Wide variation in single, daily-dose aminoglycoside pharmacokinetics in patients with burn injuries.

Five to seven mg/kg single, daily-dose aminoglycoside regimens have been recently advocated as effective alternatives to traditional aminoglycoside regimens. The rationale for single, daily-dose aminoglycoside therapy is to produce an optimal ratio between aminoglycoside peak concentrations (Cmax) and pathogen minimal inhibitory concentration to maximize bacterial killing and to produce an aminoglycoside-free period during the 24-hour dosing interval. Single, daily-dose aminoglycoside therapy has not been recommended to date for use in the population of patients with burn injuries. The purpose of this study was to determine the magnitude and variability of aminoglycoside Cmax and the duration of the aminoglycoside-free period after simulated single, daily-dose regimens in patients with burn injuries. Fifty-two patients receiving gentamicin or tobramycin in the burn unit were studied retrospectively to determine the individualized pharmacokinetic parameters and the simulated Cmax and 24-hour after the dose trough minimum concentrations for 5 and 7 mg/kg single, daily-dose aminoglycoside regimens. Patients were only included in the final analysis if they had been treated for burn wound infections and exhibited a calculated creatinine clearance exceeding 60 ml/min (N = 40). Mean [percentage coefficient of variation] Cmax/minimum concentrations were 15.4[30.5]/0.03[200.0] and 21.6[30.6]/0.04[200.0] mg/L for 5 and 7 mg/kg daily doses, respectively. The mean coefficient of variation time to reach an extrapolated concentration of 0.1 mg/L was 15.9[30.8] hours and 17.0[30.6] hours for the 5 and 7 mg/kg daily doses, respectively. Substantial variability in aminoglycoside Cmax and duration of the aminoglycoside-free period was observed. These data suggest that many patients with burn injuries are not candidates for single, daily-dose aminoglycoside therapy because of restrictive creatinine clearance criteria and pronounced variability in length of the aminoglycoside-free interval. If single, daily-dose aminoglycoside therapy is to be used in this patient population, therapeutic drug monitoring is recommended to screen for appropriate candidates and to optimize Cmax and minimal inhibitory concentration ratios and duration of the aminoglycoside-free interval.

The impact of practice guidelines on prescribing patterns of nondepolarizing neuromuscular blocking agents.

Guidelines for selecting nondepolarizing neuromuscular blocking agents (NNMBAs) were developed and implemented by an interdisciplinary team for use in our intensive care units. They suggest pancuronium as the drug of choice if the patient does not have renal insufficiency and is hemodynamically stable. If either of these criteria is not met and hepatic function is normal, vecuronium is recommended. Atracurium is reserved for patients not meeting either criterion. A 12-month retrospective chart review was performed for 24 patients 18 years of age or older who received continuous infusion of an NNMBA beginning 7 months after the guidelines were implemented. Before the guidelines, atracurium, vecuronium, and pancuronium were prescribed for 68% (17), 24% (6), and 8% (2) of patients, respectively. Their use was inappropriate based on organ function and hemodynamic stability in 88% (15), 83% (5), and 0% of patients, respectively. After guideline implementation, atracurium, vecuronium, and pancuronium were prescribed for 33% (8), 21% (5), and 46% (11) of patients, respectively, and use was inappropriate in 38% (3), 60% (3), and 0% of patients, respectively. Overall, the prevalence of inappropriate NNMBA selection decreased from 80% (20) to 25% (6). Further analysis is necessary to determine the associated pharmacoeconomic impact of decreased inappropriate NNMBA prescribing.

QTc-interval prolongation associated with slow intravenous erythromycin lactobionate infusions in critically ill patients: a prospective evaluation and review of the literature.

Intravenous erythromycin has recently been associated with significant QTc interval prolongation, torsades de pointes, and sudden cardiac death. The prolonged the QTc interval attributed to erythromycin typically is associated with rapid infusion rates in excess of 10 mg/minute. We prospectively assessed the relationship between QTc interval prolongation and erythromycin administration by slow intravenous infusion (mean rate 8.9 +/- 3.5 mg/minute, range 3.9-16.7 mg/minute). Electrocardiographic (ECG) rhythm strips were prospectively obtained in 44 critically ill patients receiving intravenous antibiotics (22 received erythromycin and 22 ceftazidime, cefuroxime, cefotaxime, ceftriaxone, or ampicillin-sulbactam as controls). The ECG recordings were obtained immediately before and within 15 minutes after drug infusions. Only the first available set of ECG strips were evaluated. Two controls had evidence of hepatic dysfunction; no patients receiving erythromycin did. The QTc interval was calculated using Bazett's formula by two blinded investigators. For controls, mean +/- 1 SD (range) QTc intervals were 423 +/- 96 (300-550) msec at baseline and 419 +/- 96 (280-610) msec after infusion (p = 0.712). In contrast, in the erythromycin group, the interval was significantly prolonged from 524 +/- 105 (360-810) msec at baseline to 555 +/- 134 (400-980) msec after infusion (p = 0.034). No patients experienced a dysrhythmia as a consequence of erythromycin infusion. Despite slow rates of infusion, QTc interval prolongation was significant. The clinical importance of this finding remains to be determined.

Resistance to nondepolarizing neuromuscular blocking agents.

Several case reports of resistance to short-term administration of nondepolarizing neuromuscular blocking agents (NNMBAs) have been reported in research and surgical settings. Recently, several reports documented resistance to NNMBAs during therapy for prolonged paralysis in critically ill patients. Adverse outcomes associated with NNMBA resistance may include inadequate ventilatory management or suppression of patient movement, and an increased risk of dose-dependent cardiovascular adverse effects. Pharmacoeconomic issues must be considered in that the cost of NNMBA therapy in a resistant patient may be significant. Although the specific etiologies of resistance are not clear, several pharmacodynamic and pharmacokinetic alterations may occur as a consequence of disease state or concomitant drug therapy. Pharmacodynamic changes include altered acetylcholine receptor physiology or sensitivity, inhibition of serum cholinesterase activity, and interaction with plasma constituents. Alterations in distribution volume, protein binding, and clearance may also contribute to resistance in several disease states.

Lorazepam stability in parenteral solutions for continuous intravenous administration.

OBJECTIVE: To determine the stability of lorazepam over a 24-hour period when prepared in polyvinyl chloride (PVC) bags at initial concentrations of 0.08 and 0.5 mg/mL. DESIGN: Each concentration was studied at room (21 degrees C) and refrigerator (4 degrees C) temperatures in dextrose 5% (D5W) and NaCl 0.9% solutions. Duplicate test solution admixtures were prepared for each lorazepam concentration, diluent, and temperature. At 0, 1, 4, 8, and 24 hours, duplicate samples were obtained for visual inspection, pH determination, and concentration determination by stability-indicating, reverse-phase HPLC analysis. Compared with baseline, peaks for lorazepam degradation products were not found on any of the study chromatograms. RESULTS: In D5W and NaCl 0.9% solutions, lorazepam loss in excess of 10% by HPLC analysis occurred for concentrations of 0.08 and 0.5 mg/mL at 1 and 4 hours, respectively. CONCLUSIONS: These data suggest that significant loss of lorazepam occurs as the probable result of sorption to PVC bags when admixed in both D5W and NaCl 0.9% solutions at 21 and 4 degrees C.

A retrospective study of sodium nitroprusside use and assessment of the potential risk of cyanide poisoning.

Sodium nitroprusside (SNP) is an effective vasodilator but is potentially dangerous due to its cyanide content. Infusion rates above 2 micrograms/kg/minute may cause cyanide to accumulate to toxic concentrations in critically ill patients. Coadministration of thiosulfate with SNP effectively and safely prevents cyanide toxicity. This study determined if patients at our institution were treated with SNP infusion rates that could cause cyanide toxicity and whether those patients were administered thiosulfate. We reviewed the charts of 36 critically ill patients treated with SNP during the previous 12 months. In 72% of patients the SNP infusion rates were above 2 micrograms/kg/minute. In 47% the rates were greater than 2 micrograms/kg/minute for 6 hours or more, and in 20% they were greater than 5 micrograms/kg/minute for up to 11 hours. None of the patients was administered thiosulfate. In a significant number of patients the infusion rates of SNP potentially exposed them to significant risk of cyanide toxicity including death.

Inappropriate vancomycin prescribing based on criteria from the Centers for Disease Control and Prevention.

Increasing reports of vancomycin resistance have raised concerns about the future effectiveness of this drug in treatment of critically ill patients with gram-positive infections. Due to these concerns the Centers for Disease Control and Prevention (CDC) recently published criteria that delineate the prudent use of vancomycin. Using these criteria, we attempted to determine the appropriateness of vancomycin prescribing patterns at our institution. A retrospective chart review was performed for 135 hospitalized patients treated between May 1993 and April 1994. Inappropriate empiric vancomycin use was documented in 81 (60%) of these patients. When culture results were available, 28 (21%) patients inappropriately received the drug. Results of this study are similar to those of other studies of vancomycin use in hospitals based on non-CDC criteria. If CDC criteria are to have a positive impact on physicians' vancomycin prescribing patterns, significant educational efforts will be required.

Atracurium resistance in a critically Ill patient.

A previously healthy 25-year-old man with metastatic testicular teratocarcinoma became resistant to atracurium-induced neuromuscular blockade as evidenced by train-of-four (TOF) monitoring combined with clinical assessment. Subsequently he had an adequate response with a standard dosage of pancuronium. During the first 10 days of neuromuscular blockade, the atracurium requirements escalated from 0.31 to 1.7 mg/kg/hour, guided by TOF monitoring, movement, and spontaneous respirations. The infusion was discontinued but later reinstituted. Despite a total atracurium loading dose of 1.4 mg/kg followed by an infusion rate titrated to 1.7 mg/kg/hour, inadequate paralysis persisted. Atracurium was terminated and an intravenous infusion of pancuronium 0.10 mg/kg/hour was started. Over the next 3 days the pancuronium infusion was titrated down to a range of 0.04-0.06 mg/kg/hour, followed by a maintenance infusion of 0.01-0.05 mg/kg/hour for 5 days. A pharmacokinetic alteration, such as increased metabolism or elimination, may have caused the atracurium resistance.

Inconsistency with train-of-four monitoring in a critically ill paralyzed patient.

Problems occurred with train-of-four (TOF) monitoring during prolonged therapy with nondepolarizing neuromuscular blocking agents (NNMBAs). A previously healthy 25-year-old male with metastatic testicular teratocarcinoma was paralyzed with an atracurium infusion to facilitate mechanical ventilation. Dosage titration was initially based on clinical assessment; however, on day 4 of atracurium, TOF monitoring was initiated. During days 4 to 10 of atracurium therapy, TOF monitoring correlated well with clinical assessment of the depth of paralysis. On day 13, atracurium was discontinued and a pancuronium infusion was initiated. During the 9 days of pancuronium therapy, TOF monitoring suggested overparalysis on several occasions (no thumb twitch at 80 mamp of ulnar nerve stimulation) despite clinical evidence of spontaneous movement or respirations. The patient was edematous and had extremely dry skin during some of these instances of inappropriate TOF response. Although these problems were rectified, TOF response continued to be erroneous. Thus we had to rely primarily on clinical assessment to monitor the duration of NNMBA therapy. This case demonstrates that TOF data and clinical assessment of neuromuscular blockade may not always correlate.

Train-of-four: to use or not to use.

A pattern of nerve stimulation called train-of-four (TOF) is frequently used to monitor therapy with nondepolarizing neuromuscular blocking agents in patients treated in intensive care units. Based on our experience with TOF monitoring in several critically ill patients, we believe its application as an indicator of neuromuscular blockade may be problematic in this setting.

Prolonged neuromuscular blockade in two critically ill patients treated with atracurium.

Recent literature suggests that the risk of prolonged neuromuscular blockade associated with atracurium compared with other nondepolarizing neuromuscular blocking agents may be minimal. Two patients experienced prolonged weakness associated with the administration of atracurium. Both received atracurium 0.5-0.7 mg/kg/hour in combination with methylprednisolone 500-600 mg/day. Electromyographic results and creatine kinase levels were suggestive of muscular weakness in both patients. Despite high-dose corticosteroid therapy, the electromyographic evidence supporting prolonged weakness did not suggest typical corticosteroid myopathy. Although some clinicians advocate routine administration of atracurium in critically ill patients due to the relative lack of reports of prolonged weakness, this may be premature. Although there are fewer reports of atracurium-associated prolonged weakness compared with pancuronium and vecuronium, the patients we describe suggest that it may occur.

A retrospective review and assessment of benzodiazepines in the treatment of alcohol withdrawal in hospitalized patients.

Little information has been published concerning differences among the benzodiazepines in treating hospitalized patients with severe symptoms of alcohol withdrawal. We attempted to determine the length and type of hospital stay, and the pattern and appropriateness of administration, dosage requirements, and costs associated with benzodiazepines in patients undergoing alcohol withdrawal. A 1-year retrospective analysis was performed for 57 hospitalized patients. Appropriate therapy was defined as lorazepam for patients 60 years and older or those with hepatic dysfunction, and chlordiazepoxide or diazepam for all other patients. Drug costs were calculated based on acquisition costs. The mean number of days of benzodiazepine treatment and length of stay in the intensive care unit (ICU) were 6.2 days (range 1-30 days) and 3.9 days (range 0-12 day), respectively. Fifty-six patients were admitted to the ICU for management or for monitoring continuous-infusion lorazepam; one patient received chlordiazepoxide on a general ward. Total mean lorazepam infusion required per patient was 324 mg (range 2-5956 mg). The total benzodiazepine acquisition cost was $56,489 (mean $1009, range $0.06-7157/patient). The total costs of benzodiazepine acquisition and ICU charge were $404,346 (mean $7462/patient). Based on our criteria, 41 of 57 patients could have been treated appropriately with chlordiazepoxide, which would have resulted in an estimated drug-acquisition cost savings of at least $37,000. Mean benzodiazepine dosage requirements in patients hospitalized for alcohol withdrawal appear higher than previously reported. Approximately 70% of our patients were not of advanced age and had no evidence of organ dysfunction, and therefore, could have been treated with an oxidized benzodiazepine (i.e., chlordiazepoxide).(ABSTRACT TRUNCATED AT 250 WORDS)

A prospective evaluation of benzodiazepine guidelines in the management of patients hospitalized for alcohol withdrawal.

Our institution adopted guidelines for the selection of benzodiazepines to be administered to patients hospitalized for alcohol withdrawal. We assessed the guidelines' impact on prescribing habits, benzodiazepine dosage requirements and costs, and length of intensive care unit (ICU) stay. A 6-month prospective, observational study was performed in 50 patients who exhibited signs of alcohol withdrawal and received benzodiazepine therapy. Appropriate therapy was defined as lorazepam for patients 60 years and older or those with hepatic dysfunction, and chlordiazepoxide for all other patients. Benzodiazepine costs were calculated based on acquisition cost. Based on our guidelines, 76% of patients were appropriate candidates for a long-acting agent such as chlordiazepoxide; 61% of these candidates actually received such a drug. Using a benzodiazepine conversion to compare doses in chlordiazepoxide equivalents, there was a significant difference in the total mean dose of chlordiazepoxide (1295.5 mg, SD +/- 1571) compared with lorazepam (365.5 mg; SD +/- 446) (p < 0.01). The mean total chlordiazepoxide acquisition cost was $61.74 (range $0.03-585.98) per patient (28 patients); prior to adoption of the guidelines, the mean cost of benzodiazepine therapy was $1008.72 (+/- $1554.45). For patients receiving chlordiazepoxide, the mean days of ICU and hospital stay were 1.1 days (range 0-9 days) and 5.6 days (range 1-17 days), respectively; before adoption of the guidelines, the mean number of days of ICU stay was significantly greater (4.1 days, p < 0.0001). The guidelines resulted in a substantial change in benzodiazepine prescribing patterns.(ABSTRACT TRUNCATED AT 250 WORDS)

Does ciprofloxacin interact with cyclosporine?

OBJECTIVE: To provide the reader with a review of the literature that evaluates whether a pharmacokinetic or pharmacodynamic drug interaction exists between ciprofloxacin and cyclosporine. DATA SOURCES: A MEDLINE search was used to identify pertinent review articles, pharmacokinetic studies, and case reports. STUDY SELECTION: As both pharmacokinetic trials and case reports were few in number, all available sources were reviewed. DATA EXTRACTION: A few case reports were reviewed; however, data were extracted primarily from prospective human studies involving cyclosporine pharmacokinetic profiles. DATA SYNTHESIS: Ciprofloxacin has been reported to interact with cyclosporine during concomitant use through an interaction with the cytochrome P-450 system or by additive nephrotoxicity. Because ciprofloxacin may be used to treat a variety of infections in transplant recipients who receive cyclosporine, it is important to determine whether an interaction exists. Although cyclosporine is known to cause nephrotoxicity, only a few reports of ciprofloxacin-induced acute renal failure exist, all involving an immune-mediated interstitial nephritis. Four case reports have suggested a possible pharmacokinetic or pharmacodynamic drug interaction between cyclosporine and ciprofloxacin; however, many pharmacokinetic studies have refuted these reports. Several studies performing cyclosporine pharmacokinetic profiles have documented no increased cyclosporine concentrations, thus supporting the premise that ciprofloxacin does not interact with cyclosporine. CONCLUSIONS: Controlled studies involving cyclosporine pharmacokinetic profiles do not support a pharmacokinetic or pharmacodynamic drug interaction between ciprofloxacin and cyclosporine. Although anecdotal case reports have suggested synergistic nephrotoxicity, no clear correlation can be made. Based on our review of the literature, it can be concluded that cyclosporine and ciprofloxacin may be used together safely at the recommended dosages without increased cyclosporine monitoring.