[Huriet's law and clinical research. Some good, some less good...].
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Biomedical subjects
Publications and source records attributed to J Marty.
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The newt (Pleurodeles waltl) is an amphibian species used in a mutagenicity test (micronucleus). This study was carried out to establish if the inducibility of hepatic cytochromes P450 of this species is similar to that of the rat. Our results showed that the newt is characterized by a lower level of hepatic cytochrome P450-dependent activities than the rat. Variations of enzymatic activities according to sex and season were observed. Specific activities in newt were characterized by an almost complete insensitivity to induction by phenobarbital pretreatment. On the other hand, pretreatment by 3-methylcholanthrene resulted in an increase in the metabolism of several hydroxycoumarin and resorufin derivatives, similar to the effects observed in rat liver. Occurrence of specific forms of cytochromes P450 was assessed by specific antibodies.
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The effects of reversal of flunitrazepam-induced sedation with flumazenil on coronary hemodynamics, myocardial oxygen consumption (MVO2), and left ventricular (LV) performance were investigated, in a double-blind trial, in 12 patients with stable coronary artery disease undergoing cardiac catheterization. Coronary sinus blood flow was measured by continuous thermodilution. Arterial and coronary sinus blood were analyzed for oxygen and lactate contents. The determinants of LV performance were obtained from the cardiac output measured by thermodilution and from left heart catheterization data. To reverse flunitrazepam-induced sedation, patients were randomly allocated to receive placebo or flumazenil (by increment, up to 1 mg) at the end of procedure. In the placebo group, no significant hemodynamic changes were observed. In the flumazenil group, heart rate, cardiac index, maximum velocity of shortening, and relaxation time constant were not significantly altered. By contrast, mean aortic pressure and LV end-diastolic pressure (baselines: 90 +/- 5 and 7.3 +/- 4.1 mmHg, respectively) increased (9%, P less than 0.05 and 67%, P less than 0.05, respectively) after flumazenil administration, but these changes represented mainly a return toward presedation values. MVO2 and coronary resistance were not significantly altered, whereas CSBF increased slightly (baseline: 119 +/- 20 ml/min; increase 10%, P less than 0.05). No electrocardiographic evidence of myocardial ischemia was observed during the study. These data show that reversal of benzodiazepine effects with flumazenil is not associated with a major alteration of LV systolic function, relaxation, or coronary hemodynamics in patients with coronary artery disease. Nevertheless, it should be cautiously used when LV end-diastolic pressure is increased at the time of its administration.
Sufentanil was compared with fentanyl as a supplement to nitrous oxide-halothane anesthesia in a double-blind study of 30 elderly patients undergoing total hip arthroplasty. Comparisons were made with respect to (a) hemodynamic (heart rate and blood pressure) and adrenergic (plasma norepinephrine and epinephrine levels) responses during surgery and recovery; (b) time to extubation after the end of surgery; and (c) postoperative analgesia. No difference was observed between the two groups with respect to demographic data, blood gas tensions, or hemodynamic and adrenergic responses to surgery and recovery. Total doses of opioids used were 0.7 +/- 0.3 micrograms/kg of sufentanil and 6 +/- 2.6 micrograms/kg of fentanyl. Times between end of surgery and extubation were not different (60 +/- 54 min in the fentanyl group and 58 +/- 52 min in the sufentanil group). The number of patients needing postoperative analgesia did not differ between the two groups, but use of analgesia was significantly delayed in the sufentanil group (168 +/- 25 vs 127 +/- 29, P less than 0.05). This study suggests that in elderly patients sufentanil confers a greater residual analgesia than fentanyl in the immediate postoperative period.
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Cardiac responses to catecholamines are known to be attenuated in chronic liver disease. To elucidate the role of beta-adrenergic receptor alteration in this phenomenon, we measured heart rate responsiveness to isoprenaline and myocardial beta-adrenergic receptor-binding characteristics in three groups of rats: those that were sham operated, those that had portal vein stenosis and those that were cirrhotic because of bile duct ligation. Responsiveness to isoprenaline was evaluated in conscious rats by the dose of isoprenaline needed to increase basal heart rate by 50 beats/min and by the maximal heart rate response. beta-Receptor characteristics in heart membranes were derived from 125I-iodocyanopindolol binding data. Compared with sham-operated controls, cirrhotic rats needed a significantly higher dose of isoprenaline to raise basal heart rate by 50 beats/min (102.3 +/- 19.1 vs. 28.3 +/- 11.3 ng/kg) and lower maximal heart rate response (104 +/- 29 vs. 158 +/- 61 beats/min). In addition, myocardial beta-receptor density was significantly lower in cirrhotic rats (26.5 +/- 4.6 vs. 37.5 +/- 10.3 fmol/mg protein) and the dissociation constant was higher (31.6 +/- 17.0 vs. 14.0 +/- 2.5 pmol/L). Analysis of beta 1/beta 2 subpopulations revealed that the decreased total beta-receptor density was entirely due to selective beta 1-receptor down-regulation. beta-Receptor affinity for agonist was not altered in cirrhotic rats. Rats with portal vein stenosis showed no significant differences in either isoprenaline responsiveness or beta-receptor characteristics when compared with controls. These results indicate that beta-adrenergic receptor down-regulation may be responsible for the myocardial hyporesponsiveness to catecholamines observed in cirrhosis.
The pathogenesis of excessive arginine vasopressin (AVP) release and hyponatraemia in euvolaemic intensive care unit (ICU) patients is poorly understood. Stress has frequently been proposed as a possible determinant, but its actual responsibility has not been adequately assessed. Therefore, water-load tests were prospectively performed in 11 patients admitted to the ICU for severe or potentially severe diseases, but who had no other condition which could result in excessive AVP release or impairment of renal diluting ability. Renal diluting ability was normal in 9 patients. Two patients exhibited very slight defects, which might be the consequence of subclinical haemodynamic alterations, since one had a pulmonary embolism and the other manifested a gastrointestinal haemorrhage just after the completion of the water load. Nevertheless, plasma AVP levels decreased in response to the water load in all the patients, resulting in a significant decrease in mean values. Plasma norepinephrine values were found to be elevated both before and after water loading. A highly significant correlation existed between the levels of norepinephrine and those of AVP measured before the load, but was lost after it. In addition, norepinephrine values were markedly elevated in two patients who exhibited strictly normal renal diluting abilities, and no correlation was found between plasma norepinephrine values and any parameter of renal water excretion. Our study shows that the stress of a serious illness and of admission to an ICU does not seem to interfere, by itself, with osmotic regulation of AVP secretion and renal diluting ability, and that sympathetic activation is not, under such circumstances, a predominant stimulus for AVP release.(ABSTRACT TRUNCATED AT 250 WORDS)
Marked cardiovascular responses to esophageal manipulation are commonly observed during transhiatal esophagectomy without thoracotomy. To delineate the mechanism and the time course of these hemodynamic changes, 10 patients undergoing this surgical procedure were studied. Heart rate (HR), mean arterial blood pressure (MAP), pulmonary capillary wedge pressure (PCWP), cardiac output (CO), cardiac index (CI), systemic vascular resistance (SVR), and arteriovenous oxygen content difference (C[a-v]O2) were measured or calculated each time the surgeon's hand entered the thorax to dissect the esophagus. Significant and simultaneous decreases in both MAP and CI were observed in all cases during manipulations (-46% from the baseline value). A significant increase in PCWP also occurred, whereas HR and SVR were unchanged. All parameters returned to control values once manipulation was stopped. The simultaneous decreases in MAP and CI were clearly related to impaired venous return and/or ventricular ejection from manual compression. From these findings, it can be assumed that long-lasting alterations in hemodynamic status could be detrimental to patients with cardiac disease; therefore, careful intraoperative hemodynamic monitoring is advisable. In addition, some patients with advanced cardiac dysfunction may not tolerate these manipulations and may require an open thoracic surgical procedure.
Cardiopulmonary bypass (CPB) has been reported to alter the disposition of numerous drugs and consequently to modify their plasma levels. The present study was designed to delineate the time course of acebutolol (a cardioselective beta-blocker) and diacetolol (its main metabolite) plasma levels in seven patients undergoing myocardial revascularization with hypothermic CPB. All patients were given oral acebutolol twice daily until 3 hours before surgery. Initiation of CPB produced an immediate and significant, but transient, decrease in acebutolol and diacetolol plasma concentrations. Cessation of CPB was not associated with an increase in plasma beta-blocker levels. It is concluded that CPB does not induce major alterations in the time course of acebutolol and diacetolol plasma concentrations.
This prospective study aimed to assess the quality of interpretation by Teaching Hospital anaesthesiologists of preoperative electrocardiograms (ECG). It was carried out over a period of 7 months, and included 500 patients scheduled for elective surgery. The ECG was first interpreted by the anaesthesiologist during the preoperative visit, and later during the postoperative period, by a cardiologist. The two interpretations were compared using the following criteria: minor anomalies, which would not influence the anaesthetic technique already selected; major anomalies, which, on the other hand, are known to increase anaesthetic morbidity and mortality rates, thereby influencing the choice of anaesthetic technique; and interpretative errors concerning only the major anomalies, i.e. anomalies not seen by the anaesthesiologist (false negatives), anomalies found which did not exist (false positives), and erroneous or incomplete interpretation. Interpretation of the ECG by the anaesthesiologist was written on the anaesthetic record for only 156 patients (31.2%). Among the 500 ECG's, 141 were found to be abnormal by the cardiologist (28.2%). Seventy-three of them had 1 or more major abnormalities. Of the 156 ECG's interpreted by an anaesthesiologist, 64 (41%) were abnormal. The overall error rate was 21.1%, the major error rate being 7.1%. The overall false negative rate was 12.8%, with 7 major ischaemic abnormalities (4.5%) having not been found, including 4 (2.6%) diagnostic errors. About 3.8% of ECG's were wrongly interpreted as abnormal by the anaesthesiologist; all errors were of minor importance, but nevertheless responsible for delayed surgery, loss of time, and extra expenditure in laboratory tests.(ABSTRACT TRUNCATED AT 250 WORDS)
Sedation is sometimes required for cardiovascular diagnostic or therapeutic procedures. Midazolam may be proposed in these situations because of its duration of action and because of its moderate haemodynamic effects. However, the use of midazolam implies that the standards of safety required for all anaesthetic techniques have been applied. The changes in haemodynamic data induced by the administration of midazolam must be taken into account in interpretation of the catheterisation report. At the end of investigation, flumazenil can be administered safely to reverse residual sedative effects of midazolam but its use does not exempt from normal monitoring during the recovery period.
Catecholamine-induced desensitization of beta-adrenergic receptors resulting in hyporesponsiveness to further stimulation has been frequently reported after an increase in endogenous catecholamines. To examine the possibility of beta-adrenoceptor desensitization due to intraoperative adrenergic activation (surgical stress), the alterations of human lymphocyte beta-adrenergic receptor density and affinity observed after anesthesia and surgery were studied using (-)125I-iodocyanopindolol binding in 19 patients undergoing noncardiac surgical procedures with general anesthesia (thiopental, fentanyl, and halothane or isoflurane). In 13 patients, repeated determinations of plasma levels of norepinephrine and epinephrine showed an increase during the surgical procedure (norepinephrine +60%; epinephrine +60%); this change was not observed in the remaining patients. A significant postoperative increase in receptor density (Bmax +25%) and a significant decrease of receptor affinity for isoproterenol (IC50 +22%) were found in the patients who experienced intraoperative adrenergic activation. By contrast, no significant change in beta-receptor density or affinity was found in the patients who had normal intraoperative adrenergic activation. In addition, heart rate responses to the postoperative changes in plasma catecholamines (an index of cardiac sensitivity to agonist) were significantly attenuated in patients who experienced both intraoperative adrenergic activation and a decrease in affinity of beta-receptor for agonist, suggesting hyporesponsiveness to beta stimulation. We conclude that beta-adrenergic receptors and, consequently, beta-adrenergic responsiveness might be altered by perioperative adrenergic activation in surgical patients.
Staining with peanut agglutinin (PNA) and with polyclonal antibody to S100 protein have both been recommended as aids in the diagnosis of histiocytosis X (Langerhans' cell histiocytosis). Although a large body of literature attests to the utility of S100 staining in this condition, the few published studies that involve PNA staining have employed varying methods of radically different results. We studied formaldehyde solution-fixed, paraffin-embedded tissue from 29 cases of histiocytosis X by using standard avidin-biotin immunostaining for S100 protein, as well as two published methods of PNA staining. All cases stained positively for S100 protein. By utilizing prior trypsinization and a three-step procedure, all cases also stained with PNA. With a two-step PNA-staining procedure, however, 9 cases failed to stain with PNA, and 3 cases showed a diffuse staining pattern that was not considered characteristic of Langerhans' and histiocytosis X cells. We concluded that both the S100 and the three-step PNA procedures are sensitive methods for the diagnosis of histiocytosis X.
To evaluate whether the function of beta-adrenergic receptors, essential to the biologic activity of catecholamines, is altered during coronary artery bypass grafting, we measured, in 16 patients undergoing myocardial revascularization, the density and the affinity of lymphocyte beta-adrenergic receptors before anesthesia induction (control) and at the end of cardiopulmonary bypass. Variations in the density and affinity of beta-adrenergic receptors were determined in vitro. Repeated determinations of plasma epinephrine and norepinephrine concentrations were also performed. Overall, no significant modification was observed in mean density and affinity of beta-adrenergic receptors at the end of cardiopulmonary bypass when compared with control values. However, a significant decrease (p less than 0.05) in affinity for isoproterenol was found in the six patients who had high catecholamine levels during cardiopulmonary bypass. In contrast, no significant modification of beta-adrenoreceptor affinity for isoproterenol was observed in the 10 patients who did not have this degree of adrenergic activation. In addition, beta-adrenoreceptor affinity for isoproterenol was decreased in the three patients in whom intraaortic balloon pumping was mandatory after discontinuation of cardiopulmonary bypass. We suggest that this decreased affinity of lymphocyte beta-adrenergic receptors could be related, at least in part, to a sustained adrenergic activation occurring in some patients during cardiopulmonary bypass.