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ABSTRACT: 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.
Pediatric Critical Care Medicine 04/2013; · 3.13 Impact Factor
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ABSTRACT: To determine the pharmacokinetics of pentobarbital in neonates, infants, and young children with congenital heart disease after open-heart surgery.
Thirty-five subjects (3.0 days-4.4 years) after open-heart surgery who received pentobarbital as standard of care were enrolled. Serial pharmacokinetic blood samples were obtained. A population-based, nonlinear mixed-effects modeling approach was used to characterize pentobarbital pharmacokinetics.
A two-compartment model with weight as a co-variate allometrically expressed on clearance (CL), inter-compartmental clearance, central (V1) and peripheral volume of distributions, bypass grafting time as a co-variate on CL and V1, and age and ventricular physiology as co-variates on CL best described the pharmacokinetics. A typical infant (two-ventricle physiology, 6.9 kg, 5.2 months, and bypass grafting time of 60 minutes) had a CL of 0.12 L/hr/kg, V1 of 0.45 L/kg, and peripheral volume of distributions of 0.98 L/kg. The bypass grafting effect was poorly estimated. For subjects <12 months age, an age effect on CL remained after accounting for weight and was precisely estimated.
Pentobarbital pharmacokinetics is influenced by age and weight. Subjects with single-ventricle physiology demonstrated a 15% decrease in clearance when compared with subjects with two-ventricle physiology.
The Journal of pediatrics 06/2011; 159(3):414-419.e1-3. · 4.02 Impact Factor
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ABSTRACT: Physicians, nurses and hospital pharmacists were surveyed to assess attitudes of hospital-based pediatric caregivers regarding the dosing of medicine to children. Our objectives were to gauge how current resources are utilized to guide the management of pediatric pharmacotherapy, assess drugs and drug classes where guidance is most critical and examine the prevalence and practice of dose adjustment in pediatric patients.
Questionnaire categories included demographics, pharmacotherapy resources, dosing adjustment and modification, and valuation of additional tools to provide improved pharmacotherapy guidance. The questionnaire was developed in collaboration with representative nurse, pharmacist and physician team members using the SurveyMonkey.com site and survey tool. The survey link was distributed to caregivers via email. The questionnaire results of 303 respondents were collected into MS Excel and imported into SAS for data summarization.
A total of 313 responses were obtained. Physician and nurse practitioner groups comprised the majority of the responses. Approximately 80% of the responders considered dosing adjustment important in pediatric pharmacotherapy. While there was general satisfaction with available resources, nearly 75% responded in support of access to predictive tools that facilitate individualized patient pharmacotherapy. The majority of respondents (> 65%) indicated that dosing outside standard practice occurs in 1-20% of their patients, while still a substantial number of respondents (a range of 8 to 20% reflecting the resident and fellow categories) estimated between 20 and 50% of their patients required adjustments outside the standard practice.
Differences in prescribing habits based on caregiver role, specialty and location were small and likely require further exploration. Existing resources are generally viewed as helpful but inadequate to guide recommendations for individual patients. Decision support systems connected to hospital-based electronic medical records offer the promise of informative and individualized pharmacotherapy guidance.
BMC Pediatrics 04/2011; 11:25. · 1.88 Impact Factor
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ABSTRACT: 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.
Anesthesia and analgesia 05/2010; 110(5):1383-92. · 3.08 Impact Factor
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ABSTRACT: An understanding of pharmacokinetics and pharmacodynamics can allow for a rational approach to prescribing medications for critically ill children. Absorption, distribution, metabolism, elimination, and the response to medications are affected by age and disease state. Various medications are used in the care of critically ill children. Many medications are prescribed for children based on dosing guidance from adult studies, however. Care providers must be cautious of the high risk for drug interactions and adverse reactions in the intensive care setting.
Pediatric Clinics of North America 07/2008; 55(3):735-55, xii. · 2.24 Impact Factor
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ABSTRACT: 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.
Journal of Chromatography B 07/2007; 852(1-2):195-201. · 2.89 Impact Factor
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Anesthesia and analgesia 05/2007; 104(4):993; author reply 993-4. · 3.08 Impact Factor
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Athena F Zuppa,
Susan C Nicolson,
Peter C Adamson,
Gil Wernovsky,
John T Mondick,
Nancy Burnham,
Timothy M Hoffman,
J William Gaynor,
Lauren A Davis,
William J Greeley,
Thomas L Spray,
Jeffrey S Barrett
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ABSTRACT: We performed a blinded, randomized pharmacokinetic study of milrinone in 16 neonates with hypoplastic left heart undergoing stage I reconstruction to determine the impact of cardiopulmonary bypass and modified ultrafiltration on drug disposition and to define the drug exposure during a continuous IV infusion of drug postoperatively. Neonates received an initial dose of either a 100 or 250 microg/kg of milrinone into the cardiopulmonary bypass circuit at the start of rewarming. Postoperatively, milrinone was infused to clinical needs. A mixed-effect modeling approach was used to characterize milrinone pharmacokinetics during cardiopulmonary bypass, modified ultrafiltration, and postoperatively using the NONMEM algorithm. All patients in this study demonstrated a modified ultrafiltration concentrating effect that occurred despite a modified ultrafiltration drug clearance of 3.3 mL x kg(-1) x min(-1). The infants in this study demonstrated an impaired renal clearance during the immediate postoperative period. A constant infusion of 0.5 microg x kg(-1) x min(-1) resulted in drug accumulation during the initial 12 h of drug administration. Postoperatively, milrinone clearance was significantly impaired (0.4 mL x kg(-1) x min(-1)), improved by the 12th postoperative hour, and approached steady-state clearance (2.6 mL x kg(-1) x min(-1)) by postoperative day 4. In the postoperative setting of markedly impaired renal function, an infusion rate of 0.2 microg x kg(-1) x min(-1) should be considered.
Anesthesia and analgesia 05/2006; 102(4):1062-9. · 3.08 Impact Factor
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ABSTRACT: The primary objective of this study was to characterize the drug exposure for children hospitalized in the authors' institution's pediatric intensive care unit for the year 2002. Secondary objectives included the examination of drug utilization differences among various age criteria and the suitability of the most prevalent resources for pediatric dosing guidance. Many of the most commonly prescribed agents in the pediatric intensive care unit fall into the broad categories of pain management/sedation and anti-infectives. Based on the generally narrow windows afforded by each of these drug classes, it is obvious that more, well-defined investigations in critically ill children are warranted. The existing dosing guidance for many of these agents is neither generalizable nor sufficient to accommodate the diversity in pediatric intensive care unit patients, and the current drug monographs fall short of any practical dosing information.
The Journal of Clinical Pharmacology 12/2005; 45(11):1305-12. · 2.91 Impact Factor
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ABSTRACT: To determine the impact of a thyroid hormone infusion (T4) on the vasopressor requirements in children with cessation of neurologic function (i.e., brain death) during evaluation for organ recovery
Retrospective cohort study.
The 1998-2002 database of a regional organ recovery program.
Children </=18 yrs with cessation of neurologic function during evaluation for organ recovery (n = 171) were included. The treated group (n = 91) received a weight-based bolus and continuous infusion of T4 according to the organ procurement agency protocol. All other children (n = 80) were considered untreated.
T4 was administered at the clinician's discretion. All children (treated and untreated) had identical goals for fluids, blood pressure, and organ function criteria. Vasopressor score ([dopamine x 1] + [dobutamine x 1] + [epinephrine x 100] + [norepinephrine x 100] + [phenylephrine x 100]) at the time of the program's involvement (T0) and at organ recovery (TOR) were recorded. The Wilcoxon rank sum and Student's two-sample t-test were used to compare the average vasopressor score at T0 vs. TOR. The Wilcoxon signed rank test was used to analyze the difference in median vasopressor score at T0 vs. TOR. Multivariable linear regression was used to assess the impact of T4 on the ability to wean vasopressor support while accounting for the effects of several potential confounders.
One hundred seventy-one subjects were included in the final analysis. T4 administration was associated with an unadjusted decrease in the vasopressor score of 32 (95% confidence interval, 12-53; p = .002). After adjusting for steroid administration, fluid balance, and baseline vasopressor score, T4 administration was associated with a decrease in vasopressor score of 24 (95% confidence interval, 6-43; p = .011).
T4 reduced vasopressor needs in children with cessation of neurologic function and hemodynamic instability. A prospective study of T4 in critically ill and hemodynamically unstable children appears warranted.
Critical Care Medicine 11/2004; 32(11):2318-22. · 6.33 Impact Factor
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ABSTRACT: There is new information supporting a resurgence of targeted use of older medications. These therapies include hydrocortisone and vasopressin. In addition to these older drugs, newer drugs, drotrecogin alpha (activated protein C) and activated factor VII concentrate (NovoSeven), have been used and may improve outcome in the treatment of critically ill patients. This review summarizes the recent experience of these agents in the adult and pediatric critically ill populations.
Preliminary findings are encouraging in selected septic children and adults for human recombinant activated protein C and protein C concentrate. Plasma vasopressin levels in pediatric septic shock and their importance have not yet been adequately studied. Recent evidence supports physiologic replacement of corticosteroids in specific adult populations. Further investigations are warranted to establish the role of activated factor VIIa in the treatment of critically ill children.
The limited experience of protein C manipulation in critically ill septic pediatric patients makes it difficult to define its role in their care. Although it has been associated with improved outcomes, its risk profile warrants judicious use. Further prospective pediatric clinical trials are needed to define the role of vasopressin in the treatment of pediatric shock and cardiac arrest. The role of corticosteroids in the treatment of septic shock in adults and children continues to be debated. Activated factor VIIa administration to adult and pediatric patients without primary bleeding disorders has been increasing. Further investigations are warranted to establish the role of activated factor VIIa in the treatment of critically ill children.
Current Opinion in Anaesthesiology 07/2004; 17(3):223-8. · 2.21 Impact Factor
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ABSTRACT: Clonidine is used for hypertension and narcotic withdrawal prophylaxis in adults and children. This study described plasma absorption of clonidine from whole and cut transdermal clonidine patches. This was a retrospective descriptive study in an 18 bed multidisciplinary pediatric intensive care unit, evaluating 15 critically ill children with a median age of 1.1 years (range 0.3-11 years) treated with transdermal clonidine for narcotic withdrawal prophylaxis, and who had plasma clonidine concentrations measured. An assessment of the relationship between clonidine dose and patch integrity (whole vs. cut) with plasma concentrations was performed, with further analysis by Spearman Correlation Coefficient. Clonidine doses averaged 7.5±4.2 μg/kg/day (range 2.3-20 μg/kg/day) for 9.8±4.3 days (range 4-20 days). There were 9 cut patches and 6 whole patches. The average prescribed dose delivered by cut patches was 6.4±3 μg/kg/day, resulting in a mean plasma concentration of 1±1.1 ng/ mL (range <0.05-3.3 ng/mL). The average prescribed dose delivered by whole patches was 7±1.7 μg/kg/day, resulting in a mean plasma concentration of 0.55±0.3 ng/mL (range 0.13-1.5 ng/mL). The Spearman Correlation Coefficient was calculated to evaluate the correlation between dose and concentration. For whole and cut patches the correlation coefficient was 0.94 (P=0.005) and 0.72 (P=0.002), respectively. Doses ranging from 1.7 to 20 μg/kg/day using whole patches resulted in no plasma concentrations >2 ng/mL. However, a plasma concentration >2 ng/mL was achieved with a dose of 8.8 μg/kg/day delivered by a cut patch. In addition, the 2 samples that resulted in undetectable concentrations were taken from patients who were treated with cut patches. The results from this pilot study suggest that critically ill children absorb clonidine from transdermal patches, but the rate and extent of absorption appears to be more predictable with the use of whole patches compared to patches that have been cut.
The journal of pediatric pharmacology and therapeutics : JPPT : the official journal of PPAG. 01/2004; 9(1):43-8.
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ABSTRACT: Esmolol is a very short-acting beta-blocker commonly used in critically ill patients. To study the pharmacokinetics of esmolol in pediatric patients, a liquid chromatography-electrospray mass spectrometry (LC-MS) method to quantitate esmolol concentration in plasma was developed. Following methylene chloride extraction from 200 microl aliquots of plasma containing internal standard and reconstitution in 0.05% formic acid, 10 microl are injected onto column, eluted using a methanol/formic acid gradient over 15 min, and monitored with selected ion recording at 296.2 and 282.2. The assay is linear between 2 and 1000 ng/ml. The intra-day and inter-day coefficients of variation are less than 8 and 10%, respectively.
Journal of Chromatography B 12/2003; 796(2):293-301. · 2.89 Impact Factor
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Pediatric Critical Care Medicine 02/2003; 4(1):124-5. · 3.13 Impact Factor
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ABSTRACT: Although ketorolac is commonly used as an analgesic in the pediatric population, there is no information on the pharmacokinetics of ketorolac available for children less than 6 months of age. The objective of this analysis was to construct a population pharmacokinetic model to describe ketorolac disposition in young children. Three neonates and 9 infants, median (range) age 0.4-32 weeks, were administered with 0.5 mg/kg of ketorolac. The data were best described by a 2-compartment model, with an allometric expression to describe body weight effects on clearance. Estimated parameters were clearance [2.8 mL x min(-1) x (kg(0.75))(-1)], intercompartmental clearance (11.5 mL/min), volume of distribution of the central compartment (535 mL), and volume of distribution of the peripheral compartment (322 mL). The clearance values in these neonates and younger group of infants are greater than that reported for older children and adults.
American journal of therapeutics 16(2):143-6.
