Clinical Focus

  • Pediatric Critical Care Medicine

Academic Appointments

Administrative Appointments

  • Program Director, Pediatric Critical Care Medicine Fellowship (2016 - Present)
  • Research Director, Revive Initiative for Resuscitation Excellence (2014 - Present)

Professional Education

  • Fellowship:Childrens Hospital of Philadelphia Pediatric Critical Care Fellowship (2006) PA
  • Board Certification: Pediatric Critical Care Medicine, American Board of Pediatrics (2006)
  • Board Certification: Pediatrics, American Board of Pediatrics (2004)
  • Fellowship, The Children’s Hospital of Philadelphia, Pediatric Critical Care Medicine (2006)
  • Residency:UT Southwestern - Children's Medical Center of Dallas (2003) TX
  • Medical Education:Northwestern University Feinberg School of Medicine (2000) IL

Research & Scholarship

Current Research and Scholarly Interests

My clinical pharmacology research is focused on investigating the impact of dynamic organ function on drug disposition and designing dosing strategies based on mathematical models that account for these changes in order to optimize safe medication administration in critically ill children.

Research through the REVIVE Initiative for Resuscitation Excellence investigates the quality of resuscitation during cardiopulmonary arrest. Areas of focus include early identification during the no-flow state prior to CPR initiation and quality of CPR simulation education.


Graduate and Fellowship Programs

  • Pediatric Critical Care Medicine (Fellowship Program)


All Publications

  • The Prognostic Value of Quantitative Diffusion-Weighted MRI after Pediatric Cardiopulmonary Arrest. Resuscitation Yacoub, M., Birchansky, B., Mlynash, M., Berg, M., Knight, L., Hirsch, K. G., Su, F., Revive Initiative at Stanford Childrens Health 2018


    OBJECTIVES: The prognostic value of quantitative diffusion-weighted magnetic resonance imaging (DWI MRI) in predicting neurologic outcomes after pediatric cardiopulmonary arrest (CPA) has not been determined. The aim of this study was to identify a DWI MRI threshold for brain volume percent that correlates with neurologic outcome in children who remain comatose or display significant neurologic deficits immediately after resuscitation from CPA.METHODS: This single-center retrospective study analyzed DWI MRIs of pediatric patients who remained neurologically impaired after CPA. Any MRI obtained within 2 weeks after CPA was analyzed. The apparent diffusion coefficient (ADC) value of each voxel within the brain was determined. Percentage brain volume with voxels below each ADC threshold between 300-1200 * 10-6 mm2/s with a step of 50 were calculated. Area under the receiver operating characteristics curve (AUC) was used to identify optimal DWI MRI thresholds for brain volume percent most predictive of poor neurologic outcome. The primary outcome measure was neurologic outcome 6-months after CPA based on Pediatric Cerebral Performance Category (PCPC) score. Poor neurologic outcome was defined as PCPC score of 3-6, or a worsening from baseline score ≥ 1 if baseline PCPC score was ≥ 3.RESULTS: Twenty-six patients were included in this study. The median age was 8.5 years (2.2-14) and median time from CPA to MRI was 4 days (2-7). Two ADC thresholds for brain volume percent had the largest AUC for predicting poor neurologic outcome. An ADC threshold of < 600 * 10-6 mm2/s in ≥ 7% of brain volume; and < 650 * 10-6 mm2/s in ≥ 11% of brain volume both demonstrated a specificity of 1.0 (0.76-1.0, 95% CI) and a sensitivity of 0.8 (0.44- 0.96, 95% CI) for poor outcome.CONCLUSIONS: In pediatric patients who remain comatose or have significant neurologic deficits after CPA, quantitative DWI MRI correlates with neurologic outcome. Both an ADC threshold of < 600 * 10-6 mm2/s in ≥ 7% of brain volume and < 650 * 10-6 mm2/s in ≥ 11% of brain volume are highly specific for predicting poor neurologic outcome. A prospective trial to validate these thresholds is needed.

    View details for DOI 10.1016/j.resuscitation.2018.11.003

    View details for PubMedID 30576784

  • Variability in the time to initiation of CPR in continuously monitored pediatric ICUs. Resuscitation Olson, M., Helfenbein, E., Su, L., Berg, M., Knight, L., Troy, L., Sacks, L., Sakai, D., Su, F., Revive Initiative at Stanford Childrens Health 2018; 127: 95–99


    AIM: To study the influence of patient characteristics and unit ergonomics and human factors on the time to initiation of CPR.METHODS: A single center study of children, 0 to 21 years old, admitted to an ICU who experienced cardiopulmonary arrest (CPA) requiring >1 min of chest compressions. Time of CPA was determined by analysis of continuous ECG, plethysmography, arterial blood pressure, and end-tidal CO2 (EtCO2) waveforms. Initiation of CPR was identified by the onset of cyclic artifact in the ECG waveform. Patient characteristics and unit ergonomics and human factors were examined including CPA cause, identification on the High-Risk Checklist (HRC), existing monitoring, ICU type, time of day, nursing shift change, and outcome.RESULTS: The median time from CPA to initiation of CPR was 50.5 s (IQR 26.5 to 127.5) in 36 CPAs. Forty-seven percent of patients experienced time from CPA to initiation of CPR of >1 min. There was no difference in CPA cause, ICU type, time of day, or nursing shift change.CONCLUSION: Nearly half of pediatric patients who experienced CPA in an ICU setting did not meet AHA guidelines for early initiation of CPR. This is an opportunity to study the recognition phase of CPA using continuous monitoring data with the aim of improving the understanding of and factors contributing to delays in initiation of CPR.

    View details for DOI 10.1016/j.resuscitation.2018.03.033

    View details for PubMedID 29605703

  • Characterization of Pediatric In-Hospital Cardiopulmonary Resuscitation Quality Metrics Across an International Resuscitation Collaborative PEDIATRIC CRITICAL CARE MEDICINE Niles, D. E., Duval-Arnould, J., Skellett, S., Knight, L., Su, F., Raymond, T. T., Sweberg, T., Sen, A. I., Atkins, D. L., Friess, S. H., de Caen, A. R., Kurosawa, H., Sutton, R. M., Wolfe, H., Berg, R. A., Silver, A., Hunt, E. A., Nadkarni, V. M., Pediat Resuscitation Quality pediR 2018; 19 (5): 421–32


    Pediatric in-hospital cardiac arrest cardiopulmonary resuscitation quality metrics have been reported in few children less than 8 years. Our objective was to characterize chest compression fraction, rate, depth, and compliance with 2015 American Heart Association guidelines across multiple pediatric hospitals.Retrospective observational study of data from a multicenter resuscitation quality collaborative from October 2015 to April 2017.Twelve pediatric hospitals across United States, Canada, and Europe.In-hospital cardiac arrest patients (age < 18 yr) with quantitative cardiopulmonary resuscitation data recordings.None.There were 112 events yielding 2,046 evaluable 60-second epochs of cardiopulmonary resuscitation (196,669 chest compression). Event cardiopulmonary resuscitation metric summaries (median [interquartile range]) by age: less than 1 year (38/112): chest compression fraction 0.88 (0.61-0.98), chest compression rate 119/min (110-129), and chest compression depth 2.3 cm (1.9-3.0 cm); for 1 to less than 8 years (42/112): chest compression fraction 0.94 (0.79-1.00), chest compression rate 117/min (110-124), and chest compression depth 3.8 cm (2.9-4.6 cm); for 8 to less than 18 years (32/112): chest compression fraction 0.94 (0.85-1.00), chest compression rate 117/min (110-123), chest compression depth 5.5 cm (4.0-6.5 cm). "Compliance" with guideline targets for 60-second chest compression "epochs" was predefined: chest compression fraction greater than 0.80, chest compression rate 100-120/min, and chest compression depth: greater than or equal to 3.4 cm in less than 1 year, greater than or equal to 4.4 cm in 1 to less than 8 years, and 4.5 to less than 6.6 cm in 8 to less than 18 years. Proportion of less than 1 year, 1 to less than 8 years, and 8 to less than 18 years events with greater than or equal to 60% of 60-second epochs meeting compliance (respectively): chest compression fraction was 53%, 81%, and 78%; chest compression rate was 32%, 50%, and 63%; chest compression depth was 13%, 19%, and 44%. For all events combined, total compliance (meeting all three guideline targets) was 10% (11/112).Across an international pediatric resuscitation collaborative, we characterized the landscape of pediatric in-hospital cardiac arrest chest compression quality metrics and found that they often do not meet 2015 American Heart Association guidelines. Guideline compliance for rate and depth in children less than 18 years is poor, with the greatest difficulty in achieving chest compression depth targets in younger children.

    View details for DOI 10.1097/PCC.0000000000001520

    View details for Web of Science ID 000435852500013

    View details for PubMedID 29533355

  • ASSOCIATION OF 2015 AHA CPR QUALITY METRICS AND 24-HOUR SURVIVAL ACROSS 10 CRITICAL CARE SITES Hunt, E., Raymond, T., Gilfoyle, E., Duval-Arnould, J., Niles, D., Sweberg, T., Wolfe, H., Jani, P., Martin, D., Tegtmeyer, K., Nett, S., Sen, A., Roberts, J., Friess, S., Su, F., Haskell, S., Silver, A., Nadkarni, V., Pediat Resuscitation Quality Colla LIPPINCOTT WILLIAMS & WILKINS. 2018: 25
  • Diagnostic Bedside Ultrasound Program Development in Pediatric Critical Care Medicine: Results of a National Survey. Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies Conlon, T. W., Kantor, D. B., Su, E. R., Basu, S., Boyer, D. L., Haileselassie, B., Petersen, T. L., Su, F., Nishisaki, A. 2018


    To assess current diagnostic bedside ultrasound program core element (training, credentialing, image storage, documentation, and quality assurance) implementation across pediatric critical care medicine divisions in the United States.Cross-sectional questionnaire-based needs assessment survey.Pediatric critical care medicine divisions with an Accreditation Council of Graduate Medical Education-accredited fellowship.Divisional leaders in education and/or bedside ultrasound training.None.Fifty-five of 67 pediatric critical care medicine divisions (82%) with an Accreditation Council of Graduate Medical Education-accredited fellowship provided responses. Overall, 63% of responding divisions (34/54) were clinically performing diagnostic bedside ultrasound studies with no difference between divisions with large versus small units. Diagnostic bedside ultrasound training is available for pediatric critical care medicine fellows within 67% of divisions (35/52) with no difference in availability between divisions with large versus small units. Other core elements were present in less than 25% of all divisions performing clinical studies, with a statistically significant increase in credentialing and documentation among divisions with large units (p = 0.048 and 0.01, respectively). All core elements were perceived to have not only high impact in program development but also high effort in implementation. Assuming that all structural elements could be effectively implemented within their division, 83% of respondents (43/52) agreed that diagnostic bedside ultrasound should be a core curricular component of fellowship education.Diagnostic bedside ultrasound is increasingly prevalent in training and clinical use across the pediatric critical care medicine landscape despite frequently absent core programmatic infrastructural elements. These core elements are perceived as important to program development, regardless of division unit size. Shared standardized resources may assist in reducing the effort in core element implementation and allow us to measure important educational and clinical outcomes.

    View details for DOI 10.1097/PCC.0000000000001692

    View details for PubMedID 30113518

  • CPR COACH ROLE IMPROVES DEPTH, RATE, AND RETURN OF SPONTANEOUS CIRCULATION Pfeiffer, S., Duval-Arnould, J., Wenger, J., Lauridsen, K., Hunt, E., Haskell, S., Atkins, D., Knight, L., Cheng, A., Gilfoyle, E., Su, F., Balikai, S., Skellett, S., Hayes, J., Mok, Y., Niles, D., Nadkarni, V., Tegtmeyer, K., Dewan, M. LIPPINCOTT WILLIAMS & WILKINS. 2018: 155
  • Optimization of Maternal Magnesium Sulfate Administration for Fetal Neuroprotection: Application of a Prospectively Constructed Pharmacokinetic Model to the BEAM Cohort. Journal of clinical pharmacology Brookfield, K. F., Elkomy, M., Su, F., Drover, D. R., Carvalho, B. 2017


    The aim of the study was to identify the optimal therapeutic maternal magnesium drug exposure and maternal serum concentration to prevent cerebral palsy in the extremely preterm fetus. We applied a previously constructed pharmacokinetic model adjusted for indication to a large cohort of pregnant women receiving magnesium sulfate to prevent cerebral palsy in their preterm offspring at 20 different US academic centers between December 1997 and May 2004. We simulated the population-based individual maternal serum magnesium concentration at the time of delivery and the total magnesium dose for each woman who received magnesium sulfate to determine the relationship between maternal serum magnesium level at the time of delivery and the development of cerebral palsy. Among 1905 women who met inclusion criteria, the incidence of cerebral palsy in the cohort was 3.6% for women who had received magnesium sulfate and 6.4% for controls. The simulated maternal serum concentration at delivery associated with the lowest probability of delivering an infant with cerebral palsy was 4.1 mg/dL (95%CI 3.7 to 4.4). Our population-based estimates of magnesium disposition suggest that to optimize fetal neuroprotection and prevent cerebral palsy, magnesium sulfate administration should target a maternal serum magnesium level between 3.7 and 4.4 mg/dL at delivery.

    View details for DOI 10.1002/jcph.941

    View details for PubMedID 28589614

  • Subglottic Stenosis Following Cardiac Surgery With Cardiopulmonary Bypass in Infants and Children. Pediatric critical care medicine Kruse, K. E., Purohit, P. J., Cadman, C. R., Su, F., Aghaeepour, N., Hammer, G. B. 2017; 18 (5): 429-433


    To determine the 1) incidence of subglottic stenosis in infants and children following cardiac surgery with cardiopulmonary bypass and 2) risk factors associated with its development.Retrospective cohort study.Tertiary children's hospital in California.Infants and children who underwent cardiac surgery with cardiopulmonary bypass.Diagnosis of subglottic stenosis by tracheoscopy.The incidence of subglottic stenosis at our institution during the study period was 0.7%. Young age (p = 0.014), prolonged cardiopulmonary bypass (p = 0.03), and prolonged mechanical ventilation (p < 0.01) were associated with the development of subglottic stenosis. Gender, chromosomal anomaly, presence of a cuffed endotracheal tube, and lowest core temperature during cardiopulmonary bypass were not associated with the development of subglottic stenosis.The incidence of subglottic stenosis was less than that previously reported in this population. Although the incidence is relatively low, subglottic stenosis is a serious complication of tracheal intubation and all measures to prevent subglottic stenosis should be undertaken.

    View details for DOI 10.1097/PCC.0000000000001125

    View details for PubMedID 28277376

  • Decreased Morphine Clearance in Neonates With Hypoxic Ischemic Encephalopathy Receiving Hypothermia JOURNAL OF CLINICAL PHARMACOLOGY Frymoyer, A., Bonifacio, S. L., Drover, D. R., Su, F., Wustoff, C. J., Van Meurs, K. P. 2017; 57 (1): 64-76


    Morphine is commonly used in neonates with hypothermic ischemic encephalopathy (HIE) during therapeutic hypothermia to provide comfort and analgesia. However, pharmacokinetic data to support morphine dosing in this vulnerable population are lacking. A prospective, two-center, clinical pharmacokinetic study of morphine was conducted in 20 neonates (birthweight 1.82-5.3 kg) with HIE receiving hypothermia. Morphine dosing was per standard of care at each center. Morphine and glucuronide metabolites (morphine-3-glucuronide and morphine-6-gluronide) were measured via a validated dried blood spot LC-MS/MS assay. From the available concentration data (n = 106 for morphine; n = 106 for each metabolite), a population pharmacokinetic model was developed using nonlinear mixed-effects modeling (NONMEM). The clearance of morphine and glucuronide metabolites were best predicted by birthweight allometrically scaled using an exponent of 1.23. In addition, the clearance of each glucuronide metabolite was influenced by serum creatinine. No other significant predictors of clearance or volume of distribution were found. For a 3.5 kg neonate, morphine clearance was 0.77 L/h (CV 48%) and the steady-state volume of distribution was 8.0 L (CV 49%). Compared to previous studies in full-term newborns without HIE, morphine clearance was markedly lower. Dosing strategies customized for this vulnerable population will be needed. Applying the final population pharmacokinetic model, repeated Monte Carlo simulations (n = 1000 per simulation) were performed to evaluate various morphine dosing strategies that optimized achievement of morphine concentrations between 10-40 ng/ml. An optimized morphine loading dose of 50 μg/kg followed by a continuous infusion of 5 μg/kg/h was predicted across birthweight. This article is protected by copyright. All rights reserved.

    View details for DOI 10.1002/jcph.775

    View details for Web of Science ID 000392014300006

    View details for PubMedID 27225747

  • Theophylline Population Pharmacokinetics and Dosing in Children Following Congenital Heart Surgery With Cardiopulmonary Bypass. Journal of clinical pharmacology Frymoyer, A., Su, F., Grimm, P. C., Sutherland, S. M., Axelrod, D. M. 2016; 56 (9): 1084-1093


    Children undergoing cardiac surgery requiring cardiopulmonary bypass (CPB) frequently develop acute kidney injury due to renal ischemia. Theophylline, which improves renal perfusion via adenosine receptor inhibition, is a potential targeted therapy. However, children undergoing cardiac surgery and CPB commonly have alterations in drug pharmacokinetics. To help understand optimal aminophylline (salt formulation of theophylline) dosing strategies in this population, a population-based pharmacokinetic model was developed using nonlinear mixed-effects modeling (NONMEM) from 71 children (median age: 5 months [90% range: 1 week - 10 years]) who underwent cardiac surgery requiring CPB and received aminophylline as part of a previous randomized controlled trial. A one-compartment model with linear elimination adequately described the pharmacokinetics of theophylline. Weight scaled via allometry was a significant predictor of clearance and volume. In addition, allometric scaled clearance increased with age implemented as a power maturation function. Compared to prior reports in non-cardiac children, theophylline clearance was markedly reduced across age. Applying the final population pharmacokinetic model, optimized empiric dosing regimens were developed via Monte Carlo simulations. Doses 50-75% lower than those recommended in non-cardiac children were needed to achieve target serum concentrations of 5-10 mg/L. This article is protected by copyright. All rights reserved.

    View details for DOI 10.1002/jcph.697

    View details for PubMedID 26712558

  • Pharmacokinetics and placental transfer of magnesium sulfate in pregnant women AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY Brookfield, K. F., Su, F., Elkomy, M. H., Drover, D. R., Lyell, D. J., Carvalho, B. 2016; 214 (6)


    Magnesium sulfate is one of the most commonly prescribed intravenous medications in obstetrics. Despite its widespread use, there are limited data about magnesium pharmacokinetics, and magnesium is prescribed empirically without dose adjustment for different indications.The aim of this study was to characterize the pharmacokinetics and placental transfer of magnesium sulfate in pregnant women and to determine key covariates that impact the pharmacokinetics.This is a prospective pharmacokinetic cohort study of pregnant women who were prescribed magnesium sulfate for preeclampsia, preterm labor, or extreme prematurity. Women received a 4-g loading dose and 2 g/h maintenance dose as clinically indicated. Maternal blood samples were obtained before and at multiple time points during and after magnesium administration. Cord blood also was sampled at delivery. A population pharmacokinetic approach that used a nonlinear mixed-effects modeling was used to characterize magnesium disposition.Pharmacokinetic profiles of 111 pregnant women were analyzed. Magnesium clearance was 3.98 L/h in preeclamptic women and 5.88 L/h non-preeclamptic women. Steady-state concentration of magnesium was 7.2 mg/dL in preeclamptic women compared with 5.1 mg/dL in non-preeclamptic women. Maternal weight significantly impacted time to steady state. The ratio of the mean umbilical vein magnesium level to the mean maternal serum magnesium level at the time of delivery was 0.94 ± 0.15.The study accurately characterizes the pharmacokinetics of magnesium administered to pregnant women. Preeclamptic status and maternal weight significantly impact serum magnesium levels. This pharmacokinetic model could be applied to larger cohorts to help tailor magnesium treatment and account for these covariates.

    View details for DOI 10.1016/j.ajog.2015.12.060

    View details for Web of Science ID 000377222800023

    View details for PubMedID 26767791

  • Pharmacokinetics of Morphine and Its Metabolites in Infants and Young Children After Congenital Heart Surgery AAPS JOURNAL Elkomy, M. H., Drover, D. R., Glotzbach, K. L., Galinkin, J. L., Frymoyer, A., Su, F., Hammer, G. B. 2016; 18 (1): 124-133


    The objective of this study was to characterize morphine glucuronidation in infants and children following cardiac surgery for possible treatment individualization in this population. Twenty children aged 3 days to 6 years, admitted to the cardiovascular intensive care unit after congenital heart surgery, received an intravenous (IV) loading dose of morphine (0.15 mg/kg) followed by subsequent intermittent IV bolus doses based on a validated pain scale. Plasma samples were collected over 6 h after the loading dose and randomly after follow-up doses to measure morphine and its major metabolite concentrations. A population pharmacokinetic model was developed with the non-linear mixed effects software NONMEM. Parent disposition was adequately described by a linear two-compartment model. Effect of growth (size and maturation) on morphine parameters was accounted for by allometric body weight-based models. An intermediate compartment with Emax model best characterized glucuronide concentrations. Glomerular filtration rate was identified as a significant predictor of glucuronide formation time delay and maximum concentrations. Clearance of morphine in children with congenital heart disease is comparable to that reported in children without cardiac abnormalities of similar age. Children 1-6 months of age need higher morphine doses per kilogram to achieve an area under concentration-time curve comparable to that in older children. Pediatric patients with renal failure receiving morphine therapy are at increased risk of developing opioid toxicity due to accumulation of morphine metabolites.

    View details for DOI 10.1208/s12248-015-9826-5

    View details for Web of Science ID 000367529900010

    View details for PubMedCentralID PMC4706285

  • Population pharmacokinetics of etomidate in neonates and infants with congenital heart disease BIOPHARMACEUTICS & DRUG DISPOSITION Su, F., El-Komy, M. H., Hammer, G. B., Frymoyer, A., Cohane, C. A., Drover, D. R. 2015; 36 (2): 104-114


    Etomidate is a rapid-onset, short-acting hypnotic medication administered for induction of anesthesia. It is currently approved by the Food and Drug Administration for use in older children and adults. Pharmacokinetic data to help guide dosing in neonates and infants is lacking.The aim of this study was to determine the pharmacokinetics of etomidate in neonates and infants with congenital heart disease undergoing cardiac surgery.Four neonates and sixteen infants, postnatal age 0.3 - 11.7 months, requiring open-heart surgery received 0.3 mg/kg of etomidate administered as a single intravenous dose prior to surgery. Blood sampling for plasma etomidate concentration occurred immediately following etomidate administration until the initiation of cardiopulmonary bypass. A population pharmacokinetic approach using nonlinear mixed-effects modeling was applied to characterize etomidate pharmacokinetics.The pharmacokinetics of etomidate was described by a two-compartment model with first-order elimination. An allometric weight-based model was applied to scale results to a 70 kg adult. Covariates including age and cardiac physiology were not found to significantly impact etomidate pharmacokinetics. The study population was found to have a central and intercompartmental clearance of 0.624 L/min/70-kg and 0.44 L/min/70-kg, respectively; central and peripheral distribution volume of 9.47 and 22.8 L/70-kg, respectively. Inter-individual variability was between 94-142% for all parameters and residual variability was 29%.The clearance of etomidate is lower in neonates and infants with congenital heart disease compared to published values for older children without congenital heart disease. In addition, etomidate pharmacokinetics is highly variable in this pediatric cardiac population. This article is protected by copyright. All rights reserved.

    View details for DOI 10.1002/bdd.1924

    View details for Web of Science ID 000351311700004

    View details for PubMedID 25377074

  • Association between Vancomycin Trough Concentration and Area under the Concentration-Time Curve in Neonates ANTIMICROBIAL AGENTS AND CHEMOTHERAPY Frymoyer, A., Hersh, A. L., El-Komy, M. H., Gaskari, S., Su, F., Drover, D. R., Van Meurs, K. 2014; 58 (11): 6454-6461
  • Association between vancomycin trough concentration and area under the concentration-time curve in neonates. Antimicrobial agents and chemotherapy Frymoyer, A., Hersh, A. L., El-Komy, M. H., Gaskari, S., Su, F., Drover, D. R., Van Meurs, K. 2014; 58 (11): 6454-6461


    National treatment guidelines for invasive methicillin-resistant Staphylococcus aureus (MRSA) infections recommend targeting a vancomycin 24-hour area under the curve (AUC24)/MIC >400. The range of vancomycin trough concentrations that best predicts AUC24 >400 in neonates is not known. This understanding would help clarify target trough concentrations for neonates when treating MRSA. A retrospective chart review from a level III neonatal intensive care unit was performed to identify neonates treated with vancomycin over a 5-year period. Vancomycin concentrations and clinical covariates were utilized to develop a one-compartment population pharmacokinetic model and examine relationships between trough and AUC24 in study neonates. Monte Carlo simulations were performed to examine the effect of dose, post-menstrual age (PMA), and serum creatinine on trough and AUC24 achievement. A total of 1702 vancomycin concentrations from 249 neonates were available for analysis. The median [interquartile range] PMA was 39 wks [32-42 wks] and weight was 2.9 kg [1.6-3.7kg]. Vancomycin clearance was predicted by weight, PMA, and creatinine. At a trough of 10 mg/L, 89% of study neonates had an AUC24 >400. Monte Carlo simulations demonstrated that troughs ranging from 7-11 mg/L were highly predictive of an AUC24 >400 across a range of PMA, serum creatinine, and vancomycin doses. However, a trough ≥10 mg/L was not readily achieved in most simulated subgroups using routine starting doses. Higher starting doses frequently resulted in troughs >20 mg/L. A vancomycin trough of ∼10 mg/L is likely adequate for most neonates with invasive MRSA infections based on AUC24 considerations. Due to pharmacokinetic and clinical heterogeneity in neonates, consistently achieving this target vancomycin exposure with routine starting doses will be difficult. More robust clinical dosing support tools are needed to help clinicians with dose individualization.

    View details for DOI 10.1128/AAC.03620-14

    View details for PubMedID 25136027

  • A Dose-Response Study of Dexmedetomidine Administered as the Primary Sedative in Infants Following Open Heart Surgery PEDIATRIC CRITICAL CARE MEDICINE Su, F., Nicolson, S. C., Zuppa, A. F. 2013; 14 (5): 499-507


    OBJECTIVE:: To evaluate the dose-response relationship of dexmedetomidine in infants with congenital heart disease postoperative from open heart surgery. DESIGN:: Prospective open-label dose-escalation pharmacokinetic-pharmacodynamic study. SETTING:: Tertiary pediatric cardiac ICU. PATIENTS:: Thirty-six evaluable infants, 1-24 months old, postoperative from open heart surgery requiring mechanical ventilation. INTERVENTIONS:: Cohorts of 12 infants were enrolled sequentially to one of the three IV loading doses of dexmedetomidine (0.35, 0.7, and 1 mcg/kg) over 10 minutes followed by respective continuous infusions (0.25, 0.5, and 0.75 mcg/kg/hr) for up to 24 hours. MEASUREMENTS AND MAIN RESULTS:: Dexmedetomidine plasma concentrations were obtained at timed intervals during and following discontinuation of infusion. Pharmacodynamic variables evaluated included sedation scores, supplemental sedation and analgesia medication administration, time to tracheal extubation, respiratory function, and hemodynamic parameters. Infants achieved a deeper sedation measured by the University of Michigan Sedation Scale score (2.6 vs 1) despite requiring minimal supplemental sedation (0 unit doses/hr) and fewer analgesic medications (0.07 vs 0.15 unit doses/hr) while receiving dexmedetomidine compared with the 12-hour follow-up period. Thirty-one patients were successfully extubated while receiving the dexmedetomidine infusion. Only one patient remained intubated due to oversedation during the infusion. While receiving dexmedetomidine, there was a decrease in heart rate compared with baseline, 132 versus 161 bpm, but there was an increase in heart rate compared with postinfusion values, 132 versus 128 bpm. There was no statistically or clinically significant change in mean arterial blood pressure. CONCLUSIONS:: Dexmedetomidine administration in infants following open heart surgery can provide improved sedation with reduction in supplemental medication requirements, leading to successful extubation while receiving a continuous infusion. The postoperative hemodynamic changes that occur in infants postoperative from open heart surgery are multifactorial. Although dexmedetomidine may play a role in decreasing heart rate immediately postoperative, the changes were not clinically significant and did not fall below postinfusion heart rates.

    View details for DOI 10.1097/PCC.0b013e31828a8800

    View details for Web of Science ID 000319920300016

    View details for PubMedID 23628837

  • Dexmedetomidine: pediatric pharmacology, clinical uses and safety EXPERT OPINION ON DRUG SAFETY Su, F., Hammer, G. B. 2011; 10 (1): 55-66


    Dexmedetomidine is an α(2)-adrenoceptor agonist with sedative, anxiolytic and analgesic properties. It is used off-label in pediatric patients due to its efficacy and lack of adverse respiratory effects. Dexmedetomidine may cause severe circulatory complications in adults. Despite its popularity, the safety of dexmedetomidine in the pediatric population has not been extensively studied.This article reviews the current literature (up to 2010) focusing on applications and safety of dexmedetomidine administered to pediatric patients.Dexmedetomidine is a useful sedative and anxiolytic drug in the pediatric intensive care unit as well as during diagnostic and therapeutic procedures. Deleterious effects of dexmedetomidine include hypotension and bradycardia. Additionally, hypertension may occur during the "loading dose" or with high infusion rates. Few studies have been performed to evaluate the safety of dexmedetomidine in pediatrics. The development of tolerance and withdrawal has not been studied in children.Despite its favorable respiratory profile, dexmedetomidine may cause deleterious cardiovascular effects. Close monitoring of circulatory dynamics and judicious titration is recommended. Further studies are needed to better define adverse effects following long-term infusions as well as in special populations such as pre-term infants.

    View details for DOI 10.1517/14740338.2010.512609

    View details for Web of Science ID 000285388700007

    View details for PubMedID 20718689

  • Population Pharmacokinetics of Dexmedetomidine in Infants After Open Heart Surgery ANESTHESIA AND ANALGESIA Su, F., Nicolson, S. C., Gastonguay, M. R., Barrett, J. S., Adamson, P. C., Kang, D. S., Godinez, R. I., Zuppa, A. F. 2010; 110 (5): 1383-1392


    Dexmedetomidine is a highly selective alpha(2)-agonist with hypnotic, analgesic, and anxiolytic properties. In adults, it provides sedation while preserving respiratory function facilitating extubation. Only limited pharmacokinetic data are available for pediatric patients. The primary aim of this study was to determine the pharmacokinetics of dexmedetomidine in infants after open heart surgery.We evaluated 36 infants, aged 1 to 24 months, after open heart surgery. Cohorts of 12 infants requiring mechanical ventilation after open heart surgery were enrolled sequentially to 1 of the 3 initial loading dose-continuous IV infusion (CIVI) regimens: 0.35-0.25, 0.7-0.5, or 1-0.75 microg/kg-microg/kg/h. The initial loading dose was administered over 10 minutes immediately postoperatively followed by a CIVI of up to 24 hours. Plasma dexmedetomidine concentrations were determined using a validated high-performance liquid chromatography tandem mass spectrometry assay. A population nonlinear mixed effects modeling approach was used to characterize dexmedetomidine pharmacokinetics.Pharmacokinetic parameters of dexmedetomidine were estimated using a 2-compartment disposition model with weight on drug clearance, intercompartmental clearance, central and peripheral volume of distributions, total bypass time as a covariate on clearance and central volume of distribution, and age and ventricular physiology as covariates on clearance. Infants demonstrated a clearance of 28.1 mL/min/kg(0.75), intercompartmental clearance of 93.4 mL/min/kg(0.75), central volume of distribution of 1.2 L/kg, and peripheral volume of distribution of 1.5 L/kg.Dexmedetomidine clearance increased with weight, age, and single-ventricle physiology, whereas total bypass time was associated with a trend toward decreasing clearance, and central volume of distribution increased as a function of total bypass time. The dependence of clearance on body weight supports current practice of weight-based dexmedetomidine dosing, whereas the clinical impact of the remaining covariate effects requires further investigation. Initial loading doses in the range of 0.35 to 1 microg/kg over 10 minutes and CIVI of 0.25 to 0.75 microg/kg/h were well tolerated in this infant population.

    View details for DOI 10.1213/ANE.0b013e3181d783c8

    View details for Web of Science ID 000277130700023

    View details for PubMedID 20418300

    View details for PubMedCentralID PMC3041635

  • Sensitive and specific liquid chromatography-tandem mass spectrometric method for the quantitation of dexmedetomidine in pediatric plasma JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES Lee, J. I., Su, F., Shi, H., Zuppa, A. F. 2007; 852 (1-2): 195-201


    Dexmedetomidine (Dex) is a lipophilic imidazole derivative used primarily for the sedation and anxiolysis of adults in the intensive care setting. Dex is being used more frequently in the pediatric intensive care unit. This report describes a selective and highly sensitive assay for Dex in pediatric plasma employing liquid chromatography-tandem mass spectrometry (LC-MS/MS). Dex was extracted from 200 microL of plasma by solid-phase extraction (SPE). High performance liquid chromatography (HPLC) separation was conducted on an YMC ODS-AQ C(18) column with a flow rate of 0.3 mL/min using a mobile phase comprised of 5 mM ammonium acetate buffer/0.03% formic acid in the solvent mixture of methanol/acetonitrile/water (20:20:60, v/v/v). The intra-day precision (coefficient of variation, % CV) and accuracy for quality control samples, ranged from 1.04 to 6.84% and 90.2 to 100.8%, respectively. The inter-day precision and accuracy ranged from 4.08 to 5.37% and 92.7 to 98.6%, respectively. Stability studies showed that Dex was stable during both the assay procedure and storage. The overall recovery was 76.6-78.3% for Dex in plasma. The analytical method showed excellent sensitivity using a small sample volume (200 microL) with a lower limit of quantitation of 5 pg/mL. This method is robust and has been successfully employed in a pharmacokinetic study of Dex in infants postoperative from cardiac surgery.

    View details for DOI 10.1016/j.jchromb.2007.01.013

    View details for Web of Science ID 000247286700027

    View details for PubMedID 17267303

  • Untying the Gordian knot ANESTHESIA AND ANALGESIA Su, F., Zuppa, A. F., Adamson, P. C. 2007; 104 (4): 993-993