Pharmacokinetics of continuous infusion fentanyl in newborns.

Although fentanyl administration by continuous infusion in newborns during ventilatory support has increased, pharmacokinetic data are lacking. Our objective was to determine the pharmacokinetics of fentanyl continuous infusions for sedation/analgesia in newborns who had undergone mechanical ventilation. Fentanyl was administered per routine care in seven newborns who had undergone mechanical ventilation and had normal hepatic, renal, and cardiac function. Five blood samples were collected from each newborn's umbilical artery catheter. Sample 1 was obtained at > or = 36 hours after constant fentanyl was infused, and sample 2 was collected 12 hours later. Fentanyl was then discontinued and meperidine given. Additional samples were obtained 6, 12, and 24 hours after fentanyl was discontinued. Decanted plasma was stored at -20 degrees C until gas chromatography analysis was performed. Total body clearance (TBC), elimination half-life, and volume of distribution at steady state were determined. Patient weights were 1.88 +/- 1.12 kg (mean +/- SD) with postnatal age 16 +/- 9 days; the mean gestational age was 32 +/- 4 weeks. Mean final fentanyl dosage was 1.28 +/- 0.58 microgram/kg/hr (range 0.53 to 1.9 micrograms/kg/hr). Mean elimination half-life was 9.5 +/- 2.6 hours (range 5.7 to 12.7 hours), and volume of distribution at steady state was 17 +/- 9 L/kg (range 10.1 to 30.3 L/kg). Mean TBC was 1154 +/- 494 ml/kg/hr (range 565 to 2000 ml/kg/hr). Significant correlation between postnatal age and TBC occurred (r = 0.80; p = 0.03). Newborns were hemodynamically stable during the sampling period. We found an increased volume of distribution at steady state and prolonged elimination half-life compared with single-dose administration in newborns. TBC was similar to reported values for infants and young children but was higher than for older patients.

Critical pathways: the time is here for pharmacist involvement. American College of Clinical Pharmacy.

Successful development, implementation, and assessment of the effectiveness of critical pathways involves many processes and tools. Numerous pathways have been developed and the value of this tool in improving patient care has been demonstrated in some patient groups.27,29 Pharmacists are becoming more involved, but the window of opportunity is small. Critical pathways are routinely being utilized to optimally sequence time-appropriate interventions of the interdisciplinary plan of care set forth to achieve patient satisfaction and desired outcomes. Pharmacists must seize the chance to provide pharmaceutical care and assure their participation in the development and implementation of critical pathways.

Phenytoin protein binding and dosage requirements during acute and convalescent phases following brain injury.

OBJECTIVE: To longitudinally evaluate unbound and total serum phenytoin concentrations during intravenous phenytoin maintenance dosage and to determine the relationship among phenytoin protein binding, serum albumin, and unbound fatty acid concentrations in patients with head injuries during intensive care unit (ICU) and convalescent care. DESIGN: Serum albumin and phenytoin unbound fraction were determined twice weekly during ICU and convalescent care in 10 patients receiving phenytoin following acute brain injury. Phenytoin protein binding was also determined in 10 healthy control subjects. MAIN OUTCOME MEASURES: Longitudinal serum phenytoin concentrations associated with dosage adjustments targeted to achieve unbound phenytoin serum concentrations between 1.0 and 2.0 mg/L were documented during ICU and convalescent care. Longitudinal phenytoin binding was correlated with serum albumin and unbound fatty acid concentrations in neurotrauma patients. RESULTS: ICU patients received intravenous therapy for a mean of 15.0 days. The mean +/- SD initial phenytoin intravenous dosage regimen of 6.0 +/- 0.7 mg/kg/d resulted in mean +/- SD total and unbound phenytoin concentrations of 3.2 +/- 2.3 and 0.3 +/- 0.2 mg/L. Two patients had seizures associated with low phenytoin concentrations. Four patients continued to receive oral phenytoin therapy during convalescent care; phenytoin dosage requirements decreased over time in these patients. During acute and convalescent care, the phenytoin unbound fraction ranged from 6.0% to 18.3% and correlated with albumin (r2 = 0.61, p < 0.0001) but did not correlate with unbound fatty acid concentrations. The mean phenytoin unbound fraction was 10.1% and 8.9% for the ICU and convalescent patients with brain injuries, respectively, and was 7.0% for the healthy volunteers. CONCLUSIONS: Phenytoin protein binding was significantly correlated with albumin and was more variable in ICU and convalescent patients with brain injuries than in healthy volunteers. The high dosage requirements and subtherapeutic unbound phenytoin concentrations observed during acute care are best explained by increased metabolism. Phenytoin dosage requirements decreased during convalescence.

Acute trauma alters morphine clearance.

Trauma is accompanied by changes in liver perfusion and acute phase proteins. Such changes have the potential to alter drug metabolism. There are few studies describing drug disposition in acute trauma. We determined the pharmacokinetics of an intermediate extraction drug, morphine, in trauma patients. Nine patients with an Injury Severity Score (ISS) > or = 16 were studied within 48 hours of trauma. Morphine 5 mg was given intravenously and serial blood and urine samples were drawn to derive pharmacokinetic parameters. Alpha acid glycoprotein (AAG) levels were determined. Total morphine clearance (CL) and volume of distribution (Vss) were decreased compared to established literature values. Area under the curve (AUC) and terminal half-life (T 1/2 alpha) were increased. AAG levels were higher than reference range. Elimination half-life was increased. The decrease we observed in Vss may be attributed to increased binding of morphine by AAG, which is increased after trauma as in our patients. Decreased clearance and increased half-life of an intermediate extraction drug may be explained by increased protein binding, decreased liver blood flow, and reduced hepatocellular function. Decreased clearance of the magnitude observed in these patients could result in drug accumulation. Better understanding of the effects of trauma on the pharmacokinetics of low, high, and intermediate extraction drugs will prevent excessive or suboptimal drug dosing.

Bioavailability of fluconazole in surgical intensive care unit patients: a study comparing routes of administration.

OBJECTIVE: Anticandidal therapy is commonly used in the surgical intensive care unit (SICU). Unfortunately, it is expensive because it is generally given intravenously, as acute trauma and abdominal surgery are often accompanied by impaired gastrointestinal function. We compared the systemic availability of fluconazole given enterally or intravenously in trauma and surgery SICU patients to determine the reliability of enteral administration. METHODS: Nine adult trauma (Injury Severity Score (> or = 18) and nine adult abdominal surgery SICU patients were randomized to receive fluconazole 100 mg via the intravenous (IV) or enteral route. Patients with a bilirubin > 4.0 mg/dL or creatinine clearance < 60 mL/min were excluded. Enteral fluconazole was crushed, dissolved, and flushed through a nasogastric or feeding tube. Eleven serial blood samples were drawn over 72 hours. Area under the curve (AUC), elimination rate constant (Ke), and terminal half-life (T1/2) were determined and compared (t test). Relative bioavailability was estimated (AUC(enteral)/AUCIV). RESULTS: Peak concentrations occurred within 2 hours after enteral dosing and 15 minutes after IV dosing. The relative bioavailability was 77%. Weight, AUC, Ke, and T1/2 did not differ between enteral and IV dosing. CONCLUSIONS: Fluconazole is significantly absorbed when crushed, dissolved, and given via a nasogastric or feeding tube in SICU patients. Nonsignificant trends toward lower systemic availability with enteral administration can be overcome with slightly higher doses. Since enteral administration of fluconazole costs 10% of fluconazole given intravenously, more liberal use of enteral administration offers tremendous savings. Such savings moderate the cost concerns of antifungal therapy.

Intraoperative awareness and recall during total hip arthroplasty.

A case of intraoperative recall and awareness in a patient with sickle cell disease who had received midazolam, 10 mg at induction of anesthesia, is reported. The patient was on opioids which may also have caused tolerance. Although the use of midazolam may have been judged to provide adequate amnesia, this was clearly not the case. Upon analysis of the reasons for recall, we predicted from a two-compartment model that the estimated blood level was 88 ng/mL-1; this level would have provided no amnesia. This case illustrates that recall can occur with the use of midazolam, especially if levels become subtherapeutic, and other measures should be taken to provide adequate anesthesia and amnesia.

Chemical compatibility of regional anesthetic drug combinations.

OBJECTIVE: To define the physical and chemical compatibilities of several classes of drugs that may be used in combination for peridural anesthesia. DESIGN: Morphine, fentanyl, bupivacaine, lidocaine, tetracaine, ketamine, and clonidine were admixed for one hour in five groups of three-drug combinations, plus one group of all seven drugs. The combinations were inspected macroscopically and microscopically to determine physical compatibility. The admixtures were evaluated by gas chromatography/mass spectroscopy (GC/MS) and compared with known standards to determine chemical compatibility. RESULTS: The admixtures showed no physical incompatibility on microscopic or macroscopic evaluation. Chemical compatibility of all mixtures was confirmed by GC/MS. Ion chromatograms of the drugs in admixtures were identical to previously established standards. CONCLUSIONS: The agents evaluated demonstrated physical and chemical compatibility under conditions that would be observed during the administration of peridural anesthesia. Combinations of these drugs therefore could be safely admixed for use in anesthesia.

Selective decontamination of the digestive tract in intensive care patients: review and commentary.

OBJECTIVE: To evaluate the benefits, risks, and costs of antimicrobial regimens used for selective decontamination of the digestive tract (SDD) in intensive care unit (ICU) patients. DATA SOURCES: Information was obtained from clinical trials, review articles, abstracts, and textbooks. Key indexing terms included antibiotics, selective decontamination, and infections. STUDY SELECTION: Research articles describing controlled clinical trials of SDD in medical or surgical ICU patients were reviewed. Trials that investigated transplant, cirrhotic, leukemic, or oncology patient populations were excluded. DATA EXTRACTION: The details of studies that evaluated nosocomial infection or nosocomial pneumonia rates were extracted. These included study design, demographics, SDD regimens, severity of illness scores, and colonization, infection, and mortality rates. DATA SYNTHESIS: The use of SDD in mechanically ventilated surgical or trauma ICU patients reduces the incidence of colonization, nosocomial pneumonia, and overall infection rates, but does not change the overall mortality rate. Administration of antibiotic and antifungal agents in a nasogastric suspension is required for SDD. The addition of systemic prophylactic antibiotics or oropharyngeal paste was not required to decrease nosocomial infections. The most frequently studied SDD regimen (colistin/amphotericin B/tobramycin) is not feasible for use in the US because of exorbitant drug costs. Less expensive alternatives include norfloxacin/nystatin, or colistin/nystatin/gentamicin. CONCLUSIONS: Additional research is required before SDD regimens can be routinely recommended in surgical and trauma ICU patients. A multicenter study is warranted to determine the long-range benefits, potential for resistance, and cost-effectiveness of SDD.

Compatibility and pH variability of four injectable phenytoin sodium products.

The interlot variability in apparent pH of injectable phenytoin sodium products and the compatibility and stability of phenytoin sodium in admixtures of these products in 0.9% sodium chloride injection were studied. Dilantin (Parke-Davis) and three generic products (Elkins-Sinn, Lyphomed, Solopak) were used. Six lots of each product were diluted to 9.2 and 18.4 mg/mL concentrations. The apparent pH values of undiluted lots and diluted product admixtures were measured. Phenytoin concentrations in the admixtures were measured by turbidimetric immunoassay. Concentration and pH were measured immediately after admixture and at 0.5, 1, and 2 hours; samples were examined for crystallization at each time, and portions were filtered to determine differences in drug concentration between the filtered and unfiltered samples. The Dilantin lots had the lowest interlot variability and significantly higher mean +/- S.D. apparent pH (12.00 +/- 0.06) than the Solopak (11.38 +/- 0.33), Elkins-Sinn (11.39 +/- 0.21), and Lyphomed (11.68 +/- 0.36) products. The apparent admixture pH was significantly higher for Dilantin than for the other products. No crystallization occurred in the Dilantin admixtures; crystallization varied in the other products. Filtration did not significantly alter phenytoin concentrations. No significant differences were detected in phenytoin concentrations between products or sampling times. Interlot variability in pH was lowest for Dilantin, and apparent pH values of the undiluted products and in the admixtures at both drug concentrations were significantly higher for Dilantin than for the other products. Microscopic evidence of physical incompatibility was noted in some generic product lots with lower apparent pH values. Stability of phenytoin in the admixtures over two hours was demonstrated for all four phenytoin sodium injectable products studied.

Methotrexate disposition following disruption of the blood-brain barrier.

Intracarotid drug administration after osmotic blood-brain barrier disruption (BBBD) enhances drug delivery to brain tumors. Despite clinical use, the pharmacokinetics of drugs following BBBD has not been described to date. Since methotrexate exhibits a concentration-toxicity response relationship, methotrexate disposition was determined following BBBD and intracarotid administration in seven patients with nonoperable brain tumors. Following a 1.5-5 g intracarotid methotrexate injection, 12 blood samples and 9 urine collections were obtained. Methotrexate concentrations in serum and urine were determined by fluorescence polarization immunoassay. The serum concentration-time data were best described by a three-compartment model. Systemic and renal clearances were consistent with previous studies. However, a prolonged mean terminal half-life of 51.5 h was observed. Serum methotrexate concentrations at 72 h exceeded 0.1 mumol/L in five of seven patients. Stomatitis occurred in one patient. Relative to previous reports, prolonged methotrexate half-life and cytotoxic methotrexate concentrations were observed in the serum of patients receiving intracarotid methotrexate following BBBD. Due to the prolonged cytotoxic methotrexate concentrations observed, extended leucovorin therapy may be indicated following BBBD and intracarotid methotrexate.

Comparison of six methods for preparing cefazolin sodium for intermittent injection.

The time and cost of preparing i.v. piggyback doses of cefazolin sodium using automated and manual methods were compared. One-gram doses of cefazolin sodium were prepared in batches of 100 using each of six methods. Total equipment process times were recorded during five trials with each method. Personnel time and total materials costs were determined. Bulk-vial reconstitution methods, including a manual syringe and three automated fluid-delivery devices (Burron Multi-Ad syringe pump, Unispense peristaltic pump, and Valleylab heart-valve cassette pump), were compared. Two prefilled container systems (Faspak flexible plastic bags with Physio-Control peristaltic pump, and glass piggyback bottles with the Multi-Ad pump) were compared with each other and with the bulk-reconstitution methods. Of the bulk-vial methods, total process times were significantly shorter for the Multi-Ad and Unispense systems. Of the prefilled container systems, total process time and personnel time were significantly shorter for the Faspak method than for the manufacturer's piggyback bottle method. Materials costs were similar for all bulk-vial methods and were significantly lower for both prefilled container systems. Overall costs were lower for prefilled systems; the cost per dose was $3.63 for the manufacturer's piggyback bottle system and $4.26 for the Faspak system. Total personnel time required by the Faspak method was 21.5 minutes per batch, approximately one third the time required by any other method. In terms of personnel time and materials costs for preparation of i.v. cefazolin sodium doses, manufacturers' prefilled container systems have advantages over bulk-reconstitution methods.