Yoshihito Fujita

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.

A comparison between dosages and plasma concentrations of dexmedetomidine in clinically ill patients: a prospective, observational, cohort study in Japan

BackgroundDexmedetomidine is a highly selective central α2-agonist with anesthetic and analgesic properties for patients in intensive care units. There is little information about the relationship between dosage and plasma concentration during long drug infusions of dexmedetomidine in critically ill patients, especially in Asians. In addition, the administration of dexmedetomidine with a dosage of 0.2–0.7xa0μg/kg/h in Japan is different from that with a dosage of 0.2–1.4xa0μg/kg/h in European countries and the USA. There has been concern about obtaining an effective concentration with a small dosage and estimating the relationship between dosage and plasma concentration. We conducted a prospective, observational, cohort study measuring plasma dexmedetomidine concentrations.MethodsPlasma dexmedetomidine concentrations of 67 samples from 34 patients in an intensive care unit for 2xa0months were measured by ultra performance liquid chromatography coupled with tandem mass spectrometry using single-blind method, and the correlation coefficient between dosages and plasma concentrations was estimated. Exclusion criteria included young patients (<16xa0years) and samples obtained from patients in which the dosage of dexmedetomidine was changed within 3xa0h.ResultsAmong the patients, 20 (58.8%) of the 34 received dexmedetomidine at 0.20–0.83xa0μg/kg/h, and in 40 of the 67 samples for which dexmedetomidine had been administered, this occurred for a median duration of 18.5xa0h (range, 3–87xa0h). The range of the dexmedetomidine plasma concentration was 0.22–2.50xa0ng/ml. By comparison with other studies, with a dosage of 0.2–0.7xa0μg/kg/h, the patients in this setting could obtain an effective dexmedetomidine concentration. The plasma dexmedetomidine concentration was moderately correlated with the administered dosage (ru2009=u20090.653, Pu2009<u20090.01). The approximate linear equation was yu2009=u20090.171xu2009+u20090.254. The range of Richmond Agitation-Sedation Scale was 0 to -5.ConclusionsWe concluded that, with a dosage of 0.2–0.83xa0μg/kg/h, the patients in this setting could obtain an effective dexmedetomidine concentration of 0.22–2.50xa0ng/ml. In addition, the plasma dexmedetomidine concentration was moderately correlated with the administered dosage (ru2009=u20090.653, Pu2009<u20090.01).Trial registrationUniversity Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR) UMIN000009115.

Markedly elevated procalcitonin in early postoperative period in pediatric open heart surgery: a prospective cohort study

BackgroundWe encountered markedly elevated procalcitonin (PCT) among pediatric patients during the early postoperative period of open heart surgery. The purpose of this study is to investigate what factors are associated with the PCT elevation.MethodsFifty-two pediatric patients undergoing cardiac surgery with cardiopulmonary bypass (CPB) were enrolled. Plasma PCT, aspartate aminotransferase/alanine aminotransferase (AST/ALT), creatinine, lactate, and C-reactive protein (CRP) were measured on admission to ICU and during the postoperative period. The patients were categorized into high (group H) and low (group L) groups according to their peak PCT levels. Aorta cross-clamp (ACC), CPB time, ICU stay, mechanical ventilation period, peak AST/ALT, creatinine, lactate, and CRP levels were compared.ResultsACC and CPB times, ICU stay period, and mechanical ventilation period were significantly longer in group H compared with group L (118.7u2009±u200951.6 vs. 49.4u2009±u200943.5xa0min, 244.5u2009±u200965.7 vs. 122.9u2009±u200963.0xa0min, 7.9u2009±u20094.6 vs. 4.0u2009±u20094.5xa0days, and 6.3u2009±u20094.1 vs. 2.9u2009±u20094.2xa0days, respectively; pu2009<u20090.01). Peak AST and creatinine were significantly higher in group H compared with group L (999.0u2009±u20091,990.3 vs. 88.3u2009±u200943.0xa0U/l and 0.84u2009±u20090.77 vs. 0.41u2009±u20090.17xa0mg/dl, respectively; pu2009<u20090.05).ConclusionsACC and CPB time-related perioperative stress is associated with elevated PCT; an association between ICU stay and mechanical ventilation period, liver enzymes, and creatinine levels was observed. PCT may be a good predictor of postoperative severity and organ dysfunction.

Estimation of the success rate of anesthetic management for thymectomy in patients with myasthenia gravis treated without muscle relaxants: a retrospective observational cohort study

Although maintaining anesthesia for myasthenia gravis (MG) with minimal muscle relaxants (MR) is common, the success rate of anesthetic management for MG without MR is not clear. We therefore retrospectively examined the success rate of anesthetic management for MG without MR among 66 consecutive cases of thymectomy for MG performed at our hospital between January 2004 and April 2010, before approval of using sugammadex. A total of 60 patients (90.9xa0%) were treated without MR (N group). Among the 60 cases, 17 (28.3xa0%) patients were not extubated in the operating room due to postoperative respiratory depression or other reasons. Therefore, the success rate of anesthetic management for thymectomy in patients with MG without treating MR was 71.7xa0% (43/60) [95xa0% confident interval (CI): 65.9–77.5xa0%]. The reasons for using MR included coughing at intubation in one case, bucking during surgery in two cases, and MR was considered to be safer by the attending anesthesiologist in three cases. The number of cases of impossible extubation requiring ventilation on that day was three in the N group and none in the R group. Finally, the success rate of anesthetic management for MG without MR was estimated to be 71.1xa0% (95xa0% CI: 65.9–77.5xa0%).

Relationship between dexmedetomidine dose and plasma dexmedetomidine concentration in critically ill infants: a prospective observational cohort study

Background Dexmedetomidine is a highly selective central α2-agonist used as a sedative in pediatric intensive care unit (PICU). However, little is known about the relationship between dexmedetomidine dose and its plasma concentration during long-term infusion. We have previously demonstrated that the sedative plasma dexmedetomidine concentration is moderately correlated with the administered dose in adults (r = 0.653, P = 0.001). We hypothesized that there would be a similar relationship between the sedative dexmedetomidine concentration and administered dose in infants. Methods All patients admitted to the PICU at Nagoya City University Hospital, Japan, between November 2012 and March 2013 were eligible for inclusion in the study. Plasma dexmedetomidine concentration was measured by ultra-performance liquid chromatography coupled with tandem mass spectrometry. Results We measured the plasma dexmedetomidine concentration in 203 samples from 45 patients. Of these, 96 samples collected from 27 patients < 2 years old were included in this study. All patients received dexmedetomidine at 0.12–1.40 µg/kg/h. The median administration duration was 87.6 hours (range: 6–540 hours). Plasma dexmedetomidine concentration ranged from 0.07 to 3.17 ng/ml. Plasma dexmedetomidine concentration was not correlated with the administered dose (r = 0.273, P = 0.007). The approximate linear equation was y = 0.690x + 0.423. Conclusions In infants, plasma dexmedetomidine concentration did not exhibit any correlation with administered dose, which is not a reliable means of obtaining optimal plasma concentration.

Cardiac arrest caused by rapidly increasing ascites in a patient with TAFRO syndrome: a case report

Thrombocytopenia, anasarca, fever, renal insufficiency, and organomegaly (TAFRO) syndrome is a newly defined systemic inflammatory disorder with gradual progression of symptoms. A 59‐year‐old man with fever and ascites of unknown cause developed sudden‐onset shock and respiratory failure in the general ward. Cardiac arrest immediately followed. Although he was resuscitated, frequent administration of adrenaline was required to maintain his blood pressure. His circulation was most effectively stabilized by drainage of fluid from his distended abdomen. The volume of discharged ascites reached 4,000 mL at that time, and several liters continued to be discharged for >1 month. The diagnosis of TAFRO syndrome was based on the clinical features and laboratory and histological findings.

Effects of landiolol on refractory tachyarrhythmia after total cavopulmonary connection: a retrospective, observational, cohort study.

The onset of tachyarrhythmia after the Fontan procedure (total cavopulmonary connection; TCPC) should be considered a medical emergency. Landiolol is an ultra-short-acting β1-selective blocker whose effect on tachyarrhythmia after TCPC is unclear. We evaluated the efficacy and safety of landiolol for tachyarrhythmia after TCPC. Consecutive patients undergoing TCPC were enrolled from January 2007 to December 2011. Of 435 pediatric open heart surgeries, 28 patients underwent TCPC. Of the 28 patients, 13 were treated with landiolol for critical tachyarrhythmia. Excluding three patients who received landiolol during surgery, we investigated the remaining 10 patients and statistical analysis was performed without a 10-year-old patient as outlier. The median age was 4.08xa0years. The subjects comprised five patients with sinus tachycardia, four with junctional ectopic tachycardia and one with paroxysmal supraventricular tachycardia. The initial dose was 4.7xa0±xa02.3xa0μg/kg/min, without a loading dose. Landiolol reduced the heart rate from 151.8xa0±xa023.2 at the start to 132.9xa0±xa020.0 at 1xa0h and 126.1xa0±xa024.9 at 2xa0h (Pxa0<xa00.01 and Pxa0<xa00.01, respectively), without blood pressure decrease (Pxa0=xa00.235). Landiolol was effective in treating critical tachyarrhythmia without hemodynamic deterioration. We believe that landiolol is a promising option for postoperative tachyarrhythmia after the Fontan procedure.

Tidal volume and airway pressure under percutaneous transtracheal ventilation without a jet ventilator: comparison of high-flow oxygen ventilation and manual ventilation in complete and incomplete upper airway obstruction models

AbstractPurposenPercutaneous transtracheal ventilation (PTV) can be life-saving in a cannot ventilate, cannot intubate situation. The aim of this study was to investigate the efficacy of PTV by measuring tidal volumes (VTs) and airway pressure (Paw) in high-flow oxygen ventilation and manual ventilation using a model lung.MethodsWe examined 14G, 16G, 18G, and 20G intravenous catheters and minitracheotomy catheters. In high-flow oxygen ventilation, the flow was set to 10xa0L/min, while the inspiratory:expiratory phases (I:E) were 1u2009s:4u2009s in the complete upper airway obstruction model and 1u2009s:1xa0s in the incomplete obstruction model. In manual ventilation, I:E were 2u2009s:4xa0s in the complete obstruction model and 2u2009s:3xa0s in the incomplete obstruction model. We ventilated through each catheter for 2xa0min and measured VT and Paw.ResultsIn high-flow ventilation, the average VTs were approximately 150xa0ml and <100xa0ml with 14G catheters in complete and incomplete upper airway obstruction, respectively. The VTs obtained were reduced when the bore size was decreased. In manual ventilation, the average VTs were over 300xa0ml and approximately 260xa0ml with 14G catheters in complete and incomplete upper airway obstruction, respectively. In high-flow ventilation, the airway pressure tended to be higher. The minitracheotomy catheters produced over 800xa0ml of VT and created almost no positive end-expiratory pressure.ConclusionsHigh-flow ventilation tends to result in higher airway pressure despite a smaller VT, which is probably due to a PEEP effect caused by high flow.

Efficacy and safety of sugammadex in patients undergoing renal transplantation

BackgroundSugammadex reverses rocuronium by encapsulating it, creating a stable complex that is mainly excreted by the kidneys. Nonetheless, in view of exposure to sugammadex during renal transplantation, current safety data are insufficient. We retrospectively investigated the safety and efficacy of sugammadex in the immediate perioperative period and over long-term follow-up.Case presentationWe studied 99 consecutive patients who underwent living renal transplantation. We investigated the efficacy of sugammadex and itsxa0perioperative complications in the first 48–72xa0h in the surgical intensive care unit and in thexa0follow-up for 6xa0months.Before transplantation, 53 patients required hemodialysis. The median serum creatinine concentration was 5.6xa0mg/dl, and blood urea nitrogen (BUN) was 30xa0mg/dl. During surgery, the median rocuronium and sugammadex dose was 160xa0mg (interquartile range 130–185xa0mg) and 200xa0mg (200–200xa0mg), respectively. After transplantation, the median serum creatinine concentration was 2.4xa0mg/dl at postoperative day 1, and BUN was 21xa0mg/dl, respectively. No adverse events were recorded during the observation period.ConclusionWe investigated whether 99 consecutive patients undergoing renal transplantation may benefit from the use of sugammadex. There were no adverse events. We concluded that, in our observational period, sugammadex was efficacious and safe in patients who underwent renal transplantation.

Anesthetic management of a patient with congenital insensitivity to pain with anhidrosis by coadministration of remifentanil

BackgroundCongenital insensitivity to pain with anhidrosis (CIPA) is a rare autosomal recessive disease characterized by unexplained fever, systemic insensitivity to pain, anhidrosis, and mental distress. Anesthetic management is challenging because autonomic dysfunction can induce perioperative complications. Only a few reports of anesthetic management of CIPA patients have been published. We herein present a case of successful management of the same patient on two occasions using small doses of fentanyl and remifentanil.Case presentationA 37-year-old man with CIPA underwent two orthopedic operations. We were able to balance the dose of remifentanil to avoid the extremes of hyperalgesia when the dose is too low and shivering when the dose is too high.ConclusionTo our knowledge, no reports have described the anesthetic management of CIPA patients with remifentanil. We consider anesthetic management with coadministration of remifentanil to be potentially useful for such patients.