Faculty Bibliography

OBJECTIVES: To evaluate the population pharmacokinetics and pharmacodynamic target attainment of vancomycin in neonates with a contemporary (1/4)-inch extracorporeal life support circuit with a Quadrox-iD Pediatric oxygenator (Maquet Cardiovascular, LLC, Wayne, NJ). DESIGN: Retrospective medical record review. SETTING: Two free-standing tertiary/quaternary pediatric children's hospitals. PATIENTS: Neonates receiving either veno-arterial or veno-venous extracorporeal life support and vancomycin for empiric or definitive therapy with resulting serum concentrations. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Twelve patients with a median gestations age of 39 weeks (range 36-41 wk) and a median postnatal age of 9.5 days (range 0-28 d) accounted for 14 courses of vancomycin therapy while on extracorporeal life support and were included in the analysis. The median weight was 3.1 kg (range 2.2-4.41 kg) with five of 12 patients (41.7%) being female. Vancomycin concentrations were best described by an one-compartment model incorporating allometric scaling of estimated glomerular filtration rate on clearance. The mean total body clearance (mL/min/kg) for the population was 3.48 +/- 1.31 mL/min/kg, and the mean total volume of distribution (L/kg) for the population was 1.2 +/- 0.4 L/kg. The intermittent and continuous infusion dosing regimens that provided for the highest percentage of trough concentrations in the range of 10-20 mg/L were the 10 mg/kg/dose IV q8h, 12.5 mg/kg/dose IV q8-12h, 15 mg/kg/dose IV q12h, and 20 mg/kg/dose IV q12h, and the 20, 25, and 30 mg/kg/d continuous infusion regimens, respectively. All regimens allowed for an area under the concentration:minimum inhibitory concentration ratio of 400:1 for minimum inhibitory concentrations of less than or equal to 0.5 mg/L for a 90% PTA. None of the simulated regimens had a greater than 90% probability of achieving an area under the concentration:minimum inhibitory concentration ratio of 400:1 for vancomycin minimum inhibitory concentrations greater than or equal to 1 mg/L while maintaining trough concentrations in the range of 10-20 mg/L. CONCLUSIONS: To our knowledge, this is the first pharmacokinetic and pharmacodynamic study of neonates receiving vancomycin with a contemporary (1/4)-inch extracorporeal life support circuit including the Quadrox-iD Pediatric oxygenator (Maquet Cardiovascular, LLC). The data suggest differences in vancomycin pharmacokinetics compared with previous extracorporeal life support data, notably a more rapid clearance, which could result in lower vancomycin concentrations. Considering this, a more aggressive initial dosing regimen may need to be employed in infants on extracorporeal life support.

OBJECTIVES: We sought to 1) evaluate how pediatricians approach situations in which families request continuation of organ support after declaration of death by neurologic criteria and 2) explore potential interventions to make these situations less challenging. DESIGN: A survey on management and personal experience with death by neurologic criteria was distributed electronically to pediatric intensivists and neurologists. We compared responses from individuals who practice in states with accommodation exceptions (accommodation states where religious or moral beliefs must be taken into consideration when declaring death: California, Illinois, New Jersey, New York) to those from non-accommodation states. SETTING: United States. SUBJECTS: The survey was opened by 254 recipients, with 186 meeting inclusion criteria and providing data about the region in which they practice; of these, 26% were from accommodation states. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: More than half of physicians (61% from both accommodation states and non-accommodation states) reported they cared for a pediatric patient whose family requested continuation of organ support after declaration of death by neurologic criteria (outside of organ donation; range, 1-17 times). Over half of physicians (53%) reported they would not feel comfortable handling a situation in which a pediatric patient's family requested care be continued after declaration of death by neurologic criteria. Nearly every physician (98%) endorsed that something needs to be done to make situations involving families who object to discontinuation of organ support after declaration of death by neurologic criteria easier to handle. Respondents felt that public education, physician education, and uniform state laws about these situations are warranted. CONCLUSIONS: It is relatively common for pediatricians who care for critically ill patients to encounter families who object to discontinuation of organ support after death by neurologic criteria. Management of these situations is challenging, and guidance for medical professionals and the public is needed.

Background. We have recently observed an increase in community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) infections among pediatric patients from Brooklyn hospitalized at a university-based teaching hospital in New York City. We performed a prospective study to determine the colonization prevalence of CA-MRSA among hospital admission, genome sequence strains causing infection and identified risk factors associated with CA-MRSA carriage in this population. Methods. Colonization data were obtained from routine infection control screening upon admission to the general pediatric and intensive care units. We used a questionnaire to identify risk factors for MRSA transmission. Additionally, single patient isolates of CA-MRSA were collected from the clinical microbiology laboratory. Medical record information was used to ascertain patient infection or colonization and to confirm community onset. Children from high-risk communities were identified via zip codes. Figure. Phylogenetic tree of clinical MRSA USA300 isolates from children living in high-risk zip codes (red), adult and pediatric patients at NYU Tisch Hospital (Blue), and USA300 Strains from around the United States (Green; Pfizer). Results. Children from the high-risk zip codes were 3 times as likely to be colonized with MRSA (9% versus 3% [p = 0.04]). No difference in methicillin-susceptible S. aureus colonization prevalence was observed between children from high-risk and low-risk communities. Likewise, the MRSA infection rate per 1000 patient days was 36 for children from high-risk zip codes, and 3.9 in children from low-risk zip codes (p < 0.0001). All isolates from patients in high risk zip codes analyzed to date belong to genotype USA300, the predominant CA-MRSA clone in the United States. Phylogenetic analyses suggest that these strains arose from expansion of an USA300 CAMRSA subclone. Potential risk factors for MRSA infection are being explored in conjunction with public health and community leaders. Conclusion. We identified a cluster of CA-MRSA strain USA300 among pediatric patients in a high risk Brooklyn community. Additional genomic comparisons and epidemiological data will be used to inform interventions and interrupt transmission. (Figure Presented)

OBJECTIVES: To describe our experience with achieving therapeutic serum vancomycin concentrations in pediatric continuous renal replacement therapy by using continuous infusion vancomycin by mixing vancomycin into the continuous renal replacement therapy solution. DESIGN: Retrospective chart review. SETTING: A 189-bed, freestanding children's tertiary care teaching hospital in Philadelphia, PA. PATIENTS: Pediatric patients receiving continuous renal replacement therapy from April 1, 2009, through December 31, 2014. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: There were a total of 21 patients who received continuous renal replacement therapy during the study period. Of these, 11 (52.3%) received vancomycin in the continuous renal replacement therapy solution. The median (range) concentration of vancomycin added to the continuous renal replacement therapy solution was 25 mg/L (18-35 mg/L). The mean vancomycin plateau level was 22.8 +/- 3.3 mg/L. All patients achieved a serum vancomycin plateau level that was greater than 15 mg/L. There were no adverse events related to the addition of vancomycin to the continuous renal replacement therapy solution. CONCLUSIONS: The addition of vancomycin to the continuous renal replacement therapy solution(s) is an effective modality that is used for delivering vancomycin continuous infusion and for ensuring therapeutic vancomycin serum plateau levels in the setting of pediatric continuous renal replacement therapy. Further studies are required to evaluate whether this delivery method can lead to improved patient outcomes.

Pharmacokinetic parameters can be significantly altered for both extracorporeal life support (ECLS) and continuous renal replacement therapy (CRRT). This case report describes the pharmacokinetics of continuous-infusion meropenem in a patient on ECLS with concurrent CRRT. A 2.8-kg, 10-day-old, full-term neonate born via spontaneous vaginal delivery presented with hypothermia, lethargy, and a ~500-g weight loss from birth. She progressed to respiratory failure on hospital day 2 (HD 2) and developed sepsis, disseminated intravascular coagulation, and liver failure as a result of disseminated adenoviral infection. By HD 6, acute kidney injury was evident, with progressive fluid overload >1500 mL (+) for the admission. On HD 6 venoarterial ECLS was instituted for lung protection and fluid removal. On HD 7 she was initiated on CRRT. On HD 12, a blood culture returned positive and subsequently grew Pseudomonas aeruginosa with a minimum inhibitory concentration (MIC) for meropenem of 0.25 mg/L. She was started on vancomycin, meropenem, and amikacin. A meropenem bolus of 40 mg/kg was given, followed by a continuous infusion of 10 mg/kg/hr (240 mg/kg/day). On HD 15 (ECLS day 9) a meropenem serum concentration of 21 mcg/mL was obtained, corresponding to a clearance of 7.9 mL/kg/min. Repeat cultures from HDs 13 to 15 (ECLS days 7-9) were sterile. This meropenem regimen was successful in providing a target attainment of 100% for serum concentrations above the MIC for >/=40% of the dosing interval and was associated with a sterilization of blood in this complex patient on concurrent ECLS and CRRT circuits.

PURPOSE: The results of a study to determine the stability of solutions of furosemide and chlorothiazide over 96 hours are reported. METHODS: Chlorothiazide and furosemide were diluted in 5% dextrose USP to final concentrations of 10 and 1 mg/mL, respectively, and combined. In addition, sample solutions of chlorothiazide in dextrose, furosemide in dextrose, and dextrose alone were prepared for control purposes. The resulting solutions were analyzed immediately after preparation and 24, 48, 72, and 96 hours later using a liquid chromatography-tandem mass spectroscopy (LC-MS/MS) system with an electrospray ionization source. Mixtures and samples were diluted 10,000-fold prior to LC-MS/MS analysis so that concentrations of both drugs would be within the assay's linear range of detection. RESULTS: LC-MS/MS analysis showed that chlorothiazide typically eluted at 2.6 minutes and furosemide at 4.8 minutes. Each compound was degraded by exposure to strong ultraviolet light in a time-dependent manner. Both unmixed and mixed solutions retained over 90% of the original concentrations of chlorothiazide and furosemide for up to 96 hours. Furosemide and chlorothiazide are commonly used concomitantly to maximize diuresis in pediatric patients; the study findings suggest that solutions of furosemide and chlorothiazide can be combined in the same syringe without loss of stability for up to 96 hours. CONCLUSION: Solutions of chlorothiazide (10 mg/mL) and furosemide (1 mg/mL) stored either separately or together in polypropylene syringes remained stable for up to 96 hours at room temperature and protected from light.

Objective, To survey the pediatric trauma programs to ascertain if and how etomidate is being used for rapid sequence intubation (RSI) in pediatric trauma patients. Design, A 25 question survey was created using REDCaps. A link to the survey was emailed to each of the pediatric and adult trauma programs that care for pediatric patients. Setting, Pediatric trauma programs and adult trauma programs caring for pediatric patients. Intervention, None. Measurements and Main Results, A total of 16% of programs responded (40/247). The majority of the centers that responded are urban, academic, teaching Level 1 pediatric trauma centers that provide care for > 200 pediatric trauma patients annually. The trauma program directors were the most likely to respond to the survey (18/40). 33/38 respondents state they use etomidate in their RSI protocol but it is not used in all pediatric trauma patients. 26/38 respondents believe that etomidate is associated with adrenal suppression and 24/37 believe it exacerbates adrenal suppression in pediatric trauma patients yet 28 of 37 respondents do not believe it is clinically relevant. Conclusions, Based on the results of the survey, the use of etomidate in pediatric trauma patients is common among urban, academic, teaching, level 1 pediatric trauma centers. A prospective evaluation of etomidate use for RSI in pediatric trauma patients to evaluate is potential effects on adrenal suppression and hemodynamics is warranted.

Neither guidelines nor best practices for the treatment of external ventricular drain (EVD) and ventriculoperitoneal shunt infections exist. An antimicrobial regimen with a broad spectrum of activity and adequate cerebrospinal fluid (CSF) penetration is vital in the management of both EVD and ventriculoperitoneal infections. In this case report, we describe the pharmacokinetics of continuous-infusion meropenem for a 2-year-old girl with Serratia marcescens ventriculitis. A right frontal EVD was placed for the management of a posterior fossa mass with hydrocephalus and intraventricular hemorrhage. On hospital day 6, CSF specimens were cultured, which identified a pan-sensitive Serratia marcescens with an initial cefotaxime minimum inhibitory concentration of 1 mug/ml or less. The patient was treated with cefotaxime monotherapy from hospital days 6 to 17, during which her CSF cultures and Gram's stain remained positive. On hospital day 26, Serratia marcescens was noted to be resistant to cefotaxime (minimum inhibitory concentration > 16 mug/ml), and the antimicrobial regimen was ultimately changed to meropenem and amikacin. Meropenem was dosed at 40 mg/kg/dose intravenously every 6 hours, infused over 30 minutes, during which, simultaneous serum and CSF meropenem levels were measured. Meropenem serum and CSF levels were measured at 2 and 4 hours from the end of the infusion with the intent to perform a pharmacokinetic/pharmacodynamic analysis. The resulting serum meropenem levels were 12 mug/ml at 2 hours and "undetectable" at 4 hours, with CSF levels of 1 and 0.5 mug/ml at 2 and 4 hours, respectively. On hospital day 27, the meropenem regimen was changed to a continuous infusion of 200 mg/kg/day, with repeat serum and CSF meropenem levels measured on hospital day 33. The serum and CSF levels were noted to be 13 and 0.5 mug/ml, respectively. The serum level of 13 mug/ml corresponds to an estimated meropenem clearance from the serum of 10.2 ml/kg/minute. Repeat meropenem levels from the serum and CSF on hospital day 37 were 15 and 0.5 mug/ml, respectively. After instituting the continuous-infusion meropenem regimen, only three positive CSF Gram's stains were noted, with the CSF cultures remaining negative. The continuous-infusion dosing regimen allowed for 100% probability of target attainment in the serum and CSF and a successful clinical outcome.

Disseminated herpes simplex virus (HSV) infection in neonates represents a devastating entity that yields high mortality. Acyclovir is the primary antiviral agent used to treat life-threatening HSV infections in neonates; however, even though the agent has reduced morbidity overall from these infections, mortality with disseminated disease remains high. Currently, to our knowledge, no data exist regarding therapeutic drug monitoring of acyclovir in the setting of extracorporeal life support (ECLS) or continuous renal replacement therapy (CRRT) coupled with ECLS. We describe the case of a 14-day-old female with disseminated HSV-1 infection that progressed to fulminant hepatic and renal failure, necessitating the use of ECLS for hemodynamic support and CRRT as a treatment modality for hepatic and renal failure. The standard dosage of acyclovir 20 mg/kg/dose intravenously every 8 hours had been initiated, but after conversion to ECLS and CRRT, the patient's dosage was increased to 30 mg/kg/dose every 8 hours. After a repeat viral load remained unchanged from the initial viral load at 1 x 10(8) copies/ml, the patient was transitioned from intermittent dosing to a continuous infusion of acyclovir added to the dialysate solution for CRRT at a concentration of 5.5 mg/L. To provide an optimal outcome, dosing was designed to maintain acyclovir plasma concentrations of at least 3 mg/L in order to maintain an acyclovir concentration of at least 1 mg/L in the cerebrospinal fluid. The patient's acyclovir serum concentrations measured at 24 and 72 hours after starting continuous-infusion acyclovir via the dialysate were 8.8 and 5.3 mg/L, respectively, allowing for a continuous serum concentration above 3 mg/L. Unfortunately, before a repeat viral load could be obtained to assess the efficacy of the continuous infusion acyclovir, the patient experienced an intracerebral hemorrhage as a complication related to ECLS after which technological support was withdrawn. This is the first report to describe the pharmacokinetics of continuous-infusion acyclovir in a neonate receiving ECLS with concurrent CRRT. These data suggest that adding acyclovir to the dialysate fluid during CRRT is effective in achieving therapeutic drug concentrations despite the complications of adding ECLS and CRRT circuits to a small patient.

OBJECTIVE: Despite a paucity of supporting literature, acetazolamide is commonly used in critically ill children with metabolic alkalosis (elevated plasma bicarbonate [pHco-3] and pH). The objective of this study was to assess the change in 18 hours after initiation of acetazolamide therapy. DESIGN: Retrospective study. SETTING: PICU of an urban, tertiary-care children's hospital. PATIENTS: Mechanically ventilated children (/= 35 mmol/L). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of 153 consecutively screened patients, 61 patients (29 female patients) were enrolled: 18 cardiac patients (after congenital heart disease repair) and 43 noncardiac patients. The cardiac patients were younger than the noncardiac patients (median [interquartile range] age, 0.6 mo [0.3-2.5 mo] vs 7.4 mo [2.8-39.9 mo]; p < 0.00001) and had higher preacetazolamide baseline diuretic scores and urine output. The pHco-3 levels 18 hours after initiation of acetazolamide were reduced in the cohort as a whole (40.2 +/- 4.8 to 36.2 +/- 5.6 mmol/L; p < 0.001) and in the noncardiac patients, but they were unchanged in the cardiac patients. The PCO2 remained unchanged after acetazolamide in both subgroups. Because young age and presence of cardiac disease were potential confounders, the 20 noncardiac patients who are 6 months old or younger were compared with the cardiac subgroup and demonstrated reduced pHco-3 after acetazolamide and lower preacetazolamide baseline diuretic score and urine output. CONCLUSION: Acetazolamide reduces pHco-3 concentration in critically ill, mechanically ventilated children overall, but it did not do so in cardiac patients in our cohort, even in comparison with noncardiac patients of a similar age. These findings do not support the current use of acetazolamide for metabolic alkalosis in critically ill children with congenital heart disease. Further study is required to determine why these cardiac patients respond differently to acetazolamide than noncardiac patients and whether this response impacts important clinical outcomes, for example, weaning mechanical ventilation.