Comparison of the sedative and amnesic effects of midazolam and propofol

OBJECTIVE: To determine normal serum bone-related biochemical variables in older African-Americans. DESIGN: A convenience sample of older African-Americans who had a health screening and blood testing for calciotropic hormones was compared with white Americans who were recruited at the end of the Systolic Hypertension in the Elderly Program (SHEP) study and were not on a thiazide diuretic. SETTING: Community-dwelling African-Americans who participated in SHEP or who attended one of two mass health screenings. PARTICIPANTS: Thirty-two African-Americans aged 68-93 years and 43 white Americans aged 70-89 years. MEASUREMENTS: Twenty-five hydroxyvitamin D (25OHD), parathyroid hormone, osteocalcin, and calcitonin. RESULTS: Serum 25OHD levels in 38% of the African-American men and 38% of African-American women were less than 8 ng/mL compared with 22% of Caucasian men and 40% of Caucasian women. Serum parathyroid hormone (PTH) was above the normal range in 25% of men and 33% of women of African-American descent and 14% of Caucasian men and 30% of Caucasian women. Serum 25OHD was lower (P < 0.05) in individuals with a previous history of fracture. Serum albumin (P < 0.05), calcitonin (P < 0.05), and osteocalcin (P < 0.05), but not 25OHD, were lower in African-Americans (men and women) when compared with Caucasians (P < 0.05). Serum calcium corrected for albumin was higher in the African-Americans than in the Caucasians (P < 0.05). As previously reported in Caucasians, PTH was inversely related to log 25OHD in African-Americans. Serum osteocalcin was positively correlated to PTH in African-Americans, as previously reported in Caucasians. Log 25OHD correlated inversely with osteocalcin in African-Americans, but this was not seen in Caucasians. CONCLUSIONS: In this limited sample, hypovitaminosis D (as assessed by 25OHD level) with secondary hyperparathyroidism occurred frequently in elderly African-Americans. Osteocalcin, a measure of osteoblast activity, correlated with 25OHD and parathyroid hormone. Osteocalcin serum levels were lower in African-Americans than Caucasians, but serum calcium corrected for albumin was higher in the former compared to the latter.     

The effect of propofol on midazolam metabolism in human liver microsome suspension

We have studied the inhibitory effects of propofol on the metabolism of midazolam using human liver microsomes. In addition, we also investigated whether the lipid in which propofol is solubilised inhibits the metabolism of midazolam. Only high concentrations of propofol (> 100 mmol), greater than those found in clinical practice, inhibited the metabolism of midazolam. The lipid had no effect on the metabolism of midazolam. This study differs from other laboratory studies looking at the inhibitory effects of propofol. These showed inhibition at concentrations similar to those seen in patients. The reasons for the differences may be explained by the use of different substrates or methodology. Propofol may be an enzyme inhibitor, but this remains to be shown to be important in patients.     

Effect of atenolol or metoprolol on waking hour dynamics of the QT interval in myocardial infarction

In subjects with a recent acute myocardial infarction, the hour immediately following awakening is associated with an abrupt exaggeration of heart rate-dependent changes and variability of the QT interval. Beta blockers were observed to blunt these waking hour changes.     

Bedside monitoring of the QT interval

Cardiac repolarization, represented on the ECG by the QT interval, is of particular clinical interest in critical care. Once it is measured and corrected for changes in heart rate, the QT interval is known as the QTc. Measurement of the QT interval is important because a prolonged QT interval is associated with ventricular tachycardia and sudden cardiac death. Despite the serious complications associated with a prolonged QT interval, the interval is not routinely measured because a standardized method for measuring it has not been established and the length of QT interval critical to the development of ventricular tachycardia has not been determined. Much has been written about the conditions associated with prolonged QT intervals and specific actions to take when complications appear. Guidelines to be used for QT analysis in the clinical area, based on currently available information, include (1) procedures for measuring QT interval and calculating QTc, (2) procedures for QT analysis, (3) warning signs that indicate increased risk of ventricular tachycardia associated with a prolonged QT interval, and (4) actions to consider once increased risk is determined.     

The prognostic value of the QT interval and QT interval dispersion in all-cause and cardiac mortality and morbidity in a population of Danish citizens

AIMS: To evaluate the prognostic value of the QT interval and QT interval dispersion in total and in cardiovascular mortality, as well as in cardiac morbidity, in a general population. METHODS AND RESULTS: The QT interval was measured in all leads from a standard 12-lead ECG in a random sample of 1658 women and 1797 men aged 30-60 years. QT interval dispersion was calculated from the maximal difference between QT intervals in any two leads. All cause mortality over 13 years, and cardiovascular mortality as well as cardiac morbidity over 11 years, were the main outcome parameters. Subjects with a prolonged QT interval (430 ms or more) or prolonged QT interval dispersion (80 ms or more) were at higher risk of cardiovascular death and cardiac morbidity than subjects whose QT interval was less than 360 ms, or whose QT interval dispersion was less than 30 ms. Cardiovascular death relative risk ratios, adjusted for age, gender, myocardial infarct, angina pectoris, diabetes mellitus, arterial hypertension, smoking habits, serum cholesterol level, and heart rate were 2.9 for the QT interval (95% confidence interval 1.1-7.8) and 4.4 for QT interval dispersion (95% confidence interval 1.0-19-1). Fatal and non-fatal cardiac morbidity relative risk ratios were similar, at 2.7 (95% confidence interval 1.4-5.5) for the QT interval and 2.2 (95% confidence interval 1.1-4.0) for QT interval dispersion. CONCLUSION: Prolongation of the QT interval and QT interval dispersion independently affected the prognosis of cardiovascular mortality and cardiac fatal and non-fatal morbidity in a general population over 11 years.     

Influence of autonomic tone on QT interval duration

The autonomic tone has been shown to influence the duration of the QT interval, however the independent contribution of sympathetic and parasympathetic tone is not fully elucidated. The influence of autonomic tone on QT duration was studied in 10 young healthy volunteers by evaluating the changes in QT and RR duration induced by i.v. isoproterenol infusion and by standing before and after i.v. administration of propranolol or atropine. Furthermore, the relationship between RR interval and QT duration was evaluated during nocturnal sinus arrhythmia and submaximal exercise test. Low doses of isoproterenol reduced RR (p < 0.01) but not QT interval duration, while higher doses influenced both RR (p < 0.0001) and QT (p < 0.001) duration. Propranolol did not influence standing-induced shortening of RR and QT intervals; on the contrary, atropine administration abolished standing-induced QT interval shortening, without influencing RR changes. QT duration resulted significantly related to preceding RR interval at peak exercise (r = 0.87, p < 0.001) and during nocturnal sinus arrhythmia (r = 0.73, p < 0.0005), however, the regression lines showing the correlation between QT and preceding RR interval were different. Both sympathetic and parasympathetic tone appear to contribute to heart rate-independent changes in QT duration. In the basal state parasympathetic more than sympathetic tone influences the relation QT-heart rate. Major increases of sympathetic nervous system activity may change the relation QT-heart rate. Thus, in case of abrupt autonomic changes, any proposed formula for heart rate correction of QT may result inappropriate, also in the normal range of heart rate.     

Effects of hormone replacement therapy on QT interval

We evaluated the electrocardiograms of 208 postmenopausal women (ages 40 to > or = 70 years) without heart disease, medications that could alter the QT interval, use of vaginal estrogens, unknown hormone replacement therapy, or electrocardiographic abnormalities both with (n = 76) and without (n = 132) hormone replacement therapy, and found no significant effects of hormone replacement therapy status on heart rate, QT interval, or the corrected QT interval. Thus, estrogen and/or progesterone effect does not explain the gender differences in myocardial repolarization.     

Normalization of acquired QT prolongation in humans by intravenous potassium

BACKGROUND: QT interval prolongation and dispersion have been implicated in serious arrhythmias in congestive heart failure (CHF) and the congenital and drug-induced long-QT syndromes (LQTS). In a subset of the congenital LQTS, infusion of potassium can correct QT abnormalities, consistent with in vitro increases in outward currents such as I(Kr) or I(Kl) when extracellular potassium concentration ([K+]o) is increased. Furthermore, increasing [K+]o decreases the potency of I(Kr)-blocking drugs in vitro. The purpose of this study was to test the hypothesis that increasing [K+]o corrects QT abnormalities in CHF and in subjects treated with quinidine. METHODS AND RESULTS: KCl (maximum, 40 mEq) was infused into (1) 12 healthy subjects treated with quinidine sulfate (5 doses of 300 mg/5 h) or placebo and (2) 8 CHF patients and age-matched normal control subjects. Mean [K+] increased from 4 to 4.2 mEq/L to 4.7 to 5.2 mEq/L. Potassium infusion significantly reversed QTUc prolongation, especially in the precordial leads (quinidine, 590+/-79 to 479+/-35 [+/-SD] ms(1/2), P<.001; CHF, 521+/-110 to 431+/-47 ms(1/2), P<.05). There was no effect in either control group. Similarly, potassium decreased QTUc dispersion (quinidine, 210+/-62 to 130+/-75 ms(1/2), P<.01; CHF, 132+/-68 to 84+/-35 ms(1/2), P=.07) and was without effect in the control subjects. QT morphological abnormalities, including U waves and bifid T waves, were reversed by potassium. CONCLUSIONS: Potentially arrhythmogenic QT abnormalities during quinidine treatment and in CHF can be nearly normalized by modest elevation of serum potassium.     

The effect of midazolam and propofol on interleukin-8 from human polymorphonuclear leukocytes

Anesthetics and sedatives contribute to postoperative immunosuppression. Interleukin-8 (IL-8) is a chemotactic and activating factor that mediates neutrophil adhesion and margination and is essential for host defense. We investigated the effect of anesthetics on isolated human polymorphonuclear leukocyte production of IL-8. Healthy human polymorphonuclear leukocytes were isolated using a single-step density gradient and stimulated with lipopolysaccharide in the presence of varying concentrations of propofol or midazolam for up to 20 h. IL-8 was measured in both culture supernatants and cell lysates using enzyme immunoassay, and IL-8 mRNA in cells was measured using Northern blotting and phosphorimaging. Data were analyzed using Kruskal-Wallis analysis of variance or the Mann-Whitney U-test as appropriate. Lipopolysaccharide increased extracellular accumulation of interleukin-8, which was suppressed by both propofol (P = 0.025) and midazolam (P = 0.028). However, intracellular IL-8 increased with exposure to lipopolysaccharide (P = 0.028) and remained increased with both anesthetics. Northern blot analysis also revealed increased IL-8 mRNA levels in the presence of both midazolam and propofol, which was confirmed by molecular imaging. These data strongly suggest that the anesthetics modulate transport or secretion of IL-8 protein from the cell. Suppression of IL-8 by anesthetics and sedatives may predispose postoperative and intensive care patients to infection. Implications: Anesthesia causes immune suppression and alters neutrophil function. We investigated the effect of propofol and midazolam on interleukin-8, a neutrophil chemotactic agent in human neutrophils. Both anesthetics decreased extracellular interleukin-8 accumulation, but intracellular levels and mRNA remained high. This suggests that propofol and midazolam alter interleukin-8 secretion from cells.     

Duration of QT interval in clinically normal dogs

The QT interval is the period from onset of the QRS complex to the end of the T wave. The QT interval is useful for monitoring drug (eg, quinidine) and electrolyte (eg, calcium) effects on the heart. It depends principally on heart rate (HR), and the relationship between QT interval and HR has been expressed for human beings and for dogs. The purpose of the study reported here was to quantify that relationship for dogs and to assess whether body weight also influenced QT interval. The ECG was recorded from 17 dogs, ranging in weight between 7 and 25 kg. Dogs were anesthetized with fentanyl/droperidol/ketamine, and HR was accelerated by administration of graded doses of atropine. A significant relationship was not found between QT interval and body weight. Despite changes in HR during sinus arrhythmia, a significant relationship was not found between QT and RR intervals. The QT interval vs HR accelerated by atropine was analyzed for all dogs and for small (7 to 10 kg, n = 5), medium (10 to 20 kg, n = 7), and large dogs (20 to 25 kg, n = 5). Equations relating QT interval to mean HR were calculated for each group. Our data may serve as a baseline with which to compare QT intervals from dogs with heart disease and/or electrolyte imbalance.     

Differential effects of etomidate, propofol, and midazolam on calcium and potassium channel currents in canine myocardial cells

BACKGROUND: Intravenous anesthetics etomidate, propofol, and midazolam produce negative inotropic effects of various degrees. The mechanism underlying these differences is largely unknown. METHODS: The effects of intravenous anesthetics on L-type Ca2+, transient outward and inward-rectifier K+ channel currents (ICa, IKto, and IK1) were compared in canine ventricular cells using the whole-cell voltage-clamp technique. ICa and IK were elicited by progressively depolarizing cells from -40 to +40 mV, and from -90 to +60 mV, respectively. The peak amplitude and time-dependent inactivation rate of ICa and IK were measured before, during, and after the administration of equimolar concentrations (5, 30, or 60 microM) of etomidate, propofol, or midazolam. RESULTS: Exposure to etomidate, propofol, and midazolam produced a concentration-dependent inhibition of ICa. Midazolam was the most potent intravenous anesthetic; at 60 microM, etomidate, propofol, and midazolam decreased peak ICa by 16 +/- 4% (mean +/- SEM), 33 +/- 5%, and 47 +/- 5%, respectively. Etomidate, propofol, and midazolam given in a 60-microM concentration decreased IKto by 8 +/- 3%, 9 +/- 2%, and 23 +/- 3%, respectively. IK1 was decreased by 60 microM etomidate and midazolam by 20 +/- 6% and 14% +/- 5%, respectively. Propofol had no effect on IK1. CONCLUSIONS: At equimolar concentrations, intravenous anesthetics decreased the peak ICa, IKto, and IK1 with various degrees of potency. Effects of anesthetics on ICa were significantly greater compared with their effects on K+ currents. These findings suggest that the negative inotropic actions of etomidate, propofol, and midazolam are related, at least in part, to decreased ICa. Some effects, such as IK inhibition, may partially antagonize effects of decreased ICa. Indeed, the final effect of these intravenous anesthetics on myocardium will be the sum of these and other sarcolemmal and intracellular effects.     

Comparison of midazolam with propofol for sedation in outpatient bronchoscopy

Two children are described who had microphthalmia (one with unilateral and one with bilateral) noted at birth, and whose early onset of poor linear growth and weight gain led to a diagnosis of hypopituitarism prior to two years of age. Both children had growth hormone and thyroid-stimulating hormone deficiencies, and evidence of partial ACTH deficiency. Administration of growth hormone resulted not only in rapid linear growth but it also reversed the poor weight gain and head growth noted in these children. These cases suggest that hypopituitarism and microphthalmia may be associated with each other more frequently than has been recognized previously.     

Prolongation of the QT interval related to cisapride-diltiazem interaction

A liquid chromatographic method was developed for the determination of nanogram quantities of 5 broad-spectrum structurally related beta-lactam antibiotics (cefazolin, cefadroxil, cephalexin, cephradine, and ampicillin) in solution. The method uses a C18 reversed-phase column, UV absorption (240 nm) detection, and an aqueous mobile phase containing isopropyl alcohol and acetic acid. Relative resolution between the antibiotic peaks ranged from 1.7 to 5.9 for all peaks. Chromatographic retention times were 2.97, 3.92, 4.57, 5.37, and 6.56 min for cefazolin, cefadroxil, cephalexin, ampicillin, and cephradine, respectively. Accuracy, precision, linearity, and long term analytical reproducibility were determined by statistical analysis. Use of the proposed method to evaluate the degradation of cephradine solutions stored at room temperature illustrated its potential as a stability-indicating assay.     

The diagnostic value of the rate-corrected QT interval in long-term type-1 diabetes mellitus

OBJECTIVE: To assess the relationship between rate-corrected QT interval (QTc interval) and cardiac reflex tests in order to determine the value of QTc interval measurements in the diagnosis of diabetic cardiac autonomic neuropathy. INVESTIGATIONS: The QTc interval was measured in the resting ECG of 97 type 1 diabetics (58 women, 39 men; mean age 35 +/- 12 years; duration of diabetes 18 +/- 10 years; HbA1c 7.8 +/- 1.8%). Age-related results were compared with five cardiac function tests (heart rate variation at rest and on forced breathing; 30/15 ratio of heart rate; Valsalva manoeuvre; orthostasis). RESULTS: The QTc interval was not prolonged ( < or = 440 ms) in 68 patients (70%), while in 29 (30%) it was prolonged ( > 440 ms). No significant differences regarding QTc interval were found between patients with autonomic cardiac neuropathy ( > or = 2 abnormal function tests) and those without ( < 2 abnormal function tests) (QTc interval 436 +/- 25 vs 426 +/- 19 ms). QTc intervals correlated with the coefficients of variation for heart rate variation at rest and on forced breathing and the 30/15 ratio of heart rate (p = 0.001; p = 0.001; p = 0.03), but not with the results of the Valsalva manoeuvre and the orthostasis test. CONCLUSION: Prolongation of the QTc interval in longstanding type 1 diabetes does not provide a reliable indication of cardiac autonomic neuropathy and this measure cannot replace conventional reflex tests for its diagnosis.     

Measurement of the QT interval and the risk associated with QTc interval prolongation: a review

The accurate measurement of the QT interval and its correction or adjustment for cycle length, age, and gender have been topics of increasing interest over the course of the past 70 years. The availability of digitized electrocardiographic recordings on large normal populations together with statistical adjustment for pertinent covariates has provided useful data for defining QT interval prolongation. Data from the International Long QT Syndrome Registry indicate that the probabilistic risk of developing malignant arrhythmias in patients with QT prolongation is exponentially related to the length of the QTc interval. The risk is further accentuated by the development of T-wave alternans, particularly at very prolonged QTc intervals.     

Corrected QT interval in relation to the severity of diabetic autonomic neuropathy

The aim of this study was to investigate to what extent the existence of objective signs of diabetic autonomic neuropathy affects the corrected QT interval (QTc) in diabetic subjects. A total of 105 diabetic subjects (type 1, n = 53; type 2, n = 52) as well as 40 matched (by age and sex) control subjects were studied. All subjects underwent the battery of five Ewing tests. Autonomic neuropathy was diagnosed if two of the five tests were abnormal. In addition, the result of each test was considered as normal (grade = 0), borderline (grade = 1) or abnormal (grade = 2), and on the basis of the sum of the scores we calculated a total score for autonomic neuropathy. The QTc interval was measured at rest, and a value > 440 ms was considered abnormal. The QTc interval was significantly more prolonged in diabetic persons with autonomic neuropathy than in those without neutopathy and in control subjects: 408.4 +/- 24.2 ms vs. 394.6 +/- 27.9 ms and 393.6 +/- 25.5 ms respectively (P = 0.001). Furthermore, multivariate analysis controlling for age, sex, systolic and diastolic blood pressure, body mass index (BMI), waist-hip ratio (WHR), smoking, type and duration of diabetes, type of treatment, HBA1c and total score of autonomic neuropathy eliminated the role of all these factors as potential confounders except for the total score of autonomic neuropathy, which was found to affect QTc interval independently and significantly (P = 0.012). In summary, the present study confirmed the well-known relation between autonomic neuropathy and QTc interval; in addition, it showed that QTc prolongation is associated with major degrees of autonomic neuropathy.     

The dose-dependent effects of oral premedication with midazolam

OBJECTIVE: The aim of this study was to examine the psychological effects, well-being and side effects after various doses of oral midazolam medication. METHODS: After informed consent has been obtained and following the approval by the institutional ethical committee, 80 adult patients in the ASA physical status I and II were randomly assigned to one of five different premedication groups: 3.75, 7.5, 11.25, 15 mg midazolam, and placebo. The medication was given in a double-blind fashion 60 min before induction of general anaesthesia for various surgical procedures. At 3 definite stages (before premedication, 30 and 60 min after premedication), blood pressure, heart rate, transcutaneous oxygen saturation and respiratory rate were measured. Sedation and well-being were graded according to a 5-point scale, and the subjective anxiety level was assessed according a visual analogue scale (range 0-100 mm). Anterograde and retrograde amnesia were measured by recall of auditive and visual stimuli. Finally, patients were asked whether in case of future surgery they would prefer the same or a different medication. RESULTS: Demographic data were similar in all groups. There was no significant difference in respiratory rate, oxygen saturation, blood pressure or heart rate. Alertness declined only after 60 min in the groups treated with 7.5 mg and more midazolam. During the entire measurement period, anxiolysis was not different from placebo in any of the midazolam groups. In comparison to placebo, all midazolam groups showed a statistically significant and dose dependent anterograde amnesia for visual stimuli. Subjective well-being scores showed no differences between the groups. Only few side effects were seen following doses of 7.5 mg and higher, including ptosis, strabismus, diplopia, speech disorders, disorientation and vertigo. The majority of patients in all groups indicated a wish for the same medication in case of future anaesthesia for surgical interventions. CONCLUSIONS: Midazolam administered orally prior to surgical procedures showed marked interindividual variability. Sedation and amnesia were dose-dependent and were evaluated by the patients as acceptable. Anxiolysis was not significantly different from placebo. A dose of 7.5 mg midazolam showed the best relation between desirable and undesirable effects. Adequate attention given to the patient by the anaesthesiologist prior to surgery seems to be as important and beneficial as oral medication with midazolam.