Clinical standardization of two controlled allergen challenge facilities: The Environmental Exposure Unit and the Biogenics Research Chamber.

BACKGROUND: Controlled allergen challenge facilities (CACF), in disparate geographic regions with dissimilar engineering and base populations, have historically functioned as single, independent sites in clinical allergy trials. We aimed to demonstrate "between-unit reproducibility" to allow controlled challenge trials of participants using 2 CACFs. OBJECTIVE: To compare and standardize 2 CACFs located in Kingston, Ontario, Canada, and San Antonio, Texas, by examining participant-reported symptom severity during qualifying and treatment visits and evaluating response to treatment, while using the same allergen. METHODS: At 2 different CACFs, participants were enrolled in a double-blind, placebo-controlled, crossover intervention trial with cetirizine 10 mg. Different distribution devices delivered common short ragweed pollen via laminar air flow and maintained an airborne concentration of 3500 ± 700 grains/m3 in both facilities. A 1-hour "sham" run with no pollen release preceded a priming exposure of 3 hours and was followed 3 days later by a qualifying/treatment 5-hour exposure. At least 14 days later, another priming exposure was followed by the crossover exposure and treatment. RESULTS: Forty-eight and 43 subjects completed the study at Kingston and San Antonio, respectively. Demographics were similar. Fewer than 10% exhibited symptoms with sham exposure. No significant differences were found between the 2 facilities in maximal total rhinoconjunctivitis symptom score, total nasal symptom score, and total ocular symptom score, nor in areas under the curve. In both facilities, no significant effects of cetirizine 10 mg over placebo were detected. CONCLUSION: The results were equivalent, demonstrating that the 2 CACFs can be used together in dual-center clinical trials and show the possibility of multicenter trials involving multiple CACFs.

Identification of FAM111A as an SV40 host range restriction and adenovirus helper factor.

The small genome of polyomaviruses encodes a limited number of proteins that are highly dependent on interactions with host cell proteins for efficient viral replication. The SV40 large T antigen (LT) contains several discrete functional domains including the LXCXE or RB-binding motif, the DNA binding and helicase domains that contribute to the viral life cycle. In addition, the LT C-terminal region contains the host range and adenovirus helper functions required for lytic infection in certain restrictive cell types. To understand how LT affects the host cell to facilitate viral replication, we expressed full-length or functional domains of LT in cells, identified interacting host proteins and carried out expression profiling. LT perturbed the expression of p53 target genes and subsets of cell-cycle dependent genes regulated by the DREAM and the B-Myb-MuvB complexes. Affinity purification of LT followed by mass spectrometry revealed a specific interaction between the LT C-terminal region and FAM111A, a previously uncharacterized protein. Depletion of FAM111A recapitulated the effects of heterologous expression of the LT C-terminal region, including increased viral gene expression and lytic infection of SV40 host range mutants and adenovirus replication in restrictive cells. FAM111A functions as a host range restriction factor that is specifically targeted by SV40 LT.

Molecular Characterization of Fusarium oxysporum and Fusarium commune Isolates from a Conifer Nursery.

ABSTRACT Fusarium species can cause severe root disease and damping-off in conifer nurseries. Fusarium inoculum is commonly found in most container and bareroot nurseries on healthy and diseased seedlings, in nursery soils, and on conifer seeds. Isolates of Fusarium spp. can differ in virulence; however, virulence and colony morphology are not correlated. Forty-one isolates of Fusarium spp., morphologically indistinguishable from F. oxysporum, were collected from nursery samples (soils, healthy seedlings, and diseased seedlings). These isolates were characterized by amplified fragment length polymorphism (AFLP) and DNA sequencing of nuclear rDNA (internal transcribed spacer including 5.8S rDNA), mitochon-drial rDNA (small subunit [mtSSU]), and nuclear translation elongation factor 1-alpha. Each isolate had a unique AFLP phenotype. Out of 121 loci, 111 (92%) were polymorphic; 30 alleles were unique to only highly virulent isolates and 33 alleles were unique to only isolates nonpathogenic on conifers. Maximum parsimony and Bayesian analyses of DNA sequences from all three regions and the combined data set showed that all highly virulent isolates clearly separated into a common clade that contained F. commune, which was recently distinguished from its sister taxon, F. oxysporum. Interestingly, all but one of the nonpathogenic isolates grouped into a common clade and were genetically similar to F. oxysporum. The AFLP cladograms had similar topologies when compared with the DNA-based phylograms. Although all tested isolates were morphologically indistinguishable from F. oxysporum based on currently available monographs, some morphological traits can be plastic and unreliable for identification of Fusarium spp. We consider the highly virulent isolates to be F. commune based on strong genetic evidence. To our knowledge, this is the first reported evidence that shows F. commune is a cause of Fusarium disease (root rot and dampingoff) on Douglas-fir seedlings. Furthermore, several AFLP genetic markers and mtSSU sequences offer potential for development of molecular markers that could be used to detect and distinguish isolates of F. oxysporum nonpathogenic to conifers and highly virulent isolates of F. commune in forest nurseries.

Effect of kappa opioid agonists on visceral nociception induced by uterine cervical distension in rats.

Although uterine distension in rats results in an escape reflex, there exists no model of uterine cervical distension (UCD), the pain stimulus during the first stage of labor. The aims of this study were to develop such a model in virgin rats and to test whether peripherally restricted kappa opioid receptor (KOR) agonists (ADL 10-0101, ADL 10-0102, ADL 10-0116) inhibit responses to UCD. Under intravenous (i.v.) pentobarbital and alpha-chloralose anesthesia, fine metal rods were inserted in both uterine cervical osses through a small midline laparotomy. UCD was performed by manual separation of the rods (25-100 g). Single-unit afferent responses in hypogastric nerve or reflex rectus abdominis electromyographic (EMG) activity were determined before and after i.v. KOR agonists. UCD resulted in a stimulus-dependent increase in single-unit afferent activity. Units could be characterized as low threshold (mean threshold 6.6+/-2.7 g), or high threshold (mean threshold 55+/-8.8 g); all were C fibers, all responded to topical bradykinin. ADL 10-0116 (10 mg/kg) reduced the afferent response to UCD. Reflex EMG response occurred over a distension force range of 25-100 g, unaffected by i.v. saline. All three KOR agonists produced a dose-dependent, naloxone-reversible inhibition of the EMG response with a potency relationship of ADL 10-0102 (ED50 0.04 mg/kg)>ADL 10-0101 (ED50 0.65 mg/kg)=ADL 10-0116 (ED50 0.60 mg/kg). These data support the use of acute UCD as a noxious stimulus, inducing afferent and reflex activity. Like other visceral stimuli, UCD is sensitive to inhibition by KOR agonists.

Rapid disappearance of protamine in adults undergoing cardiac operation with cardiopulmonary bypass.

BACKGROUND: Despite long use of protamine in cardiac operations, neither protamine concentrations nor pharmacokinetics have been reported in patients. METHODS: Twenty-eight patients (age, 26 to 80 years) undergoing various cardiac surgical procedures gave their consent to receive 250 mg of protamine sulfate administered intravenously by an infusion pump during 5 minutes. Protamine was administered at the usual intraoperative time after separation from cardiopulmonary bypass for reversal of heparin. Timed arterial blood samples were obtained after protamine infusion. Blood plasma was subjected to solid-phase extraction and high-performance liquid chromatography. Total (free + heparin-bound) protamine concentration versus time data were subjected to pharmacokinetic modeling. RESULTS: Twenty-six patients completed the study. Total plasma protamine concentrations declined rapidly. Model-independent pharmacokinetic analysis revealed median (range) values as follows: volume of distribution, 5.4 L (0.82 to 34 L); clearance, 1.4 L/min (0.61 to 3.8 L/min); and half-life, 4.5 min (1.9 to 18 min). Schwarz-Bayesian criterion identified a two-compartment exponential model with adjustment for weight in the central compartment volume of distribution as performing better than other compartmental or Michaelis-Menten models. CONCLUSIONS: Protamine has a very short (approximately 5 minutes) half-life after a single 250-mg dose in adult patients. This short half-life could underlie recurrent anticoagulation after initial apparent reversal of heparin.

Does local anesthetic stereoselectivity or structure predict myocardial depression in anesthetized canines?

BACKGROUND AND OBJECTIVES: It is unclear whether the susceptibility to myocardial depression from an accidental intravascular local anesthetic (LA) administration is associated with LA stereoselectivity or structure. By using direct left ventricular pressure monitoring and echocardiographic indices of contractile function in anesthetized, ventilated dogs, we compared the cardiac depressant effects of bupivacaine, ropivacaine, levobupivacaine, and lidocaine. METHODS: Open-chest dogs were randomized to receive escalating incremental infusions of the 4 local anesthetics until cardiovascular collapse. We assumed a concentration relationship for potency of 4:1 for lidocaine/bupivacaine, ropivacaine, and levobupivacaine. RESULTS: All LAs produced concentration-dependent increases in left ventricular end diastolic pressure (LVEDP) and decreases in dP/dtmax, ejection fraction % (EF), fractional shortening (%) (FS), and cardiac output (CO). When comparing the long-acting agents, the effect was least for ropivacaine. The effective concentration estimates for ropivacaine that produced 35% reductions in dP/dtmax and FS were 4.0 micro g/mL (95% confidence intervals [CI(95)]: 3.1 to 5.2 micro g/mL) and 3.0 micro g/mL (CI (95): 2.1 to 4.2 micro g/mL), respectively. The concentrations of levobupivacaine that produced these same end points of contractile dysfunction were significantly less: 2.4 micro g/mL (CI(95): 1.9 to 3.1 micro g/mL) and 1.3 micro g/mL (CI(95): 0.9 to 1.8 micro g/mL), respectively, and these were not different from bupivacaine. As expected, the concentrations of lidocaine that produced 35% reductions in dP/dtmax and FS were significantly greater than the longer acting agents; 8.0 micro g/mL (CI(95): 5.7 to 11.0 micro g/mL) and 5.5 micro g/mL (CI(95): 3.5 to 8.7 micro g/mL), respectively. CONCLUSIONS: This study suggests that smaller molecular size and possibly a piperidine-free structure as opposed to stereoselectivity may be the more important factor in reducing the risk of LA-induced myocardial depression.

Uterine cervical distension induces cFos expression in deep dorsal horn neurons of the rat spinal cord.

BACKGROUND: Uterine cervical distension underlies labor pain, yet its neurophysiology and pharmacology of inhibition remain unexplored. The authors examined uterine cervical distension-evoked cFos immunoreactivity in rat spinal cords, and the inhibitory effect of spinal cyclo-oxygenase inhibition on cFos expression. METHODS: Female rats were anesthetized with halothane, and pairs of metal rods were inserted in each cervical os through a mid-line laparotomy. A submaximal distension force (75 g) was applied for either 30 or 60 min, or, in control animals, no force was applied. Other animals received cervical lidocaine infiltration prior to uterine cervical distension. At the end of the experiments, the spinal cord at T12 to L2 levels was harvested and immunostained for cFos protein. Other animals received intrathecal ketorolac (0, 5, 25, and 50 microg; n = 5-6 for each group) prior to uterine cervical distension. RESULTS: Uterine cervical distension significantly increased cFos immunoreactivity in the spinal cord from T12 to L2, with most cFos expression in the deep dorsal and central canal regions. Surgical preparation alone without uterine cervical distension resulted in minimal cFos expression, primarily in the superficial dorsal horn. Uterine cervical distension-evoked cFos expression was prevented by prior infiltration of lidocaine into the cervix. Intrathecal ketorolac produced a dose-dependent inhibition of uterine cervical distension-induced cFos expression. CONCLUSION: The present study demonstrates that uterine cervical distension results in a similar pattern of spinal cord neuronal activation as seen with other noxious visceral stimuli. The inhibition of cFos expression by intrathecal ketorolac suggests that spinal cyclo-oxygenase plays a role in uterine cervical distension-induced nociception.

Levobupivacaine for axillary brachial plexus block: a pharmacokinetic and clinical comparison in patients with normal renal function or renal disease.

UNLABELLED: We compared the pharmacokinetics and clinical characteristics of 0.5% levobupivacaine for axillary block in patients with normal renal function versus patients with end-stage renal disease (ESRD). Twenty patients with normal renal function and eight patients with ESRD received an axillary block with 50-60 mL of 0.5% levobupivacaine. Patients were evaluated for onset and duration of sensory/motor block. Eleven patients with normal renal function and eight patients with ESRD underwent pharmacokinetic analysis. No differences between groups were found in the onset, duration, or quality of block. The median time to sensory block was 12.5 min and 12.9 min, and mean duration of the block was 19 h and 22 h in normal versus ESRD patients, respectively. No significant differences in noncompartmental pharmacokinetic variables (median) were found between normal and ESRD patients with an AUC(0-t) (microg. h(-1). mL(-1)) of 11 and 13, peak concentration (C(max)) (microg/mL) of 1.2 and 1.6, and a time to peak concentration (T(max)) (min) of 55 and 48, respectively. This study demonstrates the clinical efficacy and equivalence of the pharmacokinetic characteristics of 0.5% levobupivacaine for axillary brachial plexus block in patients with ESRD and normal renal function. IMPLICATIONS: This study demonstrates the clinical efficacy and equivalence of the pharmacokinetic characteristics of 0.5% levobupivacaine for axillary brachial plexus block in patients with renal disease and normal renal function.

Reduced duration of intrathecal sufentanil analgesia in laboring cocaine users.

UNLABELLED: On the basis of our previous clinical experience, we hypothesized in this study that the duration and/or quality of labor analgesia produced by intrathecal sufentanil was less in cocaine-abusing parturients compared with nonabusing parturients. Ten micro g of sufentanil was given intrathecally as part of a combined spinal-epidural (CSE) technique to two groups of laboring parturients: 1). those whose urine tested positive for cocaine (cocaine group), and 2). those whose urine tested negative for cocaine (control group). The epidural catheter was not injected with local anesthetic until the patient requested additional pain relief. The time from injection of intrathecal sufentanil until patient request for additional pain relief was defined as duration of analgesia. Baseline visual analog pain score (VAPS) and cervical dilation were measured before the CSE was performed. After injection of intrathecal sufentanil, VAPS was recorded at specific intervals. Cervical dilation was again documented when the patient requested additional analgesia. We found that both groups reported high baseline VAPS and a marked decrease in VAPS after injection of sufentanil that did not differ between groups. Geometric mean duration of pain relief with adjustment for cervical dilation was 87 min in the cocaine group compared with 139 min in the control group (P = 0.019). All patients experienced itching. We conclude that intrathecal sufentanil produces a similar quality but shorter duration of analgesia in cocaine-abusing parturients compared with nonabusing parturients. IMPLICATIONS: Intrathecal sufentanil administered as part of a combined spinal-epidural technique produces similar quality but reduced duration of labor analgesia in cocaine-abusing parturients compared with nonabusing parturients.

Men are more susceptible than women to direct pressure on unmyelinated ulnar nerve fibers.

UNLABELLED: Ulnar nerve injury, the most common form of perioperative peripheral nerve injury, has a 3:1 male/female predominance. Neither the mechanism of perioperative ulnar nerve injury nor the reasons for the increased male susceptibility are well understood. We used an experimental model with arm flexion at the elbow, direct pressure on the ulnar nerve, and arm ischemia as distinct stress mechanisms to induce adverse changes in ulnar current perception thresholds (CPTs) on 3 groups of 40 male and 40 female volunteers (a total of 240 volunteers). CPT measurements were repeated at 2000-, 250-, and 5-Hz stimulating frequencies, specific to A-beta, A-delta, and unmyelinated C-fibers, respectively. Ischemia produced significant increases in CPT with all three stimulating frequencies, and there were no detectable differences between men and women. Flexion failed to produce significant CPT increases at any of the three stimulating frequencies, with no sex-based differences. Direct pressure produced significant CPT increases at 5 and 250 Hz, indicating inhibition of both unmyelinated C-fibers and myelinated A-delta fibers. C-fibers, but not A-delta fibers, demonstrated sex differences with direct pressure; there was a 1.7-fold (95% confidence interval, 1.2- to 2.4-fold) greater effect in men. Ischemia significantly inhibited the function of all three fiber types, perhaps sufficient to overwhelm gender differences. IMPLICATIONS: The ability of direct pressure to produce a greater inhibition of unmyelinated C-fibers in male subjects compared with female subjects is consistent with, and may help explain, the male increased susceptibility to perioperative ulnar nerve dysfunction.

Side-effects after inhalational anaesthesia for paediatric cerebral magnetic resonance imaging.

BACKGROUND: The aim of this study was to evaluate the type, incidence and duration of postprocedure side-effects in 168 children within the first 72 h after inhalational anaesthesia for magnetic resonance imaging (MRI). METHODS: Premedication and induction followed standardized routines. Maintenance of anaesthesia was performed with inhalational anaesthetics solely: isoflurane (n=60 of 112; 53%), sevoflurane (n=32 of 112; 29%), desflurane (n=12 of 112; 11%) or halothane (n= 8 of 112; 7%) using a strapped on face mask (FiO2=0.4; flow 5 l.min-1). When indicated, gadolinium was administered (n=45; OF 112; 40%). RESULTS: One hundred and twelve of 168 parents (67%) responded to questionnaires. In these 112 children, pathological MR findings were found supratentorially (n=31; 28%), infratentorially (n=9; 8%), extracerebrally (n=12; 11%) or combined (n=9; 8%). In 56 of these 112 children (50%), 14 different side-effects were reported. One hour after anaesthesia, 55 children suffered between one and four side-effects. Neurological side-effects were associated with age > or = 5 years (P < 0.01) or infratentorial pathophysiology (P < 0.01) and abdominal side-effects (P < 0.02), especially nausea (P < 0.001) with age > or = 5 years. CONCLUSIONS: Our findings indicate the need to inform parents of the incidence and variability of side-effects after inhalational anaesthesia for minimally invasive, diagnostic procedures, such as MRI.

Factors associated with successful tracheal intubation of children with sevoflurane and no muscle relaxant.

UNLABELLED: Better definition of end points required to achieve successful tracheal intubation after induction with sevoflurane could improve patient care. The authors therefore designed a study that could determine, with meaningful confidence intervals, the time required to successfully intubate 80% of children by using 8% inspired sevoflurane and no muscle relaxant. We hypothesized that the time required could vary by age or body mass index. One-hundred fifty-three ASA physical status I or II patients received induction with 8% sevoflurane in 60% nitrous oxide with discontinuation of nitrous oxide 1 min after the start of the induction. The time until laryngoscopy remained close to the time required to achieve 80% successful intubation by varying induction time according to the success rate in each group of five patients. A probit model of induction time and age found that both were predictive of successful intubation (P values of 0.006 and 0.02, respectively). The induction times needed to achieve 80% successful intubation were 137 s (95% confidence interval, 94.6-159 s) and 187 s (153-230 s) for ages 1-4 yr and 4-8 yr, respectively. The persistence of spontaneous ventilation at the time of laryngoscopy, despite attempts to control ventilation, was associated with poor intubation conditions (P < 0.001). IMPLICATIONS: To successfully intubate 80% of children by using sevoflurane and no muscle relaxant, induction times of 137 and 187 s were needed in children of 1-4 yr and 4-8 yr, respectively.

Pulmonary artery catheter placement for elective coronary artery bypass grafting: before or after anesthetic induction?

UNLABELLED: Pulmonary arterial catheters (PACs) are often used during and after coronary artery bypass grafting. We hypothesized that placement of a PAC would be faster in anesthetized patients. We further hypothesized that the presence or absence of a PAC during the induction of anesthesia would make no difference in hemodynamics, vasoactive drug use, or IV fluid administration during the induction. Patients (n = 200) undergoing elective coronary artery bypass grafting were assigned to PAC insertion either before or after the induction of anesthesia. Total time for PAC insertion, number of finder needle and venous catheter insertion attempts, incidence of carotid artery puncture, arrhythmias or ST segment changes, arterial blood gas analysis, hemodynamic variables, IV fluids, and vasoactive drugs required during and after the anesthetic induction were recorded. Thirty-two different physicians placed the PACs. PAC placement was faster (10 versus 12 min, P = 0.0003) and required fewer punctures with a finder needle (P = 0.0107) in anesthetized patients. There were no significant differences between groups in hemodynamic values or use of vasoactive or anesthetic drugs or IV fluids during the induction. There were also no significant differences between groups in the incidence of myocardial ischemia, arterial hypoxemia, or hypercarbia. Placement of a PAC before the induction of anesthesia consumes more time and fails to improve hemodynamic stability or lessen vasoactive drug use during the induction of anesthesia. IMPLICATIONS: Insertion of pulmonary artery catheters (PACs) before the induction of anesthesia requires more needle sticks and takes longer than insertion after the induction of anesthesia; moreover, previous PAC insertion has no significant effect on hemodynamics or use of vasoactive drugs or IV fluid associated with the induction of anesthesia.

The pharmacokinetics of epsilon-aminocaproic acid in children undergoing surgical repair of congenital heart defects.

UNLABELLED: epsilon-Aminocaproic acid (epsilonACA) is often administered to children undergoing cardiac surgery by using empiric dosing techniques. We hypothesized that children would have different pharmacokinetic variables and require a dosing scheme different from adults to maintain stable and effective serum epsilonACA concentrations. Eight patients were enrolled in our study. epsilonACA 50 mg/kg was administered three times IV: before, during, and after cardiopulmonary bypass (CPB). Nine serum samples were obtained. epsilonACA plasma concentrations were measured by using high-performance liquid chromatography, and pharmacokinetic modeling was done by using NONMEM. The best fit was seen with a two-compartment model with volume of distribution (V(1)) adjusted for weight and CPB. Compared with published results in adults, modeling suggests that weight-adjusted V(1) is larger in children than in adults before, during, and after CPB. Clearance from the central compartment (k(10)) was also greater in children than adults, and declined during CPB. Redistribution rates from the central compartment, k(12) and k(21), were greater in children and not affected by CPB. We modeled several different dosing regimens for epsilonACA based on the larger V(1), and higher redistribution and clearance variables. We conclude that, because of the developmental differences in pharmacokinetic variables of epsilonACA, when compared with adult patients, a larger initial dose and faster infusion rate as well as an addi-tional dose on CPB are needed to maintain similar concentrations. IMPLICATIONS: Pharmacokinetic modeling of epsilon-aminocaproic acid in children undergoing cardiac surgery suggests that there are developmental differences in pharmacokinetic variables. Based on these data, a dosing modification in children is suggested which may better maintain serum concentrations in children when compared with adults.

Pharmacokinetics of tranexamic acid during cardiopulmonary bypass.

BACKGROUND: Tranexamic acid (TA) reduces blood loss and blood transfusion during heart surgery with cardiopulmonary bypass (CPB). TA dosing has been empiric because only limited pharmacokinetic studies have been reported, and CPB effects have not been characterized. We hypothesized that many of the published TA dosing techniques would prove, with pharmacokinetic modeling and simulation, to yield unstable TA concentrations. METHODS: Thirty adult patients undergoing elective coronary artery bypass grafting, valve surgery, or repair of atrial septal defect received after induction of anesthesia: TA 50 mg/kg (n = 11), TA 100 mg/kg (n = 10), or TA 10 mg/kg (n = 10) over 15 min, with 1 mg x kg(-1) x hr(-1) maintenance infusion for 10 h. TA was measured in plasma using high performance liquid chromatography. Pharmacokinetic modeling was accomplished using a mixed effects technique. Models of increasing complexity were compared using Schwarz-Bayesian Criterion (SBC). RESULTS: Tranexamic acid concentrations rapidly fell in all three groups. Data were well fit to a 2-compartment model, and adjustments for CPB were supported by SBC. Assuming a body weight of 80 kg, our model estimates V1 = 10.3 l before CPB and 11.9 l during and after CPB; V2 = 8.5 l before CPB and 9.8 l during and after CPB; Cl1 = 0.15 l/s before CPB, 0.11 l/s during CPB, and 0.17 l/s after CPB; and Cl2 = 0.18 l/s before CPB and 0.21 l/s during and after CPB. Based on simulation of previous studies of TA efficacy, we estimate that a 30-min loading dose of 12.5 mg/kg with a maintenance infusion of 6.5 mg x kg(-1) x hr(-1) and 1 mg/kg added to the pump prime will maintain TA concentration greater than 334 microm, and a higher dose based on 30 mg/kg loading dose plus 16 mg x kg(-1) x h(-1) continuous infusion and 2 mg/kg added to the pump prime would maintain TA concentrations greater than 800 microm. CONCLUSIONS: Tranexamic acid pharmacokinetics are influenced by CPB. Our TA pharmacokinetic model does not provide support for the wide range of TA dosing techniques that have been reported. Variation in TA efficacy from study to study and confusion about the optimal duration of TA treatment may be the result of dosing techniques that do not maintain stable, therapeutic TA concentrations.

Unconscious sedation in children: a prospective multi-arm clinical trial.

BACKGROUND: We report the evaluation of six sedative-hypnotic and analgesic combinations administered to children undergoing brief periods of unconscious (or deep) sedation for painful procedures. METHODS: In a prospective, open-label, randomized, controlled study of six groups of 27-30 children each, patients were randomly assigned to receive propofol or methohexital for sedation-hypnosis, and one of three incremental doses of fentanyl or remifentanil, respectively. RESULTS: An infusion of methohexital (10 mg.ml-1) combined with remifentanil (6.67 micro g.ml-1) provided significantly shorter geometric mean times to initial emergence, to eye-opening and to discharge, and required airway interventions that were not significantly more frequent than all groups sedated with propofol and fentanyl. CONCLUSIONS: The combination of methohexital and remifentanil appears to be a satisfactory method for unconcious sedation for short painful procedures in children.

Dexmedetomidine-induced sedation in volunteers decreases regional and global cerebral blood flow.

UNLABELLED: Dexmedetomidine is a selective alpha(2)-agonist approved for sedation of critically ill patients. There is little information on the effects of dexmedetomidine on cerebral blood flow (CBF) or intracranial hemodynamics, despite considerable other pharmacodynamic data. We hypothesized that therapeutic doses of dexmedetomidine would decrease CBF. Therefore, nine supine volunteers, aged 24-48 yr, were infused with a 1 micro g/kg IV loading dose of dexmedetomidine, followed by an infusion of 0.2 micro g. kg(-1). h(-1) (LOW DEX) and 0.6 micro g. kg(-1). h(-1) (HIGH DEX). Hemodynamic and CBF (via positron emission tomography) measurements were determined at each experimental time point. Dexmedetomidine decreased both cardiac output and heart rate during and 30 min after drug administration. Blood pressure decreased from 12% to 16% during and after the dexmedetomidine administration. Global CBF was decreased significantly from baseline (91 mL. 100 g(-1). min(-1) [95% confidence interval, 72-114] to 64 mL. 100 g(-1). min(-1) [51-81] LOW DEX and 61 mL. 100 g(-1). min(-1) [48-76] HIGH DEX). This decrease in CBF remained constant for at least 30 min after the dexmedetomidine infusion was discontinued, despite the plasma dexmedetomidine concentration decreasing 40% during this same time period (628 pg/mL [524-732] to 380 pg/mL [253-507]). IMPLICATIONS: Dexmedetomidine-induced sedation decreased cerebral blood flow (CBF) by congruent with 33%, which could be due to direct alpha(2)-receptor cerebral smooth muscle vasoconstriction or to compensatory CBF changes caused by dexmedetomidine-induced decreases in the cerebral metabolic rate.