produced significant increases in heart rate and arterial pressures, and decreased stroke volume, ejection fraction, pulse pressure, and right-ventricular end-diastolic pressure and volume. Cardiac output was not changed by atropine administration. Nitroprusside reduced arterial pressures to a greater extent in atropinized horses but increased heart rate in both atropinized and non-atropinized horses. Dobutamine increased mean arterial pressure in both non-atropinized and atropinized horses but increased heart rate, diastolic arterial pressure, and systemic vascular resistance only in atropinized horses. Propranolol did not affect any of the hemodynamic variables that were measured. Phenylephrine, in the presence of beta-adrenergic blockade, increased mean arterial pressure and reduced cardiac output. This study showed that low doses of nitroprusside, dobutamine, and phenylephrine produce significant hemodynamic effects in conscious, healthy horses and that these effects are modified by prevailing parasympathetic tone.
  • Article
    Twenty-four patients with septic shock (cardiac index [CI] greater than or equal to 4 L.min-1.m-2, systemic vascular resistance index [SVRI] less than or equal to 350 dyne.sec.cm-5.m-2, systolic BP less than or equal to 90 mm Hg, oliguria less than 30 ml/h) were treated with norepinephrine (NE) infused either alone or in combination with dopamine and/or dobutamine. In all patients, NE resulted in either an increase in BP, no change, or an increase in CI and restored SVRI to the normal range. In 20 patients, normalization of systemic hemodynamics was followed by re-establishment of urine flow, decrease in serum creatinine, and increase in creatinine clearance. None of these 20 patients received low dose dopamine or furosemide. Four patients remained oliguric. Two of these four patients died and two developed acute renal failure. These findings suggest that NE infusion does not worsen renal ischemia related to hemodynamic disturbances in septic shock patients, and may have beneficial effects on renal function.
  • Article
    Hemodynamic and oxygen transport effects of dopamine and dobutamine were studied in a series of 25 critically ill postoperative general surgical patients by a prospective, randomized crossover design after maximal response to fluids had been obtained. Dopamine increased MAP, HR, CI, PvO2, DO2, and Qsp while decreasing PaO2. Dobutamine increased HR, CI, SI, stroke work, DO2, VO2, and Qsp while decreasing PAWP and SVRI and PVRI. In general, the effects of the two drugs were greater in patients in the first 72 hours after surgery. The effects of dobutamine on flow and oxygen transport were greater than those of dopamine, especially in the early postoperative period. The effects were smaller and not significant in patients more than three days after surgery, as well as in those with sepsis, respiratory failure, renal failure, age over 65 years, and hyperdynamic states, in part because of the small number of patients in each group. These data are consistent with the hypothesis that the beta 2-adrenergic action of dobutamine vasodilates the previously constricted peripheral circulation, enhances tissue perfusion by improving micro-circulatory flow distribution, and improves DO2 and VO2.
  • Article
    Vasodilators have demonstrated efficacy in neonates with depressed myocardial function. The magnitude of benefit depends on the preexisting hemodynamic state and concurrent treatment modalities. In patients with increased filling pressures, vasodilators increase cardiac output with negligible effect on MAP, with volume resuscitation to restore pretreatment filling pressures offering additional benefit. The rationale for use in neonatal respiratory disease remains less clear, with no vasoactive drug showing selective pulmonary vasodilatation. Benefit no doubt accrues from the improved coronary perfusion that occurs with reduction in filling pressures. In addition, reduced interventricular diastolic dependence and thereby improved ventricular compliance, as well as the afterload-reducing effect of decreased chamber size, may significantly reduce the effect of the lung disease on myocardial functioning.
  • Article
    We compared the effects of three different sympathetic-type agonist drugs upon cardiac output (pump function) and its determinants during hypoxemia, a condition of increased endogenous catecholamines. At 1-3 days after birth, 15 lambs were instrumented with catheters in the aorta, the left atrium, and a vein, and thermistors were placed in the abdominal aorta for cardiac output sampling. In eight animals, a pressure transducer was placed in the left ventricle. After a 2- to 3-day recovery, sequential measurements were made of blood gases, cardiac output, aortic and left atrial pressure and left ventricular maximal first derivative of pressure with respect to time (LV dP/dtmax) in room air and in hypoxemia (FiO2 = 0.08-0.10). Measurements were repeated during continued hypoxemia with increasing doses of isoproterenol (0.1, 0.4, 0.7, and 1.0 microgram/kg/min) and dopamine and dobutamine (10, 20, 40, and 80 micrograms/kg/min). Hypoxemia alone was associated with no significant change in cardiac output, but cardiac output rose significantly during continued hypoxemia with each drug (maximum increases-dobutamine 58%, isoproterenol 51%, dopamine 31% all p less than 0.05). Studies with continued hypoxemia alone showed no rise in cardiac output over time. Augmentation of contractility, demonstrated by a doubling of LV dP/dtmax by each of the drugs, contributed to the increases in cardiac output. Differences in cardiac output responses could not be explained by contractile effects of the drugs alone, since LV dP/dtmax increased in similar fashion for all three. The relatively limited cardiac output response and downward trend at the highest dosage of dopamine occurred with a reduction in heart rate and an increase in systemic vascular resistance.(ABSTRACT TRUNCATED AT 250 WORDS)
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  • Article
    Hemodynamic and respiratory effects of 5 h of unvarying 1.57%, end-tidal (1.2 MAC) isoflurane in O2 anesthesia were characterized in ten left laterally recumbent horses. Compared to base line values at 30 min of constant dose isoflurane, cardiac output, hematocrit, total plasma solids, PaCO2, and peak inspired gas flow progressively and significantly (P less than 0.05) increased over the course of study. Arterial blood pressure increased (P less than 0.05) during the first 2 h of constant dose of isoflurane then decreased and remained near base line values. Inspiratory time progressively decreased with time of anesthesia. All horses recovered from anesthesia uneventfully within 1 h of termination of isoflurane.
  • Article
    Cardiopulmonary function was studied in 10 full-term healthy foals from birth to 14 days of age. Systemic and pulmonary haemodynamics were recorded in lateral recumbency via indwelling aortic and pulmonary artery catheters. Mean body weight increased from 45.4 +/- 2.4 kg on Day 1 to 70.6 +/- 6.1 kg on Day 14. All foals had a continuous murmur of patent ductus arteriosus for 3-6 days. From Day 1 (12 h old) to Day 14, heart rate increased (89 +/- 4 to 95 +/- 5/min), mean aortic pressure increased (87.7 +/- 1.9 to 100.3 +/- 3.2 mmHg), mean pulmonary artery pressure decreased (38.6 +/- 4.6 to 27.4 +/- 3.0 mmHg), mean right atrial pressure was unchanged (4.5 +/- 0.5 to 4.6 +/- 0.9 mmHg), mean pulmonary artery wedge pressure was unchanged (7.6 +/- 0.9 mmHg to 8.1 +/- 0.7 mmHg), cardiac output increased (8.03 +/- 0.59 to 15.88 +/- 1.90 l/min), cardiac index increased (180.5 +/- 10.3 to 222.1 +/- 21.6 ml/kg/min), stroke volume increased (90.4 +/- 5.7 to 164.2 +/- 25.9 ml), stroke volume index was unchanged (2.04 +/- 0.10 to 2.30 +/- 0.35 ml/kg), pulmonary vascular resistance decreased (314 +/- 39 to 104 +/- 21 aru), systemic vascular resistance decreased (858 +/- 70 to 497 +/- 87 aru), and pulmonary/systemic resistance ratio decreased (38 +/- 6 to 21 +/- 5%). All changes were gradual, although pulmonary artery pressure and pulmonary vascular resistance decreased rapidly in the first 24 h. Catheters were well tolerated over several days, indicating their feasibility for studying cardiovascular function in full-term or premature equine neonates.
  • Article
    The effects of iv dobutamine and dopamine infusions were studied at six incremental doses (range 5 to 160 micrograms/kg.min) in two groups of five dogs. Dobutamine decreased the systemic vascular resistance (SVR), without significant changes in mean arterial pressure (MAP), or pulmonary vascular resistance (PVR). Dopamine increased MAP, SVR, and PVR, except for a decrease at 10 micrograms/kg.min. Both drugs produced dose-related increases in cardiac output and venous admixture; however, with dopamine the dose-response curve reached a plateau at doses greater than 40 micrograms/kg.min. While the oxygen consumption (VO2) increased progressively in both groups, the oxygen availability ratio (DO2/VO2) and arteriovenous oxygen content difference (CaO2 - CvO2) were maintained mainly by increased cardiac output in the dobutamine group and hemoglobin concentration in the dopamine group. Thirty minutes after termination of drug infusions, the DO2/VO2 dropped, and CaO2 - CvO2 increased significantly in both groups. These changes were mainly due to sustained high VO2; however, in the dopamine group, a larger imbalance resulted from further decreases in cardiac output to levels below the control value.
  • Article
    Circulatory and respiratory function was monitored in nonmedicated, spontaneously breathing horses (n = 7) immediately before, during, and 1 hour after 85 +/- 4.1 (X +/- SEM) minutes of constant 1.57% isoflurane in O2 anesthesia. Comparison of values during anesthesia with those obtained while horses were awake revealed a significant (P less than 0.05) decrease in arterial blood pressure that was related to a slight, but insignificant, decrease in cardiac output and peripheral vascular resistance. Although isoflurane anesthesia and recumbency resulted in a significant (P less than 0.05) decrease in stroke volume, cardiac output did not decrease significantly because heart rate tended to increase. Isoflurane and recumbency also significantly (P less than 0.05) increased PaCO2, peak expiratory gas flow, total expiratory time, and PCV and significantly decreased PaO2, minute expired ventilation, and the ratio of peak inspired to expired gas flow. Differences imposed by isoflurane anesthesia were reversed by 1.5 hour after anesthesia.
  • Article
    The hemodynamic changes induced by constant infusions of dopamine or dobutamine (each 3, 5, and 10 micrograms/kg/min) were observed in halothane-anesthetized horses. Left ventricular dp/dt and cardiac output were increased in horses given dobutamine at dosage of 3 micrograms/kg/min and in those given either of the drugs at dosages of 5 and 10 micrograms/kg/min. Concomitant increases in systemic arterial blood pressure occurred at lower infusion dosage rates of dobutamine than those of dopamine and were modulated by dosage-related changes in peripheral vascular resistance that were different between the 2 drugs. Total peripheral vascular resistance was unchanged by the 3 micrograms/kg/min dosage of dopamine, significantly (P less than 0.05) decreased at the 5 micrograms/kg/min dosage of dopamine, and returned to base line in horses when given the largest dosage. Dobutamine had no effect on total peripheral vascular resistance. Heart rate was significantly (P less than 0.05) decreased by the 2 smaller dosages of dobutamine, but returned to base line at the 10 micrograms/kg/min dosage. Heart rates did not change significantly in response to dopamine over the range of the dosages. Sinus tachycardia with atrioventricular conduction block was noted in some horses given either of the drugs. The results of the present study indicate that the hemodynamic responses in horses given dopamine or dobutamine infusions are similar to those in other species, and are the net result of the different adrenergic pharmacologic profiles of the 2 drugs combined with autonomic nervous system reflexes.
  • Article
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    The effects of dobutamine ([+/-]-4-[2-[[3-(p-hydroxyphenyl)-1-methyl propyl] amino] ethyl] pyrocatechol hydrochloride), a new synthetic cardioactive sympathomimetic amine, were examined on direct and continuous measurements of left ventricular (LV) diameter (D), pressures (P), velocity of shortening (V), dP/dt, dP/dt/P, arterial pressure, cardiac output, and regional blood flows in the left circumflex coronary, mesenteric, renal, and iliac beds in healthy, conscious dogs. At the highest dose of dobutamine examined, 40 mug/kg/min, the drug increased dP/dt/P from 65+/-3 to 128+/-4 s(-1) and isolength velocity from 72+/-4 to 120+/-7 mm/s without affecting LV end diastolic D significantly. Mean arterial P rose from 92+/-2 to 104+/-3 mm Hg and heart rate from 78+/-3 to 111+/-7 beats/min, while LV end systolic D fell from 24.1+/-1.4 to 19.9+/-1.8 mm, reflecting a rise in stroke volume from 30+/-4 to 42+/-3 ml. Cardiac output rose from 2.41+/-0.23 to 4.35+/-0.28 liter/min, while calculated total peripheral resistance declined from 0.042+/-0.005 to 0.028+/-0.003 mm Hg/ml/min. The greatest increases in flow and decreases in calculated resistance occurred in the iliac and coronary beds, and the least occurred in the renal bed. Propranolol blocked the inotropic and beta(2) dilator responses while vasoconstricting effects mediated by alpha adrenergic stimulation remained in each of the beds studied. When dobutamine was infused after a combination of practolol and phentolamine, dilatation occurred in each of the beds studied. These observations indicate that dobutamine is a potent positive inotropic agent with relatively slight effects on preload, afterload, or heart rate, and thus may be a potentially useful clinical agent. The one property of this drug which is not ideal is its tendency to cause a redistribution of cardiac output favoring the muscular beds at the expense of the kidney and visceral beds.
  • Article
    Studies were performed in anesthetized dogs to evaluate the cardiac and systemic effects of intravenously administered dobutamine and to determine its direct effects on the renal and femoral vascular beds. The results demonstrated that dobutamine possessed an inotropic efficacy similar to that of isoproterenol and norepinephrine; its chronotropic effect was similar to or greater than that of norepinephrine. In contrast to norepinephrine, dobutamine increased cardiac output and reduced total peripheral resistance with minimal effects on mean aortic pressure. Studies on the denervated hind limb demonstrated that dobutamine stimulated both alpha and beta receptors. The dose of dobutamine which produced a 50% increase in femoral blood flow was 180 times the required dose of isoproterenol and the dose which produced a 50% increase in contractile force was 43 times the required dose of isoproterenol. Studies on the renal vasculature demonstrated that dobutamine caused no dopamine-like renal vasodilator activity and only minor vasodilation mediated by beta receptors. We concluded that dobutamine is more cardioselective than is isoproterenol. The dobutamine-induced decrease in peripheral resistance observed in the whole dog was presumably due to increased myocardial contractility coupled with a greater net effect of beta-adrenergic vasodilation than alpha-adrenergic vasoconstriction. Studies with reserpine-treated dogs showed that all dobutamine-induced effects were due to a direct action on receptors.
  • Article
    The effects of norepinephrine (0.1 and 1.0 μg/kg, iv) on coronary blood flow and resistance, left ventricular pressure and diameter, dP/dt, (dP/dt)/P, and the velocity (V(iso)) of myocardial fiber shortening were studied in conscious dogs. When the heart rate was held constant, norepinephrine caused an initial reduction in coronary vascular resistance which was associated with increases in mean arterial blood pressure, systolic left ventricular pressure, end diastolic diameter, dP/dt, (dP/dt)/P, and V(iso). After this brief coronary vasodilator response, a sustained increase occurred in mean coronary vascular resistance (+0.55 ± 0.07 mm Hg/ml min-1), and increases persisted in mean arterial blood pressure (+67 ± 7 mm Hg), left ventricular systolic pressure (+74 ± 6 mm Hg), left ventricular end diastolic pressure (+4 ± 1 mm Hg), left ventricular internal diameter (+1.3 ± 0.3 mm), peak dP/dt (+1660 mm Hg/sec), (dP/dt)/P (+15 ± 2 sec-1), and V(iso) (+11 ± 2 mm/sec); coronary sinus Po2 decreased. Beta receptor blockade prevented the inotropic effects of norepinephrine, attenuated the early coronary vasodilator effects, and increased the late vasoconstrictor effects. Alpha receptor blockade abolished the late coronary vasoconstrictor effects of norepinephrine; only dilatation occurred. In contrast to the effects of norepinephrine in conscious dogs without autonomic blockade, norepinephrine (1.0 μg/kg, iv) failed to produce late coronary vasoconstriction in anesthetized, open chest dogs; only dilatation occurred. Thus, in the normal conscious dog, norepinephrine exerts an important coronary vasoconstrictor effect which is sufficiently intense to counteract completely the simultaneous tendency toward metabolic vasodilatation.
  • Article
    In rat anococcygeus muscle, dobutamine produced concentration-related submaximal contractions which were antagonized competitively by phentolamine (pKB = 8.3) and dobutamine antagonized norepinephrine-induced contractions in a competitive manner with an equilibrium dissociation constant for the alpha adrenoceptor of 20 nM (pKB = 7.7). Therefore, dobutamine satisfied criteria for a partial agonist of alpha adrenoceptors having an affinity for alpha adrenoceptors 25 times that of norepinephrine (pKA = 6.3) in this tissue. An estimate of the relative efficacy of dobutamine showed one-fortieth the the efficacy of norepinephrine at the alpha adrenoceptors. Dobutamine contracted rabbit aorta and produced concentration-related relaxations at 1000 times greater concentrations after alkylation of alpha adrenoceptors by phenoxybenzamine. In noncontracted canine saphenous vein, dobutamine had no visible agonist activity but did produce contractions after propranolol. In partially contracted saphenous vein, dobutamine produced a small contraction which was converted to a propranolol-sensitive relaxation of tone after phentolamine. Dobutamine was a full beta adrenoceptor agonist in guinea-pig trachea under spontaneous tone but a partial agonist after strong contraction by bethanechol. This allowed measurement of the pKB of dobutamine at beta adrenoceptors (pKB = 5.35) and estimation of efficacy at beta adrenoceptors relative to isoproterenol (eDob/eIso = 1/20). No evidence for beta adrenoceptor selectivity was found in studies of potency ratios and relative efficacy using isoproterenol for comparison. Dobutamine showed a slight (2-fold) selectivity for inotropy in vitro when compared to isoproterenol in guinea-pig right and left atria. This selectivity was removed by phentolamine suggesting a cardiac alpha-like adrenoceptor effect; this finding was confirmed in propranolol-treated guinea-pig left atria. These results are discussed in terms of the in vivo effects of dobutamine and its use as a tool for classification of beta adrenoceptors, particularly the putative presynaptic beta adrenoceptor.
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    The myocardial responsiveness of conscious, instrumental dogs to exogenously administered isoproterenol and norepinephrine was investigated in neonatal, 6-wk-old, and adult animals. Comparable base-line values for peak left ventricular derivative of pressure with respect to time were observed in all age categories. However, when compared with adult responses, the sympathomimetic amine-induced increases in neonatal left ventricular dP/dt were significantly blunted at each concentration of adrenergic agonist examined, whereas the 6-wk-old puppies displayed an intermediate inotropic response. To investigate the cellular mechanisms of this blunted neonatal response, we correlated physiologic and biochemical measurements of the myocardial responses to catecholamines in each age category. When compared with adult myocardial membrane preparations, neonatal cardiac membranes were characterized in vitro by an increased density of beta-adrenergic binding sites, comparable affinity for adrenergic agonists and antagonists, and an enhanced coupling of adenylate cyclase activation to receptor occupancy. Simultaneous changes in either the serum catecholamine concentration or the membrane content of other intrinsic proteins failed to account for the observed neonatal increase in beta-adrenergic receptor density. These findings are most consistent with a compensatory mechanism of the cardiac cell membrane, whereby an inherent depression in the adrenergic responsiveness of the immature myocardium appears to induce the increase in receptor density and activation of adenylate cyclase.
  • Article
    Dobutamine and its stereoisomers were evaluated for alpha and beta adrenergic activities in vitro. The racemate and the (--)-isomer were found to be potent partial agonists of alpha adrenergic receptors in rat aorta. The (+)-isomer lacked alpha agonist activity. The affinities of (+/-)-, (+)- and (--)-dobutamine for the alpha adrenergic receptor were high (--log KB values of 7.01, 7.02 and 7.07, respectively) and not significantly different from one another. These data indicate that (+)- and (--)- dobutamine bind equally to the alpha adrenergic receptor, however, subsequent to binding, only the (--)-isomer is capable of activating the receptor and eliciting an alpha adrenergic response. The (+)-isomer, which has the same affinity as the (--)-isomer but which lacks agonist activity, is a potent competitive alpha blocker. Both stereoisomers of dobutamine were agonists of beta adrenergic receptors of cat papillary muscle and right atria. In contrast to the alpha adrenergic effects, the more potent isomer at the beta adrenergic receptor was (+)- dobutamine. The isomeric activity ratio for the stereoisomers of dobutamine was approximately 1 log unit in favor of the (+)-isomer with respect to both inotropic and chronotropic responses. Dose-response curves to the racemate were always situated between the stereoisomers, approximately 2-fold to the right of (+)-dobutamine. These results indicate that the stereochemical requirements of alpha and beta adrenergic receptors are opposite for the stereoisomers of dobutamine with the alpha receptor favoring the (--)-isomer and the beta receptor favoring the (+)-isomer.
  • Article
    Respiratory measurements and blood-gas and acid-base values are reported in nine term induced foals. Measurements were performed at 2, 15, 30 and 60 mins, 4, 12, 24 and 48 h, and four and seven days after birth. Minute respiratory volume was significantly lower at birth than values from 12 h old. Tidal volume peaked at 60 mins old, while respiration rate decreased significantly at 15 mins after birth. Oxygen consumption was high at birth and decreased to its lowest values at 24 and 48 h. The respiratory exchange ratio and ventilatory equivalent showed few significant changes to seven days, as did the minute alveolar ventilation and physiological deadspace. The blood-gas and acid-base values indicated that the foals rapidly establish adequate pulmonary ventilation within minutes of birth, and that those values changed little from 12 h to seven days after birth. Body position had a significant effect on arterial oxygen tension with Pao2 values in lateral recumbency being, on average, 14 mmHg lower than when the foals were standing.
  • Article
    The minimum anesthetic concentration (MAC) of isoflurane was determined in five pediatric age groups. MAC was 1.6% in infants 0-1 month of age, 1.87% in those 1-6 months of age, 1.8% in those 6-12 months of age, 1.6% in those 1-3 yr of age, and 1.6% in children 3-5 yr of age. MAC in neonates was less than predicted.
  • Article
    Although isoflurane is not the ideal anesthetic, in many ways it is superior to other potent inhaled anesthetics. It is physically stable. Its low blood solubility (which is lower than that of other potent inhaled anesthetics) facilitates control of anesthetic depth and speeds recovery from anesthesia. The usual absnce of myocardial depression when isoflurane is administered in the 1-2 MAC range sets it apart from enflurane or halothane, which both cause depression. Similarly, arrhythmias secondary to epinephrine injection are least likely to occur during isoflurane anesthesia. Isoflurane and enflurane potentiate the effect of muscle relaxants and do so more than halothane. This action reduces the likelihood of postoperative relaxant hangover. Neither halothane nor isoflurane has enflurane's capacity to produce seizure activity. Cerebral blood flow and intracranial pressure may be less increased by isoflurane than by halothane or enflurane anesthesia; control of intracranial pressure probably is more readily accomplished during isoflurane anesthesia. Of great significance is the fact that isoflurane biodegradation is one-tenth that of enflurane and one-hundredth that of halothane. Therefore, hepatotoxicity and nephrotoxicity are absent or extremely rare. Some of the limitations of isoflurane are shared by enflurane and/or halothane. Although all three anesthetics decrease blood pressure, only enflurane and isoflurane increase heart rate in unstimulated humans. Enflurane and isoflurane are mildly pungent while halothane is not. This pungency limits the rate of induction. All three depress ventilation; enflurane is clearly most depressant and halothane probably least depressant. All may produce malignant hyperthermia. All cause uterine relaxation and at anesthetic levels probably increase uterine bleeding at delivery. Isoflurane has two disadvantages relative to enflurane and halothane. It is more expensive and the clinical experience with it is far less. Thus, some presently unknown noxious effect may be revealed by future use. We also may compare isoflurane with the nitrous-narcotic (balanced) approach to anesthesia. This approach is often chosen over enflurane or halothane because of the minimal myocardial depression that balanced anesthesia produces, and because organ toxicity is probably nonexistent. These reasons carry less force vis-a-vis isoflurane: isoflurane has little myocardial depressant effects over the usual range of anesthesia in normal patients (1-2 MAC), and the near absence of isoflurane biodegradation correlates with the inability to demonstrate hepatotoxicity or nephrotoxicity following isoflurane anesthesia. Some differences in cardiovascular or other effects may still cause anesthetists to choose the balanced approach to anesthesia. Pulse rate does not increase and blood pressure remains normal or increases. Intracranial pressure is decreased when the balanced approach is used (unless hypercapnia is permitted). Uterine bleeding is not increased during therapeutic suction abortion or delivery, and malignant hyperthermia is unlikely even in patients susceptible to this condition. Conversely, isoflurane has several advantages over the balanced approach. Although both anesthetic techniques depress respiration, isoflurane does not produce a 'stiff chest' or recurrent postoperative depression of breathing. Blood pressure may be controlled and the work of the heart decreased with isoflurane. Awareness is less likely during isoflurane anesthesia. Recovery is rapid and may be less frequently accompanied by nausea or recurrent somnolence. Management of postoperative pain is not made difficult by the need to administer narcotic antagnonists. As with other potent inhaled agents, isoflurane itself can produce adequate relaxation; the balanced approach requires the use of muscle relaxants. Isoflurane potentiates the effect of all muscle relaxants to a far greater extent than does the balanced approach. Potent general anesthetics do not cause constriction of gut muscle or the sphincter of Oddi. Finally, the ease of anesthetic management with isoflurane-oxygen anesthesia nearly equals that with isoflurane-nitrous oxide-oxygen anesthesia; conversely, the absence of nitrous oxide may compromise the ease of use and safety of the balanced technique. For these reasons, isoflurane is likely to play a major role in the future delivery of anesthetic care.
  • Article
    The cardiorespiratory responses to an I.V. infusion of dobutamine hydrochloride were assessed in eight anaesthetized, mechanically ventilated dogs As the rate of infusion of dobutamine was increased from 2 to 30 μg kg−1min−1, there was a progressive decrease in arterial pressure, pulmonary wedge pressure and arterial pH. There was a significant decrease in arterial oxygen tension at the greater doses of dobutamine (15 and 30 μgkg−1 min−1) from initial control values. Carbon dioxide output, arterial carbon dioxide tension, venous admixture and oxygen consumption increased during the infusion of dobutamine. However, oxygen supply increased further so that the oxygen consumption: supply ratio decreased It is concluded that dobutamine may decrease arterial oxygen tension, but that the increased cardiac output and decreased arterial pH produced by dobutamine may increase oxygen supply to the tissues in spite of this.
  • Article
    The hemodynamic effects of dobutamine were studied in 33 infants and children with cardiogenic or septic shock. Dobutamine was administered at doses of 2.5, 5.0, 7.5, and 10.0 micrograms/kg/minute. Significant increases above preinfusion values were observed in cardiac index, left ventricular stroke work index, and pulmonary wedge pressure. Significant decreases from preinfusion values were observed in systemic arteriolar resistance index. No significant differences occurred in heart rate, mean systemic arterial pressure, mean pulmonary arterial pressure, right atrial pressure, or pulmonary arteriolar resistance index. Analysis of the data also revealed significant effects of age and diagnosis on the hemodynamic responses. These data suggest that dobutamine is a useful drug in the pharmacologic management of children in shock, especially in children older than 12 months with cardiogenic shock not complicated by severe hypotension.
  • Although isoproterenol is the sympathomimetic amine used most often to augment cardiovascular function in infants and children, little is known about the hemodynamic effects of this drug on the immature cardiovascular system. To compare the hemodynamic effect of isoproterenol in the young animal with that in the mature animal, we infused the drug into 11 puppies of 12-38 days of age, 12 puppies of 56-89 days of age and 10 adult beagle dogs. The animals were chronically instrumented and nonsedated during the study. Isoproterenol was infused in doses of 0.05, 0.125, 0.25 and 0.5 microgram/kg/min. Isoproterenol decreased systemic arterial mean blood pressure, increased heart rate and had no effect on renal blood flow in all three groups of animals. While cardiac output was increased and systemic vascular resistance decreased in the adult dogs, neither changed in puppies. Stroke volume increased slightly in adult dogs, but decreased in puppies. This refractoriness to change of cardiac output in immature dogs may be a function of elevated resting cardiac output, developmental changes of contractility or ventricular compliance or developmental changes of vascular smooth muscle responsiveness.
  • Article
    To study if metabolic stress modifies the thermogenic effect of dobutamine. Prospective, increasing dose, pharmacologic study. Laboratory of the Department of Intensive Care Unit at a university hospital. Twelve normal volunteers. Dobutamine hydrochloride was infused to 12 healthy male volunteers starting at a dose of 2 micrograms/min/kg and gradually increased to 4 and 6 micrograms/min/kg. Each dose of dobutamine was infused for 20 mins. Metabolic stress was induced in six of the 12 volunteers using a triple hormone infusion (epinephrine, cortisol, and glucagon) before dobutamine, and was continued at a constant rate during the dobutamine infusion. The remaining six volunteers served as the control group and received only dobutamine. Oxygen consumption (VO2) was measured using a metabolic monitor. Arterial blood pressure was measured noninvasively, and cardiac output was monitored by Doppler echocardiography. Plasma concentrations of dopamine, norepinephrine, and epinephrine were measured in both groups. In the triple hormone group, blood was sampled to measure concentrations of insulin, glucagon, cortisol, free fatty acids, and glycerol to ensure the presence of a metabolic stress reaction. At the maximum dose, dobutamine induced a 19% increase (from 140 +/- 17 to 166 +/- 17 mL/min/m2) in VO2 in the control group and an 11% increase (from 167 +/- 10 to 184 +/- 13 mL/min/m2) in the triple hormone group (p < .05 between the two groups) compared with baseline. No change in the respiratory exchange ratio was seen. The triple hormone infusion alone induced hypermetabolism, a marked hemodynamic response, and increased lipolysis. Stress, induced by a triple hormone infusion, diminishes the thermogenic effect of dobutamine. In the clinical setting, a > 10% to 15% increase in VO2 in response to dobutamine may not be explained just by the thermogenic effect of the drug.
  • Article
    To determine the relationships between plasma concentrations of norepinephrine, epinephrine, and dopamine and oxygen consumption (VO2) during infusion of these catecholamines. Prospective, randomized variable dose, pharmacologic study in which a noncumulative infusion-rate design was used. Laboratory of the Department of Anesthesiology at a University Hospital. Twenty-one normal volunteers. After a control period of 20 mins, norepinephrine (three infusion rates; 0.06 to 0.2 microgram/kg/min; n = 7), epinephrine (four infusion rates; 0.02 to 0.2 microgram/kg/min; n = 7), or dopamine (three infusion rates; 3 to 12 micrograms/kg/min; n = 7) was administered to normal volunteers (n = 21) for the purpose of constructing plasma concentration/VO2 response curves. Systolic and diastolic blood pressure, heart rate, plasma concentrations of norepinephrine, epinephrine, and dopamine, and VO2 were measured at the end of the control period and at the end of each catecholamine infusion. VO2 was measured using a ventilated canopy system and a differential oxygen sensor. Typical hemodynamic responses to vasopressors were seen during adrenergic receptor agonist infusions. VO2 increased from 132 +/- 7 to 153 +/- 10 mL/min/m2 during the highest infusion rate of norepinephrine, from 133 +/- 7 to 182 +/- 11 mL/min/m2 during the highest infusion rate of epinephrine, and from 132 +/- 13 to 163 +/- 8 mL/min/m2 during the highest infusion rate of dopamine (p < .05; paired t-test). Increases in VO2 were correlated with the logarithms of the corresponding plasma catecholamine concentrations. Effects on VO2 and hemodynamic responses occurred at similar plasma concentrations for each of the three catecholamines. Administration of norepinephrine, epinephrine, or dopamine results in marked increases in VO2 in volunteers. In patients, the administration of catecholamines or sympathomimetics to attain optimal values of cardiac index, oxygen delivery (DO2), and VO2 may increase the oxygen demand and thus obscure the DO2-VO2 relationship.
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