RESUMO
Previous studies have demonstrated the presence of myocardial depression in clinical and experimental septic shock. This depression is associated with the presence of a circulating myocardial depressant substance with physical characteristics consistent with cytokines. The present study utilized an in vitro myocardial cell assay to examine the role of various human recombinant cytokines, including tumor necrosis factor (TNF)alpha and interleukin (IL)1beta, in depression of cardiac myocyte contractile function induced by serum from humans with septic shock. The extent and velocity of electrically paced rat cardiac myocytes in tissue culture was quantified by a closed loop video tracking system. Individually, TNF-alpha and IL-1beta each caused significant concentration-dependent depression of maximum extent and peak velocity of myocyte shortening in vitro. In combination, TNF-alpha and IL-1beta induced depression of myocardial cell contractility at substantially lower concentrations consistent with a synergistic effect. Using immunoabsorption, removal of both TNF-alpha and IL-1beta (but not either alone) from the serum of five patients with acute septic shock and marked reversible myocardial depression resulted in elimination of serum myocardial depressant activity. IL-2, -4, -6, -8, -10, and interferon gamma failed to cause significant cardiac myocyte depression over a wide range of concentrations. These data demonstrate that TNF-alpha and IL-1beta cause depression of myocardial cell contraction in vitro and suggest that these two cytokines act synergistically to cause sepsis-associated myocardial depression in humans.
Assuntos
Citocinas/farmacologia , Coração/fisiologia , Interleucina-1/farmacologia , Contração Miocárdica/imunologia , Miocárdio/imunologia , Choque Séptico/sangue , Fator de Necrose Tumoral alfa/farmacologia , Animais , Relação Dose-Resposta a Droga , Coração/efeitos dos fármacos , Humanos , Técnicas In Vitro , Interferon gama/farmacologia , Interleucinas/farmacologia , Cinética , Masculino , Contração Miocárdica/efeitos dos fármacos , Ratos , Ratos Endogâmicos Lew , Proteínas Recombinantes/farmacologia , Choque Séptico/imunologia , Fatores de TempoRESUMO
Survivors of both human and animal bacterial shock develop a characteristic pattern of progressive changes in cardiovascular function over a period of 7-10 d. In this present study, we examined whether endotoxin (a product of Gram-negative bacteria) or TNF (a cytokine released from macrophages) could reproduce the same complex cardiovascular changes observed in septic shock over a period of 7-10 d. To test this hypothesis, we implanted a thrombin-fibrin clot containing purified endotoxin from E. coli into the peritoneal cavity of eight dogs, and infused TNF into eight different dogs. Over the next 10 d, serial simultaneous heart scans and thermodilution cardiac outputs were performed in these awake nonsedated animals. By day 2 after challenge with either endotoxin or TNF, animals developed a decrease (p less than 0.05) in both mean arterial pressure and left ventricular ejection fraction. With fluid resuscitation, animals manifested left ventricular dilatation (increased [p less than 0.05] end diastolic volume index), increased or normal cardiac index, and decreased or normal systemic vascular resistance index. In surviving animals, these changes returned to normal with 7-10 d. The time course of these changes was concordant (p less than 0.05) with that previously described in a canine model of septic shock using viable bacteria. During the 10-d study, control animals receiving sterile clots or heat-inactivated TNF had not significant changes in hemodynamics. The results from this canine model demonstrate that either endotoxin or TNF alone can produce many of the same hemodynamic abnormalities seen in human septic shock and in a canine septic shock model induced by live bacteria. These findings support the hypothesis that the action of endogenous mediators (TNF) responding to bacterial products (endotoxin) is the common pathway that produces the serial cardiovascular changes found in septic shock.
Assuntos
Sistema Cardiovascular/fisiopatologia , Endotoxinas , Choque Séptico/induzido quimicamente , Fator de Necrose Tumoral alfa , Animais , Pressão Sanguínea , Débito Cardíaco , Modelos Animais de Doenças , Cães , Escherichia coli , Humanos , Masculino , Choque Séptico/fisiopatologia , Volume Sistólico , Resistência VascularRESUMO
BACKGROUND AND OBJECTIVES: Packed red blood cell transfusion has been associated with increased infection in a variety of critically ill patient populations. We evaluated the microbiology and time course of infection in transfused patients in the intensive care unit (ICU) as no data exist on these parameters. MATERIALS AND METHODS: We performed a retrospective review of data for all patients admitted to a 24-bed medical-surgical ICU at Cooper University Hospital from July 2003 to September 2006 and entered in the Project Impact database. RESULTS: A total of 2432 patients were admitted during the study period, of which 609 underwent transfusion. Transfused patients were more likely to develop a nosocomial infection (10.5% vs. 4.9%, P < 0.001). ICU and hospital length of stay were longer in the transfused group (P < 0.001 for both). Mortality was also greater (13.1% vs. 8.7%, P = 0.001). Transfused patients had a shorter time from hospital admission to first infection (P < 0.001) and ICU admission to first infection (P < 0.001). Multivariate analysis confirmed transfusion as an independent risk factor for infection, mortality, hospital and ICU length of stay. Methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococcus and Acinetobacter occurred more often in transfused patients. Acinetobacter accounted for a disproportionate share of infections among transfused patients (P < 0.001). CONCLUSIONS: Transfused ICU patients have a higher incidence of nosocomial infection and worse outcomes. Transfused patients had a shorter onset of infection. Acinetobacter infection appears to be particularly common among these patients. Further investigation is merited to better elucidate the mechanism for these findings and their therapeutic and clinical implications.
Assuntos
Infecções Bacterianas/microbiologia , Infecções Bacterianas/mortalidade , Infecção Hospitalar/microbiologia , Infecção Hospitalar/mortalidade , Transfusão de Eritrócitos , Unidades de Terapia Intensiva , Idoso , Infecções Bacterianas/transmissão , Estado Terminal , Infecção Hospitalar/transmissão , Feminino , Humanos , Incidência , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
BACKGROUND AND OBJECTIVES: With the increasing demand for one-lung ventilation in both thoracic surgery and other procedures, identifying the correct placement becomes increasingly important. Currently, endobronchial intubation is suspected based on a combination of auscultation and physiological findings. We investigated the ability of the visual display of airflow-induced vibrations to detect single-lung ventilation with a double-lumen endotracheal tube. METHODS: Double-lumen tubes were placed prior to surgery. Tracheal and endobronchial lumens were alternately clamped to produce unilateral lung ventilation of right and left lung. Vibration response imaging, which detects vibrations transmitted to the surface of the thorax, was performed during both right- and left-lung ventilation. Geographical area of vibration response image as well as amount and distribution of lung sounds were assessed. RESULTS: During single-lung ventilation, the image and video obtained from the vibration response imaging identifies the ventilated lung with a larger and darker image on the ventilated side. During single-lung ventilation, 87.2 +/- 5.7% of the measured vibrations was detected over the ventilated lung and 12.8 +/- 5.7% over the non-ventilated lung (P < 0.0001). It was also noted that during single-lung ventilation, the vibration distribution in the non-ventilated lung had a majority of vibration detected by the medial sensors closest to the midline (P < 0.05) as opposed to the midclavicular sensors when the lung is ventilated. CONCLUSIONS: During single-lung ventilation, vibration response imaging clearly showed increased vibration in the lung that is being ventilated. Distribution of residual vibration differed in the non-ventilated lung in a manner that suggests transmission of vibrations across the mediastinum from the ventilated lung. The lung image and video obtained from vibration response imaging may provide useful and immediate information to help one-lung ventilation assessment.
Assuntos
Diagnóstico por Computador/métodos , Intubação Intratraqueal/métodos , Pulmão/diagnóstico por imagem , Respiração Artificial/métodos , Processamento de Sinais Assistido por Computador , Cirurgia Torácica , Vibração , Adulto , Idoso , Desenho de Equipamento , Feminino , Humanos , Intubação Intratraqueal/instrumentação , Masculino , Pessoa de Meia-Idade , Monitorização Intraoperatória/instrumentação , Monitorização Intraoperatória/métodos , Radiografia , Respiração Artificial/instrumentação , Sons Respiratórios/fisiologia , Processamento de Sinais Assistido por Computador/instrumentação , Resultado do TratamentoRESUMO
Lipid X, a precursor of lipid A (the toxic moiety of endotoxin), has been shown to protect animals from the lethal effects of endotoxin challenge. We investigated the mechanism of action of lipid X and 3-aza-lipid X, a diamino-analogue, in vitro, using the ability of lipopolysaccharide (LPS) to prime neutrophils for an enhanced release of toxic oxygen radicals. Lipid X and 3-aza-lipid X inhibited LPS-induced neutrophil priming in a concentration-dependent manner. At high concentrations, 3-aza-lipid X was a partial agonist of priming. Lipid X was found to inhibit LPS-induced priming by directly interacting with the neutrophil in contrast to polymyxin B, which neutralized LPS by binding to it. Increasing concentrations of lipid X shifted the LPS dose response curve of neutrophils rightward but did not prevent maximum priming at higher LPS concentrations, a finding consistent with competitive inhibition. These results suggest that lipid X, a compound structurally related to lipid A, may block neutrophil priming by competing with LPS for cellular binding sites. Lipid X appears to have a novel mechanism of inhibiting LPS effect and may have efficacy in the treatment of gram-negative sepsis.
Assuntos
Endotoxinas/farmacologia , Glicolipídeos/farmacologia , Neutrófilos/efeitos dos fármacos , Salmonella , Relação Dose-Resposta a Droga , Endotoxinas/antagonistas & inibidores , Humanos , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Concentração OsmolarRESUMO
Neutrophils can be "primed" for an enhanced respiratory burst by lipopolysaccharide (LPS) in concentrations measurable in patients with septic shock. Leukotriene B4 (LTB4) is the primary eicosanoid product of neutrophils and is felt to be a mediator of host defense and inflammation. We investigated the in vitro effects of LPS on neutrophil production of LTB4 and the omega-oxidation metabolites of LTB4. Incubation of neutrophils with LPS in concentrations ranging from 0.01 to 100 ng/ml did not result in production of LTB4 or metabolites in the absence of a second stimulus. Priming neutrophils with LPS and then stimulating with opsonized zymosan, phorbol-myristate-acetate or a low concentration of the calcium ionophore A23187 resulted in enhanced production of LTB4. LPS priming of neutrophils occurred in a concentration dependent manner. LPS did not result in LTB4 production in response to the chemoattractant peptide FMLP. LPS priming of neutrophils had no effect on cytosolic calcium concentrations of resting or zymosan-stimulated cells. These results suggest that LPS might effect host defense and tissue injury by potentiating the effect of other stimulants on neutrophil production of LTB4. This LPS induced enhancement may represent an important pathogenetic pathway in patients with gram negative sepsis.
Assuntos
Leucotrieno B4/sangue , Lipopolissacarídeos/farmacologia , Neutrófilos/metabolismo , Calcimicina/farmacologia , Cálcio/sangue , Citosol/metabolismo , Humanos , Cinética , N-Formilmetionina Leucil-Fenilalanina/farmacologia , Neutrófilos/efeitos dos fármacos , Proteínas Opsonizantes , Oxirredução , Salmonella , Acetato de Tetradecanoilforbol/farmacologia , Zimosan/farmacologiaRESUMO
We have previously described a subpopulation of patients with septic shock who had a reversible depression of radionuclide-determined left ventricular ejection fraction (EF). To investigate the mechanism of this myocardial depression, an in vitro model of mammalian myocardial cell performance was established employing primary spontaneously beating rat myocardial cells. The contraction of a single cardiac cell was quantitated by recording the changes in area occupied by the cell during contraction and relaxation. In 20 septic shock patients during the acute phase, the mean left ventricular EF was decreased (mean = 0.33, normal mean = 0.50), and serum obtained during this acute phase induced a mean (+/- standard error of the mean) 33 +/- 4% decrease in extent and 25 +/- 4% decrease in velocity of myocardial cell shortening during contraction (P less than 0.001). In contrast, serum obtained from 11 of these same patients before shock (n = 2) or after recovery (n = 9) of the left ventricular EF (mean = 0.50) showed a return toward normal in extent and velocity of shortening (P less than 0.001). Sera from 17 critically ill nonseptic patients, from 10 patients with structural heart disease as a cause for a depressed EF, and from 12 healthy laboratory personnel, induced no significant changes in in vitro myocardial cell performance. In 20 patients during the acute phase of septic shock, the decreased EF in vivo demonstrated a significant correlation (r = +0.52, P less than 0.01) with a decrease in the extent of myocardial cell shortening in vitro. The quantitative and temporal correlation between the decreased left ventricular EF and this serum myocardial depressant substance argues for a pathophysiologic role for this depressant substance in producing the reversible cardiomyopathy seen during septic shock in humans.
Assuntos
Cardiopatias/etiologia , Choque Séptico/sangue , Adolescente , Adulto , Idoso , Animais , Células Cultivadas , Criança , Depressão Química , Feminino , Hemodinâmica , Humanos , Masculino , Pessoa de Meia-Idade , Peso Molecular , Contração Miocárdica/efeitos dos fármacos , Miocárdio , Neoplasias/complicações , Fotomicrografia/instrumentação , Ratos , Choque Séptico/complicações , Volume SistólicoRESUMO
A canine sepsis model that simulates the human cardiovascular response to septic shock was produced in 10 conscious unsedated dogs by implanting an Escherichia coli-infected clot into the peritoneum, resulting in bacteremia. By employing serial, simultaneous measurements of radionuclide scan-determined left ventricular (LV) ejection fraction (EF) and thermodilution cardiac index (CI), the end-diastolic volume index (EDVI) was calculated (EDVI = stroke volume index divided by EF). By using three different methods of quantifying serial ventricular performance (EF, shifts in the Starling ventricular function curve using EDVI vs. stroke work index, and the ventricular function curve response to volume infusion), this study provides evidence (P less than 0.01) that septic shock produces a profound, but reversible, decrease in systolic ventricular performance. This decreased performance was not seen in controls and was associated with ventricular dilatation (P less than 0.01); the latter response was dependent on an adequate volume infusion. Further studies of EDVI and pulmonary capillary wedge pressure during diastole revealed a significant, though reversible, shift (P less than 0.001) in the diastolic volume/pressure (or compliance) relationship during septic shock.
Assuntos
Modelos Animais de Doenças , Bactérias Gram-Negativas , Coração/fisiopatologia , Sepse/fisiopatologia , Choque Séptico/fisiopatologia , Animais , Análise Química do Sangue , Pressão Sanguínea , Diástole , Cães , Frequência Cardíaca , Pressão Propulsora Pulmonar , Volume Sistólico , Sístole , Resistência VascularRESUMO
Using different types of bacteria and a canine model simulating human septic shock, we investigated the role of endotoxin in cardiovascular dysfunction and mortality. Either Escherichia coli (a microorganism with endotoxin) or Staphylococcus aureus (a microorganism without endotoxin) were placed in an intraperitoneal clot in doses of viable or formalin-killed bacteria. Cardiovascular function of conscious animals was studied using simultaneous radionuclide heart scans and thermodilution cardiac outputs. Serial plasma endotoxin levels were measured. S. aureus produced a pattern of reversible cardiovascular dysfunction over 7-10 d that was concordant (P less than 0.01) with that of E. coli. Although this cardiovascular pattern was not altered by formalin killing (S. aureus and E. coli), formalin-killed organisms produced a lower mortality and less myocardial depression (P less than 0.01). S. aureus, compared to E. coli, produced higher postmortem concentrations of microorganisms and higher mortality (P less than 0.025). E. coli produced significant endotoxemia (P less than 0.01), though viable organisms (versus nonviable) resulted in higher endotoxin blood concentrations (P less than 0.05). Significant endotoxemia did not occur with S. aureus. Thus, in the absence of endotoxemia, S. aureus induced the same cardiovascular abnormalities of septic shock as E. coli. These findings indicate that structurally and functionally distinct microorganisms, with or without endotoxin, can activate a common pathway resulting in similar cardiovascular injury and mortality.
Assuntos
Doenças Cardiovasculares/fisiopatologia , Endotoxinas/sangue , Choque Séptico/fisiopatologia , Animais , Doenças Cardiovasculares/sangue , Modelos Animais de Doenças , Cães , Escherichia coli , Hemodinâmica , Choque Séptico/sangue , Staphylococcus aureusRESUMO
Persistent vasodilation characteristic of septic shock may result from overproduction of nitric oxide and can lead to pressor-refractory hypotension and death. To evaluate the significance of cytokine-inducible nitric oxide synthase (iNOS) in the pathogenesis of sepsis, we used a clinically relevant mouse model of sepsis and compared mortality and microvascular reactivity in wild-type (WT) mice and transgenic mice deficient in iNOS. WT C57BL/6 and iNOS-deficient mice were made septic by cecal ligation and puncture. Treated mice were given fluids and antibiotics every 6 hours. Microvascular vasoconstriction in response to topical norepinephrine was measured in cremasteric arterioles (15 to 30 microm) by videomicroscopy. Mortality at 48 hours was significantly lower in treated septic iNOS-deficient mice (45%) than in treated septic WT mice (76%), untreated septic iNOS-deficient mice (87%), or untreated WT mice (100%) (P<0.01). Norepinephrine-induced vasoconstriction was decreased in WT septic mice (EC(50) 200+/-56 nmol/L) compared with WT and iNOS-deficient shams (16+/-4 and 13+/-6 nmol/L), and vasoconstriction was significantly improved in septic iNOS-deficient mice (35+/-13 nmol/L, P<0.01). Microvascular catecholamine responsiveness and survival were improved in iNOS-deficient mice in a clinically relevant model of sepsis, suggesting that iNOS plays an important, but not exclusive, role in refractory vasodilation in patients with septic shock.
Assuntos
Arteríolas/fisiopatologia , Microcirculação/fisiopatologia , Óxido Nítrico Sintase/metabolismo , Sepse/fisiopatologia , Animais , Arteríolas/efeitos dos fármacos , Arteríolas/fisiologia , Morte , Técnicas In Vitro , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Microcirculação/efeitos dos fármacos , Microcirculação/fisiologia , Microscopia de Vídeo , Óxido Nítrico Sintase/deficiência , Óxido Nítrico Sintase/genética , Óxido Nítrico Sintase Tipo II , Norepinefrina/farmacologia , Sepse/enzimologia , Vasoconstrição/efeitos dos fármacos , Vasoconstrição/fisiologiaRESUMO
Oxidative metabolism and its possible modulation by nitric oxide (NO) was examined in endothelial-intact and endothelial-denuded segments of porcine carotid arteries. Endothelial-intact arteries displayed appropriate NO-mediated vasorelaxation to acetylcholine (ACh). Endothelial-denuded arteries demonstrated absent vasorelaxation to ACh stimulation and depressed contractile responsiveness to K(+) depolarization, which was normalized by inhibition of NO synthesis by N(omega)-nitro-L-arginine methylester (L-NAME). Confirmation that carotid arteries continued to produce NO despite removal of the endothelium was indicated by detection of NO metabolites in the incubation medium bathing the arteries. O(2) consumption and the oxidation of glucose and fatty acid were depressed in endothelial-denuded arteries. Depression of O(2) consumption and glucose oxidation was completely reversed by treatment with L-NAME. We conclude that endogenous NO produced by non-endothelial vascular cells depresses contractility, O(2) consumption, and oxidation of energy substrates in vascular smooth muscle. The endothelium may play a role in oxidative metabolism of vascular smooth muscle possibly by modulating the effects of NO produced by other cells of the vessel wall, or by other factors.
Assuntos
Artérias Carótidas/metabolismo , Endotélio Vascular/metabolismo , Óxido Nítrico/farmacologia , Acetilcolina , Animais , Ácidos Graxos/metabolismo , Glucose/metabolismo , Técnicas In Vitro , Contração Muscular , NG-Nitroarginina Metil Éster , Nitritos/análise , Norepinefrina , Oxirredução , Consumo de Oxigênio , Suínos , Fatores de Tempo , VasodilataçãoRESUMO
The effects of fatty acids of different chain lengths on aerobic glycolysis, lactic acid production, glycogen metabolism and contractile function of vascular smooth muscle were investigated. Porcine carotid artery segments were treated with 50 microM iodoacetate and perchloric acid tissue extracts were then analyzed by 31P-NMR spectroscopy to observe the accumulation of phosphorylated glycolytic intermediates so that the activity of the Embden-Myerhof pathway could be tracked under various experimental paradigms. Aerobic glycolysis and lactate production in resting arteries were almost completely inhibited with 0.5 mM octanoate, partially inhibited with 0.5 mM acetate and unaffected by 0.5 mM palmitate. Inhibition of glycolysis by octanoate was not attributable to inhibition of glucose uptake or glucose phosphorylation. Basal glycogen synthesis was unchanged with palmitate and acetate, but was inhibited by 52% with octanoate incubation. The characteristic glycogenolysis which occurs upon isometric contraction with 80 mM KCl in the absence of fatty acid in the medium was not demonstrable in the presence of any of the fatty acids tested. Glycogen sparing was also demonstrable in norepinephrine contractions with octanoate and acetate, but not with palmitate. Additionally, norepinephrine-stimulated isometric contraction was associated with enhanced synthesis of glycogen amounting to 6-times the basal rate in medium containing octanoate. Contractile responses to norepinephrine were attenuated by 20% in media containing fatty acids. Thus, fatty acids significantly alter metabolism and contractility of vascular smooth muscle. Fatty acids of different chain lengths affect smooth muscle differentially; the pattern of substrate utilization during contraction depends on the contractile agonist and the fatty acid present in the medium.
Assuntos
Ácidos Graxos/fisiologia , Glicogênio/metabolismo , Glicólise , Músculo Liso Vascular/metabolismo , Animais , Artérias Carótidas , Gliceraldeído-3-Fosfato Desidrogenases/metabolismo , Iodoacetatos/farmacologia , Ácido Iodoacético , Espectroscopia de Ressonância Magnética , Contração Muscular , Norepinefrina/fisiologia , Potássio/fisiologia , SuínosRESUMO
In studies on metabolism of vascular smooth muscle, it was observed that incubation of intact porcine carotid artery strips with 3% bovine or porcine serum albumin had profound effects on the oxidation of substrates and O2 consumption. Arteries incubated over 180 min with charcoal-treated and dialyzed albumin demonstrated time-dependent stimulation of glucose oxidation (145%; P < 0.0001, n=6) and O2 consumption (116%; P< 0.001, n=6). These results were not mimicked by incubation with 3% solutions of ovalbumin or porcine skin gelatin. However, the oxidation of the medium chain fatty acid octanoate was inhibited in the presence of albumin over a broad range of octanoate concentrations (0.5-5.0 mM). Short chain fatty acid oxidation (acetate, 5 mM), in contrast, was not inhibited by albumin. Wash-out of albumin only partially reversed the stimulation of O2 consumption and incubation of arteries with a polyanionic compound, polyethylene sulfonate (5 mg/ml), blunted the stimulatory effect of albumin on O2 consumption. Albumin also produced anaplerosis of the Krebs cycle, and an increase in the content of glutamate and alanine (P < 0.005, n=8). The metabolic effects of albumin were associated with time-dependent uptake of albumin (30.9 +/- 1.5 nmol/g per 210 min; P<0.01, n=15). ATP-dependent proteolysis of the albumin taken up was also observed. These results demonstrate novel and important intracellular effects of serum albumin on energy metabolism of vascular smooth muscle.
Assuntos
Glucose/metabolismo , Músculo Liso Vascular/metabolismo , Albumina Sérica/metabolismo , Acetatos/química , Animais , Caprilatos/química , Artérias Carótidas , Ciclo do Ácido Cítrico/efeitos dos fármacos , Glucose/química , Ácido Glutâmico/análise , Técnicas In Vitro , Músculo Liso Vascular/química , Músculo Liso Vascular/efeitos dos fármacos , Oxirredução , Consumo de Oxigênio/efeitos dos fármacos , Palmitatos/química , Albumina Sérica/farmacologia , Soroalbumina Bovina/metabolismo , Soroalbumina Bovina/farmacologia , SuínosRESUMO
The oxidation of octanoate and acetate was measured in segments of porcine carotid arteries to ascertain whether the oxidation of exogenous fatty acid substrates (acetate and octanoate) is augmented during contraction induced by K(+)-depolarization. The oxidation of acetate increased from 7 +/- 1 to 14 +/- 2 nmol/min/g (P < 0.01) during sustained isometric contraction. Octanoate oxidation increased from 11 +/- 1 to 14 +/- 1 nmol/min/g (P < 0.05). The rate of oxidation of neither acetate nor octanoate was affected by the presence or absence of glucose either in resting or contracting arteries Acetate or octanoate oxidation could account for the majority of O2 consumption during contraction. Octanoate but not acetate inhibited glucose uptake and glycolysis in resting muscles. In contrast to augmented acetate and octanoate metabolism during contraction, there was a "down-regulation" of glucose metabolism in contracting muscles as evidenced by a decrease in the rate of glucose uptake, glycolysis and lactic acid production during sustained isometric contraction. Thus, contractile activation of vascular smooth muscle is associated with a shifting pattern of substrate utilization. Exogenous acetate or octanoate can serve as the primary oxidative substrate during sustained isometric contraction.
Assuntos
Acetatos/metabolismo , Caprilatos/metabolismo , Glucose/metabolismo , Contração Muscular/fisiologia , Músculo Liso Vascular/metabolismo , Animais , Artérias Carótidas , Glicogênio/análise , Glicólise/fisiologia , Peróxido de Hidrogênio/metabolismo , Ácido Láctico/biossíntese , Técnicas de Cultura de Órgãos , Oxirredução , Consumo de Oxigênio , Cloreto de Potássio/farmacologia , SuínosRESUMO
BACKGROUND: Coronary endothelial dysfunction may be an early marker for cardiac allograft vasculopathy (CAV) in orthotopic heart transplant recipients. Using serial studies with intravascular ultrasound and Doppler flow-wire measurements, we have previously demonstrated that annual decrements in coronary endothelial function are associated with progressive intimal thickening. The present study tested whether endothelial dysfunction predicts subsequent clinical events, including cardiac death and CAV development. METHODS AND RESULTS: Seventy-three patients were studied yearly beginning at transplantation until a prespecified end point was reached. End points were angiographic evidence of CAV (>50% stenosis) or cardiac death (graft failure or sudden death). At each study, coronary endothelial function was measured with intracoronary infusions of adenosine (32-microgram bolus), acetylcholine (54 microgram over 2 minutes), and nitroglycerin (200 microgram) into the left anterior descending coronary artery; intravascular ultrasound images and Doppler velocities were recorded simultaneously. Of the 73 patients studied, 14 reached an end point during the study (6 CAV and 8 deaths, including 4 with known CAV, 1 graft failure, and 3 sudden). On the last study performed, the group with an end point had decreased epicardial (constriction of 11.1+/-2.9% versus dilation of 1.7+/-2.2%, P=0.01) and microvascular (flow increase of 75+/-20% versus 149+/-16%, P=0.03) endothelium-dependent responses to acetylcholine compared with the patients who did not reach an end point. Responses to adenosine and nitroglycerin did not differ significantly. CONCLUSIONS: Endothelial dysfunction, as detected by abnormal responses to acetylcholine, preceded the development of clinical end points. These data implicate endothelial dysfunction in the development of clinically significant vasculopathy and suggest that serial studies of endothelial function have clinical utility.
Assuntos
Doença das Coronárias/fisiopatologia , Endotélio Vascular/fisiopatologia , Transplante de Coração , Doenças Vasculares/fisiopatologia , Acetilcolina/farmacologia , Adenosina/farmacologia , Adolescente , Adulto , Criança , Angiografia Coronária , Circulação Coronária/efeitos dos fármacos , Doença das Coronárias/cirurgia , Vasos Coronários/diagnóstico por imagem , Vasos Coronários/efeitos dos fármacos , Vasos Coronários/fisiopatologia , Morte , Feminino , Rejeição de Enxerto/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Nitroglicerina/farmacologia , Valor Preditivo dos Testes , Prognóstico , Sensibilidade e Especificidade , Ultrassonografia de Intervenção , Vasodilatadores/farmacologiaRESUMO
Eight patients with refractory ovarian cancer were treated on a pilot protocol of verapamil plus Adriamycin (Adria Laboratories, Columbus, OH). This trial was based on our previous laboratory studies which demonstrated that Adriamycin resistance in human ovarian cancer cell lines could be partially reversed by exposure of the cells to high concentrations of verapamil (3,000 ng/mL). Patients were treated in an intensive care unit with continuous cardiovascular monitoring. The dose of verapamil was escalated in each patient until hypotension or heart block developed, and this dose was maintained for 72 hours. Adriamycin (50 mg/m2) was infused over 24 hours during the second day of the verapamil infusion and verapamil alone was administered on the third day in an effort to block efflux from drug-resistant cells. This intensive approach led to a median plasma verapamil level of 1,273 ng/mL (range, 720 to 2,767). However, the high infusion rates of verapamil (9 micrograms/kg/min) required to achieve these plasma levels produced an unacceptable degree of cardiac toxicity. Two patients developed transient atropine-responsive complete heart block and four patients developed transient congestive heart failure with increases in pulmonary capillary wedge pressure. There was no evidence that the noncardiac toxicities of Adriamycin were enhanced by verapamil. There were no objective responses to therapy. Future studies should use less cardiotoxic calcium channel blockers that can be safely administered to produce the plasma levels required for in vitro sensitization of drug resistant cells.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ovarianas/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/metabolismo , Pressão Sanguínea/efeitos dos fármacos , Doxorrubicina/administração & dosagem , Resistência a Medicamentos , Feminino , Cardiopatias/induzido quimicamente , Frequência Cardíaca/efeitos dos fármacos , Humanos , Cinética , Projetos Piloto , Volume Sistólico/efeitos dos fármacos , Verapamil/administração & dosagemRESUMO
The administration of interleukin 2 (IL-2) and lymphokine-activated killer (LAK) cells can mediate the regression of cancer. Treatment with IL-2 is associated with significant cardiorespiratory effects, as well as a leaky capillary syndrome requiring careful fluid management. A mild reversible depression of cardiac function is also associated with IL-2 treatment. All patients treated with recombinant IL-2 alone, with transfer of LAK cells, or with cyclophosphamide between December 1984 and September 1987 (total of 423 treatment courses in 317 total patients) were evaluated as to the development of significant cardiorespiratory toxicity. Of the 423 treatment courses, only 1.8% were associated with severe peripheral edema and only 2.8% and 3.1% respectively, were associated with significant ascites or pleural effusions. Thirty-nine of 423 patients (9.2%) had severe respiratory distress and 27 patients required intubation (6.4%). Cardiovascular effects included tachycardia and hypotension requiring vasopressor administration in 65% and intravenous (IV) fluid administration. Weight gain greater than or equal to 10% of body weight was noted in 32% of the 423 patients. Arrhythmias were primarily supraventricular (9.7%) and responded well to conventional medical treatments. Angina or ischemic changes were noted in 2.6% of patients and myocardial infarction in 1.2%. IL-2 caused peripheral vasodilation, with a significant decrease in peripheral vascular resistance (2,254 +/- 398 v 1,303 +/- 351 dyne.s.cm-5, P less than .0001), and an increase in heart rate (66.2 +/- 10 v 104.3 +/- 9.6 beats/min, P less than .0001). There was also evidence of mild cardiac dysfunction, with a significant decrease in the left ventricular stroke work (LVSW) index (P less than .0001) and ejection fraction (LVEF) (from 58% +/- 10% to 52% +/- 9%, P less than .03). A repeat LVEF performed after 1 to 3 months, had returned to baseline values (60% +/- 10%). A mean 64% increase in the rate of disappearance of radioactive iodine (125I) albumin (P less than .05) consistent with the development of a leaky capillary syndrome was noted. Patients with underlying cardiorespiratory diseases may be at greater risk during IL-2 administration and should not be selected to undergo this treatment.
Assuntos
Doenças Cardiovasculares/etiologia , Hemodinâmica , Interleucina-2/efeitos adversos , Pneumopatias/etiologia , Neoplasias/terapia , Adulto , Feminino , Humanos , Interleucina-2/uso terapêutico , Ativação Linfocitária , Linfocinas/administração & dosagem , Linfocinas/isolamento & purificação , Masculino , Pessoa de Meia-IdadeRESUMO
OBJECTIVES: We sought to determine whether men and women are equally likely to receive coronary angiography and revascularization after acute myocardial infarction (AMI) when they are risk stratified according to American College of Cardiology/American Heart Association (ACC/AHA) practice guidelines for post-MI care. BACKGROUND: Several previous studies have suggested that women may undergo angiography and revascularization procedures less frequently than men. METHODS: In 439 consecutive patients admitted to a public hospital with AMI, rates of coronary angiography and revascularization were compared in men and women categorized, according to ACC/AHA practice guidelines, as having strong (class I or IIa) or weaker (class IIb) indications for angiography. RESULTS: Women were older and more likely to be diabetic or hypertensive, but men and women were equally likely to meet class I/IIa criteria for post-MI angiography (both 51%). Angiography rates were nearly identical in men and women overall (63% vs. 64%), as well as in patients in class I/IIa (80% vs. 82%) and class IIb (46% vs. 46%) (all p > 0.80, with >80% power to detect important differences); the only multivariate predictors of post-MI angiography were age and ACC/AHA class. Significant coronary artery disease was equally prevalent in men and women undergoing angiography, and men and women were equally likely to undergo revascularization, whether they were in class I/IIa (both 55%, p = 0.90) or class IIb (59% vs. 58%, p = 0.88). No significant differences in mortality were noted between men and women. CONCLUSIONS: Despite being older and having more risk factors than men, women were equally likely to undergo coronary angiography and revascularization procedures after AMI, and they had in-hospital clinical outcomes that were at least as favorable.
Assuntos
Angiografia Coronária/estatística & dados numéricos , Infarto do Miocárdio/epidemiologia , Revascularização Miocárdica/estatística & dados numéricos , Adulto , Fatores Etários , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/diagnóstico por imagem , Infarto do Miocárdio/terapia , Guias de Prática Clínica como Assunto , Fatores de Risco , Fatores Sexuais , Resultado do Tratamento , Estados Unidos/epidemiologiaRESUMO
BACKGROUND: In the mid 1990s, two unstable angina risk prediction models were proposed but neither has been validated on separate population or compared. OBJECTIVES: The purpose of this study was to compare patient outcome among high, medium and low risk unstable angina patients defined by the Agency for Health Care Policy and Research (AHCPR) guideline to similar risk groups defined by a validated model from our institution (RUSH). METHODS: Four hundred sixteen patients consecutively admitted to the hospital with unstable angina between January 1, 1995, and December 31, 1997, were prospectively evaluated for risk factors. The presence of major adverse events such as myocardial infarction (MI), death and heart failure was assessed for each patient by chart review. RESULTS: The composite end point of heart failure, MI or death occurred in 3% and 5% of the RUSH and AHCPR low risk categories, respectively, and in 8% and 10% of AHCPR and RUSH high risk categories, respectively. Recurrent ischemic events were best predicted by the RUSH model (high: 24% vs. medium: 12% and low: 10%, p = 0.029), but not by the AHCPR model (high: 14% vs. medium: 13% and low: 9%, p = 0.876). The RUSH model identified five times more low risk patients than the AHCPR model. CONCLUSIONS: Both models identify patients with low and high event rates of MI, death or heart failure. However, the RUSH model allowed for five times more patients to be candidates for outpatient evaluation (low risk) with a similar observed event rate to the AHCPR model; also, the RUSH model more successfully predicted ischemic complications. We conclude that the RUSH model can be used clinically to identify patients for early noninvasive evaluation, thereby improving cost effectiveness of care.
Assuntos
Angina Instável/epidemiologia , Medição de Risco , Idoso , Angina Instável/complicações , Humanos , Tempo de Internação , Pessoa de Meia-Idade , Modelos Estatísticos , Estudos ProspectivosRESUMO
OBJECTIVES: The goal of this review is to reevaluate the unstable coronary syndromes in the setting of new therapies and biochemical markers. BACKGROUND: Patients with acute coronary syndromes comprise a large subset of many cardiology practices. Patients with unstable angina (UA) and non-Q wave myocardial infarction (NQMI) may sustain a small amount of myocardial loss but have significant amounts of viable, yet ischemic, myocardium, placing them at high risk for future cardiac events. In the past, enzyme differentiation of NQMI from UA was considered important to assess prognosis and direct therapy. METHODS: Manuscripts published in peer-reviewed journals over the past three decades were reviewed and selected for this review. Recent abstracts were also considered and cited where appropriate. RESULTS: In the late 1990's, although UA and NQMI remain parts of a spectrum, it is apparent that the distinction between these two entities is no longer sufficient to identify high risk patients; rather, specific electrocardiographic changes, aspects of the clinical history, newer biochemical markers, and angiographic findings help to better distinguish higher risk individuals from a large patient population with unstable coronary syndromes and these factors usually determine therapy. CONCLUSIONS: Based on these results, it is likely that newer therapies such as glycoprotein IIb/IIIa receptor antagonists, low molecular weight heparins, and coronary stents will be directed toward these high risk patients.