Jean Marty

Aging increases pharmacodynamic sensitivity to the hypnotic effects of midazolam.

The effect of aging on the pharmacodynamics of midazolam was investigated in a double-blinded study involving 39 consenting patients ranging in age from 39 to 77 yr. Midazolam was infused intravenously (IV) using a pharmacokinetic model-driven drug infusion device to achieve a plasma midazolam concentration that was held constant for the 10-min duration of the study. Blood samples were obtained from the radial artery at 5 and 10 min for subsequent measurement of the plasma midazolam concentrations. With the 10-min sample, the patients were also assessed for the presence or absence of responsiveness to verbal command. To ensure that the pharmacodynamic end-point was assessed under the condition of a relative steady-state effect-site midazolam concentration, only those patients (n = 33) in whom the plasma midazolam concentration at 10 min was within 30% of the measured concentration at 5 min were included in the subsequent data analyses. Logistic regression was used to fit the verbal command response/no response data to a mathematical model that included patient age and the plasma midazolam concentration measured at 10 min. Cp50, the steadystate plasma midazolam concentration at which 50% of patients would be expected not to respond to a specific stimulus (e.g., verbal command), was calculated as a function of age from the parameterized logistic model. The midazolam Cp50 for response to verbal command decreased significantly (P = 0.034) with increasing patient age, demonstrating that aging increases pharmacodynamic sensitivity to the hypnotic effects of midazolam independent of pharmacokinetic factors. (Anesth Analg 1995;80:143-8)

Severe traumatic head injury in adults: Which patients are at risk of early hyperthermia?

ObjectivePrevention of secondary insults, such as hyperthermia, is a major goal after traumatic brain injury. The aim of our study was to identify risk factors for early hyperthermia in severe head-injured patients.DesignRetrospective cohort study.SettingA 17-bed multidisciplinary ICU of a 700-bed teaching hospital.PatientsA total of 101 adult patients admitted from January 1999 to December 2001 requiring continuous monitoring of intracranial pressure according to international guidelines.Measurement and resultsForty-four patients experienced early hyperthermia (at least one episode of body temperature >38.5°C within the first 2xa0days). On univariate analysis five variables were associated with early hyperthermia: sex; body temperature; white blood cell count on admission; prophylactic use of acetaminophen; and diabetes insipidus within 2xa0days. On multivariate analysis, white blood cell count >14.5×109/l on admission (odds ratio, 7.1; 95% confidence interval, 2.4–20.5; p=0.001) and a body temperature on admission >36°C (odds ratio, 6.7; 95% confidence interval, 2.3-20.1) were strong risk factors of early hyperthermia. Prophylactic use of acetaminophen was negatively associated with early hyperthermia (odds ratio, 0.1; 95% confidence interval, 0.02–0.4). Patients who experienced early hyperthermia were less prone to have good recovery (GOS=5; p=0.03). More patients with severe or moderate disability (GOS=3 or 4) experienced early hyperthermia (p=0.01).ConclusionWe identified a subgroup of patients at high risk of early hyperthermia, which is common in severe head-injured patients. These results could have clinical implications for prevention of hyperthermia after traumatic brain injury in adults.

A comparison of two depths of prolonged neuromuscular blockade induced by cisatracurium in mechanically ventilated critically ill patients

AbstractnObjectives. To compare two levels of continuous cisatracurium-induced curarization in hypoxemic, ventilated patients.nDesign and setting. An open-labeled, multicenter, prospective, randomized study.nPatients. Hundred two patients with a ratio between arterial oxygen tension and inspired oxygen tension (PaO2/FIO2) less than 200 despite optimization of sedation and ventilation were randomized into group 1 (n=52) with an end point of no response at orbicularis oculi to train-of-four (TOF) stimulation or group 2 (n=50) with an end point of two responses.nMeasurements and results. The PaO2/FIO2 and end-inspiratory plateau airway pressure (Pplat) were evaluated at baseline (before curarization) and at regular intervals once TOF end points had been attained for up to 2xa0h afterwards (T2xa0h). A decrease of 1xa0cmH2O or more of Pplat at T2xa0h compared to baseline was observed in 37% and 50% of the patients in groups 1 and 2, respectively (p=0.17). Time courses of PaO2/FIO2 (mmHg) and Pplat (cmH2O) [mean (SD)] were equivalent in both groups, with a mild increase in PaO2/FIO2 [p=0.0014; from 126 (33) to 141 (55) and from 134 (40) to 152 (52), respectively, in groups 1 and 2] and decrease in Pplat [p=0.016; from 29.1 (8.9) to 28.5 (8.8) and from 27.7 (7.5) to 26.6 (7.6)]. Median total durations of curarization were 28.9xa0h (3.1–219.7) in group 1 and 31.4xa0h (1.6–650.6) in group 2. Median cisatracurium infusion rates were 5.2xa0µgxa0kg–1xa0min–1 (2.1–13.7) in group 1 and 3.6xa0µgxa0kg1xa0min–1 (1.0–13.5) in group 2. The median delay to recovery from paralysis was shorter in group 2 (0.75xa0h vs 1.25xa0h; p=0.0008).nConclusion. When a prolonged curarization is decided upon in an ICU patient, a blockade at 2/4xa0at TOF at orbicularis oculi has similar effects on respiratory parameters as a blockade at 0/4, allowing a decrease in total administered doses and a shortening of the recovery of muscle strength after cessation of infusion.

Effects of Midazolam on the Coronary Circulation in Patients with Coronary Artery Disease

The effects of midazolam on coronary sinus blood flow (CSBF), myocerdial oxygen consmption (MVO2), and myocardial laclate balance were investigated in eight 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 content. The determinants of left ventricular (LV) performance were obtained from the cardiac output measured by thermodilution and from left heart catheterization data. All data were obtained before, and 5 and 15 min after midazolam, 0.2 mg kg−1 iv. Sleep was induced in all patients after administration of midazolam and persisted throughout the entire study period. Mean aortic and LV end-diastolic pressure were decreased from control values (−15 and −44%, respectively), as well as cardiac index and stroke index (−10 and −15%, respectively), Heart rate increased moderately (+8%), while no change in systemic vascular resistance and maximum velocity of shortening (Vmax) were observed, Midazolam administration was followed by a decrease of CSBF (−24%) and of MVO2, (−26%). Coronary vascular resistance did not change, but coronary sinus oxygen tension increased slightly, suggesting a mild alteration in normal autoregulation. However, no evidence of myocardial ischemia occurred, as judged by the absence of changes in the: 1) ECG, 2) myocardial lactate extraction, and 3) relaxation time constant. These results suggest tht midazolam may be used safely in patients with coronary artery disease

Beta-adrenergic receptor function is acutely altered in surgical patients.

Catecholamine-induced desensitization of β-adrenergic receptors resulting in hyporesponsivness to further stimulation has been frequently reported after an increase in endogenous catecholamines. To examine the possibility of β-adrenoceptor desensitization due to intraoperative adrenergic activation (surgical stress), the alterations of human lymphocyte β-adrenergic receptor density and affinity observed after anesthesia and surgery Were studied using (−)251I-iodocyanopilldolol 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 β-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 β-receptor for agonist, suggesting hyporesponsiveness to β stimulation. We conclude that β-adrenergic receptors and, consequently, β-adrenergic responsiveness might be altered by perioperative adrenergic activation in surgical patients.

Coronary and Left Ventricular Hemodynamic Responses Following Reversal of Flunitrazepam-induced Sedation with Flumazenil in Patients with Coronary Artery Disease

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.

Acebutolol and diacetolol plasma levels in patients undergoing myocardial revascularization with hypothermic cardiopulmonary bypass

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.