Winnie Seto

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 occurence 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.

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 childs 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 ≥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.

Drug formulations that require less than 0.1 mL of stock solution to prepare doses for infants and children

Intravenous doses of medications require formulations that permit accurate preparation and administration. Current equipment does not permit accurate measurement of volumes less than 0.1 mL. In a study of four hypothetical standard pediatric patients, we found that 28 common medications required less than 0.1 mL of available formulation to prepare the dose. In a clinical study of actual use in a pediatric intensive care unit (ICU), 5245 (7.4%) of 71 218 intravenous doses required preparation from less than 0.1 mL of stock solution. For 28.5% of the 1531 ICU admissions, at least one dose was prepared from a volume of less than 0.1 mL. Our findings identify a substantial source of dosing error. Correction will require revision of preparation methods, regulatory requirements and manufacturing practices.

Determination of area under the whole blood concentration versus time curve after first intravenous cyclosporine dose in children undergoing hematopoietic stem cell transplant: limited sampling strategies.

Achievement of target trough cyclosporine whole blood concentrations after hematopoietic stem cell transplant (HSCT) reduces the risk of acute graft versus host disease (aGvHD). In solid organ transplant, prevention of acute graft rejection correlates with achievement of target area under the whole blood concentration versus time curve during the 12-hour dosing interval (AUC-12) after oral administration. This study describes a limited sampling strategy for determination of cyclosporine AUC-12 after administration of the first intravenous (IV) dose in children undergoing HSCT and explores the relationships between individual whole blood concentrations during the dosing interval and the AUC. Children undergoing HSCT and receiving cyclosporine prophylaxis were eligible to participate. The first cyclosporine dose was given as a 2 hour infusion, and eight cyclosporine concentrations were determined at 2 (end of the infusion), 2.5, 3, 4, 6, 8, 10, and 12 hours after the start of the IV infusion. The relationship between AUC-12 and whole blood cyclosporine concentrations at individual time points after IV administration was assessed by the Spearman rho correlation coefficient. Limited sampling strategies were developed using three to six time points by way of multiple linear regression analysis. The agreement between the AUC-12 calculated using all eight data points and the limited sampling strategies was assessed by intraclass coefficient and Bland-Altman analysis. Twenty-four children (0.5-16.9 yr) participated. The mean AUC-12 calculated using all eight concentration versus time points was 2793 ± 1165.6 μg/L·hr. Whole blood cyclosporine concentrations obtained within the first 4 hours from the start of the infusion correlated strongly with AUC-12 (Spearman rho coefficient, 0.717-0.868). Limited sampling strategies were developed to estimate AUC-12 with adjusted r2 of 0.955 to 0.998, mean bias of 0% to 0.93%, and precision of 1.6% to 8.1%. The actual AUC-12 and predicted AUC-12 values agreed strongly (intraclass coefficient, 0.981-0.999). Limited sampling strategies using three to six data points have been developed that will estimate cyclosporine AUC-12 after administration of the first IV dose given over 2 hours. Information regarding the possible association between aGvHD and cyclosporine AUC-12 is not available. The limited sampling strategies described here will facilitate the prospective evaluation of the clinical importance of cyclosporine AUC-12 in the prevention of aGvHD.

Pharmacokinetics of Sirolimus-Eluting Stents Implanted in the Neonatal Arterial Duct

Background—Sirolimus-eluting stents may have clinical advantages over bare-metal stents in the extremely proliferative environment of the neonatal arterial duct. However, sirolimus has immunosuppressive actions and little is known regarding sirolimus pharmacokinetics in the newborn. Methods and Results—This is a retrospective review of sirolimus pharmacokinetics in neonates who underwent sirolimus-eluting stent implantation in the arterial duct for pulmonary blood flow augmentation. Pharmacokinetic parameters were obtained by noncompartmental analysis and by a Bayesian one-compartment nonlinear mixed model. Nine neonates received a single sirolimus-eluting stent with a total sirolimus dose of 245 &mgr;g (n=1), 194 &mgr;g (n=5), or 143 &mgr;g (n=3). Peak sirolimus concentrations were 13.6±4.5 &mgr;g/L (24.8 &mgr;g/L highest) and clearance was 0.042±0.03 L/hour (noncompartmental analysis) and 0.051 L/hour (95% credible intervals 0.037–0.069, nonlinear mixed model). Sirolimus remained >5 &mgr;g/L, the trough level used in oral immunosuppressive therapy, for (95% credible interval) 15.9 (11.4, 22.8), 12.9 (7.6, 19.0), and 8.4 (2.3, 14.5) days for the 245, 194, and 143 &mgr;g sirolimus dose stents, respectively. Estimates of the duration of systemic immunosuppression are provided for combinations of 2 stents. Conclusions—In neonates after sirolimus-eluting stent implantation, peak sirolimus levels were 20× higher and clearance 30× lower than previously reported in older children and adults. Sirolimus levels were within the immunosuppressive range for a prolonged period, but with no observable clinically significant adverse outcomes.

A prospective study evaluating tobramycin pharmacokinetics and optimal once daily dosing in burn patients

BACKGROUND Once-daily aminoglycoside dosing (ODA) is used in most patient populations to optimize antibacterial activity and reduce toxicity. Unfortunately, burn patients are excluded from ODA due to concerns over altered pharmacokinetics resulting in a shortened half-life and low peak aminoglycoside concentrations. Retrospective studies suggest that ODA may be appropriate if higher milligram/kilogram doses are used. However, no prospective clinical trials in burn patients exist to confirm these findings. OBJECTIVE To determine the adequacy of once daily tobramycin dosed at 10mg/kg in adult burn patients. METHODS This prospective single dose pharmacokinetic clinical trial was conducted at the Ross Tilley Burn Centre. Patients with a total burn surface area (TBSA) of <20% and creatinine clearance ≥50mL/min were eligible. A first-order one compartment model was used to determine the pharmacokinetic profile from 3 or 5 tobramycin levels over a 24h period per patient. Monte Carlo simulation (MCS) was performed to determine the probability of target level attainment. RESULTS The mean percent TBSA, partial, and full thickness burn were 10%, 6%, and 4%, respectively. Nine of the ten patients recruited achieved peak concentrations of ≥20mg/L (mean of 29.4±5.7mg/L) and all patients had a trough level ≤0.5mg/L. The mean half-life, volume of distribution, and clearance were 2.58h, 0.33L/kg, and 7.40L/h, respectively. The MCS determined probability of attaining target peak concentrations with the 10mg/kg dose was 97%, which almost doubled that predicted with the usual 7mg/kg dose. CONCLUSION Burn patients with adequate renal function and <20% TBSA are candidates for ODA. Tobramycin half-life was similar to healthy, non-burn patients. The larger than normal volume of distribution supports the use of the higher empiric dose of 10mg/kg total body or adjusted weight in non-obese and obese patients, respectively, with further dose adjustment based on therapeutic drug monitoring.

Concurrent intravenous drug administration to critically ill children: Evaluation of frequency and compatibility

Purpose: To evaluate the frequency of concurrent drug administration and drug‐drug incompatibility of concurrently administered drugs in critically ill children based on available references. Materials and methods: We retrospectively evaluated concurrent intravenous drug administration in children admitted to a single centre. Eligible patients included those admitted to the critical care unit for at least 6‐hours in the ten‐year period ending 30 July 2015 and received two or more IV drug administrations. Compatibilities were classified using local reference documents. Results: The 16,863 eligible patients were admitted to ICU for 2,212,326 h and received 3,664,667 concurrent administrations. Concurrent infusions ran for 6,263,600 h. There were 2,284,066 (62%) concurrent administrations; 334,144 (9%) were compatible, 293,856 (8%) were incompatible, 293,856 (8%) required pharmacist consultation, and 752,601 (21%) had ‘unknown’ compatibility. Individual patients received a median (IQR) of 33 (10 − 132) concurrent administrations, comprised of 7 (1 − 30) concurrent injections 1 (0–5) concurrent infusions and 13 (0–74) concurrently administered injections and infusions. Conclusions: Concurrent IV‐drug administration is frequent in critically ill children. Known incompatible concurrent administration occurs, however the compatibilities of many drug‐drug pairs were unknown ‐ adding complexity to routine bedside management and identifying information gaps for future research. HIGHLIGHTSIntravenous‐drug administration and concurrent administration are frequent in critically ill children.Important knowledge gaps that affect more than a third of concurrent drug administration in critically ill children exist.Drug administration is complex, and has significant clinical implications on line, lumen and patient complications.

Nevirapine Pharmacokinetics and Safety in Neonates Receiving Combination Antiretroviral Therapy for Prevention of Vertical HIV Transmission.

Background: Nevirapine (NVP)-based combination antiretroviral therapy is routinely prescribed to infants deemed at high risk of vertical HIV infection in our centers. We evaluated NVP pharmacokinetics and safety of this regimen. Methods: Neonates were recruited prospectively between September 2012 and April 2015 or enrolled retrospectively if treated similarly before prospective study initiation. NVP was dosed at 150 mg/m2 daily for 14 days, then twice daily for 14 days. NVP levels were drawn at weeks 1, 2, and 4 [target trough (NVP-T): 3–8 mg/L]. Results: Thirty-three neonates were included (23 prospectively). Median gestational age (GA) and birth weight were 38 weeks (32–41 weeks) and 2.9 kg (1.5–4.2 kg), respectively. Median NVP-Ts were 8.2 mg/L (1.6–25.1 mg/L), 3.5 mg/L (1.6–6.8 mg/L), and 4.3 mg/L (0.1–19.9 mg/L) at weeks 1, 2, and 4, respectively. The proportions with therapeutic NVP-T were 42%, 61%, and 73% at these same timepoints. Median apparent oral clearance (CL/F) increased from 0.05 L·kg−1·h−1 (0.01–0.50 L·kg−1·h−1) at week 2 to 0.18 L·kg−1·h−1 (0.01–0.78 L·kg−1·h−1) at week 4. Increased drug exposure [area under the curve (AUC&tgr;)] correlated with younger GA (r = 0.459, P = 0.032) and lower birth weight (r = 0.542, P = 0.009). The most common adverse events potentially attributable to combination antiretroviral therapy were transient asymptomatic hyperlactatemia (26%), anemia (24.7%), and neutropenia (22.1%). Conclusions: Treatment dose NVP was generally well-tolerated and associated with normalization of trough levels over time in most cases without dose adjustment. Lower empiric dosing is recommended for infants <34 weeks of GA. Routine therapeutic drug monitoring may not be required for infants ≥34 weeks of GA.