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.

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.

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.

Anti-infective agents and hepatic disease.

Numerous factors such as changes in plasma protein binding, tissue binding, hepatic blood flow, hepatic metabolism, and distribution may occur in hepatic disease. The impact of these physiologic changes on pharmacokinetic and pharmacodynamic parameters of anti-infective agents is likely to be clinically significant. Unfortunately, these issues have not been thoroughly investigated. Even within the same type of liver disease, there is considerable interpatient variability in pharmacokinetic variables, rendering it difficult to predict drug disposition accurately. Pharmacokinetics of selected anti-infective agents are altered in hepatic disease, necessitating careful monitoring and dosage titration to avoid enhanced drug concentrations and risk of toxicity.