Development of a stable isotope dilution UPLC‐MS/MS method for quantification of dexmedetomidine in a small amount of human plasma

Dexmedetomidine (Dex) is a selective central α2‐agonist with anesthetic properties and has been used in clinical practice for sedation in the intensive care unit (ICU) after operations. In this study, an analytical assay for the determination of Dex in a small amount of plasma was developed for the application to pediatric ICU trials. The quantification of Dex was constructed using the original stable isotope Dex‐d₃ for electrospray ionization‐tandem mass spectrometry (ESI‐MS/MS) in the selected reaction monitoring mode. A rapid ultra‐performance liquid chromatography technique was adopted using ESI‐MS/MS with a runtime of 3 min. Efficacious concentration levels (50 pg/mL to 5 ng/mL) could be evaluated using a very small amount of plasma (10 μL) from patients. The lower limit of the quantification was 5 pg/mL in the plasma (100 µL). For sample preparation, a solid‐phase extraction was used along with the OASIS‐HLB cartridge type. Recovery values ranged from 98.8 to 100.3% for the intra‐ [relative standard deviation (RSD), 0.9–1.3%] and inter‐ (RSD, 0.9–1.5%) day assays. A stable test had recovery values that ranged from 97.8 to 99.7% with an RSD of 1.0–1.9% for the process/wet extract, bench‐top, freeze–thaw and long‐term tests. This method was used to measure the Dex levels in plasma from pediatric ICU patients. In the clinical ICU trial, the small amount of blood (approximate plasma volume, 200 μL) remaining from blood gas analysis was reused and targeted for the clinical analysis of Dex in plasma. Copyright © 2013 John Wiley & Sons, Ltd.     

A mathematical model for the admission process in intensive care units

A mathematical model is given for the admission process in Intensive Care Units (ICUs). It is shown that the model exhibits bistability for certain values of its parameters. In particular, it is observed that in a two-dimensional parameter space, two saddle-node bifurcation curves terminate at a single point of the cusp bifurcation, creating an enclosed region in which the model has one unstable and two stable states. It is shown that in the presence of bistability, variations in the value of parameters may lead to undesired outcomes in the admission process as the value of state variables abruptly changes. Using numerical simulations, it is also discussed how such outcomes can be avoided by appropriately adjusting the parameter values.     

Using an Integer Programming Model to Determine the Price of Combination Vaccines for Childhood Immunization

The Recommended Childhood Immunization Schedule has become sufficiently crowded that the prospect of adding additional vaccines to this schedule may not be well received by either health-care providers or parents/guardians. This has encouraged vaccine manufacturers to develop combination vaccines that can permit new vaccines to be added to the schedule without requiring children to be exposed to an unacceptable number of injections during a single clinic visit. This paper develops an integer programming model to assess the economic premium that exists in having combination vaccines available. The results of this study suggest that combination vaccines provide a cost effective alternative to individual vaccines and that further developments and innovations in this area by vaccine manufacturers can provide significant economic and societal benefits.     

Quantitative ultra‐high‐performance liquid chromatography–tandem mass spectrometry for determination of dexmedetomidine in pediatric plasma samples: Correlation with genetic polymorphisms

Dexmedetomidine is an important sedative agent administered as premedication to achieve procedural sedation in children. To describe the correlation between the genetic state and the concentration of dexmedetomidine, it is necessary to develop a specific, time‐saving and economical method for detection of dexmedetomidine in plasma samples. In this work, an ultra‐high‐performance liquid chromatography (UHPLC)–tandem mass spectrometry method has been established and validated for detection of dexmedetomidine in plasma from pediatric population. After a simple liquid–liquid extraction with an organic solution, the analytes were separated on an ACQUITY BEH C₁₈ column (2.1 mm × 50 mm, 1.7 μm particle size) by gradient elution with the mobile phase of acetonitrile and 1‰ aqueous formic acid (flow rate 0.3 mL min^?1). Mass spectrometry measurements were performed under the positive selected reaction monitoring and the mass transitions monitored were m/z 201.3 → 95.1, 204.2 → 98.0 for dexmedetomidine and deuterated medetomidine (internal standard), respectively. Validation of the method based on China Food and Drug Administration guidelines showed acceptable selectivity. The UHPLC method employed a stable isotope‐labeled internal standard, showed good specificity and was successfully used to detect dexmedetomidine in plasma samples from 260 pediatric patients. A subsequent application of this method to a pharmacogenetic study was also described. Importantly, this is the first study to report the correlation between CYP2A6 rs835309 activity and concentration of dexmedetomidine.     

重型颅脑损伤患者早期进入ICU监护治疗的临床意义

目的研究早期进入ICU监护治疗的方式对救治重型颅脑损伤患者的影响。方法选择2013年1月—2015年7月收治的200例重型颅脑损伤患者作为研究对象,随机分为治疗组和对照组,每组100例。对照组采用常规普通病房治疗,治疗组采用早期进入ICU监护治疗。观察比较两组患者实施各项治疗措施所需时间、治疗4周内病死率、治疗4周后生存患者平均神经功能缺损(NIHSS)评分、治疗4周后生存患者平均Barthel指数评分。结果治疗组在人工辅助通气道建立、高热缓解、术前准备等各项治疗措施平均耗时显著少于对照组(P0.05)。治疗组治疗4周内病死率2.0%,显著低于对照组病死率10.0%(P0.05)。治疗4周后,治疗组生存患者平均神经功能缺损评分显著低于对照组(P0.05),治疗组生存患者平均Barthel指数评分显著高于对照组(P0.05)。结论早期进入ICU监护治疗的方式对救治重型颅脑损伤患者治疗效果显著,能够更快的完成治疗措施、改善预后、改善神经功能恢复情况、降低死率。     

A sensitive and selective liquid chromatography-tandem mass spectrometry method for the simultaneous quantification of actinomycin-D and vincristine in children with cancer

We describe a selective and a highly sensitive assay for actinomycin-D (Act-D) and vincristine (VCR) in plasma employing high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) detection. The intraday precision (as defined by the coefficient of variation, CV) based on the standard deviation of replicates of quality control samples ranged from 4.9 to 7.5% and 6.5 to 11.3% with accuracy ranging from 90.7 to 98.1% and 91.2 to 103% for Act-D and VCR, respectively. The interday precision ranged from 7.2 to 10.0% and 11.3 to 13.0% and the accuracy ranged from 94.3 to 102% and 90.7 to 91.6% for Act-D and VCR, respectively. Stability studies showed that Act-D and VCR were stable both during the assay procedure and long-term storage. The lower limit of quantitation (LLOQ) for both Act-D and VCR was 0.05 ng/ml. The analytical method showed excellent sensitivity, precision, and accuracy. This method is robust and is being successfully employed in a pharmacokinetic study of these agents in children with cancer, and is expected to support several ongoing and future pediatric trials.     

小儿内科急性腹痛的临床诊断分析

目的研究小儿内科急性腹痛的临床诊断。方法选择96名因为急性腹痛住院的患儿进行研究,进行系统性分析。结果这96名患儿的患病情况分别为:消化性溃疡20名、急性胃炎14名、急性肠炎12名、肠系膜淋巴结炎22名、胰腺炎12名、过敏性紫癜6名、阑尾炎2名、肠套叠4名、腹型癫痫4名。这些患儿通过正确的诊断治疗,都基本治愈。结论小儿内科急性腹痛是比较常见的疾病,通常是因为消化道引起的疾病,在检查过程中应该详细问诊一下所患病史,以便更好的进行诊断,避免漏诊和误诊现象发生。     

Evaluation of dosimetry and image of very low-dose computed tomography attenuation correction for pediatric positron emission tomography/computed tomography: phantom study

In this study, phantom was used to evaluate attenuation correction computed tomography (CT) dose and image in case of pediatric positron emission tomography (PET)/CT scan. Three PET/CT scanners were used along with acryl phantom in the size for infant and ion-chamber dosimeter. The CT image acquisition conditions were changed from 10 to 20, 40, 80, 100 and 160 mA and from 80 to 100, 120 and 140 kVp, which aimed at evaluating penetrate dose and computed tomography dose index_volume (CTDI_vol) value. And NEMA PET Phantom? was used to obtain PET image under the same CT conditions in order to evaluate each attenuation-corrected PET image based on standard uptake value (SUV) value and signal-to-noise ratio (SNR). In general, the penetrate dose was reduced by around 92% under the minimum CT conditions (80 kVp and 10 mA) with the decrease in CTDI_vol value by around 88%, compared with the pediatric abdomen CT conditions (100 kVp and 100 mA). The PET image with its attenuation corrected according to each CT condition showed no change in SUV value and no influence on the SNR. In conclusion, if the minimum dose CT that is properly applied to body of pediatric patient is corrected for attenuation to ensure that the effective dose is reduced by around 90% or more compared with that for adult patient, this will be useful to reduce radiation exposure level.     

HPLC quantification of metoprolol with solid-phase extraction for the drug monitoring of pediatric patients

Although the analytical literature seems abundant for the determination of metoprolol in human plasma, a method using standard equipment providing a sensitive and simple high-performance liquid chromatographic (HPLC) method for limited blood volume, e.g. where 1 mL of blood in a 1 kg infant equals 70 mL of adult blood volume, has rarely been addressed. Therefore, in 500 microL of plasma, metoprolol was extracted using an internal standard and solid-phase extraction columns. Chromatographic analysis was performed on a Spherisorb C(6) column (5 microm particle size) at ambient temperature and fluorimetric detection with an excitation wavelength of 225 nm, and emission wavelength of 310 nm. The mobile phase [30% acetonitrile and 70% 0.25 m potassium acetate buffer (pH 4)] was pumped with 1 mL/min. Metoprolol recovery was determined at 73.0 +/- 20.5%, and the limit of quantitation was 2.4 ng/mL. Precision values of intra- and inter-assay were below 15.5% and those for accuracy were between 90 and 110%. This method was developed for monitoring and determination of pharmacokinetic parameters of metoprolol in pediatric patients and therefore metoprolol plasma concentrations in a 2-year-old child with ventricular tachycardia are reported. .