Remifentanil for Sedation of Children With Traumatic Brain Injury.

OBJECTIVE: To determine whether remifentanil would provide adequate sedation while allowing frequent and reproducible neurologic assessments in children admitted to the pediatric intensive care unit (PICU) with traumatic brain injury (TBI) during mechanical ventilation. DESIGN: Retrospective review. SETTING: Tertiary care PICU. PATIENTS: Thirty-eight patients over a 30-month period. MEASUREMENTS AND MAIN RESULTS: Median age was 9 years (interquartile range [IQR] 2.25-12 years). The median Glasgow Coma Scale (GCS) was 9 (IQR: 8-10). All patients were tracheally intubated and receiving mechanical ventilation. A continuous infusion of remifentanil was started at 0.1 µg/kg/min, and bolus doses of 0.25 to 1 µg/kg were administered every 3 to 5 minutes as needed to reach the desired sedation level. Infusions were stopped at least hourly to perform neurologic examinations. The median remifentanil dose was 0.25 µg/kg/min with an IQR of 0.1 and 0.6 µg/kg/min. The maximum dose for any patient in the cohort was 2 µg/kg/min. Median duration of therapy with remifentanil was 20 hours (IQR: 8-44 hours). Adequate sedation was achieved with sedation scores (State Behavioral Scale) meeting target levels with a median value of 100% of the time (IQR: 79%-100%). Neurologic examinations were able to be performed within a median of 9 minutes (IQR: 5-14 minutes) of pausing the infusion. No serious safety events occurred. In 68% of the patients, neurologic examinations remained reassuring during remifentanil infusion, and patients were extubated. The remaining patients were transitioned to traditional sedative agents for long-term management of their traumatic injuries once the neurologic status was deemed stable. CONCLUSION: This data suggest that remifentanil is a suitable sedative agent for use in children with TBI. It provides a rapid onset of sedation with recovery that permits reliable and reproducible clinical examination.

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.

Augmentation of the Inotropic Effects of Dopamine Following Linezolid Administration in an Infant.

Although generally safe and effective, one of the unique properties of linezolid is its weak inhibitory effect on monoamine oxidase. As such, it may interact with other medications that act through the adrenergic or serotonergic systems, including selective-serotonin reuptake inhibitors and vasoactive agents. We present a 3-month-old infant who was being treated with dopamine to maintain mean arterial pressure during mechanical ventilation following viral-induced respiratory failure. Hypertension and tachycardia developed during the administration of linezolid on two separate occasions. The physiology of catecholamine metabolism is reviewed including the role of the monoamine oxidase system. The potential interaction between linezolid and vasoactive agents such as dopamine is discussed.

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.

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.

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.

Empiric Vancomycin Reduction in a Pediatric Intensive Care Unit.

BACKGROUND: At our institution, empirical vancomycin is overused in children with suspected bacterial community-acquired infections (CAIs) admitted to the PICU because of high community rates of methicillin-resistant Staphylococcus aureus (MRSA). Our goal was to reduce unnecessary vancomycin use for CAIs in the PICU. METHODS: Empirical PICU vancomycin indications for suspected CAIs were developed by using epidemiological risk factors for MRSA. We aimed to reduce empirical PICU vancomycin use in CAIs by 30%. After retrospectively testing, the indications were implemented and monthly PICU empirical vancomycin use during baseline (May 2017-April 2018) and postintervention (May 2018-July 2019) periods. Education was provided to PICU providers, vancomycin indications were posted, and the antibiotic order set was revised. Statistical process control methods tracked improvement over time. Proven S aureus infections for which vancomycin was not empirically prescribed and linezolid or clindamycin use were balancing measures. RESULTS: We identified 1620 PICU patients with suspected bacterial CAIs. Empirical vancomycin decreased from a baseline of 73% to 45%, a 38% relative reduction. No patient not prescribed empirical vancomycin later required the addition of vancomycin or other MRSA-targeted antibiotics. There was no change in nephrotoxicity or in the balancing measures. CONCLUSIONS: Development of clear and concise recommendations, combined with clinician education and decision support via an order set, was an effective and safe strategy to reduce PICU vancomycin use. Retrospective validation of the recommendations with local data were key to obtaining PICU clinician buy in.

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.

In vitro drug adsorption and plasma free hemoglobin levels associated with hollow fiber oxygenators in the extracorporeal life support (ECLS) circuit.

The purpose of this study was to identify the percentage of fentanyl or morphine sulfate lost from adhesion to either the polyvinylchloride (PVC) tubing or the surface of two different hollow fiber oxygenators used in current extracorporeal life support circuits and to identify any difference in the plasma free hemoglobin (PFH) levels generated when using these oxygenator and/or drug combinations. For each drug examined, six simple circuits were assembled; for each drug, two circuits contained tubing without an oxygenator (control), two circuits contained the Jostra Quadrox D (Maquet Cardiopulmonary, AG Hirrlingen, Germany), and two circuits contained the Terumo Baby Rx (Terumo Cardiovascular Systems Corp., Ann Arbor, MI). Fentanyl or morphine sulfate was added to yield initial circuit concentrations equal to 1430 ng/mL, respectively. Throughout the 6-hour in vitro testing, samples to evaluate the drug and PFH levels were drawn at various time intervals. Significance in this study is defined as p < .05. Fentanyl's initial adsorption seems to be 80% in circuits without oxygenators, 86% in the circuits containing the Quadrox D oxygenator, and 83% in the circuits with the Baby Rx oxygenator. Morphine sulfate seems to be initially adsorbed at a rate of 40% in all circuits and does not seem to be adsorbed by either of the tested oxygenators. The PFH levels were significantly (p < .05) elevated in the fentanyl circuits. The type of oxygenator does not seem to play a significant role in drug adsorption. During this in vitro study, the majority of both drugs were lost to the PVC tubing. The type of oxygenator did not seem to significantly affect PFH. However, fentanyl in any combination or alone was associated with increased PFH levels.