No influence of large volume blood loss on serum vancomycin concentrations during orthopedic procedures.

We prospectively studied orthopedic patients with either large or small blood loss who also received vancomycin prophylaxis to determine the effect of intraoperative volume shifts on serum vancomycin concentrations. There were 6 index patients in the large blood loss group (greater than 2 L), and 7 in the control group (less than 2 L). Mean estimated blood loss for index and controls was 4.4 L and 1.0 L, respectively. Mean intraoperative fluid resuscitation, excluding blood products, was 12.4 L and 5.1 L, respectively. There was a modest inverse correlation between blood loss and intraoperative serum half-life of vancomycin. Although controls maintained slightly higher intraoperative vancomycin concentrations at each time-point, there was no statistically significant difference between the groups with regard to absolute concentrations or rate of decline. After 8 hours, the serum vancomycin concentration exceeded the MIC-90 for Staphylococcus aureus by approximately eightfold in all but one case patient. This was a morbidly obese patient with massive blood loss. Thus, blood loss during orthopedic procedures has minimal effects on intraoperative kinetics of vancomycin. Redosing is rarely indicated, although a preoperative 1.5 gram-dose should be considered for patients weighing more than 90 kg.

Diltiazem improves resuscitation from experimental ventricular fibrillation in dogs.

OBJECTIVE: To determine the effect of diltiazem on survival immediately after cardiac arrest and cardiopulmonary resuscitation (CPR) in dogs. DESIGN: Prospective, double-blind, randomized trial. SETTING: Laboratory at a large, university-affiliated medical center. SUBJECTS: Twenty-eight mongrel dogs, weighing 12 to 16 kg. INTERVENTIONS: After the administration of anesthesia, catheters were placed in the pulmonary artery, aortic arch, left ventricle, right ventricle, and great cardiac vein (12 dogs) for sample collection, pressure determinations, and induction of ventricular fibrillation. Dogs were randomized to receive either diltiazem, calcium chloride, or placebo (saline) either before or early during CPR. Dogs underwent 3 mins of unassisted fibrillatory arrest followed by 10 mins of standard CPR using a pneumatic device. After 13 mins of ventricular fibrillation, defibrillation was attempted repeatedly for less than or equal to 10 mins. Successful resuscitation was defined as an organized rhythm with an unassisted systolic BP of greater than 60 mm Hg for greater than or equal to 2 mins. MEASUREMENTS AND MAIN RESULTS: The resuscitation rate was significantly greater in diltiazem-treated animals (100%) than in those dogs receiving calcium (57%) or placebo (29%). Diltiazem-treated animals were resuscitated faster and required fewer defibrillation attempts than did dogs in the other groups. During CPR, coronary artery perfusion pressure and blood gases (arterial, venous, and myocardial) were similar among treatment groups. CONCLUSIONS: Diltiazem improves the resuscitation from experimentally induced ventricular fibrillation when administered before or early during CPR. This response may have important clinical implications in the treatment of patients undergoing cardiac arrest and CPR.

The effect of CPR on plasma diltiazem concentrations in dogs.

STUDY OBJECTIVE: To determine the effect of cardiac arrest with CPR on diltiazem concentrations in dogs. DESIGN: Prospective, double-blind, randomized trial. SETTING: Laboratory at a large university-affiliated medical center. TYPE OF PARTICIPANTS: Twenty mongrel dogs. INTERVENTIONS: Following administration of anesthesia, catheters were placed in the pulmonary artery, aortic arch, left ventricle, and right ventricle. Dogs were randomized to receive diltiazem (0.5 mg/kg) either 60 minutes before or during cardiac arrest with CPR. After 13 minutes of cardiac arrest, defibrillation was attempted. MEASUREMENTS AND MAIN RESULTS: Frequent blood samples for diltiazem concentrations were obtained before, during, and after cardiac arrest. The mean diltiazem concentration rose 70% during CPR in the group that received diltiazem before cardiac arrest. The group that received diltiazem during CPR had concentrations five times greater than expected during sinus rhythm. CONCLUSION: Increased diltiazem concentrations are observed during CPR and are probably related to altered distribution encountered during CPR.

Cranial postoperative site: assessment with contrast-enhanced MR imaging.

To define duration and patterns of postoperative contrast material enhancement, the authors evaluated magnetic resonance (MR) images obtained with gadolinium diethylenetriaminepentaacetic acid (DTPA) in 46 patients who had undergone major intracranial surgery. Intervals between surgery and MR imaging ranged from 1 day to 40 years (median, 1.3 years). Moderate or marked brain and dural enhancement was noted in nearly every patient imaged within 3 months of surgery, but all brain enhancement was gone by 1 year. Abnormal dural enhancement was noted in every patient imaged within 1 year of surgery and in approximately 50% at 1-2 years afterward. One patient had persistent mild enhancement of the dura 40 years after surgery. MR images revealed enhancement in several sites not frequently recognized on computed tomographic (CT) scans. Brain and meningeal enhancement with Gd-DTPA at cranial operative sites was more extensive and persisted much longer than is commonly seen on contrast-enhanced CT scans. Enhancement of the brain or pia mater does not normally last beyond 1 year, but dural enhancement may persist for decades.

Sexual dimorphism of the human corpus callosum studied by magnetic resonance imaging: fact, fallacy and statistical confidence.

Magnetic resonance (MR) imaging was performed in 120 normal right-handed individuals (60 males, 60 females) to clarify existing contradictory data concerning possible sexual dimorphism of the human corpus callosum (CC). Five linear and three area measurements of the CC and brain were obtained directly at the MR scanner console from midline sagittal T1-weighted images. The anteroposterior length of the CC was significantly larger in males than in females (p = 0.0005). No other differences in absolute callosal measurements between the sexes could be demonstrated. However, several size ratios did achieve statistical significance (p less than 0.05), being consistently larger in females: splenial width/length CC, splenial width/brain length, and area of CC/area of brain. Where no statistically significant differences were obtained, precision, tolerance, and confidence interval calculations are presented. The data in this large series support a limited but definite sexual dimorphism of the CC in right-handed individuals.

Clinical pharmacokinetics of controlled-release disopyramide in patients with cardiac arrhythmias.

UNLABELLED: The pharmacokinetics of the controlled-release preparation of disopyramide phosphate (Norpace CR, Searle Laboratories, Chicago, IL) were studied in ten patients with cardiac arrhythmias. Multiple-serum disopyramide concentrations were obtained after a 300-mg oral dose. Each patient then received chronic oral therapy with the controlled-release preparation (400 to 1000 mg/day) on an every-12-hour schedule. At steady state, disopyramide trough concentrations were obtained. Serum disopyramide concentrations were determined by high performance liquid chromatography. The regimen was well tolerated by all patients. The mean (+/- SD) time to maximum concentration, maximum concentration, and concentrations 11 and 24 hours after the initial dose were 5.5 +/- 1.3 hours and 2.8 +/- 0.8, 2.0 +/- 0.9, and 1.2 +/- 0.5 micrograms/mL, respectively. A low Cmax to trough concentration ratio of 1.35 +/- 0.26 was observed after the initial dose. Linear regression analysis of the serum disopyramide concentrations 11 hours after initial dose (trough) versus trough concentrations at steady state (dose adjusted) showed a strong correlation (r = 0.87, intercept = 0.03, and slope = 1.9). Regression analysis also showed a strong relationship between the area under the curve (AUC) from time 0 to 11 hours after the initial dose and the trough at steady state (r = 0.86). CONCLUSIONS: The controlled-release preparation of disopyramide, when administered every 12 hours in patients with cardiac arrhythmias, should produce low peaks to trough fluctuations. Because disopyramide concentrations after the initial dose correlate well with trough concentrations at steady state, these concentrations may provide a simple and convenient method for prospective monitoring of disopyramide therapy in patients receiving the controlled-release preparation.

Transfer from immediate-release disopyramide to controlled-release disopyramide.

Simulation of serum disopyramide concentrations during transfer from steady-state immediate-release (IR) disopyramide to a sustained-release disopyramide preparation was performed based on pharmacokinetic parameters obtained from IR disopyramide and serum concentrations measured following an initial dose of controlled-release (CR) disopyramide phosphate. Based on the results of simulation, a typical patient with good cardiac, renal, and hepatic function can be transferred from a q 6 h IR disopyramide to an equivalent daily dose of controlled-release disopyramide administered q 12 h beginning at 6 hours after the final IR disopyramide dose.

Antifibrillatory effects of lidocaine and bretylium immediately postcardiopulmonary resuscitation.

The antifibrillatory effects of lidocaine and bretylium in the postcardiopulmonary resuscitation (CPR) setting were examined using ventricular fibrillation threshold (VFT) determinations in anesthetized dogs. The dogs were fibrillated and CPR was carried out with a pneumatic device. Lidocaine and bretylium were administered intravenously at the onset of CPR, and VFT was serially determined after defibrillation following three consecutive 3-minute CPR periods. A dose of 2 mg/kg of lidocaine caused a significant increase in VFT determinations after the first but not subsequent 3-minute CPR periods; a dose of 1 mg/kg of lidocaine was ineffective at any time point. A dose of 5 mg/kg of bretylium elevated the VFT after the second and third but not the first 3-minute period. In dogs who received lidocaine, a significant elevation of VFT determinations were found to be associated with a high blood lidocaine concentration (mean 13.8 +/- 8.3 micrograms/ml). The present study demonstrates that a 2 mg/kg dose of lidocaine administered during CPR rapidly increases VFT determinations after CPR (within 5 minutes), whereas, a 5 mg/kg dose of bretylium significantly elevates VFT determinations but at a later time (within 10 minutes). The observed significant effect of lidocaine appears to be associated with high lidocaine blood concentrations (greater than 6 micrograms/ml).

Predicting plasma procainamide concentrations resulting from a sustained-release preparation.

Two methods of predicting plasma procainamide concentrations (PPCs) for a sustained-release procainamide (SRP) dosage form were compared using previously published data on 12 healthy subjects. Methods A and B were both based on a one-compartment pharmacokinetic model requiring an elimination rate constant and area under the concentration-time curve from an immediate-release oral procainamide dosage form and in vitro dissolution data from the SRP product. Method A also used an absorption rate constant. The predicted versus measured PPCs for two sets of peak and trough concentrations in each subject were evaluated using linear regression. The mean predicted PPCs by both methods followed the measured PPCs closely; however, the time of peak concentration was predicted more accurately by method A. The evaluation of predictive performance showed good precision and a small but statistically significant bias with either method, peak values were overpredicted and trough values were underpredicted. These two methods adequately predicted plasma procainamide concentrations in healthy subjects following a sustained-release procainamide preparation.