Dose Escalation Pharmacokinetic Study of Intranasal Atomized Dexmedetomidine in Pediatric Patients With Congenital Heart Disease.

BACKGROUND: Atomized intranasal dexmedetomidine is an attractive option when sedation is required for pediatric patients as either premedication or the sole agent for noninvasive, nonpainful procedures. While intranasal dexmedetomidine is used frequently in this population, it is still unclear what dose and time of administration relative to the procedure will result in the optimal effect. Knowledge regarding the maximum concentration (C max ) and time to reach maximum concentration (T max ) of intranasally administered dexmedetomidine is the first step toward this. The risk of hemodynamic instability caused by increasing doses of dexmedetomidine necessitates a greater understanding of the pharmacokinetics in children. METHODS: Sixteen pediatric patients 2 to 6 years of age undergoing elective cardiac catheterization received 2 or 4 µg/kg dexmedetomidine intranasally. Plasma concentrations were determined by liquid chromatography-tandem mass spectrometry with a validated assay. Descriptive noncompartmental analysis provided estimates of peak concentrations and time to reach peak concentrations. A population pharmacokinetic model was developed using nonlinear mixed-effects modeling. Simulations were performed using the final model to assess dose concentrations with an alternative dosing regimen of 3 µg/kg. RESULTS: A median peak plasma concentration of 413 pg/mL was achieved 91 minutes after 2 µg/kg dosing, and a median peak plasma concentration of 1000 pg/mL was achieved 54 minutes after 4 µg/kg dosing. A 1-compartment pharmacokinetic model adequately described the data. Three subjects in the 4 µg/kg dosing cohort achieved a dose-limiting toxicity (DLT), defined as a plasma dexmedetomidine concentration >1000 pg/mL. None of these subjects had any significant hemodynamic consequences. Simulations showed that no subjects would experience a level >1000 pg/mL when using a dose of 3 µg/kg. CONCLUSIONS: Concentrations associated with adequate sedation can be achieved with intranasal dexmedetomidine doses of 2 to 4 µg/kg in children 2 to 6 years of age. However, 50% of our evaluable subjects in this cohort reached a plasma concentration >1000 pg/mL. Doses of 3 µg/kg may be optimal in this population, with simulated concentrations remaining below this previously established toxicity threshold. Further studies correlating concentrations with efficacy and adverse effects are needed.

A Narrative Review of Analytics in Pediatric Cardiac Anesthesia and Critical Care Medicine.

Congenital heart disease (CHD) is one of the most common birth anomalies, and the care of children with CHD has improved over the past 4 decades. However, children with CHD who undergo general anesthesia remain at increased risk for morbidity and mortality. The proliferation of electronic health record systems and sophisticated patient monitors affords the opportunity to capture and analyze large amounts of CHD patient data, and the application of novel, effective analytics methods to these data can enable clinicians to enhance their care of pediatric CHD patients. This narrative review covers recent efforts to leverage analytics in pediatric cardiac anesthesia and critical care to improve the care of children with CHD.

Development of a novel method for the determination of aqueous inorganic 129I speciation.

The objective of this research was to develop a method suitable for the determination of aqueous concentrations of radioactive iodine as I2, I(-), and IO3(-). As one of the primary risk-drivers and contaminants of concern at nuclear waste repositories, the accurate determination of (129)I in aqueous systems is of significant concern. The redox-active nature of iodine makes its mobility and fate in the environment difficult to predict, thus underscoring the importance of species-specific determination of iodine concentrations. The developed method couples solid phase extraction with liquid scintillation counting, and scintillating anion exchange with a flow-cell detection system for a sequential measurement of each iodine species. Solid phase extraction disks were impregnated with polyvinylpyrrolidone for the selective extraction and stabilization of I2 with subsequent analysis by liquid scintillation counting. Aqueous I(-) was concentrated and measured by a previously developed flow-cell system utilizing scintillating anion-exchange resin. A subsequent chemical reduction of IO3(-) to I(-) in the effluent was used to quantify IO3(-) by the same flow-cell system. Nearly quantitative results were found for standardized single-species samples of I2 (95%), I(-) (101%), and IO3(-) (91%), respectively, while consistent measurements were obtained for multispecies samples using the developed method and algorithm.

Successful implementation of a perioperative glycemic control protocol in cardiac surgery: barrier analysis and intervention using lean six sigma.

Although the evidence strongly supports perioperative glycemic control among cardiac surgical patients, there is scant literature to describe the practical application of such a protocol in the complex ICU environment. This paper describes the use of the Lean Six Sigma methodology to implement a perioperative insulin protocol in a cardiac surgical intensive care unit (CSICU) in a large academic hospital. A preintervention chart audit revealed that fewer than 10% of patients were admitted to the CSICU with glucose <200 mg/dL, prompting the initiation of the quality improvement project. Following protocol implementation, more than 90% of patients were admitted with a glucose <200 mg/dL. Key elements to success include barrier analysis and intervention, provider education, and broadening the project scope to address the intraoperative period.

Online detection of radioactive iodine in aqueous systems through the use of scintillating anion exchange resin.

The objective of this research was to develop a scintillating anion exchange resin selective for monitoring (129)I at concentrations at or below ~0.4 Bq/L. One of the primary long-term risk-drivers and contaminants associated with nuclear waste sites is (129)I. Synthesis of scintillating anion exchange resin consisted of diffusing a fluor, 2-(1-naphthyl)-5-phenyloxazole (α-NPO), into a polymeric resin. The resultant scintillating resin was further modified by amination with N-methyldi-n-octylamine (MDOA) to serve as an anion exchange group. Radiochromatography columns were prepared with the synthesized resin for use in a variety of flow-cell experiments utilizing a standard (129)I solution in a synthetic groundwater to determine the properties (selectivity, interferences, loading efficiency, kinetics, capacity, and detection efficiency) of the resin. Column effluents were quantified by liquid scintillation. Average loading and detection efficiencies have been measured at 91 ± 9% and 50 ± 4%, respectively. Finally, batch sorption studies indicated fast iodide sorption rates (90% loading in ~10 min) for the resin, and dynamic sorption tracer studies indicated an iodide capacity of approximately 7,800 µg/g at 10% breakthrough.

Distributions of radionuclide sorption coefficients (Kd) in sub-surface sediments and the implications for transport calculations.

The effect of the spatial variability of K(d) on calculations of contaminant travel time in the vadose zone was determined. Depth discrete measurements of K(d) were made for a suite of radionuclides ((109)Cd, (57)Co, (60)Co, (85)Sr, (137)Cs, and (88)Y) utilizing a sediment core from the E-Area at the Savannah River Site. The K(d)'s were ordered as (85)Sr(2+) < (137)Cs(+) < (109)Cd(2+) < (57)Co(2+) = (60)Co(2+) << (88)Y(3+) and the values generally fell below or near the lowest quartile of values reported in the literature. Correlations were generally weak between soil properties and K(d) values. Most importantly, all of the K(d) distributions could be reasonably approximated as log-normal. Deterministic and stochastic calculations of contaminant travel time to the water table were made. The deterministic calculations were based on each of three conceptual models of the vadose zone: complete stratification (17 strata, each with a different K(d)), two strata (two sections of the vadose zone, each characterized by a single, average K(d)), and unstratified (a single zone with an average K(d)). Stochastic calculations were based on log-normal fits to the K(d) data. The two strata model generally yielded travel times 2x greater than those in the completely stratified model. The unstratified model yielded travel times that were between 3 and 5 times greater than the completely stratified model. The stochastic mean travel times were comparable to those of the two strata model.

Prognostic value of troponin I levels for predicting adverse cardiovascular outcomes in postmenopausal women undergoing cardiac surgery.

BACKGROUND: Adverse cardiac events that follow cardiac surgery are an important source of perioperative morbidity and mortality for women. Troponin I provides a sensitive measure of cardiac injury, but the levels after cardiac surgery may vary between sexes. Our purpose in this study was to evaluate the prognostic value of troponin I levels for predicting cardiovascular complications in postmenopausal women undergoing cardiac surgery. METHODS: The cohort of this study were women enrolled in a previously reported clinical trial evaluating the neuroprotective potential of 17beta-estradiol in elderly women. In that study, 175 postmenopausal women not receiving estrogen replacement therapy and scheduled to undergo coronary artery bypass graft (with or without valve surgery) were prospectively randomized to receive 17beta-estradiol or placebo in a double-blind manner beginning the day before surgery and continuing for 5 days postoperatively. Serial 12-lead electrocardiograms were performed and serum troponin I concentrations were measured before surgery, after surgery on arrival in the intensive care unit, and for the first four postoperative days. The primary end-point of the present study was major adverse cardiovascular events (MACE) defined as a Q-wave myocardial infarction, low cardiac output state or death within 30 days of surgery. The diagnosis of Q-wave myocardial infarction was made independently by two physicians blinded to treatment and patient outcomes with the final diagnosis requiring consensus. Low cardiac output state was defined as cardiac index <2.0 L x min(-1) x m(-2) for >8 h regardless of treatment. RESULTS: Troponin I levels on postoperative day 1 were predictive of MACE (area under the receiver operator curve = 0.862). A cutoff point for troponin I of >7.6 ng/mL (95% confidence interval, 6.4-10.8) provided the optimal sensitivity and specificity for identifying patients at risk for MACE. The negative predictive value of a troponin I level for identifying a patient with a composite cardiovascular outcome was high (96%) and the positive predictive value moderate (40%). Postoperative troponin I levels were not different between women receiving perioperative 17beta-estradiol treatment compared with placebo and the frequency of MACE was not influenced by 17beta-estradiol treatment. CONCLUSIONS: In postmenopausal women, elevated troponin I levels on postoperative day 1 are predictive of MACE. Monitoring of perioperative troponin I levels might provide a means for stratifying patients at risk for adverse cardiovascular events.

A novel process for introducing a new intraoperative program: a multidisciplinary paradigm for mitigating hazards and improving patient safety.

BACKGROUND: Since the Institute of Medicine's report, To Err is Human, was published, numerous interventions have been designed and implemented to correct the defects that lead to medical errors and adverse events; however, most efforts were largely reactive. Safety, communication, team performance, and efficiency are areas of care that attract a great deal of attention, especially regarding the introduction of new technologies, techniques, and procedures. We describe a multidisciplinary process that was implemented at our hospital to identify and mitigate hazards before the introduction of a new technique: high-dose-rate intraoperative radiation therapy, (HDR-IORT). METHODS: A multidisciplinary team of surgeons, anesthesiologists, radiation oncologists, physicists, nurses, hospital risk managers, and equipment specialists used a structured process that included in situ clinical simulation to uncover concerns among care providers and to prospectively identify and mitigate defects for patients who would undergo surgery using the HDR-IORT technique. RESULTS: We identified and corrected 20 defects in the simulated patient care process before application to actual patients. Subsequently, eight patients underwent surgery using the HDR-IORT technique with no recurrence of simulation-identified or unanticipated defects. CONCLUSION: Multiple benefits were derived from the use of this systematic process to introduce the HDR-IORT technique; namely, the safety and efficiency of care for this select patient population was optimized, and this process mitigated harmful or adverse events before the inclusion of actual patients. Further work is needed, but the process outlined in this paper can be universally applied to the introduction of any new technologies, treatments, or procedures.

Brain protection in cardiac surgery.

Brain injury is a major source of patient morbidity after cardiac surgery, and is associated with prolonged hospitalization, excessive operative mortality, high hospital costs, and altered quality of life. Frequency and the clinical manifestations depend on multiple factors, including the completeness and timing of neurologic testing. Ischemic brain infarctions may or may not be associated with stroke or postoperative neurocognitive dysfunction, but the long-term implications of these lesions on neurologic function have not yet been extensively evaluated. This article reviews the current views on the pathophysiologic basis of cerebral injury after cardiac surgery and provides a summary of measures aimed at reducing its occurrence.