Dose derivation of once-daily dosing guidelines for gentamicin in critically ill pediatric patients.

OBJECTIVES: To determine dose and eligibility criteria for once-daily dosing (ODD) of gentamicin in critically ill pediatric patients. METHODS: Retrospective chart review of patients admitted to the Pediatric Intensive Care Unit or Cardiac Critical Care Unit at The Hospital for Sick Children (SickKids) who received traditionally dosed intravenous (IV) gentamicin (January 2008 to June 2010). Statistically significant patient characteristics associated with gentamicin pharmacokinetic (PK) parameters were determined by multiple linear regression. Binary partitioning was used to set critical values for these characteristics to derive dose for ODD of gentamicin. Feasibility of implementing ODD of gentamicin in critically ill children was assessed using individualized PK parameters to simulate area under the concentration-time curves and drug-free intervals while targeting a maximum concentration (C(max)) of 16-20 mg/L. Eligibility criteria were determined by patient characteristics that had a statistically significant impact on gentamicin PK. RESULTS: Volume of distribution (V(d)) and elimination rate constant (k(e)) were calculated for 140 patients. Weight and admission unit were significantly associated with weight-normalized V(d) (Vd/kg), whereas age and serum creatinine (SCr) were significantly associated with k(e). Weight <5 kg and SCr ≥20% over age-specific upper normal limit before gentamicin initiation were associated with prolonged gentamicin elimination. Gentamicin 6 mg/kg IV every 24 hours, the dose at which the highest percentage of patients achieved C(max), area under the curve, and drug-free interval within target ranges simultaneously, was selected as the proposed ODD regimen. CONCLUSIONS: A regimen of gentamicin 6 mg/kg IV every 24 hours for Pediatric Intensive Care Unit/Cardiac Critical Care Unit patients at SickKids weighing ≥5 kg with SCr <20% above age-specific upper normal limit before initiation of gentamicin is proposed.

Systematic evaluation of errors occurring during the preparation of intravenous medication.

INTRODUCTION: Errors in the concentration of intravenous medications are not uncommon. We evaluated steps in the infusion-preparation process to identify factors associated with preventable medication errors. METHODS: We included 118 health care professionals who would be involved in the preparation of intravenous medication infusions as part of their regular clinical activities. Participants performed 5 infusion-preparation tasks (drug-volume calculation, rounding, volume measurement, dose-volume calculation, mixing) and prepared 4 morphine infusions to specified concentrations. The primary outcome was the occurrence of error (deviation of > 5% for volume measurement and > 10% for other measures). The secondary outcome was the magnitude of error. RESULTS: Participants performed 1180 drug-volume calculations, 1180 rounding calculations and made 1767 syringe-volume measurements, and they prepared 464 morphine infusions. We detected errors in 58 (4.9%, 95% confidence interval [CI] 3.7% to 6.2%) drug-volume calculations, 30 (2.5%, 95% CI 1.6% to 3.4%) rounding calculations and 29 (1.6%, 95% CI 1.1% to 2.2%) volume measurements. We found 7 errors (1.6%, 95% CI 0.4% to 2.7%) in drug mixing. Of the 464 infusion preparations, 161 (34.7%, 95% CI 30.4% to 39%) contained concentration errors. Calculator use was associated with fewer errors in dose-volume calculations (4% v. 10%, p = 0.001). Four factors were positively associated with the occurrence of a concentration error: fewer infusions prepared in the previous week (p = 0.007), increased number of years of professional experience (p = 0.01), the use of the more concentrated stock solution (p < 0.001) and the preparation of smaller dose volumes (p < 0.001). Larger magnitude errors were associated with fewer hours of sleep in the previous 24 hours (p = 0.02), the use of more concentrated solutions (p < 0.001) and preparation of smaller infusion doses (p < 0.001). INTERPRETATION: Our data suggest that the reduction of provider fatigue and production of pediatric-strength solutions or industry-prepared infusions may reduce medication errors.

Use of milrinone in critically ill children.

BACKGROUND: Optimal dose adjustment of milrinone in critically ill children is challenging because of conflicting information about the association between dose and outcomes in this age group. OBJECTIVES: To describe the use of milrinone in critically ill children and to explore associations between milrinone dosing and clinical outcomes, specifically effectiveness and adverse events. METHODS: This retrospective cohort study was performed in a consecutive sample of children admitted to a university-affiliated critical care unit (January to June 2004). The relations between milrinone dosing and its effectiveness (based on prevention of low cardiac output syndrome, defined as a difference in oxygen saturation between arterial and mixed venous blood of at least 30% or an increase in serum lactate > 2 mmol/L) and its adverse effects (thrombocytopenia, arrhythmia) were evaluated by logistic regression. RESULTS: A total of 197 children from 213 admissions (ranging in age from newborn to 18 years) were included in the study. Milrinone was initiated with a median loading dose of 99.2 µg/kg (range 22.1-162.2 µg/kg). The initial loading dose was higher if given in the operating room rather than the Critical Care Unit (median 99.7 versus 51.0 µg/kg; p < 0.001). Subsequent loading doses, for patients who received them, were lower (median 49 µg/kg). Milrinone was infused at a median rate of 0.64 µg/kg per minute (range 0.13-2.08 µg/kg per minute) for a median of 43.1 h. There was no relation between serum creatinine level and the maintenance dose of milrinone (r2 ≤ 0.0335). Low cardiac output syndrome was relatively frequent (166 [77.9%] of the 213 admissions). There was a trend for occurrence of this syndrome in patients with greater average milrinone dose rate (odds ratio [OR] 8.21, 95% confidence interval [CI] 0.98-69.15, p = 0.053) and with longer duration of milrinone therapy (OR 1.01, 95% CI 1.01-1.02, p < 0.05). Adverse events were relatively frequent (thrombocytopenia for 27 admissions [12.7%], arrhythmia for 82 admissions [38.5%]) but were not significantly associated with milrinone dosing. CONCLUSIONS: A retrospective evaluation of milrinone use in critically ill children revealed variable utilization and frequent occurrence of both low cardiac output syndrome and adverse events. Further prospective research is needed to understand the impact of individual pharmacokinetic differences on pharmacodynamic responses, to guide optimal dose adjustment, improve outcomes, and minimize toxic effects.

12-hour versus 24-hour creatinine clearance in critically ill pediatric patients.

Measurement of renal function is important to optimize drug dosing in critically ill pediatric patients and to prevent dose-related toxicities caused by medications that are eliminated or metabolized by the kidney. In clinical practice, the 24-h creatinine clearance (CrCl) is used as a surrogate marker of renal function. However, a 24-h urine collection period delays the availability of the result and increases the potential for collection errors. This prospective, observational study was performed to determine whether a 12-h CrCl is comparable to the traditional 24-h CrCl and to assess whether CrCl could be reliably predicted by the Schwartz equation, which mathematically estimates a child's GFR. A 24-h urine sample was collected in two 12-h aliquots from 60 catheterized critically ill children (age 2 d to 18 y). CrCl and Schwartz glomerular filtration rate (GFR) estimates were determined for each 12- and 24-h period. Agreement between 12- and 24-h CrCl and between CrCl and Schwartz GFR estimates was assessed using intraclass correlation coefficients (ICCs). An ICC > or =0.8 was considered to indicate excellent agreement. The ICC between the first 12-h CrCl and 24-h CrCl was 0.9605. The ICC between the second 12-h CrCl and 24-h CrCl was 0.9602. The ICC between the 24-h CrCl and Schwartz GFR was only 0.7046. All comparisons of 12- and 24-h CrCl indicated excellent agreement. In summary, the Schwartz equation was not a reliable estimate of renal function in critically ill children, and a 12-h CrCl is just as accurate as the standard 24-h CrCl to assess renal function and guide drug dosing.