Julianne K. Whipple

Effect of individualized pharmacokinetic dosing on patient outcome

ObjectiveTo study the effect of individualized pharmacokinetic dosing of aminoglycosides on patient outcome. DesignProspective, randomized study. SettingTertiary care hospital. PatientsNinety-five patients with documented Gram-negative infections received 97 courses of aminoglycoside therapy. InterventionsPatients were randomized between pharmacokinetic dose adjustment and monitoring or traditional physician-directed techniques. Patients were stratified by severity of underlying illness before randomization. Measurement and Main ResultsSixty-two courses of treatment were satisfactorily completed. Patients in the severely ill group (eight kinetic, eight traditional) had significantly (p < .05) better survival (7 kinetic, 3 traditional) when managed with pharmacokinetic consultation. The kinetic arm received greater doses (156 ±PT 59 mg/dose; 2.4 ±PT 0.6 mg/kg) than the traditional arm (81 ±PT 27 mg/dose; 1.5 ±PT 0.6 mg/kg) (p < .001). In addition, the dose per day (mg/kg) was greater in the kinetic arm (4.1 ±PT 1.5) than the traditional arm (3.2 ±PT 1.3) (p < .001). The improved survival was achieved by attaining therapeutic peak serum concentrations earlier in the course of the infection and by administering more total aminoglycoside without increasing toxicity. ConclusionsWe conclude that pharmacokinetic management of aminoglycoside dosing may improve the outcome of severely ill patients.

Glucose response to abrupt initiation and discontinuation of total parenteral nutrition.

Plasma glucose was studied during the initiation of total parenteral nutrition (TPN) and the discontinuation of TPN without a tapering schedule. Blood was sampled every 5 minutes for 2 hours after the start of TPN and 1 week later as TPN was discontinued. A total of 14 initiations and 14 discontinuations were studied in 18 patients. Severity of illness in patients ranged from stable condition postoperatively to multiple-system failure; six patients had diabetes mellitus. The TPN solution was a 3:1 admixture that provided a caloric intake equal to 1.2 times the resting energy expenditure, with 40% fat and 60% carbohydrate calories. An average of 1963 kcal was provided per day (340 g of glucose, 79 g of fat). During the initiation phase, the mean increase in plasma glucose was 60 mg/dL. The increase for diabetic patients was 79 +/- 14 mg/dL compared with 52 +/- 23 mg/dL for the nondiabetics. During the discontinuation phase, the mean plasma glucose decreased 40 +/- 20 mg/dL; two patients with high concentrations of regular insulin (50 and 100 units) showed an increase in plasma glucose when the TPN was stopped. Plasma glucose returned to the preinfusion baseline after discontinuation. During both initiation and discontinuation, plasma glucose showed little change after the first 60 minutes. No clinical symptoms of hypoglycemia were observed. In conclusion, TPN as a 3:1 admixture can be safely started as full nutrition support and stopped abruptly without a tapering schedule. Plasma glucose response is rapid, predictable, and mostly complete within 60 minutes.

Prospective comparison of traditional and pharmacokinetic aminoglycoside dosing methods.

Aminoglycoside (gentamicin, tobramycin) dosage regimens and subsequent serum concentrations were compared in 30 patients treated initially using traditional physician-determined methods and then switched to a pharmacokinetic-based treatment program. Patients received more drug during the kinetic phase (median 5 mg/kg) than during the traditional phase (median 3.6 mg/kg) and achieved greater peak serum concentration (5.9 vs. 4.4 micrograms/ml). Seventy-three percent of kinetic peak values but only 27% of traditional peak values exceeded 5.0 micrograms/ml. Trough concentrations were comparable in both phases of study and no nephrotoxicity was observed. This pharmacokinetic-based management program achieved more consistently greater therapeutic peak concentrations and provided more individualized therapy than did physicians. The use of pharmacokinetic consultants may be of benefit in administering safely optimal aminoglycoside therapy.

Narcotic Use in the Hospital: Reasonably Safe?

OBJECTIVE: To determine the causes and frequency of overdoses associated with the administration of opioid analgesics in hospitalized patients. DESIGN: Case series. SETTING: Two acute care teaching hospitals. PATIENTS: Eighty-one hospitalized patients who received naloxone for a clinically suspected narcotic overdose. INTERVENTIONS: Three investigators reviewed each patient who received naloxone during a 12-month period. The patients were judged to have a narcotic overdose if caregivers documented an immediate improvement in mental status, respiratory rate, or blood pressure after naloxone administration. MAIN OUTCOME MEASURES: The number and causes of narcotic overdoses were determined. The frequency of morphine and meperidine overdoses was calculated. The number of incidents reported using incident or adverse drug reaction reports or the appropriate International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) code. RESULTS: In the 22 overdoses that occurred, 14 (64 percent) were caused by medication prescribing, compounding, or administration errors and potentially were preventable. The remaining eight patients experienced an overdose despite receiving appropriate amounts of opioids. The frequency of overdoses was 0.4 and 0.2 percent of total patients receiving morphine or meperidine, respectively, at the two hospitals. Nonreporting of these narcotic overdoses was frequent. In one hospital, 1 incident report and 3 adverse drug reactions were reported for 17 overdoses. At the second hospital, 1 incident report and 1 adverse drug reaction were reported for 6 overdoses. None of the patient charts included an ICD-9-CM code that documented the problem. CONCLUSIONS: The causes of overdoses are not limited to prescribing and administration errors. Some patients, despite proper execution of appropriate orders, develop a narcotic overdose. Caregivers must be aware of this problem and monitor patients for a decrease in mental status and respiratory rate. In addition, we conclude that an important number of hospitalized patients develop an overdose even though the frequency is low related to the number of patients receiving narcotics.

Current patterns of prescribing and administering morphine in trauma patients

We attempted to characterize the current prescribing practices and administration patterns for intravenous intermittent morphine in trauma patients in a multicenter, open prospective, observational study. The subjects were 141 patients admitted to the surgical intensive care units (ICU) of five United States trauma centers within 12 hours of injury who received intermittent intravenous morphine for pain relief. The study was conducted from April 15, 1992, to February 15, 1993. Data obtained during the first 32 hours of the ICU stay included morphine regimen, doses administered, and time between doses. One hundred sixty‐one orders were prescribed by surgeons. The most frequently ordered dose was 2–4 mg and the most frequently ordered interval was every hour as necessary. There was no relationship between the severity of injury and the minimum dose ordered. During the 492 nursing shifts studied, 1257 doses were administered. Of these, 44% were at or below the minimum amount prescribed by the surgeons. Thirty‐three percent of the patients received a dose at an interval of more than 3 hours. We concluded that small amounts of narcotic analgesics are given to severely injured patients, and amount ordered is not affected by the severity of injury.

Difficulties in Diagnosing Narcotic Overdoses in Hospitalized Paitents

OBJECTIVE: To describe the clinical presentation of narcotic overdose in hospitalized patients and to differentiate this circumstance from other conditions often misdiagnosed as overdose. DESIGN: Case series. SETTING: Two acute-care teaching hospitals. PATIENTS: Forty-three hospitalized patients who received naloxone for a clinically suspected narcotic overdose. INTERVENTIONS: Two investigators independently evaluated each incident to determine whether the patient had a narcotic overdose. The patients were judged to have had an overdose if caregivers documented an immediate improvementin mental status, respiratory rate, or blood pressure after naloxone administration. MEASUREMENTS: The clinical presentation of a narcotic overdose in hospitalized patients was defined. Conditions misdiagnosed as an overdose were determined. MAIN RESULTS: Symptoms improved rapidly with the administration of naloxone in 28 incidents (65 percent) and were designated overdose. In 15 other instances there was no improvement in symptoms; these patients were designated nonoverdose. Only half of the overdose patients had a respiratory rate <8 breaths/min immediately prior to naloxone administration. Only two of the overdose patients had the classic triad of symptoms (respiratory depression, coma, and pinpoint pupils). Other overdose patients had only one or two of the classic signs. The clinical presentation of narcotic overdoses in hospitalized patients did not include respiratory depression, hypotension, or coma in the majority of patients. All overdose patients showed a decrease in mental status. The majority of nonoverdose patients had pulmonary conditions that were misdiagnosed as a narcotic overdose. CONCLUSIONS: Narcotic overdoses in hospitalized patients seldom fit the classic description. The lack of respiratory depression does not mean the absence of a narcotic overdose. Patients who receive narcotics and develop a signficant decrease in mental status should be evaluated for a possible overdose. Pulmonary, neurologic, cardiovascular, and electrolyte abnormalities often are misdiagnosed as a narcotic overdose in hospitalized patients.

Pharmacokinetic evaluation of a new oral cyclosporine formulation

Study Objective. To compare the pharmacokinetics of a new oral cyclosporine preparation with those of cyclosporine solution diluted in Isocal and the intravenous formulation.