A pilot study of the efficacy of oral midazolam for sedation in pediatric dental patients.
Oral midazolam is being used for conscious sedation in dentistry with little documentation assessing its efficacy. In order to accumulate preliminary data, a randomized, double-blind, controlled, crossover, multi-site pilot study was conducted. The objective was to determine if 0.6 mg/kg of oral midazolam was an equally effective or superior means of achieving conscious sedation in the uncooperative pediatric dental patient, compared with a commonly used agent, 50 mg/kg of oral chloral hydrate. Twenty-three children in three clinics who required dentistry with local anesthetic and were determined to exhibit behavior rated as "negative" or "definitely negative" based on the Frankl scale were assessed. They were evaluated with respect to acceptance of medication; initial level of anxiety at each appointment; level of sedation prior to and acceptance of local anesthetic; movement and crying during the procedure; and overall behavior. The results showed that the group randomly assigned to receive midazolam had a significantly greater initial level of anxiety for that appointment (P < 0.02), a finding that could clearly confound further determination of the efficacy of these drugs. Patients given oral midazolam had an increased level of sedation prior to the administration of local anesthetic compared with those given chloral hydrate (P < 0.015). No statistically significant differences were noted in any of the other parameters. The age of the patient was found to have no correlation with the difference in overall behavior (r = -0.09). These preliminary data warrant further clinical trials. (+info
Comparison of oral chloral hydrate with intramuscular ketamine, meperidine, and promethazine for pediatric sedation--preliminary report.
Fifteen consecutive pediatric patients ranging from 3 to 5 years old were selected to receive one of three sedative/hypnotic techniques. Group 1 received oral chloral hydrate 50 mg/kg, and groups 2 and 3 received intramuscular ketamine 2 mg/kg and 3 mg/kg, respectively. In addition to ketamine, patients in groups 2 and 3 received transmucosal intramuscular injections of meperidine and promethazine into the masseter muscle. Sedation for the satisfactory completion of restorative dentistry was obtained for over 40 min on average in the chloral hydrate group, but completion of dental surgery longer than 40 min was achieved in groups 2 and 3 only by intravenous supplements of ketamine. (+info
Metabolism and toxicity of trichloroethylene and S-(1,2-dichlorovinyl)-L-cysteine in freshly isolated human proximal tubular cells.
Trichloroethylene (Tri) caused modest cytotoxicity in freshly isolated human proximal tubular (hPT) cells, as assessed by significant decreases in lactate dehydrogenase (LDH) activity after 1 h of exposure to 500 microM Tri. Oxidative metabolism of Tri by cytochrome P-450 to form chloral hydrate (CH) was only detectable in kidney microsomes from one patient out of four tested and was not detected in hPT cells. In contrast, GSH conjugation of Tri was detected in cells from every patient tested. The kinetics of Tri metabolism to its GSH conjugate S-(1,2-dichlorovinyl)glutathione (DCVG) followed biphasic kinetics, with apparent Km and Vmax values of 0.51 and 24.9 mM and 0.10 and 1.0 nmol/min per mg protein, respectively. S-(1,2-dichlorovinyl)-L-cysteine (DCVC), the cysteine conjugate metabolite of Tri that is considered the penultimate nephrotoxic species, caused both time- and concentration-dependent increases in LDH release in freshly isolated hPT cells. Preincubation of hPT cells with 0.1 mM aminooxyacetic acid did not protect hPT cells from DCVC-induced cellular injury, suggesting that another enzyme besides the cysteine conjugate beta-lyase may be important in DCVC bioactivation. This study is the first to measure the cytotoxicity and metabolism of Tri and DCVC in freshly isolated cells from the human kidney. These data indicate that the pathway involved in the cytotoxicity and metabolism of Tri in hPT cells is the GSH conjugation pathway and that the cytochrome P-450-dependent pathway has little direct role in renal Tri metabolism in humans. (+info
Anaesthetic agents inhibit gastrin-stimulated but not basal histamine release from rat stomach ECL cells.
By mobilizing histamine in response to gastrin, the ECL cells in the oxyntic mucosa play a key role in the control of the parietal cells and hence of gastric acid secretion. General anaesthesia suppresses basal and gastrin- and histamine-stimulated acid secretion. The present study examines if the effect of anaesthesia on basal and gastrin-stimulated acid secretion is associated with suppressed ECL-cell histamine secretion. A microdialysis probe was implanted in the submucosa of the ventral aspect of the acid-producing part of the stomach (32 rats). Three days later, ECL-cell histamine mobilization was monitored 2 h before and 4 h after the start of intravenous infusion of gastrin (5 nmol kg(-1) h(-1)). The rats were either conscious or anaesthetized. Four commonly used anaesthetic agents were given 1 h before the start of the experiments by intraperitoneal injection: chloral hydrate (300 mg kg(-1)), pentobarbitone (40 mg kg(-1)), urethane (1.5 g kg(-1)) and a mixture of fluanisone/fentanyl/midazolam (15/0.5/7.5 mg kg(-1)). In a parallel series of experiments, basal- and gastrin-induced acid secretion was monitored in six conscious and 25 anaesthetized (see above) chronic gastric fistula rats. All anaesthetic agents lowered gastrin-stimulated acid secretion; also the basal acid output was reduced (fluanisone/fentanyl/midazolam was an exception). Anaesthesia reduced gastrin-stimulated but not basal histamine release by 55 - 80%. The reduction in gastrin-induced acid response (70 - 95%) was strongly correlated to the reduction in gastrin-induced histamine mobilization. The correlation is in line with the view that the reduced acid response to gastrin reflects impaired histamine mobilization. Rat stomach ECL cells were purified by counter-flow elutriation. Gastrin-evoked histamine mobilization from the isolated ECL cells was determined in the absence or presence of anaesthetic agents in the medium. With the exception of urethane, they inhibited gastrin-evoked histamine secretion dose-dependently, indicating a direct effect on the ECL cells. Anaesthetized rats are widely used to study acid secretion and ECL-cell histamine release. The present results illustrate the short-comings of such an approach in that a number of anaesthetic agents were found to impair not only acid secretion but also the secretion of ECL-cell histamine - some acting in a direct manner. (+info
Carcinogenicity of chloral hydrate administered in drinking water to the male F344/N rat and male B6C3F1 mouse.
Male B6C3F1 mice and male F344/N rats were exposed to chloral hydrate (chloral) in the drinking water for 2 years. Rats: Measured chloral hydrate drinking water concentrations for the study were 0.12 g/L, 0.58 g/L, and 2.51 g/L chloral hydrate that yielded time-weighted mean daily doses (MDDs) of 7.4, 37.4, and 162.6 mg/kg per day. Water consumptions, survival, body weights, and organ weights were not altered in any of the chloral hydrate treatments. Life-time exposures to chloral hydrate failed to increase the prevalence (percentage of animals with a tumor) or the multiplicity (tumors/animal) of hepatocellular neoplasia. Chloral hydrate did not increase the prevalence of neoplasia at any other organ site. Mice: Measured chloral hydrate drinking water concentrations for the study were 0.12 g/L, 0.58 g/L, and 1.28 g/L that gave MDDs of 13.5, 65.0, and 146.6 mg/kg per day. Water consumptions, survival, body and organ weights, were not altered from the control values by any of the chloral hydrate treatments. Enhanced neoplasia was observed only in the liver. Prevalence and multiplicity of hepatocellular carcinoma (HC) were increased only for the high-dose group (84.4%; 0.72 HC/animal; p < or = 0.05). Values of 54.3%; 0.72 HC/animal and 59%; 1.03 HC/animal were observed for the 13.5- and 65.0-mg/kg per day treatment groups. Prevalence and multiplicity for the control group were 54.8%; 0.74 HC/animal. Hepatoadenoma (HA) prevalence and multiplicity were significantly increased (p < or = 0.05) at all chloral hydrate concentrations: 43.5%; 0.65 HA/animal, 51.3%; 0.95 HA/animal and 50%; 0.72 HA/animal at 13.5, 65.0, and 146.6 mg/kg per day chloral hydrate compared to 21.4%; 0.21 HA/animal in the untreated group. Altered foci of cells were evident in all doses tested in the mouse, but no significant differences were observed over the control values. Hepatocellular necrosis was minimal and did not exceed that seen in untreated rats and mice. Chloral hydrate exposure did not alter serum chemistry and hepatocyte proliferation in rats and mice or increase hepatic palmitoyl CoA oxidase in mice at any of the time periods monitored. It was concluded that chloral hydrate was carcinogenic (hepatocellular neoplasia) in the male mouse, but not in the rat, following a lifetime exposure in the drinking water. Based upon the increased HA and combined tumors at all chloral hydrate doses tested, a no observed adverse effect level was not determined. (+info
Hyperintense signal abnormality in subarachnoid spaces and basal cisterns on MR images of children anesthetized with propofol: new fluid-attenuated inversion recovery finding.
BACKGROUND AND PURPOSE: MR imaging is the method of choice for pediatric neuroimaging. Sedation is often needed to suppress patient motion and ensure diagnostic image quality, and propofol is rapidly becoming the preferred anesthetic. The purpose of this study was to document a new finding on fast fluid-attenuated inversion recovery (fast-FLAIR) MR images of children anesthetized with propofol that can be mistaken for subarachnoid space pathologic abnormality. METHODS: A retrospective analysis was conducted of 55 MR images of the brain for children who ranged in age from 1 week to 12 years. Forty-two patients received chloral hydrate, and 13 received propofol anesthetic. Multiplanar MR images were studied to detect the presence or absence of hyperintense signal (artifact) in the subarachnoid spaces and basal cisterns. The T1 values and null times of chloral hydrate, propofol, and CSF were determined in vitro at room temperature by using an inversion recovery pulse sequence at 1.5 T. RESULTS: The fast-FLAIR images of all 13 patients who received propofol had hyperintense signal abnormality. For 10 (77%) of 13 patients, this artifact was in the basal cisterns and subarachnoid spaces overlying the brain convexity. For three (23%) of 13 patients, this artifact was in the convexity region only. Two patients underwent follow-up MR imaging with a nonpropofol anesthetic agent, and the artifact resolved. None of the images of the children who received chloral hydrate had this artifact. The T1 value of chloral hydrate was 0.2 s, of propofol was 1.86 s, and of CSF was 2.32 s at room temperature. CONCLUSION: The fast-FLAIR images of children anesthetized with propofol have artifactual hyperintense signal in the basal cisterns and subarachnoid spaces, and this artifact mimics disease of the subarachnoid space. The T1 value of propofol approaches that of CSF. Depending on the chosen null time, there may be incomplete nulling of signal coming from propofol. To account for this observation, other possible causes include increased CSF pulsation in children creating motion artifact, changes in arterial oxygen concentration intrinsic to propofol or related to the supplemental oxygen normally administered, or changes in CSF protein levels related to propofol binding to proteins for uptake into CSF. (+info
Chronic cold stress reduces the spontaneous activity of ventral tegmental dopamine neurons.
The dopamine (DA) neurons in the ventral tegmental area and medial substantia nigra (VTA/mSN) projecting to the limbic forebrain and prefrontal cortex have long been postulated to play a major role in cognitive and behavioral effects of stress. In this study, the effects of a chronic stressor (prolonged exposure to cold) on the spontaneous activity of DA neurons in the VTA/mSN were examined. Extracellular single-unit recordings of DA neurons were performed in rats following a 17-day continuous exposure to a cold (4 degrees C) environment. Compared to controls, cold-exposed rats displayed 64% fewer spontaneously active DA neurons. The average spike activity (average firing rate, average spikes fired in bursts) of the DA cells that remained active in the cold-exposed rats did not differ significantly from controls. However, a significantly larger proportion of those cells showed excessive burst activity, compared to the DA cell population in controls. These results show that chronic stress can lead to the cessation of spontaneous activity in a subpopulation of VTA/mSN DA cells. These changes may indicate that unlike acute stress, which can potently activate the mesolimbic/mesocortical DA systems, chronic stress leads to an adaptive reduction in the number of active DA cells, perhaps altering the response of these systems to subsequent stressors. (+info
Cytochrome p450-dependent metabolism of trichloroethylene in rat kidney.
The metabolism of trichloroethylene (Tri) by cytochrome P450 (P450) was studied in microsomes from liver and kidney homogenates and from isolated renal proximal tubular (PT) and distal tubular (DT) cells from male Fischer 344 rats. Chloral hydrate (CH) was the only metabolite consistently detected and was used as a measurement of P450-dependent metabolism of Tri. Pretreatment of rats with pyridine increased CH formation in both liver and kidney microsomes, whereas pretreatment of rats with clofibrate increased CH formation only in kidney microsomes. Pyridine increased CYP2E1 expression in both liver and kidney microsomes, whereas clofibrate had no effect on hepatic but increased renal CYP2E1 and CYP2C11 protein levels. These results suggest a role for CYP2E1 in both the hepatic and renal metabolism of Tri and a role for CYP2C11 in the renal metabolism of Tri. Studies with the general P450 inhibitor SKF-525A and the CYP2E1 competitive substrate chlorzoxazone provided additional support for the role of CYP2E1 in both tissues. CH formation was higher in PT cells than in DT cells and was time and reduced nicotinamide adenine dinucleotide phosphate (NADPH) dependent. However, pretreatment of rats with either pyridine or clofibrate had no effect on CYP2E1 or CYP2C11 protein levels or on CH formation in isolated cells. These data show for the first time that Tri can be metabolized to at least one of its P450 metabolites in the kidneys and quantitate the effect of P450 induction on Tri metabolism in the rat kidney. (+info