Stability of parenteral nutrition admixtures containing organic phosphates.

The use of organic phosphates to avoid calcium phosphate precipitation in parenteral nutrition mixtures has been proposed. The purpose of this study was to evaluate the stability of total parenteral nutrition admixtures containing glucose-1-phosphate or glycerol phosphate as the phosphate source over 3 days. Three parenteral nutrition admixtures, each containing glucose-1-phosphate (30.0 mmol), glycerol phosphate (31.4 mmol) or inorganic phosphate (30.0 mmol), and their corresponding aqueous phases were prepared in 3-L ethylene vinyl acetate plastic bags and infusion bottles, and stored at 5 +/- 1 degrees C or 22 +/- 3 degrees C without light protection. Physical stability analysis and sampling for chemical analysis was performed at 0, 24, 48 and 72 h. Aqueous phases were subjected to physical stability analysis, including pH measurement, visual inspection and nephelometry. Admixtures were subjected to physical stability analysis consisting of pH measurement, and evaluation of emulsion stability by visual inspection, degree of creaming, phase contrast microscopy, zone sensing technique and photon correlation spectroscopy. Chemical analyses of amino-acids, dextrose, triglycerides, phospholipids, Na, K, Cl, Mg, Ca, glucose-1-phosphate, glycerolphosphate and inorganic phosphate were performed. No precipitation was detected in any of the aqueous phases. Admixtures remained acceptable with respect to visual and microscopic appearance, mean droplet diameter and droplet size distribution. All nutrient concentrations assayed in the three admixtures remained constant over the study period. Total parenteral nutrition admixtures for adult patients containing glucose-1-phosphate or glycerolphosphate are physically and chemically stable for 3 days when stored under refrigeration or controlled room temperature without light protection.

Randomised double-blind clinical trial of intermediate- versus high-dose chloral hydrate for neuroimaging of children.

Orally administered chloral hydrate is the most widely used sedative in children undergoing MRI. We compared intermediate- and high-dose oral chloral hydrate in 97 consecutive children undergoing MRI in a prospective, controlled, double-blind, randomised clinical trial. There were 50 girls and 47 boys, mean weight (+/- SD) 14.7 +/- 6.4 kg, and mean age 38 +/- 31. The children were randomly allocated to receive chloral hydrate syrup either 70 mg/kg (group A, n = 50) or 100 mg/kg (group B, n = 47). These two groups were not significantly different in sex, weight, age, diagnosis or ambulatory medication. The mean initial dose (+/- SEM) was 64 +/- 2 mg/kg for group A and 93 +/- 2 mg/kg for group B. Because adequate sedation was not achieved, 14 patients in group A and 6 in group B required a second dose, giving a mean total dose of 70 +/- 2 mg/kg for group A and 96 +/- 2 mg/kg for group B. The percentage of successful examinations after the initial dose (A: 64%, B: 87%; p < 0.05) and the total dose (A: 92%, B:100%; p = 0.14) was higher in group B. Significant differences were found for the time of onset of sedation (A:28 +/- 2 min, B: 21 +/- 1 min; p < 0.05), but not for the time to spontaneous awakening after the completion of the examination. The rate of adverse reactions was similar (A: 20%, B: 21%; p = 1.00). We conclude that high-dose oral chloral hydrate improves the management of children undergoing MRI.

Expanded gentamicin volume of distribution in critically ill adult patients receiving total parenteral nutrition.

Aminoglycoside antibiotics distribute into the extracellular fluid compartment and are eliminated by the kidney via glomerular filtration. Malnutrition and total parenteral nutrition influence the fluid and electrolyte status of the patient, and cause organ changes. The purpose of this clinical study was to characterize the kinetic behaviour of gentamicin in the parenterally fed critically ill adult patient. Eighty-six critically ill adult patients treated with gentamicin for severe Gram-negative infections were enrolled in the study (mean +/- SD): age, 60 +/- 14 years; weight, 69.4 +/- 10.2 kg; height, 163 +/- 10 cm; 22 females and 64 males. Four study groups were defined (2 x 2): total parenteral nutrition vs. fluid therapy, and acute renal failure vs. normal renal function. The drug was administered by intermittent intravenous infusion. Blood samples were drawn at steady-state, 5 min before the next dose ('trough') and 30 min after the termination of the infusion ('peak'). Gentamicin serum concentration was determined by fluorescence polarization immunoassay. Gentamicin pharmacokinetic parameters were estimated by non-linear regression analysis, assuming a one-compartment model and first-order elimination from the central compartment. Treatment of malnutrition with total parenteral nutrition increased gentamicin volume of distribution (P < 0.001), but did not affect total body clearance (P = 0.75). This change tended to produce lower peak concentrations (< 4 micrograms/ml, P = 0.07), thus potentially compromising therapeutic effectiveness. There was no significant influence on trough concentrations (P = 0.56). Patients receiving fluid therapy had a volume of distribution of 0.34 +/- 0.08 litre/kg, while those fed by the intravenous route showed larger values (0.43 +/- 0.12 litre/kg), irrespective of their renal function. This may be explained by the extracellular water expansion caused by stress, malnutrition, and parenteral refeeding. Gentamicin dosage regimens in critically ill adult patients on total parenteral nutrition should be formulated on the basis of larger volumes of distribution and to attain therapeutic serum concentrations higher doses may be required.

Critically-ill patients receiving total parenteral nutrition show altered amikacin pharmacokinetics.

The purpose of this clinical study was to characterise the kinetic behavior of amikacin in the parenterally-fed critically-ill adult patient. 22 critically-ill adult patients treated with amikacin (15.5 +/- 7.9 mg/kg/day) for severe gram-negative infections were enrolled into a non-randomised control trial. Malnourished patients were administered total parenteral nutrition (TPN, n = 11), while well-nourished patients received fluid therapy (FT, n = 11). Amikacin pharmacokinetic parameters were estimated by non-linear regression analysis, assuming a one-compartment model and central first-order elimination. Patients receiving TPN showed an expanded amikacin distribution volume (0.403 +/- 0.0961/kg vs. FT 0.298 +/- 0.083 l/kg, p < 0.05), and a tendency towards increased total body clearance (0.089 +/- 0.029 l/kg/h vs. FT 0.069 +/- 0.0201/kg/h, p = 0.09). TPN produced lower peak concentrations (19.3 +/- 3.1 mcg/ml vs. 23.1 +/- 3.5 mcg/ml, p < 0.05), but had no significant influence on trough concentrations (p = 0.56). Patients on TPN also showed increased body temperature (p < 0.05) and fluid intake (p < 0.05), and decreased hematocrit (p < 0.05). Stress, malnutrition, parenteral nutrition itself, fluid and osmotic overload, and fever often occur concurrently in parenterally-fed patients and appear to produce lower amikacin serum levels. Consequently, critically-ill patients receiving TPN need higher amikacin doses and individualised treatment by monitoring serum concentrations, to ensure optimal therapeutic response.

[Oligoamnios associated with the use of magnesium dipyrone]. / Oligoamnios asociado al uso de dipirona magnésica.

Oligohydramnios induced by indomethacin has been documented both clinically and experimentally. The same is not true for all the drugs inhibiting the synthesis of prostaglandins. The case of a full term pregnant woman diagnosed with renal cholic and treated with high doses of magnesium dipyrone who developed echographically diagnosed oligohydramnios at 60 h of initiation of the treatment is presented. Delivery was induced by the double intracervical application of 0.5 mg of prostaglandin E2 over an interval of 24 h. At 35 h of the discontinuation of magnesium dipyrone the patient was echographically reevaluated with the volume of the amniotic fluid being found to be normal. Although no reports have been found concerning oligohydramnios by magnesium dipyrone, the negative effect of this drug on urine flow in healthy individuals is known. In the absence of other hypotheses, the authors suggest that the use of high doses of this drug may significantly reduce fetal urine flow and be responsible for a drastic reduction in amniotic fluid. The adverse effect was determined as possible by evaluation of secondary effects by Naranjo's algorithm.

Oral chloral hydrate provides effective and safe sedation in paediatric magnetic resonance imaging.

Sedation is routinely required for successful Magnetic Resonance imaging in infants and children. Five hundred and ninety-six paediatric patients (270 female and 326 male, age (mean +/- SD) 41 +/- 30 months and weight 14.8 +/- 6.5 kg) entered an open, non-comparative, prospective study to assess oral chloral hydrate sedation in a large and homogeneous paediatric population undergoing Magnetic Resonance imaging. Chloral hydrate syrup 70 mg/ml was administered 20-40 min prior to the procedure. Effective sedation was reached in 94.1% with a total dose (mean +/- SEM) of 68 +/- 1 mg/kg (range 20-170 mg/kg). Statistical analysis of sedation failures vs. successful examinations after the total dose showed significant differences for dose (62 +/- 4 vs. 69 +/- 1 mg/kg; P < 0.05), age (64 +/- 7 vs. 40 +/- 1 months; P < 0.001) and weight (19.8 +/- 1.5 vs. 14.5 +/- 0.0 kg; P < 0.001). Effectiveness fell to around 80% in children with encephalic white matter alterations, medullary tumours or syringohydromyela (P = 0.07). The mean time of onset of sedation was 26 +/- 1 min, and the mean time to spontaneous awakening after the completion of the Magnetic Resonance examination was 38 +/- 2 min. Fifty-nine children (9.9%) experienced adverse reactions, with nausea and vomiting being the most common (n = 41), followed by nervousness and unusual excitement (n = 6). Discriminant function analysis identified age and total dose as the quantitative variables helping to differentiate between sedation failures and satisfactory examinations (sensitivity = 0.73, and specificity = 0.61; r = 0.20, P < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Selection of optimal prophylactic aminoglycoside dosage in cancer patients: population pharmacokinetic approaches.

We report an alternative dose-finding approach for the selection of optimal prophylactic aminoglycoside dosage in specific (sub)populations of patients. Relative a priori utility of several intervals of gentamicin or tobramycin (AMG) peak and trough serum levels were assigned by a group of pharmacokinetics experts, assuming prophylactic administration for laryngectomy interventions. A group of 27 adult patients, with normal renal function, undergoing elective surgery for laryngeal problems and treated prophylactically with gentamicin (80 mg t.i.d.) or tobramycin (100 mg t.i.d.) was studied. Two blood samples (peak and trough) were drawn at steady-state for AMG assay. Three different methods, standard two-stage (STS), extended least-squares non-linear regression [MULTI(ELS)] and non-parametric expected maximization (NEPM), were used to estimate the pharmacokinetic (PK) population parameters. PK simulations were applied to estimate the AMG steady-state concentrations from the PK population parameters. From these data, relative utility values were calculated, allowing the selection of the optimal dosage schedule for this group of patients. There were no statistically significant differences between the PK population estimates as generated by the three methods. Using the STS estimates, the simulation of several dosages indicated that the optimal dosage is 170 mg every 8 h. Conversely, using the individual PK parameters and the mean AMG levels simulated from them, the dose with best relative utility is 130 mg every 8 h. This important difference points out the relevance of the use of relative utilities for the AMG serum concentrations in the selection of optimal a priori dosage. We propose the use of 120 mg every 8 h as the safer dose for our population. Further studies are needed to validate this proposal in patients similar to ours.

Pharmacokinetic interaction between high-dose methotrexate and amoxycillin.

A case report of toxicity following concurrent administration of high-dose methotrexate and amoxycillin is presented. A 16-year-old male patient was administered 10 high-dose methotrexate cycles for treatment of a fully malignant osteogenic sarcoma. Methotrexate was administered at a dosage of 8 g/m2 and infused intravenously over a 6-h period. The patient received pre- and posttreatment hydration and sodium bicarbonate for alkalinization of urine. Calcium folinate rescue was performed when appropriate. During the 10th cycle, coadministration of amoxycillin (1 g/6 h, p.o.) resulted in prolonged and marked enhancement of methotrexate serum levels. Pharmacokinetic parameters obtained in cycle 10 indicate significant differences for total plasma clearance, mean residence time, and distribution half-life when compared to those in cycles 1-9. Amoxycillin decreased the renal clearance of methotrexate, probably by competition at the common tubular secretion system and by secondary methotrexate-induced renal impairment. The patient experienced acute and subacute toxicity with renal failure, myelosuppression, mucositis, nausea, vomiting, fever, and dermatologic abnormalities. Patients receiving amoxycillin during methotrexate therapy should be closely monitored to avoid severe toxicity.

Administration of oral chloral hydrate to paediatric patients undergoing magnetic resonance imaging.

Sedation is frequently required in children undergoing magnetic resonance imaging (MRI). 172 Paediatric patients (82 female and 90 male, age 42 +/- 26 months, weight 14.7 +/- 5.6 kg) entered an open, non-comparative, prospective study to assess the utilization of oral chloral hydrate. Chloral hydrate syrup (70 mg/ml) was administered 20-30 min prior to the procedure. Effective sedation was reached in 80.3% with an average initial dose of 55 mg/kg and in 93.6% with an average total dose of 65 mg/kg. Significant differences in effectivity were correlated with the dose (54 +/- 11 mg/kg in failure cases versus 66 +/- 16 mg/kg in effective cases; p < 0.05) and diagnosis (effectivity falls to 62.5% and 76.0% in children with medullar tumours and encephalic white matter alterations, respectively; p < 0.01). Average sleep induction time was 30 +/- 19 min, and average duration of sleep was 62 +/- 24 min. Adverse reactions occurred in 4.7%, with nausea, vomiting and stomach pain being the most common side-effects (3.5%). Multivariate statistical analysis selects total dose and age into the discriminant function, with a 100% relative percentage of correct classification. A simple method for optimizing the chloral hydrate dose in children is proposed: the dose in mg/kg is calculated as half the age in months + 50.

Population pharmacokinetics of gentamicin in premature infants.

The population kinetics of gentamicin were studied in 97 newborn patients with a gestational age ranging between 28 and 43 weeks and a postnatal age ranging between 2 and 30 days undergoing routine therapeutic monitoring of their serum gentamicin levels. The individual kinetic analysis of serum drug levels was performed using a single-compartment model. The clearance and apparent distribution volume were calculated in each patient. The population model employed assumes the existence of residual variability in the serum concentrations and interindividual variability in the pharmacokinetic parameters. The effects of demographic variables on the clearance, distribution volume, and optimum daily dose of gentamicin were established using multiple linear regression. Gestational age is the best predictive variable of the clearance and the optimum dose/day in the whole population studied. In the premature infant patients, the predictive capacity increases with postconceptional age. Weight is a good predictive variable of all of the parameters, especially of the apparent distribution volume in the overall population of newborns. Analysis of the population kinetic behavior and optimum dose/day in each subgroup recommends that the interval of drug administration should be increased, keeping the same dose/day ratio, due to the tendency of the drug to accumulate its long half-life, especially in premature babies.