Ketamine for conscious sedation in pediatric emergency care

The literature concerning the efficacy and safety of ketamine for conscious sedation during procedures in pediatric emergency departments was reviewed. Data were obtained from the Guidelines for Monitoring and Management of Pediatric Patients During and After Sedation for Diagnostic and Therapeutic Procedures developed by the American Academy of Pediatrics Committee on Drugs, and from a MEDLINE search (January 1966-July 2004). Search terms were conscious sedation, ketamine, and emergency department; articles relevant to pediatric age group were selected. Clinical end points were efficacy and adverse effects associated with ketamine. Ketamine was effective for conscious sedation in 89-100% of patients in various studies using intravenous, intramuscular, or oral routes of administration. The efficacy of ketamine was similar to or greater than that of other drugs, such as midazolam and the combination of meperidine, promethazine, and chlorpromazine. The main adverse effects of ketamine were emesis, recovery agitation, and emergence phenomena. Ketamine appears to be an effective and well-tolerated agent for conscious sedation in pediatric patients. Overall physician and parent satisfaction with the administration of this agent for conscious sedation was high.     

Prospective randomized trial evaluating ketamine for advanced endoscopic procedures in difficult to sedate patients

Background Adequate patient sedation is mandatory for advanced endoscopic procedures such as ERCP and EUS. Aim To evaluate the effectiveness and safety of ketamine in difficult to sedate patients undergoing advanced endoscopic procedures. Methods This was a prospective, randomized trial of all patients undergoing ERCP or EUS who were not adequately sedated despite administration of meperidine 50 mg, midazolam 5 mg and diazepam 5 mg. Patients during endoscopy were then randomized to receive either intravenous ketamine (20 mg) every 5 min or continue to receive standard sedation using meperidine and diazepam. Results Of 175 patients, 82 were randomized to receive ketamine and 93 standard sedatives. Compared with standard sedation, qualitative physician rating (P < 0.0001) and depth of sedation (P < 0.001) were superior in the ketamine group with shorter recovery times (P < 0.0001). Both patient discomfort and sedation‐related technical difficulty were significantly less among patients randomized to receive ketamine (P < 0.0001). More patients in the standard sedation group were crossed‐over to the ketamine group due to sedation failure (35.5 vs. 3.7%, P < 0.0001). Nine patients who received ketamine, developed adverse events that were managed conservatively. Conclusions Ketamine is a useful adjunct to conscious sedation in patients who are difficult to sedate. Its use results in better quality and depth of sedation with shorter recovery times than patients sedated using benzodiazepines and meperidine alone. Further prospective studies evaluating the effectiveness and safety of ketamine for endoscopic sedation are needed.     

Differential Effects of Anesthetic Regimens on Gentamicin Pharmacokinetics in the Rat: A Comparison with Chronically Catheterized Conscious Animals

The intravenous disposition of gentamicin was compared in the conscious chronically catheterized rat with that in rats anesthetized using five injectable laboratory anesthetics. Gentamicin plasma clearance in the conscious rat was significantly higher than in animals anesthetized with urethane, fentanyl/ fluanisone/midazolam, pentobarbitone, or ketamine/midazolam but similar to that in rats anesthetized with alphaxolone/alphadolone. Urethane anaesthesia resulted in a significantly lower gentamicin clearance than in all other groups. Gentamicin clearance in rats anesthetized with alphaxolone/alphadolone was significantly higher than in rats anesthetized with either fentanyl/fluanisone/midazolam or urethane. No significant differences in the volume of distribution of gentamicin were observed between any of the groups studied, either anesthetized or conscious. Carboxyinulin blood clearance in the conscious group was significantly higher than that with urethane, fentanyl/fluanisone/midazolam, pentobarbitone, or ketamine/midazolam but not significantly different from alphaxolone/ alphadolone-anesthetized animals. The differences in carboxyinulin clearance were noted to be proportional to the differences in gentamicin clearance (r ² = 0.98). These results demonstrate that the choice of anesthetic used in laboratory pharmacokinetic studies is important. Gentamicin clearance was higher in conscious than anesthetized rats, and it may be prudent to use chronically catheterized animals in pharmacokinetic studies.     

鞘内注射咪唑安定对妇科手术蛛网膜下腔麻醉效果的影响

摘要 目的：比较鞘内注射布比卡因复合咪唑安定对妇科手术蛛网膜下腔麻醉效果的影响。方法：86例择期行子宫肌瘤切除术患者随机分为2组,每组43例。A组蛛网膜下腔给予0.5%布比卡因3.0 mL+0.4 mL生理盐水;B组给予0.5%布比卡因3.0 mL+0.4 mL咪唑安定（2 mg）。观察2组躯体感觉/运动阻滞开始时间、持续时间以及术后不良反应等。结果： B组感觉阻滞持续时间较A组延长,差异有统计学意义(P<0.05),但2组运动阻滞时间、持续时间及镇静评分差异无统计学意义（P > 0.05)。但B组恶心呕吐发生率低于A组,差异有统计学意义(P <0.05)。结论：鞘内注射布比卡因复合2 mg咪唑安定可延长麻醉镇痛时间,减少不良反应,但不延长运动阻滞时间。     

Potential of ketamine and midazolam, individually or in combination, to induce apoptotic neurodegeneration in the infant mouse brain

Recently, it was reported that anesthetizing infant rats for 6 h with a combination of anesthetic drugs (midazolam, nitrous oxide, isoflurane) caused widespread apoptotic neurodegeneration in the developing brain, followed by lifelong cognitive deficits. It has also been reported that ketamine triggers neuroapoptosis in the infant rat brain if administered repeatedly over a period of 9 h. The question arises whether less extreme exposure to anesthetic drugs can also trigger neuroapoptosis in the developing brain. To address this question we administered ketamine, midazolam or ketamine plus midazolam subcutaneously at various doses to infant mice and evaluated the rate of neuroapoptosis in various brain regions following either saline or these various drug treatments. Each drug was administered as a single one-time injection in a dose range that would be considered subanesthetic, and the brains were evaluated by unbiased stereology methods 5 h following drug treatment. Neuroapoptosis was detected by immunohistochemical staining for activated caspase-3. It was found that either ketamine or midazolam caused a dose-dependent, statistically significant increase in the rate of neuroapoptosis, and the two drugs combined caused a greater increase than either drug alone. The apoptotic nature of the neurodegenerative reaction was confirmed by electron microscopy. We conclude that relatively mild exposure to ketamine, midazolam or a combination of these drugs can trigger apoptotic neurodegeneration in the developing mouse brain.     

小剂量氯胺酮咪达唑仑辅助硬膜外麻醉用于小儿手术的研究

目的对比观察小儿手术选用连续硬膜外麻醉时,静脉辅助麻醉用药的效果。方法选择5～10岁可配合麻醉操作的患儿,行下腹部位以下部位择期手术60例,在硬膜外麻醉效果满意后,随机分为两组,各30例。Ⅰ组：选氯胺酮100mg和地西泮10mg混合,按氯胺酮2．5mg／kg单次静脉注射。Ⅱ组：选氯胺酮100mg和咪达唑仑5mg混合,按氯胺酮1mg／kg单次静脉注射。分组记录用药前、用药后1min、5min、15min及术毕5min小儿HR、BP、SpO2、RR值;记录手术时间、面罩给氧例数、追加用药例数、术毕5min苏醒例数和术毕5min小儿OAA／S评分。结果两组术中镇静、抑制牵拉反应效果均满意。两组BP、HR、SpO2、RR均平稳;术毕5min两组OAA／S评分均为4～5分。结论小剂量氯胺酮咪达唑仑同样对小儿循环系统和呼吸系统干扰轻,且用药量少,安全实用。     

氯胺酮单次注射对创伤后应激障碍模型动物场景恐惧行为的影响及机制

目的在大、小鼠创伤后应激障碍(PTSD)模型上评价氯胺酮单次预防给药对大、小鼠场景恐惧表达的影响,并基于脑源性神经营养因子(BDNF)表达调节研究其作用机制。方法建立小鼠条件性恐惧和大鼠时间依赖性敏化(TDS)2种PTSD动物模型,在条件性恐惧训练前不同时间点进行不同剂量的单次给药,采用僵住行为测试评价氯胺酮在2个模型上对场景恐惧的影响。在小鼠条件性恐惧模型中,训练前0.5 h单次预防性给予氯胺酮10 mg·kg-1,分别于造模训练后24 h和第14天取脑,采用Western印迹法检测大脑皮质BDNF的表达。结果行为学测试结果表明,在小鼠条件性恐惧模型上,氯胺酮10 mg·kg-1分别在训练前第7天、24 h和0.5 h单次预防给药,训练后24 h场景恐惧测试中各组小鼠僵住时间百分率无明显差异;而训练前0.5 h单次预防性ip氯胺酮10 mg·kg-1,在训练后第14天显著降低小鼠僵住时间百分率(P<0.05);在大鼠TDS模型上,条件性恐惧训练前0.5 h单次ip氯胺酮10 mg·kg-1可显著降低TDS大鼠僵住次数百分率(P<0.05)。Western印迹结果显示,在训练后24 h和第14天,与正常对照组相比,模型组小鼠大脑皮质BDNF表达均显著降低(P<0.05);训练前0.5 h给予氯胺酮10 mg·kg-1组,在训练后24 h和第14天小鼠皮质BDNF的表达较模型组均显著升高(P<0.05)。结论氯胺酮单次预防性给药可减少小鼠场景恐惧的表达,该作用与给药剂量有关,且具有延迟起效的特点,但延迟起效作用与恐惧记忆形成后大脑皮质BDNF表达改变在时间上不具有一致性;氯胺酮单次给药可降低TDS增敏的大鼠场景恐惧的表达,此作用与给药时间点密切相关。     

腰-硬联合麻醉下咪达唑仑清醒镇静的研究

目的:探讨咪达唑仑靶控输注(TCI)系统用于腰-硬联合麻醉下患者清醒镇静的可行性及其靶控血药浓度。方法:对60例ASAⅠ~Ⅱ级择期行下肢手术的患者,运用警觉、镇静(OAA/S)评分和脑电双频指数(BIS)评估镇静深度。采用咪达唑仑TCI行清醒镇静,以血浆室为靶控目标,确定相应靶控血药浓度及其与BIS相关性,记录不同OAA/S评分时的血药浓度(Cp)、BIS、平均动脉压、心率、脉搏血氧饱和度。结果:适度清醒镇静(OAA/S评分3分)时所需靶控血药浓度为(122.8±20.8)ng.mL-1。BIS与Cp具有良好的相关性,BIS=—3.28Cp+355.22(r=—0.862 5,P<0.01)。结论:咪达唑仑TCI系统用于腰-硬联合麻醉患者清醒镇静可控性良好,镇静深度适宜,对血流动力学和呼吸功能无明显影响。     

Therapeutic effect of Kalpaamruthaa,a herbal preparation on adjuvant induced arthritis in wistar rats

The present study was performed in order to establish the efficacy of Kalpaamruthaa (KA), a modified indigenous Siddha preparation in adjuvant induced arthritic rat (AIA) model with reference to mediators of inflammation (lysosomal enzymes) and its effect on proteoglycans. Albino rats of Wistar strain were divided into seven Groups of six animals each. Arthritis was induced to rats by subcutaneous injection of 0.1 ml of Complete Freund’s Adjuvant into the plantar surface of the left hind paw. Group I served as normal control rats receiving 0.5 ml of olive oil as vehicle, Group II arthritic rats served as induced-untreated and Group III (50 mg/kg), Group IV (100 mg/kg), Group V (150 mg/kg), Group VI (200 mg/kg) and Group VII (250 mg/kg) were KA treated rats at different dose levels orally in 0.5 ml of olive oil from 14^th day of adjuvant injection and was terminated on day 28. Animals were then sacrificed on the day 29, blood was collected, liver and kidney were dissected out, washed and 10% homogenates were prepared. The activities of lysosomal enzymes (β-glucuronidase, β-galactosidase, acid phosphatase, β-N-acetyl glucosaminidase and cathepsin-D), aminotransferases (alkaline phosphatase, aspartate and aminotransferases) and levels of plasma protein bound carbohydrate components of glycoproteins were determined and were found to be elevated in arthritic rats when compared to control animals. After administration of KA, the activities of lysosomal enzymes, aminotransferases and protein-bound carbohydrate component levels were significantly normalized. The data obtained evidently indicate that Kalpaamruthaa is effective at the dose of 150 mg/kg b.wt. in AIA and plays an important role in lysosomal membrane stabilization. This was further confirmed by radiological, histological and electron microscopic studies. Received 21 November 2006; revised 6 April 2007; accepted 13 April 2007     

An assessment of resedation following flumazenil-induced antagonism of intravenous midazolam: comparison of psychomotor and amnesic recovery with a non-sedated reference group

The specific benzodiazepine antagonist flumazenil can enhance patient recovery following local anaesthetic day-case surgery performed under sedation. However, in view of its short elimination half-life, concerns have been expressed about the risk of resedation following its use. An open, randomised, parallel group study was designed to explore this question. Eighty-five patients were studied. Group A (n=43) patients underwent local anaesthetic cystoscopy with intravenous (i.v.) midazolam sedation. Following cystoscopy, and 30 min after the injection of midazolam, a bolus dose of flumazenil (0.5 mg i.v.) was given. Group B (n=42) patients underwent no operation and received no drugs but, in all other respects, were treated in an identical fashion to patients in group A. Tests of psychomotor function and memory were administered at baseline and again at 0.5, 1, 2, 3 and 4 h (or equivalent times for group B patients) following the injection of flumazenil. The test results showed no evidence of resedation, but there was evidence of incomplete reversal, as shown by significant differences in critical flicker fusion and delayed word recall at the 0.5-h test point. Group B patients showed no evidence of practice effects but did demonstrate an impairment in test performance possibly related to motivational factors. In conclusion, this study provides no evidence of resedation when using flumazenil to reverse the acute effects of midazolam. Incomplete reversal of amnesia need not delay patient discharge but has important implications with respect to the timing and nature of information imparted to patients prior to their release from hospital.     

Effect of 7-day exposure to midazolam on electroencephalogram pharmacodynamics in rats: a model to study multiple pharmacokinetic-pharmacodynamic relationships in individual animals

The objective of this study was to determine the concentration-electroencephalogram (EEG) relationships for midazolam, a full-agonist benzodiazepine ligand, on multiple occasions in individual rats, and to examine the effect of chronic midazolam exposure on that relationship. Rats were chronically instrumented with venous and arterial cannulas, and cortical EEG electrodes. The rats received either: 7 days of midazolam 10 mg kg(-1) intravenously once a day (midazolam group); or midazolam on days 1 and 7 and vehicle on days 2-6 (vehicle group). Concentration-effect relationships were determined on days 1, 4 and 7 from multiple blood and EEG samples before and after the administration of the midazolam dose. The concentration-EEG effect relationships were consistent with a sigmoidal Emax (maximal effect) model. No differences in pharmacokinetic or pharmacodynamic parameters were found between day 1 and day 7 in either group. However, in the midazolam group, both the fraction unbound of midazolam in serum and the EC50 (concentration at half-maximal effect) for free midazolam increased from days 1-7 by 35 +/- 3% and 54 +/- 25%, respectively (means +/- s.d., P< 0.05). This may be related to decreased serum albumin levels in the midazolam group (-19+5%, P < 0.05) which, in turn, could be explained by the sedation associated with daily midazolam treatment. We concluded that concentration-EEG effect relationships can be studied on multiple occasions in individual animals, reducing animal use and variability. A modest degree of tolerance to midazolam was found with this paradigm, the effect only being evident after correction for the fraction unbound of midazolam.     

Assessment of cardiac function by echocardiography in conscious and anesthetized mice: importance of the autonomic nervous system and disease state

In this study, the authors sought to evaluate the mechanisms responsible for echocardiographically determined differences in cardiac structure and function between conscious and anesthetized mice to determine whether such differences were more or less evident in diseased states. Cardiac parameters were determined by transthoracic echocardiography. Mice anesthetized with a mixture of ketamine and xylazine showed reductions in heart rate (HR, 252 +/- 16 beats/min versus 734 +/- 9 beats/min) and fractional shortening (FS, 35% +/- 2% versus 59% +/- 2%) compared with conscious mice. Conscious mice responded little to the beta-agonist isoproterenol or atropine, but showed profound reductions in HR and FS in response to the beta(1)-antagonist atenolol. In contrast, both isoproterenol and atropine led to increases in HR and FS in anesthetized mice. The stress in conscious animals was reduced by the sedative midazolam, leading to partial restoration of responses to isoproterenol. Mice with constitutive activation of the beta-adrenergic system, due to cardiac overexpression of beta(2)-adrenergic receptors or with heart disease (myocardial infarct and pressure-overload hypertrophy) showed few differences in functional parameters between conscious and anesthetized states, attributable to pre-existing activation of the sympathetic and beta-adrenergic systems, even during anesthesia. The results indicate that the autonomic nervous system plays a critical role in the observed differences in cardiac structure and function between anesthetized and conscious mice.     

Time course observation of thyroid proliferative lesions and serum levels of related hormones in rats treated with kojic acid after DHPN initiation.

Time course changes in thyroid proliferative lesions as well as related hormone levels in the blood of male F344 rats given N-bis(2-hydroxypropyl)nitrosamine (DHPN: 2800 mg/kg body weight, single s.c. injection) as an initiation treatment followed by pulverized basal diet containing 0% (Group 2), 2% (Group 3) or 4% (Group 4) kojic acid (KA) were examined at Weeks 1, 2, 4, 8 and 12. As an untreated control group (Group 1), rats were given basal diet for 13 weeks and examined in the same manner. Serum T3/T4 levels in the DHPN + 2% KA and DHPN + 4% KA groups were significantly reduced as compared with the DHPN-alone group at each time point. Serum TSH levels in both DHPN + KA groups were significantly increased at each time point in a treatment period-dependent manner from Weeks 1 to 12, and the extent of elevation was more remarkable in the DHPN + 4% KA group. At Week 2, there were no statistically significant intergroup differences in liver T4-UDP-GT activities on a milligram microsomal protein basis. Histopathologically, no thyroid proliferative lesions were observed in the untreated control group or the DHPN-alone group. However, diffuse follicular cell hypertrophy and decreased colloid in the thyroid were apparent in all rats of the DHPN + KA groups at each time point. In addition, focal follicular cell hyperplasias and adenomas of the thyroid were observed at high incidence in the DHPN + 2% KA group from Week 4 and in the DHPN + 4% KA group from Week 8. Multiplicities of focal follicular cell hyperplasias and adenomas of the thyroid in the DHPN + 2% KA group were significantly greater than those in the DHPN + 4% KA group at Week 8. In the pituitary, an increase in the number of TSH producing cells with expanded cytoplasm was apparent from Weeks 4 to 12 in both DHPN + KA groups. These results strongly suggest that thyroid proliferative lesions were induced by KA administration due to continuous serum TSH stimulation through the negative feedback mechanism of the pituitary-thyroid axis, resulting from depression of serum T3 and T4.     

氯胺酮诱导大鼠条件性位置偏爱的消退特点

目的:探讨氯胺酮在大鼠模型上形成的条件性位置偏爱(CPP)的消退特点。方法:24只SD♂大鼠随机分为3组:对照组、氯胺酮依赖自然消退组和氯胺酮依赖训练消退组,每组8只。氯胺酮依赖组交替隔天腹腔注射氯胺酮和等容量生理盐水16d使大鼠形成条件性位置偏爱,对照组每天给予等容量生理盐水。在实验的d18,CPP形成后氯胺酮(10-15mg.kg-1)依赖训练消退组进行生理盐水消退训练,然后各组分别在不同时段(d19,d24-26,d54-56)进行CPP测试。结果:氯胺酮处理的大鼠出现了明显的CPP,自然消退组大鼠CPP在训练后d38仍存在,训练消退组经生理盐水消退训练后大鼠CPP迅速消失。结论:氯胺酮诱导的大鼠CPP可维持38d以上,生理盐水消退训练可加速其消退。     

Effects of some antiepileptic and proconvulsant drugs on kainic acid-induced limbic epilepsy in cats

The effects of parenteral administration of diazepam (3 mg/kg), DL-C-allylglycine (60–80 mg/kg), and ketamine (20 mg/kg) on kainic acid (KA)-induced limbic seizures were investigated in cats. Single microinjections of KA (1–4 μg) into the amygdaloid complex were followed by local sustained paroxysmal discharges in the limbic system. Seizures consisted of tonic clonic EEG discharges accompanied by orienting reaction to the ipsilateral side of injection and masticatory movements, facial jerks, and aggressive behaviour. Ictal discharges occurred every 5–10 min during the first hours after KA injection and then progressively disappeared within 1 wk. Interictal discharges remained for longer periods, but after 3 or 4 wk they were abolished. Diazepam completely blocked limbic seizures but not high-frequency discharges in the site of injection and the ipsilateral hippocampus. The animals were protected for 30 to 60 min. At the same time, diazepam decreased multiple-unit activity in the pontine reticular formation and the lateral geniculate nucleus and produced a general hypotonia state. DL-C-allylglycine activated KA amygdaloid focus during the remission state and ketamine produced independent epileptiformlike activity which interfered with that produced by KA injection.     

The pharmacokinetics of ketamine following intramuscular injection to F344 rats

Ketamine is a glutamate N‐methyl‐D‐aspartate receptor antagonist that is a rapid‐acting dissociative anesthetic. It has been proposed as an adjuvant treatment along with other drugs (atropine, midazolam, pralidoxime) used in the current standard of care (SOC) for organophosphate and nerve agent exposures. Ketamine is a pharmaceutical agent that is readily available to most clinicians in emergency departments and possesses a broad therapeutic index with well‐characterized effects in humans. The objective of this study was to determine the pharmacokinetic profile of ketamine and its active metabolite, norketamine, in F344 rats following single or repeated intramuscular administrations of subanesthetic levels (7.5 mg/kg or 30 mg/kg) of ketamine with or without the SOC. Following administration, plasma and brain tissues were collected and analyzed using a liquid chromatography–mass spectrometry method to quantitate ketamine and norketamine. Following sample analysis, the pharmacokinetics were determined using non‐compartmental analysis. The addition of the current SOC had a minimal impact on the pharmacokinetics of ketamine following intramuscular administration and repeated dosing at 7.5 mg/kg every 90 minutes allows for sustained plasma concentrations above 100 ng/mL. The pharmacokinetics of ketamine with and without the SOC in rats supports further investigation of the efficacy of ketamine co‐administration with the SOC following nerve agent exposure in animal models.     

长托宁与力月西在小儿氯胺酮麻醉前用药的临床分析

目的:探讨长托宁(盐酸戊乙奎醚)力月西(复合咪达唑仑)作为麻醉前用药,在小儿氯胺酮麻醉中对血压、心率的影响及镇静程度和麻醉苏醒期的精神反应情况.方法:56例ASA Ⅰ-Ⅱ级5～10岁患儿随机分为长托宁组和阿托品组,每组28例,均行氯胺酮静脉麻醉.记录各时点的MAP、HR、SpO<,2>,观察患儿用长托宁或阿托品复合力月西后的镇静程度和苏醒期的精神反应情况.结果:两组病例用药后的镇静程度及麻醉苏醒期的精神反应情况比较差异无显著性(P>0.05).HR、MAP与基础值比较,阿托品组用药后HR明显增快,MAP升高(P<0.05);长托宁组HR、MAP基本不变.氯胺酮麻醉后,阿托品组HR显著增快,MAP显著升高(P<0.01),长托宁组HR、MAP略有上升,但差异无显著性(P>0.05),其中HR未超过基础值.结论:长托宁或阿托品复合力月西作为小儿氯胺酮麻醉前用药,均可产生良好的镇静作用,减少麻醉苏醒期的精神反应,但长托宁可使患儿HR、MAP保持稳定,较阿托品更适合作为小儿氯胺酮麻醉的麻醉前用药.     

Biliary clearance of bromosulfophthalein in anesthetized and freely moving conscious rat

The aim of this study was to investigate the effect of anesthesia on the pharmacokinetics of bromosulfophthalein (BSP) with focus on biliary clearance. The plasma concentration profile and biliary clearance of intravenously administered BSP was compared in conscious freely moving bile duct catheterized rats and rats anesthetized with ketamine or Zoletil. The plasma concentration of BSP in conscious rats was similar to that of anesthetized rats, irrespective of the anesthetic used. There was no significant difference in the volume of distribution, total body clearance and mean residence time of BSP between the groups. The biliary clearance of BSP in rats anesthetized using ketamine or Zoletil was also similar to that of conscious rats. Only bile flow was increased under anesthetization compared with conscious rats. These results demonstrate that the pharmacokinetics of BSP, including biliary clearance, in ketamine or Zoletil anesthetized rats is virtually identical to that in conscious rats and it may be related to blood flow limited hepatic disposition of BSP. Furthermore, they suggest the conscious rat model does not offer methodological advantage and the anesthesia model is suitable for a realistic approximation of the hepatobiliary transport of BSP. Copyright © 2009 John Wiley & Sons, Ltd.     

Dose-threshold for thyroid tumor-promoting effects of orally administered kojic acid in rats after initiation with N-bis(2-hydroxypropyl) nitrosamine.

In order to evaluate the threshold dose of thyroid tumor-promoting effects of KA, male F344 rats were initiated with N-bis(2-hydroxypropyl) nitrosamine (DHPN; 2000 mg/kg body wt., single s.c. injection) and, starting 1 week later, received pulverized basal diet containing 0%, 0.002%, 0.008%, 0.03%, 0.125%, 0.5% or 2%KA for 20 weeks. Five rats each in the 0%, 0.125%, 0.5% and 2%KA groups were sacrificed at week 12, and 10 rats each in all groups at week 20. As an additional experiment, three groups without DHPN initiation received basal diet, a diet containing 0.5% or 2%KA for 20 weeks. The serum T4 levels were significantly decreased in the DHPN-initiated groups given 0.125%KA or more at week 12. No significant decreases in serum T3 levels were observed in the groups treated with DHPN + KA and a significant increase was evident in the 2%KA-alone group at week 20. Some rats in the DHPN + 2%KA group at weeks 12 and 20 and the 2%KA-alone group at week 20 showed pronounced elevation of serum TSH. Thyroid weights were significantly increased in the DHPN-initiated groups receiving 0.5% and 2%KA at weeks 12 and 20 and in the 2%KA-alone group at week 20. Histopathologically, the incidences of focal thyroid follicular cell hyperplasias in the DHPN-initiated groups treated with 0.125%, 0.5% and 2%KA at week 20 were 5/10, 10/10 and 8/8 rats, respectively. At week 20, adenomas were observed in 7/10 rats in the DHPN + 0.5%KA group and 8/8 rats in the DHPN + 2%KA group, and carcinomas were observed in 6/8 rats in the DHPN + 2%KA group. In the groups without DHPN initiation, only focal follicular cell hyperplasia was observed in 1/9 rats in the 2%KA-alone group. These results suggest that the no-observed-adverse effect for the thyroid tumor-promoting effect of KA is 0.03% (15.5 mg/kg/day) under the present experimental conditions, and that KA possesses weak tumorigenic activity in rats due to continuous serum TSH stimulation by a non-genotoxic mechanism.     

Adverse Events Associated With Procedural Sedation in Pediatric Patients in the Emergency Department

Purpose:

To determine the agents used by emergency medicine (EM) physicians in pediatric procedural sedation and the associated adverse events (AEs) and to provide recommendations for optimizing drug therapy in pediatric patients.

Methods:

We conducted a prospective study at Stanford Hospital’s pediatric emergency department (ED) from April 2007 to April 2008 to determine the medications most frequently used in pediatric procedural sedation as well as their effectiveness and AEs. Patients, 18 years old or younger, who required procedural sedation in the pediatric ED were eligible for the study. The data collected included medical record number, sex, age, height, weight, procedure type and length, physician, and agents used. For each agent, the dose, route, time from administration to onset of sedation, duration of sedation, AEs, and sedation score were recorded. Use of supplemental oxygen and interventions during procedural sedation were also recorded.

Results:

We found that in a convenience sample of 196 children (202 procedures) receiving procedural sedation in a university-based ED, 8 different medications were used (ketamine, etomidate, fentanyl, hydromorphone, methohexital, midazolam, pentobarbital, and thiopental). Ketamine was the most frequently used medication (88%), regardless of the procedure. Only twice in the study was the medication that was initially used for procedural sedation changed completely. Fracture reduction was the most frequently performed procedure (41%), followed by laceration/suture repair (32%). There were no serious AEs reported.

Conclusion:

EM-trained physicians can safely perform pediatric procedural sedation in the ED. In the pediatric ED, the most common procedure requiring conscious sedation is fracture reduction, with ketamine as the preferred agent.