Dexmedetomidine as Single Continuous Sedative During Noninvasive Ventilation: Typical Usage, Hemodynamic Effects, and Withdrawal.

OBJECTIVES: Dexmedetomidine use in pediatric critical care is increasing. Its prolonged effects as a single continuous agent for sedation are not well described. The aim of the current study was to describe prolonged dexmedetomidine therapy without other continuous sedation, specifically the hemodynamic effects, discontinuation strategies, and risk factors for withdrawal. DESIGN: Retrospective chart review. SETTING: Large, single-center, quaternary care pediatric academic institution. PATIENTS: Data from 382 children, less than 18 years old admitted to the PICU who received dexmedetomidine for more than 24 hours without other infusions for sedation during noninvasive positive pressure ventilation. INTERVENTIONS: Usual care practices for dexmedetomidine use were described. Discontinuation strategies were categorized as abrupt discontinuation, wean from dexmedetomidine infusion, and transition to enteral clonidine. MEASUREMENTS AND MAIN RESULTS: Median peak and cumulative doses with interquartile range were 1 µg/kg/hr (0.6-1.2 µg/kg/hr) and 30 µg/kg (20-50 µg/kg), respectively, and median duration was 45 hours (34-66 hr). Four hours after reaching peak dose, we observed a decrease in heart rate (p < 0.01) with 28% prevalence of bradycardia and an increase in systolic blood pressure (p < 0.01) with 33% prevalence of hypertension and 2% hypotension. During the escalation phase, the prevalence of bradycardia and hypotension were 75% and a 30%, respectively. Three-hundred thirty-six patients (88%) had abrupt discontinuation, 37 (10%) were weaned, and nine (2%) were transitioned to clonidine. Nineteen patients (5%) experienced withdrawal. Univariate risk of withdrawal was most associated with duration: odds ratio equal to 1.5 (1.3-1.7) for each 12-hour period (p < 0.01). By multivariate analysis including age, discontinuation group, dexmedetomidine cumulative dose, and peak dose, only cumulative dose remained significant with an odds ratio equal to 1.3 (1.1-1.5) for each 10 µg/kg (p < 0.01). CONCLUSIONS: Dexmedetomidine use for noninvasive positive pressure ventilation sedation in pediatric critical care has predictable hemodynamic effects including bradycardia and hypertension. Although withdrawal was associated with higher cumulative dose, these symptoms were effectively managed with short-term enteral clonidine.

Evaluation of an Enteral Clonidine Taper following Prolonged Dexmedetomidine Exposure in Critically Ill Children.

The aim of the current study is to evaluate the use of an enteral clonidine transition for the prevention or management of dexmedetomidine withdrawal symptoms in critically ill children not exposed to other continuous infusion sedative agents. A retrospective, single-center study was conducted in patients ≤ 18 years of age admitted to the pediatric intensive care unit who received a continuous infusion of dexmedetomidine for ≥ 24 hours and who were prescribed enteral clonidine within 72 hours of dexmedetomidine discontinuation. Predefined withdrawal terminology was established to assess for hypertension, tachycardia, agitation, tremors, and decreased sleep. A total of 105 patients were included and received enteral clonidine for prevention or management of dexmedetomidine withdrawal symptoms, with 13 patients (12.4%) requiring a taper modification to manage withdrawal symptoms. The median duration of dexmedetomidine infusion was 120.5 hours (95.5, 143.5) and median peak infusion rate was 1 µg/kg/h (1, 1.2). A higher cumulative dexmedetomidine dose of 119.2 µg/kg (96.6, 154.9) and duration of 142.9 hours (122.6, 158.3) were noted in patients who required a taper modification. Risk factors for dexmedetomidine withdrawal such as dexmedetomidine duration and cumulative dose may help predict patients at the highest risk of withdrawal that would benefit from an enteral clonidine taper to prevent dexmedetomidine withdrawal symptoms. An enteral clonidine taper can be effective in the prevention and management of dexmedetomidine withdrawal symptoms.

Acute Hepatic Dysfunction Related to Chronic Acetaminophen Administration.

Toxicity related to acetaminophen is most encountered with the acute ingestion of large doses. However, toxicity may also result from chronic ingestion, even when recommended doses are administered over a prolonged period of time. We present the case of a 20-month-old female toddler who received therapeutic recommended doses of acetaminophen (oral or intravenous) following multiple surgical interventions for treatment of a tracheo-esophageal fistula following ingestion of a button battery. The potential role of chronic acetaminophen administration in the etiology of hepatoxicity is discussed and prevention strategies are presented.

Creation of a Combination Antibiogram for Pseudomonas aeruginosa in a Pediatric Intensive Care Unit.

OBJECTIVE: This study describes the creation of a combination antibiogram directed toward Pseudomonas aeruginosa to determine the most appropriate empiric antimicrobial regimen(s). METHODS: P aeruginosa isolates were collected from all sites between January 2013 and December 2017 for patients admitted to the PICU. Patients with cystic fibrosis and isolates from the same site and susceptibility pattern obtained within 30 days were excluded. ß-Lactam susceptibilities were determined and compared with the addition of an aminoglycoside or fluroquinolone and summarized in a combination antibiogram. RESULTS: One hundred ninety-nine P aeruginosa isolates were included for analysis. The addition of a second agent to piperacillin-tazobactam was shown to have the most significant improvement among the ß-lactams, with 70% susceptibility as monotherapy and increases to above 90% with the addition of an aminoglycoside or fluroquinolone. The addition of an aminoglycoside or fluroquinolone to cefepime and meropenem increased coverage to above 95%. The addition of a second agent was likely to increase susceptibility of a monotherapy backbone; however, as the susceptibility of the first-line agent decreased, the susceptibility of the second agent needed to be higher to achieve a 95% coverage threshold. CONCLUSIONS: Our results support use of a second agent to significantly improve the likelihood of appropriate empiric coverage of P aeruginosa. Use of a combination antibiogram may be more beneficial than a simple antibiogram for units with increasing resistance rates, or for coverage of specific resistant organisms.

A Quality Improvement Approach to Influence Value-based Mucolytic Use in the PICU.

INTRODUCTION: High-cost medication administration, despite lacking evidence for use, results in poor healthcare value. This work aimed to reduce dornase-alfa utilization in critically ill mechanically ventilated children. METHODS: The project employed an observational pre-post design to develop a value-based clinical pathway to guide provider choice in mucolytic utilization in a quaternary pediatric intensive care unit. This pathway was designed to continue using low-cost mucolytic aerosols (hypertonic saline, N-acetylcysteine) but decrease new starts and total doses per 100 patient days (P100PD) dornase-alfa among patients for whom there is little to no supporting evidence. Interventions included a departmental journal club for fellow and attending physicians and a rolling introduction of the pathway to residents and respiratory therapists. Control charts serially tracked ordering changes and location-specific dornase alfa orders. RESULTS: New dornase-alfa starts P100PD decreased by 53% (1.17-0.55), and total doses P100PD decreased by 75% (16-4). N-acetylcysteine ordering more than doubled; however, total doses of P100PD remained unchanged after the intervention. The use of 3% sodium chloride increased significantly from 0.28 to 4.15 new starts and 4.37 to 38.84 total doses P100PD. Mechanical ventilation days P100PD decreased, suggesting there were no measured adverse effects of pathway implementation. The reduction in dornase-alfa utilization resulted in a cumulative and sustained 59% mucolytic cost reduction ($2183.08-$885.77 P100PD). CONCLUSION: A clinical pathway prioritizing pharmacoeconomics when evidence for use is lacking can improve health care value without adversely affecting patient outcomes.

Modified surface coatings and their effect on drug adsorption within the extracorporeal life support circuit.

A recently completed study quantified the percent of fentanyl or morphine sulfate lost to uncoated polyvinylchloride (PVC) tubing or to one of two hollow fiber oxygenators within the extracorporeal life support (ECLS) circuit. The results demonstrated the majority of drug loss was due to adsorption by the PVC tubing. The purpose of this study was to determine if a tubing coating process affects fentanyl or morphine Sulfate adsorption. The goal was to quantify fentanyl or morphine sulfate lost due to adhesion within surface modified tubing. The following surface modifications were studied: 1) Maquet Safeline (synthetic immobilized albumin); 2) Maquet Softline (a heparin free biopassive polymer); 3) Maquet Bioline (recombinant human albumin + heparin) (Maquet Cardiopulmonary AG, Hirrlingen, Germany); 4) Terumo X Coating (poly2methoxylacrylate)) (Terumo Cardiovascular Systems Corporation, Ann Arbor, MI); 5) Medtronic Carmeda (covalently bonded heparin); and 6) Medtronic Trillium (covalently bonded heparin) (Medtronic, Minneapolis, MN). A total of 36 individual circuits were built from the above six available modified surface coatings, for a total of six individual circuits of each coating type. Blood samples were drawn at 5 minutes, 120 minutes, and 360 minutes followed by High-Performance Liquid Chromatography to determine available circulating levels of either fentanyl or morphine sulfate. Fentanyl concentrations decreased to an average final available concentration of 35% (+/- 5%) within the 18 circuits. Morphine sulfate however, decreased to a final available concentration of 57% (+ 1%) in all Maquet tubing and the Medtronic Trillium tubing, while it decreased to a final concentration of 35% (+ 1%) in the Medtronic Carmeda coated tubing and in the Terumo X Coating tubing. Biocompatible ECLS circuit surface coatings affected drug-adsorption and availability. Further evaluation is necessary to understand the adsorptive loss of other drugs administered to our patients while on modified surface coated ECLS circuits.

Intravenous Ribavirin for Parainfluenza and Respiratory Syncytial Virus in an Infant Receiving Extracorporeal Membrane Oxygenation and Continuous Renal Replacement Therapy.

BACKGROUND: Viral bronchiolitis remains a significant cause of hospitalization as well as morbidity and mortality during the first year of life, with treatment options beyond supportive care being limited. In cases of severe illness, ribavirin may offer therapeutic benefit. OBJECTIVE: We report the use of intravenous (IV) ribavirin in an infant requiring concomitant venovenous extracorporeal membrane oxygenation (VV-ECMO) and continuous venovenous hemofiltration (CVVH) for respiratory syncytial virus (RSV) and parainfluenza virus (PIV) coinfection. PATIENTS AND METHODS: A 5-week-old male former 33-week preterm infant was admitted with respiratory failure and subsequently tested positive for RSV and PIV-type 1 infection. Progressive clinical deterioration subsequently required the initiation of both VV-ECMO and CVVH. Although the patient received combined VV-ECMO and CVVH, IV ribavirin was administered, and serial plasma and ultrafiltrate samples were obtained for pharmacokinetic analyses after the first dose (collection period 1) and again after an estimated 5 half-lives (collection period 2). RESULTS: Pharmacokinetics for collection period 1 demonstrated a calculated Cmax of 11.99 mg/L, an AUC0-24 of 43.32 mg·hr/L, ke 0.26 hr-1, t½ 2.69 hr, Vd 10.04 L (2.92 L/kg, using patient's dosing weight 3.43 kg), CLT 43.47 mL/min, and CLCVVH 6.75 mL/min. Pharmacokinetics for collection period 2 demonstrated a calculated Cmax of 10.31 mg/L, AUC0-6 of 52.55 mg· hr/L, ke 0.06 hr-1, t½ 10.69 hr, Vd 17.5 L (5.1 L/kg), and CLT 17.44 mL/min. The sieving coefficient during collection period 1 was 1.17 (range, 1.07-1.37). The percent decline between prefilter and postfilter oxygenator was 19.1%. CONCLUSION: Our patient demonstrated therapeutic concentrations of ribavirin, despite drug removal via CVVH and the ECMO oxygenator. Standard ribavirin dosing used and resultant concentrations achieved were associated with viral clearance and clinical improvement.

An empiric antibiotic protocol using risk stratification improves antibiotic selection and timing in critically ill children.

RATIONALE: Timely and appropriate empiric antibiotics can improve outcomes in critically ill patients with infection. Evidence and guidelines to guide empiric antibiotic decisions are lacking for critically ill children. OBJECTIVES: To evaluate the impact of an empiric antibiotic protocol on appropriateness of initial antibiotics and time to appropriate antibiotics in critically ill children with suspected infection. METHODS: A computer order entry-based, pediatric intensive care unit-specific, empiric antibiotic protocol including risk stratification for healthcare-associated infections was implemented in a tertiary pediatric intensive care unit. Antibiotic and culture data were evaluated for a total of 556 infectious episodes in 491 patients from 2004 (preprotocol, n = 252) and 2007 (protocol, n = 304) with suspected infection. Antibiotics appropriateness based on risk factors and culture results was assessed, as was time from initial culture to appropriate antibiotics. MEASUREMENTS AND MAIN RESULTS: Patients treated using the protocols were more likely to receive appropriate empiric antibiotics based on risk factors (76 vs. 15%; P < 0.0001) and culture results (89 vs. 64%; P < 0.0001). Patients treated after protocol implementation had a shorter time to appropriate antibiotics (median, 5.9 vs. 9.6 h; P < 0.0001), particularly in those who grew healthcare-associated pathogens (5.8 vs. 24 h; P = 0.0001). No significant baseline characteristic differences were seen. CONCLUSIONS: An empiric antibiotic protocol in the pediatric intensive care unit incorporating risk stratification for healthcare-associated infections resulted in increased appropriateness of empiric antibiotics and in decreased time to appropriate antibiotics in critically ill children with infection.

Timing of correct parenteral antibiotic initiation and outcomes from severe bacterial community-acquired pneumonia in children.

BACKGROUND: The impact of timing of appropriate antibiotic initiation for critically ill children with severe bacterial community-acquired pneumonia (CAP) is unknown. We hypothesized that longer time to initiation of correct parenteral antibiotic would be associated with longer durations of mechanical ventilation, intensive care unit length of stay, and hospital length of stay. METHODS: We retrospectively reviewed medical records of children admitted to Nationwide Children's Hospital between January 2004 and December 2006 with bacterial CAP treated with mechanical ventilation, excluding those with documented viral infection. Time to correct antibiotic was defined as time from presentation to any emergency department to the initiation of a parenteral antibiotic to which cultured pathogens were susceptible. RESULTS: In all, 45 patients, median age 17 months, were identified. Median time to correct antibiotic was 10.3 hours, with 71% of patients receiving correct empiric therapy. After adjusting for severity of illness, longer time to correct antibiotic was independently associated with longer hospital stay (P = 0.007). For the 23 patients in the cohort for whom pneumonia was the primary diagnosis, longer time to correct antibiotic was independently associated with longer durations of mechanical ventilation (P = 0.01), intensive care unit stay (P = 0.001), and hospital stay (P = 0.006). Delays in antibiotic administration as short as 2 to 4 hours were associated with adverse outcomes in this group. CONCLUSIONS: In our critically ill children with severe bacterial CAP, longer delays in receipt of appropriate empiric antibiotics were independently associated with adverse outcomes.