RESUMO
OBJECTIVES: The integrity of the parathyroid axis was tested in 18 infants and young children undergoing repair of congenital heart disease with cardiopulmonary bypass. BACKGROUND: Infants are believed to have an immature parathyroid hormone response to hypocalcemia. Whereas adults are known to respond appropriately to hypocalcemia during cardiopulmonary bypass, children have not been studied carefully. METHODS: Calcium, magnesium, parathyroid hormone, phosphate and total protein were measured in blood samples withdrawn at defined times before, during and after cardiopulmonary bypass. RESULTS: At the initiation of cardiopulmonary bypass, ionized calcium decreased markedly in 12 infants less than or equal to 24 months old (mean +/- SEM 1.11 +/- 0.04 to 0.29 +/- 0.05 mM) and decreased significantly in 6 young children greater than 24 months old (1.19 +/- 0.02 to 0.42 +/- 0.12 mM). In response to hypocalcemia, parathyroid hormone concentration increased significantly in both the infants (from 42 +/- 8 to 103 +/- 29 and 85 +/- 22 pg/ml) and the young children (from 39 +/- 8 to 44 +/- 20 and 92 +/- 30 pg/ml). Before separation from cardiopulmonary bypass, increased parathyroid hormone concentration restored ionized calcium concentration to 0.75 +/- 0.03 mM in the infants and to 0.92 +/- 0.07 mM in the young children. There was no significant influence of either age or the use of deep hypothermia and circulatory arrest on either calcium or parathyroid hormone responses. Total magnesium and total protein concentrations decreased on initiation of cardiopulmonary bypass and thereafter remained stable. Phosphate concentrations were unchanged during the study. CONCLUSIONS: In infants and young children undergoing cardiac surgery, the parathyroid hormone response to both hypocalcemia and to rising ionized calcium concentrations was at least as great as that of adults. Thus, the calcium-parathyroid-vitamin D axis functions in infants and young children as it does in adults.
Assuntos
Cálcio/sangue , Ponte Cardiopulmonar/efeitos adversos , Cardiopatias Congênitas/cirurgia , Hipocalcemia/sangue , Hormônio Paratireóideo/sangue , Proteínas Sanguíneas/análise , Criança , Pré-Escolar , Feminino , Homeostase , Humanos , Hipocalcemia/etiologia , Lactente , Recém-Nascido , Íons , Magnésio/sangue , Masculino , Glândulas Paratireoides/fisiopatologia , Fosfatos/sangueRESUMO
To measure the depth of the local anesthetic binding site within the neuronal membrane, biotin-containing polyethylene glycols having zero, three, and six ethylene glycol subunits were added to the p-amino termini of tetracaine and procaine, thereby interposing a pharmacologically inert "spacer" molecule between the local anesthetic and the biotin moiety. These biotinyl-local anesthetic derivatives produced "tonic" inhibition of the compound action potential of split, desheathed frog sciatic nerves in a concentration-dependent, reversible manner. However, no inhibition of the action potential occurred when sufficient avidin, a 66,000-MW protein that binds four biotins, was present to bind and anchor the biotin-containing end of each derivative outside the plasma membrane. Increasing the "leashed" anesthetic derivative's concentration to 4 times that which reduced impulse height by 50% in the absence of avidin still produced no detectable block when equimolar avidin was present. Apparently, the "spacer" in the derivative compound was too short to permit the avidin-complexed anesthetic to reach its site of action on the sodium channel. In a similar fashion, the local anesthetic derivatives produced "use-dependent" block when drug-treated nerves were stimulated at 40 Hz in the absence of equimolar avidin, but failed to produce "use-dependent" block when equimolar avidin was present. In common with others, we assume that tertiary amine local anesthetics may reach their binding site via hydrophobic (transmembrane) pathways without necessarily entering the cytoplasm. Thus, since our longest local anesthetic derivative, that containing six ethylene glycol subunits, placed the local anesthetic group a maximum of 15-18 A from the surface of the avidin moiety, we conclude that the local anesthetic binding site for block of sodium channels of amphibian nerve must be greater than or equal to 15 A from the outer surface of the plasma membrane.
Assuntos
Anestésicos Locais/farmacologia , Condução Nervosa/efeitos dos fármacos , Potenciais de Ação/efeitos dos fármacos , Animais , Avidina/farmacologia , Biotina , Membrana Celular/fisiologia , Fenômenos Químicos , Química , Feminino , Canais Iônicos/efeitos dos fármacos , Masculino , Polietilenoglicóis , Procaína/análogos & derivados , Procaína/farmacologia , Rana pipiens , Nervo Isquiático/fisiologia , Sódio/metabolismo , Relação Estrutura-Atividade , Tetracaína/análogos & derivados , Tetracaína/farmacologiaRESUMO
Epinephrine and other beta-adrenergic receptor (beta AR) agonists are often administered during cardiopulmonary resuscitation, a time when acid-base abnormalities and arrhythmias also commonly occur. We tested whether beta 2AR binding is influenced by pH or the antiarrhythmic drug lidocaine, and whether pH might influence the interaction of lidocaine with beta 2ARs. With institutional review board approval and informed consent, 32 venous blood samples were obtained from volunteers. Lymphocytes (which bear beta 2ARs similar to those found in heart) were isolated by density gradient centrifugation. Specific binding of the beta AR ligand 3H-dihydroalprenolol (3H-DHA) was determined with lidocaine concentrations ranging from 10(-6) to 10(-2) mol/L (n = 18 experiments), and with and without lidocaine (n = 10 experiments), 100 mumol/L, and with and without QX314 (a permanently charged lidocaine derivative), 1 mmol/L (n = 4 experiments). Data are presented as percent of control-specific binding measured at a pH of 7.4. Statistical analysis consisted of Spearman's rank-test. 3H-DHA-specific binding increased (p < .001) with pH. Thus, alkaline conditions favored binding of 3H-DHA to the receptor. Lidocaine inhibited 3H-DHA binding to beta 2ARs in a concentration-dependent manner. The concentration that inhibited specific binding of 3H-DHA by 50% was 3.1 x 10(-4) mol/L (95% confidence limits, 1.3 x 10(-4) to 7.5 x 10(-4) mol/L). Lidocaine potency at inhibiting beta 2AR binding also increased with increasing pH; thus, there was limited benefit (in terms of increasing binding to beta 2ARs) to increasing pH when lidocaine was present. QX314, despite being present in a 10-fold greater concentration than lidocaine, had no effect on 3H-DHA binding at any tested pH. The affinity of beta 2 ARs for both 3H-DHA and lidocaine increased with pH. Thus, the response to beta 2AR agonists (when no lidocaine is present) might be expected to be greater with normal or alkalotic pH than under acidotic conditions, supporting the correction of metabolic acidosis to achieve optimal effects from beta 2AR agonists during resuscitation.
Assuntos
Antagonistas Adrenérgicos beta/metabolismo , Antiarrítmicos/farmacologia , Reanimação Cardiopulmonar , Di-Hidroalprenolol/metabolismo , Concentração de Íons de Hidrogênio , Lidocaína/farmacologia , Receptores Adrenérgicos beta/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Linfócitos , Estudos Prospectivos , Receptores Adrenérgicos beta/metabolismoRESUMO
STUDY OBJECTIVE: To evaluate the efficacy of amrinone for facilitating weaning from cardiopulmonary bypass (CPB). DESIGN: Prospective, randomized, double-blind, placebo-controlled trial with epinephrine as "rescue" therapy. SETTING: Operating room of a large, metropolitan tertiary-care center. PATIENTS: Thirty-nine patients with preoperative left ventricular dysfunction undergoing cardiac surgery. Thirty-three patients underwent aortocoronary bypass grafting; six patients underwent valve replacement for severe mitral or aortic regurgitation. INTERVENTIONS: Patients received either amrinone (1.5 mg/kg loading dose plus 10 micrograms/kg/min maintenance infusion; n = 20) or placebo (n = 19) in a randomized double-blind fashion shortly (median, 10.5 min; range, 2 to 24 min) before separation from CPB. Inotropic drugs (other than the study drug) were withheld prior to separation from CPB unless safety considerations demanded that the protocol be broken. Patients who could not be weaned from CPB, as well as those with a cardiac index of 2.2 L/min/m2 or less after weaning from CPB, received epinephrine (60 to 120 ng/kg/min) by infusion. MEASUREMENTS AND RESULTS: Fourteen of 19 patients receiving placebo but only 1 of the 20 patients receiving amrinone (p = 0.00001) required epinephrine infusion to separate from bypass. The cardiac index of 4 patients receiving placebo (but no patients with amrinone) failed to exceed 2.2 L/min/m2 despite epinephrine infusion, requiring the protocol to be broken (p < 0.08). Blood concentrations of amrinone determined (only in the amrinone group) after separation from CPB confirmed that the dosage of amrinone produced an effective blood concentration. Fourteen of 19 patients receiving placebo and 17 of 20 patients receiving amrinone required an infusion of phenylephrine titrated to maintain systolic blood pressure less than 90 mm Hg. Seven patients (four with amrinone and three with placebo) required antiarrhythmic drug therapy. The outcome at 3 months was similar in the 2 groups. CONCLUSIONS: Amrinone by itself is an effective agent to facilitate weaning from CPB, and therapy with amrinone reduced the need for individualized titration of epinephrine. Amrinone is as effective as individualized titration of epinephrine (after CPB) to improve cardiac function. Patients in the group receiving amrinone had no greater need for vasoconstricting agents than did patients in the group receiving placebo; however, proactive administration of amrinone before separation from CPB appears to offer no greater benefit to high-risk patients than selective administration of drugs (epinephrine) only to those patients who demonstrate the need for drug support at the time of weaning.
Assuntos
Amrinona/uso terapêutico , Baixo Débito Cardíaco/tratamento farmacológico , Procedimentos Cirúrgicos Cardíacos , Adulto , Idoso , Idoso de 80 Anos ou mais , Amrinona/farmacocinética , Baixo Débito Cardíaco/etiologia , Baixo Débito Cardíaco/fisiopatologia , Ponte Cardiopulmonar/efeitos adversos , Método Duplo-Cego , Epinefrina/uso terapêutico , Feminino , Hemodinâmica/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Contração Miocárdica/efeitos dos fármacos , Estudos Prospectivos , Função Ventricular Esquerda/efeitos dos fármacosRESUMO
To contrast the effect of increasing blood calcium concentrations on the cardiovascular actions of intravenous beta-adrenergic agonists and phosphodiesterase inhibitors, 46 patients recovering from aortocoronary bypass surgery received either dobutamine or amrinone both in the presence and absence of a calcium infusion. Cardiac output, systemic arterial pressure, pulmonary arterial pressure, central venous pressure, pulmonary artery occlusion pressure, heart rate, and blood ionized calcium concentration were measured before and during infusions of dobutamine (2.5 and 5.0 micrograms/kg/min) and amrinone (0.75 mg/kg bolus + 10 micrograms/kg/min or 2.25 mg/kg bolus + 20 micrograms/kg/min). After the initial dobutamine infusion period, patients were randomly and blindly assigned to receive either a calcium or placebo infusion, and the dobutamine infusions were repeated. Because of the long duration of amrinone's actions, the amrinone maintenance infusion was continued while randomized, blinded infusion of either calcium or placebo was added. Dobutamine (5 micrograms/kg/min) increased cardiac output from 7.1 +/- 0.3 L/min to 9.1 +/- 0.4 L/min, and increased heart rate from 93 +/- 4 beats/min to 107 +/- 4 beats/min. Systemic vascular resistance decreased and stroke volume increased. Dobutamine had no significant effects on other hemodynamic values. Amrinone (2.25 mg/kg bolus + 20 micrograms/kg/min) increased cardiac output from 5.6 +/- 0.4 L/min to 6.9 +/- 0.5 L/min, and increased heart rate from 87 +/- 3 beats/min to 98 +/- 3 beats/min. Amrinone decreased mean arterial pressure, systemic vascular resistance, pulmonary artery occlusion pressure, central venous pressure, and pulmonary artery pressure. Calcium infusion increased arterial pressure (8 to 13 percent) but had no significant effects on any other hemodynamic parameters. Calcium reduced the increase in cardiac output produced by dobutamine by 30 percent, but it did not alter the cardiotonic actions of amrinone. Thus, calcium inhibits the cardiotonic actions of certain beta-adrenergic agonists, most likely by interfering with signal transduction through the beta-adrenergic receptor complex.
Assuntos
Amrinona/farmacologia , Cálcio/farmacologia , Dobutamina/farmacologia , Hemodinâmica/efeitos dos fármacos , Amrinona/administração & dosagem , Pressão Sanguínea/efeitos dos fármacos , Cálcio/sangue , Débito Cardíaco/efeitos dos fármacos , Dobutamina/administração & dosagem , Método Duplo-Cego , Feminino , Frequência Cardíaca/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Estimulação QuímicaRESUMO
The hemodynamic and oxygen transport effects of low-dose (0.75 mg/kg loading dose + 10 micrograms/kg/min infusion, n = 12) and high-dose (2.25 mg/kg loading dose + 20 micrograms/kg/min infusion, n = 12) amrinone were evaluated in extubated patients 24 h after CABG. At both doses, amrinone significantly (p less than 0.05) increased HR, but decreased mean arterial, mean pulmonary artery, central venous and pulmonary artery occlusion pressures. High-dose amrinone significantly decreased systemic vascular resistance. Arterial oxygen saturation decreased significantly following both low- (97.8 +/- 0.4 to 95.6 +/- 0.9 percent) and high- (98.8 +/- 3.4 to 93.9 +/- 1.2 percent) dose amrinone. Pulmonary shunt increased significantly following low-dose amrinone and markedly increased Qs/Qt after high-dose amrinone. Although amrinone significantly increased cardiac index in a dose-dependent fashion (low:3.0 +/- 0.2 to 3.3 +/- 0.3 L/min/m2; high:2.7 +/- 0.2 to 3.4 +/- 0.2 L/min/m2), mixed venous oxygen saturation did not change. Thus, mixed venous oxygen saturation may not predict the hemodynamic response to amrinone infusion in postoperative surgical patients.
Assuntos
Amrinona/farmacologia , Débito Cardíaco/efeitos dos fármacos , Ponte de Artéria Coronária , Oxigênio/sangue , Amrinona/administração & dosagem , Cálcio/farmacologia , Relação Dose-Resposta a Droga , Feminino , Hemodinâmica/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Período Pós-OperatórioRESUMO
In experimental animals, coadministration of calcium (Ca) salts with beta-adrenergic receptor agonists reduces the increased blood pressure and cyclic AMP (cAMP) produced by beta-adrenergic receptor agonists alone. In patients, coadministration of these drugs reduces the increased cardiac output and blood glucose produced by selective administration of beta-adrenergic agonists. The mechanism by which Ca might produce catecholamine resistance remains unclear. Healthy volunteers donated venous blood from which lymphocytes were isolated. The cAMP production was measured by radioimmunoassay under control conditions and after incubation with epinephrine or colforsin (forskolin) in the presence and absence of inhibitors. Epinephrine and colforsin produced concentration-dependent increases in cAMP production. Extracellular Ca concentration over the range from 0 to 8 mM did not inhibit basal cAMP production or that stimulated by either colforsin or epinephrine. The calcium channel agonist Bay K 8644 (50 microM) combined with normal extracellular Ca concentration significantly attenuated colforsin-induced increases in cAMP production. When barium was substituted for Ca in the extracellular fluid, the cAMP response to colforsin was restored, despite Bay K 8644. Inhibition of Ca channel permeability with cadmium or cobalt ions partially restored colforsin-stimulated cAMP production, despite the presence of extracellular Ca and Bay K 8644. These results suggest that entry of Ca ions through Ca channels attenuates adenylyl cyclase. The inhibition appears specific for Ca ions over other permeant divalent cations, and favors a possible physiologic role for the recently cloned Ca-inhibited adenylyl cyclase.
Assuntos
Adenilil Ciclases/metabolismo , Cálcio/fisiologia , AMP Cíclico/biossíntese , Éster Metílico do Ácido 3-Piridinacarboxílico, 1,4-Di-Hidro-2,6-Dimetil-5-Nitro-4-(2-(Trifluormetil)fenil)/farmacologia , Adenilil Ciclases/efeitos dos fármacos , Cálcio/análise , Células Cultivadas , Colforsina/farmacologia , Epinefrina/farmacologia , Espaço Extracelular/química , Humanos , Linfócitos/metabolismoRESUMO
BACKGROUND: Dopexamine and dobutamine are traditionally described as having primarily beta 2-adrenergic agonist properties; norepinephrine is generally classified as beta 1-selective; and epinephrine, isoproterenol, and dopamine are considered mixed beta 1- and beta 2-receptor agonists. Much of this selectivity is designated from studies conducted with intact cardiovascular systems in which indirect actions (eg, norepinephrine release from presynaptic nerve terminals) are not separated from direct agonist-receptor interactions. OBJECTIVE: To assess the relative efficacy and potency of dopamine, dobutamine, dopexamine, epinephrine, isoproterenol, and norepinephrine for directly stimulating cyclic adenosine monophosphate (cAMP) production in human lymphocytes, a model of beta 2-adrenoceptor function. DESIGN: Open-label, prospective paired studies of lymphocytes from nine healthy human volunteers (seven men). SETTING: Experimental laboratory of a large, university-affiliated medical center. INTERVENTIONS: Concentration-response curves were generated for each adrenergic agonist; maximal cAMP production was used to compare efficacy. For the agonists that more than doubled basal cAMP concentrations, EC50 calculations were used to compare potency. MEASUREMENTS AND MAIN RESULTS: Isoproterenol and epinephrine produced the greatest concentrations of cAMP of the agonists tested. cAMP production was increased by isoproterenol at concentrations 1/10 to 1/10,000 that of the other agonists. Norepinephrine stimulated cAMP production only one third as much as epinephrine and isoproterenol, but more than double the level of dopamine, dobutamine, and dopexamine. EC50 concentrations for norepinephrine were 10-fold higher than epinephrine and 50-fold higher than isoproterenol. CONCLUSIONS: Epinephrine and isoproterenol are the most efficacious and potent direct-acting beta 2-adrenergic receptor agonists using this lymphocyte cAMP model. Norepinephrine exhibits significant effects on the beta-receptors on lymphocytes, suggesting beta 2-adrenoceptor effects with high concentrations of this drug. The very low cAMP levels generated by dopamine, dobutamine, and dopexamine (even in high concentrations) support other evidence that these agents have little direct effect on the beta 2-adrenoceptor.
Assuntos
Agonistas Adrenérgicos beta/farmacologia , AMP Cíclico/biossíntese , Linfócitos/enzimologia , Agonistas Adrenérgicos beta/administração & dosagem , Análise de Variância , Dobutamina/administração & dosagem , Dobutamina/farmacologia , Dopamina/administração & dosagem , Dopamina/análogos & derivados , Dopamina/farmacologia , Relação Dose-Resposta a Droga , Epinefrina/administração & dosagem , Epinefrina/farmacologia , Feminino , Humanos , Isoproterenol/administração & dosagem , Isoproterenol/farmacologia , Linfócitos/efeitos dos fármacos , Masculino , Norepinefrina/administração & dosagem , Norepinefrina/farmacologia , Estudos Prospectivos , Receptores Adrenérgicos beta 1/efeitos dos fármacos , Receptores Adrenérgicos beta 2/efeitos dos fármacosRESUMO
OBJECTIVE: Dopexamine hydrochloride is a novel synthetic adrenergic agonist that combines the renal effects of dopamine with the hemodynamic effects of dobutatmine. Our study is designed to compare the hemodynamic, diuretic, and natriuretic effects of dopexamine and dobutamine in patients with reduced cardiac index following heart surgery. DESIGN: Prospectively randomized, blinded study. SETTING: Operating room and intensive care unit of a large, urban, academic medical center. PATIENTS: Twenty-eight patients undergoing elective coronary artery bypass grafting (CABG) with preoperative ejection fraction of at least 40 percent gave informed consent. The study group consisted of the ten patients who had a cardiac index < or = 2.5 L/min/m2 (while receiving no inotropic medication) immediately after separation from cardiopulmonary bypass. INTERVENTIONS AND MEASUREMENTS: Study patients were randomly given a starting dose of either 5 micrograms/kg/min of dobutamine (n = 5) or 2 micrograms/kg/min of dopexamine (n = 5). During the initial 30 min following separation from bypass, dosages were titrated incrementally to maintain cardiac index > or = 3.0/L/min/m2. Further titrations of the drug were done only if cardiac index fell below 3.0 L/min/m2 or if sustained tachycardia occurred during the 24-h study period. Data were collected at 5- and 10-min intervals for the first 30 min after separation from bypass, hourly for the next 8 h, then every 2 h for the remainder of the study period. RESULTS: Both drugs increased cardiac index by more than 50 percent over baseline (dobutamine 2.2 +/- 0.1 to 3.5 +/- 0.2 [p < 0.05]; dopexamine, 2.3 +/- 0.1 to 3.5 +/- 0.1 [p < 0.05] L/min/m2). The mean dose required to maintain cardiac index > or = 3.0L/min/m2 was 1.5 micrograms/kg/min for dopexamine and 3.5 micrograms/kg/min for dobutamine. There were no significant differences in either urinary output or net sodium excretion in the dopexamine group compared with the dobutamine group, and tachycardia (heart rate > 120 beats/min) was more common in the dopexamine group. CONCLUSIONS: Our study demonstrates that dopexamine produces hemodynamic, diuretic, and natriuretic effects similar to dobutamine in patients with reduced cardiac index following CABG.
Assuntos
Antagonistas Adrenérgicos beta/uso terapêutico , Baixo Débito Cardíaco/tratamento farmacológico , Ponte de Artéria Coronária , Dobutamina/uso terapêutico , Dopaminérgicos/uso terapêutico , Dopamina/análogos & derivados , Rim/efeitos dos fármacos , Complicações Pós-Operatórias/tratamento farmacológico , Antagonistas Adrenérgicos beta/efeitos adversos , Antagonistas Adrenérgicos beta/farmacologia , Idoso , Baixo Débito Cardíaco/epidemiologia , Baixo Débito Cardíaco/fisiopatologia , Diurese/efeitos dos fármacos , Dobutamina/efeitos adversos , Dobutamina/farmacologia , Dopamina/efeitos adversos , Dopamina/farmacologia , Dopamina/uso terapêutico , Dopaminérgicos/efeitos adversos , Dopaminérgicos/farmacologia , Método Duplo-Cego , Hemodinâmica/efeitos dos fármacos , Humanos , Rim/fisiopatologia , Pessoa de Meia-Idade , Natriurese/efeitos dos fármacos , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/fisiopatologia , Estudos Prospectivos , Estatística como AssuntoRESUMO
OBJECTIVES: To determine if renal dose dopamine (3 microg/kg/min) alters the heart rate (HR) by itself, or if a dopamine infusion alters the HR response to bolus doses of the beta-adrenergic agonist isoproterenol in healthy human subjects. DESIGN: Prospective study. SETTING: Clinical laboratory of a university-affiliated academic medical center. SUBJECTS: A total of 15 healthy nonpregnant women and men aged 21 to 44 years. INTERVENTIONS: Subjects were monitored continuously with bedside ECG, pulse oximetry, and ambulatory ECG recording to measure the maximal HR response to separate injections of 10, 20, and 30 ng/kg of isoproterenol, given before, during, and after the infusion of 3 microg/kg/min of dopamine. MEASUREMENTS AND MAIN RESULTS: Dopamine in the absence of isoproterenol did not alter baseline HR significantly (62.7+/-2.2 beats/min without dopamine; 65.4+/-2.2 with dopamine; p=0.15). All three doses of isoproterenol increased HR significantly above baseline, both in the presence and absence of dopamine (p<0.001). Dopamine infusion resulted in a higher HR following isoproterenol only for the 20-ng/kg dose. The incremental increases in HR, defined as the difference between peak HR following isoproterenol and baseline HR, were not increased during dopamine infusion for any of the doses of isoproterenol. Nausea was reported by 5 of the 15 subjects during the dopamine infusion. CONCLUSIONS: In healthy human subjects, infusion of 3 microg/kg/min of dopamine does not significantly increase the HR when combined with beta-adrenergic stimulation using isoproterenol, suggesting neither an additive nor antagonistic interaction between the two drugs. While our study did not demonstrate an increase in HR in healthy subjects, the risk of increasing the chronotropic response to beta-adrenergic inotropic medications with "renal dose" dopamine in critically ill patients needs to be investigated. The frequency of nausea during dopamine infusion also may influence consideration of using dopamine to augment splanchnic blood flow and renal function in conscious patients.
Assuntos
Agonistas Adrenérgicos beta/farmacologia , Dopamina/farmacologia , Frequência Cardíaca/efeitos dos fármacos , Isoproterenol/farmacologia , Adulto , Dopamina/administração & dosagem , Dopamina/efeitos adversos , Relação Dose-Resposta a Droga , Interações Medicamentosas , Eletrocardiografia Ambulatorial , Feminino , Humanos , Masculino , Náusea/induzido quimicamente , Estudos Prospectivos , Circulação Renal/efeitos dos fármacosRESUMO
OBJECTIVES: The positive inotropic and vasodilator actions of phosphodiesterase (PDE) inhibitor drugs may offer therapeutic alternatives to beta-agonists in critically ill patients. We hypothesized that milrinone administration would increase cardiac index (CI) and oxygen delivery (Do2) in ICU patients, and that a pharmacokinetic model previously developed in cardiac surgery patients may be used to predict milrinone plasma concentrations in a medical-surgical ICU population. SETTING: ICU in two tertiary-care, university medical centers. DESIGN AND INTERVENTIONS: A prospective, open-label, multicenter, dose-escalating study in three successive groups of eight ICU patients who received a 10-min loading dose of milrinone (25 micrograms/kg [LOW], 50 micrograms/kg [MED], and 75 micrograms/kg [HIGH]). In addition, all patients then received a milrinone infusion of 0.5 microgram/kg/min for 1 h. MEASUREMENTS: Hemodynamic measurements included heart rate (HR); mean arterial, pulmonary artery, central venous, and pulmonary artery occlusion pressures; and thermodilution cardiac output. Oxygen transport indexes included arterial and venous blood oxygen tensions to determine Do2 and oxygen consumption (Vo2). Data were analyzed by univariate repeated measures analysis of covariance, with baseline values utilized as covariate regressors. RESULTS: Twenty-four adult ICU patients 20 to 84 years of age completed the study. The three groups did not differ, except that the patients in the MED group were significantly older (67 +/- 4 years, mean +/- SEM) compared with either the patients in the LOW (48 +/- 7 years) or HIGH (47 +/- 6 years) group. While HR did not change in the LOW group (90 +/- 4 to 93 +/- 3 beats/min), HR increased significantly in the HIGH group (94 +/- 5 to 112 +/- 8 beats/min) (baseline to 60 min infusion time points). All milrinone doses increased both CI and Do2. At the end of the 10-min loading dose, CI increased 0.3 L/min/m2 in the LOW group, 1.1 L/min/m2 in the MED group, and 0.9 L/min/m2 in the HIGH group. Do2 increased 8% in the LOW group, 33% in the MED group, and 23% in the HIGH group, similar to the changes in CI. Mixed venous oxygen saturation increased 3 to 5% during the 10-min loading dose of milrinone. During this same time period, mean arterial pressure decreased 6 to 16% and pulmonary artery pressures decreased 9 to 15%. Peak plasma milrinone concentrations increased as a function of the loading dose (159 +/- 9 ng/mL in the LOW group, 302 +/- 33 ng/ml in the MED group, and 411 +/- 45 ng/mL in the HIGH group). However, milrinone concentrations were similar in all three groups after the 1-h infusion; 113 +/- 14 ng/ml (LOW), 147 +/- 22 ng/mL (MED), and 119 +/- 14 ng/ml (HIGH). In all patients with final plasma milrinone concentrations greater than 100 ng/mL (15/23), the CI increased by at least 0.4 L/min/m2 (range, 0.4 to 1.8 L/min/m2). CONCLUSIONS: Our study confirms that a milrinone loading dose of 50 micrograms/kg/min followed by an infusion of 0.5 microgram/kg/min achieves adequate plasma concentrations of 100 ng/mL or greater, which significantly increases both CI and Do2. In addition, a previously established pharmacokinetic model of milrinone disposition is confirmed in this mixed ICU population.
Assuntos
Estado Terminal/terapia , Oxigênio/sangue , Inibidores de Fosfodiesterase/farmacocinética , Inibidores de Fosfodiesterase/uso terapêutico , Piridonas/administração & dosagem , Piridonas/farmacocinética , Adulto , Idoso , Idoso de 80 Anos ou mais , Débito Cardíaco/efeitos dos fármacos , Feminino , Hemodinâmica/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Milrinona , Consumo de Oxigênio/efeitos dos fármacos , Inibidores de Fosfodiesterase/farmacologia , Estudos Prospectivos , Piridonas/farmacologia , Vasodilatadores/farmacocinética , Vasodilatadores/farmacologia , Vasodilatadores/uso terapêuticoRESUMO
Contrary to what would have been expected, an antagonist of substance P (SP) [Arg5,D-Trp7,9]SP-(5-11) inhibited the neurogenic contraction of isolated guinea-pig hilus bronchi more readily than a contraction produced by exogenous SP. Furthermore, it has previously been shown that a tachykinin antagonist given intrathecally produced motor blockade as do local anaesthetic drugs. We therefore examined whether tachykinin antagonists had a depressant action on axonal neurotransmission. The compound action potential (APc) of the frog isolated sciatic nerve was suppressed in a concentration-dependent manner by the tachykinin antagonists [D-Pro2,D-Trp7,9]SP and [Arg5,D-Trp7,9]Sp-(5-11), both being about 4 times more potent than lidocaine. SP itself was without effect. Similarly in the rat isolated sciatic nerve [D-Pro2,D-Trp7,9]SP suppressed the APc. It was more potent in the A alpha- than in the C-fibres. SP did not affect conduction in either fibre type. In conscious guinea-pigs [D-Pro2,D-Trp7,9]SP injected adjacent to the sciatic nerve was found to block motor but not sensory functions of the limb. Thus, commonly used tachykinin antagonists, but not SP itself, have potent local anaesthetic properties. This should be considered when these agents are employed as pharmacological tools.
Assuntos
Anestésicos Locais , Brônquios/efeitos dos fármacos , Proteínas do Tecido Nervoso/antagonistas & inibidores , Nervo Isquiático/efeitos dos fármacos , Substância P/farmacologia , Potenciais de Ação/efeitos dos fármacos , Animais , Cobaias , Técnicas In Vitro , Músculo Liso/efeitos dos fármacos , Fragmentos de Peptídeos/farmacologia , Rana pipiens , Ratos , Ratos Endogâmicos , Especificidade da Espécie , Substância P/análogos & derivados , TaquicininasRESUMO
Upon admission, 17 of 223 (8%) consecutive patients with severe head injury exhibited a flaccid, wholly unresponsive motor examination. In this study alcoholic intoxication neither caused depressed motor responsiveness in head-injured patients with high serum ethanol levels nor accounted for the motor examination in those exhibiting the flaccid state. Flaccidity was attributed principally to impaired ventilation in 4 patients, a major intracranial mass in 12, and a spinal cord injury in 1. Compared to the larger group of head-injured patients, the flaccid patients had a significantly greater incidence of hypercapnia (P less than 0.001), acidosis (P less than 0.01), and both elevated and uncontrollable intracranial pressure (ICP) (P less than 0.001). These findings and the high mortality rate (76%) in this study suggest that the magnitude of respiratory complications and the severity of mechanical brain injury are greater in flaccid patients. The flaccid patients undergoing surgical decompression for major intracranial mass lesions (11 cases) have all died and, although still small in number, this group may represent an important subset with a poor prognosis. Nonetheless, a protocol that encourages rapid radiological and electrophysiological assessment and vigorous surgical and ICP management until the probable cause of flaccidity is identified and treated has benefit. The flaccid state was reversed and a good recovery was attained after the restoration of blood pressure and/or ventilation in 2 patients who appeared to have sustained a very grave head injury. In another patient, absent somatosensory evoked potentials greatly facilitated the diagnosis of a spinal subdural hematoma. This program of prompt diagnosis and intense therapy did not result in a protracted course or undue numbers of severely brain-damaged survivors.
Assuntos
Traumatismos Craniocerebrais/complicações , Hipotonia Muscular/etiologia , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Etanol/sangue , Potenciais Evocados Auditivos , Potenciais Evocados Visuais , Feminino , Humanos , Pressão Intracraniana , Masculino , Pessoa de Meia-Idade , Hipotonia Muscular/diagnóstico , Hipotonia Muscular/terapia , Exame Neurológico , Transtornos Respiratórios/etiologia , Tomografia Computadorizada por Raios XRESUMO
Low grade papilledema after acute, severe head injury was identified in 15 (3.5%) of 426 patients. Papilledema was recognized immediately after head injury in 1 patient, during the 1st week in 10 patients, and in the 2nd week or after in 4 patients. Initial computed tomographic scans showed evidence of brain injury in 11 of these patients. The intracranial pressure (ICP) was monitored continuously for 3 or more days in 9 patients; it was mildly elevated (20 to 40 mm Hg) in 7 patients and moderately elevated (40 to 60 mm Hg) in 2 patients. Intracranial hypertension was controllable in each patient. A sudden, severe, but transient increase in ICP best explained the immediate development of papilledema and survival of 1 patient. Sustained but mild to moderately elevated ICP accounted for papilledema appearing in the 1st week. Papilledema in the 2nd week or after occurred from impaired cerebrospinal fluid absorption and consequent communicating hydrocephalus or delayed focal or diffuse cerebral swelling. A lesser degree of head injury in patients with posttraumatic papilledema was suggested by a higher Glasgow coma score, milder and controllable elevations in ICP, and the absence of any fatality in this group. The favorable outcome was significant compared to the mortality of the more severely injured patients (chi square-4.327; P less than 0.04). Papilledema did not occur in 6 patients with sustained, severely elevated ICP (greater than 60 mm Hg) for 3 or more days. Each of these patients died. The severity of the trauma apparently accounts for the failure of papilledema to develop, possibly by arresting axoplasmic production and transport in retinal nerve fibers.
Assuntos
Lesões Encefálicas/complicações , Papiledema/etiologia , Doença Aguda , Adolescente , Adulto , Idoso , Lesões Encefálicas/fisiopatologia , Feminino , Angiofluoresceinografia , Humanos , Pressão Intracraniana , Masculino , Pessoa de Meia-Idade , Papiledema/fisiopatologia , Prognóstico , Fatores de Tempo , Tomografia Computadorizada por Raios XRESUMO
A prospective and consecutive series of 225 patients with severe head injuries who were managed in a uniform way was analyzed to relate outcome to several clinical variables. Good recovery or moderate disability were achieved by 56% of the patients, 10% remained severely disabled or vegetative, and 34% died. Factors important in predicting a poor outcome included the presence of intracranial hematoma, increasing age, abnormal motor responses, impaired or absent eye movements or pupil light reflexes, early hypotension, hypoxemia or hypercarbia, and elevation of intracranial pressure over 20 mm Hg despite artificial ventilation. Most of these predictive factors were assessed on admission, but a subset of 158 patients was identified in whom coma was present on admission and was known to have persisted at least until the following day. Although the mortality in this subset (40%) was higher than in the total series, it was lower than in several comparable reported series of patients with severe head injury. Predictive correlations were equally strong in the entire series and in the subset of 158 patients with coma. A plea is made for inclusion in the definition of "severe head injury" of all patients who do not obey commands or utter recognizable words on admission to the hospital after early resuscitation.
Assuntos
Hemorragia Cerebral/terapia , Coma/terapia , Traumatismos Craniocerebrais/terapia , Adolescente , Adulto , Fatores Etários , Idoso , Hemorragia Cerebral/complicações , Criança , Pré-Escolar , Coma/complicações , Traumatismos Craniocerebrais/complicações , Traumatismos Craniocerebrais/mortalidade , Manifestações Oculares , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos ProspectivosRESUMO
Acute traumatic brain injury is a leading cause of morbidity and mortality. Intensive management is aimed at early evacuation of intracranial mass lesions, control of intracranial hypertension, and prevention of medical complications.
Assuntos
Lesões Encefálicas/fisiopatologia , Lesões Encefálicas/líquido cefalorraquidiano , Lesões Encefálicas/terapia , Circulação Cerebrovascular , Traumatismos Craniocerebrais , Cuidados Críticos , Humanos , Pressão IntracranianaRESUMO
The availability of newer and better inotropic agents has led to their widespread application in critically ill medical and surgical patients. Although the elective use of inotropic drugs has been associated with adverse outcomes in patients with cardiomyopathy and chronic heart failure, inotropic drugs used as part of treatment protocols designed to optimize oxygen delivery to tissues have been shown to improve outcome in critical illness. Future research must be aimed toward better definition of clinical settings in which outcome can be improved with inotropes and toward identifying safer agents with fewer adverse side effects.
Assuntos
Cardiotônicos , Estado Terminal , Animais , Procedimentos Cirúrgicos Cardíacos , Cardiotônicos/efeitos adversos , Cardiotônicos/farmacologia , Cardiotônicos/uso terapêutico , Ensaios Clínicos como Assunto , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/fisiopatologia , Hemodinâmica/efeitos dos fármacos , Humanos , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/fisiopatologia , Choque/tratamento farmacológico , Choque/fisiopatologiaRESUMO
STUDY OBJECTIVE: To determine if, using a variation of the "timing" principle, 0.6 mg/kg of rocuronium can achieve an onset time and intubating conditions similar to those achieved with succinylcholine. STUDY DESIGN: Prospective, randomized, double-blind clinical comparison. SETTING: Operating room in a university medical center. PATIENTS: 42 ASA physical status I and II patients undergoing general anesthesia for elective surgery. INTERVENTIONS: All patients were fitted with a Grass FT-10 force transducer attached to the thumb. Supramaximal stimulation was applied to the ulnar nerve with a variable current peripheral nerve stimulator. 22 patients (succinylcholine group) received a placebo bolus injection followed 20 seconds later by thiopental 4 to 5 mg/kg and succinylcholine 1 mg/kg; 20 additional patients (rocuronium group) received a bolus dose of rocuronium 0.6 mg/kg followed 20 seconds later by thiopental 4 to 5 mg/kg and a placebo bolus injection. MEASUREMENTS AND MAIN RESULTS: We measured the onset time from administration of the muscle relaxant to 95% twitch reduction and assessed the quality of intubating conditions 60 seconds after the induction of anesthesia. There was a significant difference in the mean onset time of rocuronium (72 sec) versus succinylcholine (42 sec, p < 0.0001). However, there was no significant difference in intubating conditions 60 seconds after administration of thiopental. CONCLUSION: Rocuronium given 20 seconds prior to thiopental provides intubating conditions equivalent to thiopental-succinylcholine for rapid-sequence inductions, circumventing rocuronium's longer onset time to 95% neuromuscular blockade.