The Effects of General Anaesthesia and Light on Behavioural Rhythms and GABAA Receptor Subunit Expression in the Mouse SCN.

General anaesthesia (GA) is known to affect the circadian clock. However, the mechanisms that underlie GA-induced shifting of the clock are less well understood. Activation of γ-aminobutyric acid (GABA)-type A receptors (GABAAR) in the suprachiasmatic nucleus (SCN) can phase shift the clock and thus GABA and its receptors represent a putative pathway via which GA exerts its effect on the clock. Here, we investigated the concurrent effects of the inhalational anaesthetic, isoflurane, and light, on mouse behavioural locomotor rhythms and on α1, ß3, and γ2 GABAAR subunit expression in the SCN of the mouse brain. Behavioural phase shifts elicited by exposure of mice to four hours of GA (2% isoflurane) and light (400 lux) (n = 60) were determined by recording running wheel activity rhythms in constant conditions (DD). Full phase response curves for the effects of GA + light on behavioural rhythms show that phase shifts persist in anaesthetized mice exposed to light. Daily variation was detected in all three GABAAR subunits in LD 12:12. The γ2 subunit expression was significantly increased following GA in DD (compared to light alone) at times of large behavioural phase delays. We conclude that the phase shifting effect of light on the mouse clock is not blocked by GA administration, and that γ2 may potentially be involved in the phase shifting effect of GA on the clock. Further analysis of GABAAR subunit expression in the SCN will be necessary to confirm its role.

General Anaesthesia Shifts the Murine Circadian Clock in a Time-Dependant Fashion.

Following general anaesthesia (GA), patients frequently experience sleep disruption and fatigue, which has been hypothesized to result at least in part by GA affecting the circadian clock. Here, we provide the first comprehensive time-dependent analysis of the effects of the commonly administered inhalational anaesthetic, isoflurane, on the murine circadian clock, by analysing its effects on (a) behavioural locomotor rhythms and (b) PER2::LUC expression in the suprachiasmatic nuclei (SCN) of the mouse brain. Behavioural phase shifts elicited by exposure of mice (n = 80) to six hours of GA (2% isoflurane) were determined by recording wheel-running rhythms in constant conditions (DD). Phase shifts in PER2::LUC expression were determined by recording bioluminescence in organotypic SCN slices (n = 38) prior to and following GA exposure (2% isoflurane). Full phase response curves for the effects of GA on behaviour and PER2::LUC rhythms were constructed, which show that the effects of GA are highly time-dependent. Shifts in SCN PER2 expression were much larger than those of behaviour (c. 0.7 h behaviour vs. 7.5 h PER2::LUC). We discuss the implications of this work for understanding how GA affects the clock, and how it may inform the development of chronotherapeutic strategies to reduce GA-induced phase-shifting in patients.

Impact of anaesthesia on circadian rhythms and implications for laboratory experiments.

General anaesthesia is a widely used tool to enable surgery in animal experimentation. There is now convincing evidence that general anaesthesia can cause profound and strongly time-dependant shifts in circadian rhythms of behaviour (sleep-wake cycles), physiology (core body temperature, blood pressure, heart rate and hormone release) and cognitive parameters (learning and memory) in a range of species. These effects have the potential to confound laboratory experiments, and may lead to misinterpretation of results. Here, we summarise these effects and advise caution to those conducting laboratory experiments in which anaesthesia forms part of the protocol.

How does general anaesthesia affect the circadian clock?

Post-operative patients experience sleep disturbances. Animal studies demonstrate that general anaesthesia (GA) can disrupt circadian rhythms and cause changes in the molecular clock, indicating that anaesthesia contributes to post-operative circadian disruption. Here we review the effect of anaesthesia on the circadian clock and its rhythms in order to summarise current findings outline commonalities between studies and propose mechanisms by which effects may be mediated. KEY POINTS: 1) GA has strong effects on the main neurotransmitter systems linked with circadian control (Gamma aminobutyric acid/N-methyl-D-aspartate (GABA/NMDA)) and may act by interfering with light-entrainment of the clock. 2) Expression of the core clock gene per2 is inhibited by GA (possibly via a NMDA/glycogen synthase kinase 3ß (GSK3ß) pathway). 3) GA's effect on circadian rhythms appears greatest when administered during animals' active phases 4) GA may have different effects when administered under free-running and entrained conditions. 5) Anaesthesia may mimic the mechanism involved in adaptation of the clock to changes in daylength. There is agreement that GA can strongly affect the circadian clock. How anaesthesia-induced changes in the molecular clock lead to changes in behaviour remains unclear. The answer, and what it may mean for patients post-operatively, will rely on systematic studies at molecular, behavioural, and clinical levels using standardised protocols.

The effects of the general anaesthetic isoflurane on the honey bee (Apis mellifera) circadian clock.

General anaesthesia administered during the day has previously been shown to phase shift the honey bee clock. We describe a phase response curve for honey bees (n=105) to six hour isoflurane anaesthesia. The honey bee isoflurane PRC is "weak" with a delay portion (maximum shift of -1.88 hours, circadian time 0 - 3) but no advance zone. The isoflurane-induced shifts observed here are in direct opposition to those of light. Furthermore, concurrent administration of light and isoflurane abolishes the shifts that occur with isoflurane alone. Light may thus provide a means of reducing isoflurane-induced phase shifts.

Way-finding in displaced clock-shifted bees proves bees use a cognitive map.

Mammals navigate by means of a metric cognitive map. Insects, most notably bees and ants, are also impressive navigators. The question whether they, too, have a metric cognitive map is important to cognitive science and neuroscience. Experimentally captured and displaced bees often depart from the release site in the compass direction they were bent on before their capture, even though this no longer heads them toward their goal. When they discover their error, however, the bees set off more or less directly toward their goal. This ability to orient toward a goal from an arbitrary point in the familiar environment is evidence that they have an integrated metric map of the experienced environment. We report a test of an alternative hypothesis, which is that all the bees have in memory is a collection of snapshots that enable them to recognize different landmarks and, associated with each such snapshot, a sun-compass-referenced home vector derived from dead reckoning done before and after previous visits to the landmark. We show that a large shift in the sun-compass rapidly induced by general anesthesia does not alter the accuracy or speed of the homeward-oriented flight made after the bees discover the error in their initial postrelease flight. This result rules out the sun-referenced home-vector hypothesis, further strengthening the now extensive evidence for a metric cognitive map in bees.

Clevidipine compared with nitroglycerin for blood pressure control in coronary artery bypass grafting: a randomized double-blind study.

PURPOSE: We tested the hypothesis that clevidipine, a rapidly acting dihydropyridine calcium channel blocker, is not inferior to nitroglycerin (NTG) in controlling blood pressure before cardiopulmonary bypass (CPB) during coronary artery bypass grafting (CABG). METHODS: In this double-blind study from October 4, 2003 to April 26, 2004, 100 patients undergoing CABG with CPB were randomized at four centres to receive intravenous infusions of clevidipine (0.2-8 µg·kg(-1)·min(-1)) or NTG (0.4 µg·kg(-1)·min(-1) to a clinician-determined maximum dose rate) from induction of anesthesia through 12 hr postoperatively. The study drug was titrated in the pre-CPB period with the aim of maintaining mean arterial pressure (MAP) within ± 5 mmHg of a clinician-predetermined target. The primary endpoint was the area under the curve (AUC) for the total time each patient's MAP was outside the target range from drug initiation to the start of CPB, normalized per hour (AUCMAP-D). The predefined non-inferiority criterion for the primary endpoint was a 95% confidence interval (CI) upper limit no greater than 1.50 for the geometric means ratio between clevidipine and NTG. RESULTS: Total mean [standard deviation (SD)] dose pre-bypass was 4.5 (4.7) mg for clevidipine and 6.9 (5.4) mg for NTG (P < 0.05). The geometric mean AUCMAP-D for clevidipine was 283 mmHg·min·hr(-1) (n = 45) and for NTG was 292 mmHg·min·hr(-1) (n = 48); the geometric means ratio was 0.97 (95% CI 0.74 to 1.27). The geometric mean AUCMAP-D during aortic cannulation was 357.7 mmHg·min·hr(-1) for clevidipine compared with 190.5 mmHg·min·hr(-1) for NTG. Mean (SD) heart rate with clevidipine was 76.0 (13.8) beats·min(-1) compared with 81.5 (14.4) beats·min(-1) for NTG. There were no clinically important differences between groups in adverse events. CONCLUSION: During CABG, clevidipine was not inferior to NTG for blood pressure control pre-bypass.

Identifying advanced and delayed sleep phase disorders in the general population: a national survey of New Zealand adults.

The aim was to estimate the prevalence of, and identify independent risk factors for, Advanced (ASPD) and Delayed Sleep Phase Disorder (DSPD) among Maori (indigenous New Zealanders) and non-Maori adults using a self-report questionnaire. The Munich Chronotype Questionnaire was mailed to a stratified sample of 9100 adults (5100 Maori and 4000 non-Maori) aged 20-59 years randomly selected from the electoral rolls (54% response rate). Different definitions for ASPD and DSPD were developed using combinations of symptoms including self-reported bed and rising times, current chronotype, and a desire to change sleep schedule. Logistic regression models were used to model the likelihood of reporting ASPD or DSPD separately after adjusting for ethnicity (Maori versus non-Maori), sex (males versus females), age (in decades), socio-economic deprivation (NZDep2006 deciles) and employment status (unemployed, night work versus employed with no night work). The prevalence of ASPD ranged from 0.25% to 7.13% whereas the prevalence of DSPD was 1.51 to 8.90% depending on the definition used. The prevalence of ASPD was higher among men and increased with age. The prevalence of DSPD was higher among those living in more deprived areas and decreased with age. After controlling for ethnicity, gender, age, socio-economic deprivation and employment status, people with ASPD were more likely to report excessive daytime sleepiness, whereas those with DSPD were more likely to report poor or fair self-rated health. Reporting ASPD and DSPD were associated with self-reported night work. In this large sleep timing survey, we found no differences in the prevalence of self-identified ASPD and DSPD between Maori and non-Maori. This has implications for the development and provision of sleep health services and strategies for managing the significant impact of work patterns on sleep.

Brachial arterial temperature as an indicator of core temperature: proof of concept and potential applications.

There is potential for heat loss and hypothermia during anesthesia and also for hyperthermia if heat conservation and active warming measures are not accurately titrated. Accurate temperature monitoring is particularly important in procedures in which the patient is actively cooled and then rewarmed such as during cardiopulmonary bypass surgery (CPB). We simultaneously measured core, nasopharyngeal, and brachial artery temperatures to investigate the last named as a potential peripheral temperature monitoring site. Ten patients undergoing hypothermic CPB were instrumented for simultaneous monitoring of temperatures in the pulmonary artery (PA), aortic arterial inflow (AI), nasopharynx (NP), and brachial artery (BA). Core temperature was defined as PA temperature before and after CPB and the AI temperature during CPB. Mean deviations of BA and NP temperatures from core temperature were calculated for three steady-state periods (before, during, and after CPB). Mean deviation of BA and NP temperatures from AI temperature was also calculated during active rewarming. A total of 1862 measurements were obtained and logged from eight patients. Mean BA and NP deviations from core temperature across the steady-state periods (before, during, and after CBP) were, respectively: .23 +/- .25, -.26 +/- .3, and -.09 +/- .05 degrees C (BA), and .11 +/- .19, -.1 +/- .47, and -.04 +/- .3 degrees C (NP). During steady-state periods, there was no evidence of a difference between the mean BA and NP deviation. During active rewarming, the mean difference between the BA and AI temperatures was .14 +/- .36 degrees C. During this period, NP temperature lagged behind AI and BA temperatures by up to 41 minutes and was up to 5.3 degres C lower than BA (mean difference between BA and NP temperatures was 1.22 +/- .58 degrees C). The BA temperature is an adequate surrogate for core temperature. It also accurately tracks the changing AI temperature during rewarming and is therefore potentially useful in detecting a hyperthermic perfusate, which might cause cerebral hyperthermia.

A honey bee (Apis mellifera) light phase response curve.

The authors report a phase response curve (PRC) for individual honey bees (Apis mellifera) to single 1-h light pulses (1000 lux) using an Aschoff Type 1 protocol (n = 134). The bee PRC is a weak (Type 1) PRC with a maximum advance of 1.5 h between circadian time (CT) 18 and 3 and a maximum delay of 1.5 h between CT 12 and 18. This is the first published honey bee light PRC and provides an important resource for chronobiologists and honey bee researchers. It may also have practical applications for what is an economically important species frequently transported across different time zones.

General anesthesia alters time perception by phase shifting the circadian clock.

Following general anesthesia, people are often confused about the time of day and experience sleep disruption and fatigue. It has been hypothesized that these symptoms may be caused by general anesthesia affecting the circadian clock. The circadian clock is fundamental to our well-being because it regulates almost all aspects of our daily biochemistry, physiology, and behavior. Here, we investigated the effects of the most common general anesthetic, isoflurane, on time perception and the circadian clock using the honeybee (Apis mellifera) as a model. A 6-h daytime anesthetic systematically altered the time-compensated sun compass orientation of the bees, with a mean anticlockwise shift in vanishing bearing of 87° in the Southern Hemisphere and a clockwise shift in flight direction of 58° in the Northern Hemisphere. Using the same 6-h anesthetic treatment, time-trained bees showed a delay in the start of foraging of 3.3 h, and whole-hive locomotor-activity rhythms were delayed by an average of 4.3 h. We show that these effects are all attributable to a phase delay in the core molecular clockwork. mRNA oscillations of the central clock genes cryptochrome-m and period were delayed by 4.9 and 4.3 h, respectively. However, this effect is dependent on the time of day of administration, as is common for clock effects, and nighttime anesthesia did not shift the clock. Taken together, our results suggest that general anesthesia during the day causes a persistent and marked shift of the clock effectively inducing "jet lag" and causing impaired time perception. Managing this effect in humans is likely to help expedite postoperative recovery.

Validating the use of wrist-level light monitoring for in-hospital circadian studies.

This clinical methods comparison study describes the difference between light levels measured at the wrist (Actiwatch-L) and at the eye (Daysimeter) in a postoperative in-patient population. The mean difference between the two devices was less than 10 lux at light levels less than 5000 lux. Agreement between the devices was found to decrease as eye-level light exposure increased. Measurements at eye level of 5000 lux or more corresponded to a difference between the devices of greater than 100 lux. Agreement between the eye- and wrist-level light measurements also appears to be influenced by time of day. During the day, the measurement differences were on average 50 lux higher at eye level, whereas at night they were on average 50 lux lower. Although the wrist-level monitor was found to underestimate light exposure at higher light levels, it was well tolerated by participants in the clinical setting. In contrast, the eye-level monitor was cumbersome and uncomfortable for the patients to wear. This study provides light-exposure data on patients in real conditions in the clinical environment. The results show that wrist-level monitoring provides an adequate estimate of light exposure for in-hospital circadian studies.

Circadian-related sleep disorders and sleep medication use in the New Zealand blind population: an observational prevalence survey.

STUDY OBJECTIVES: To determine the prevalence of self-reported circadian-related sleep disorders, sleep medication and melatonin use in the New Zealand blind population. DESIGN: A telephone survey incorporating 62 questions on sleep habits and medication together with validated questionnaires on sleep quality, chronotype and seasonality. PARTICIPANTS: PARTICIPANTS WERE GROUPED INTO: (i) 157 with reduced conscious perception of light (RLP); (ii) 156 visually impaired with no reduction in light perception (LP) matched for age, sex and socioeconomic status, and (iii) 156 matched fully-sighted controls (FS). SLEEP HABITS AND DISTURBANCES: The incidence of sleep disorders, daytime somnolence, insomnia and sleep timing problems was significantly higher in RLP and LP compared to the FS controls (p<0.001). The RLP group had the highest incidence (55%) of sleep timing problems, and 26% showed drifting sleep patterns (vs. 4% FS). Odds ratios for unconventional sleep timing were 2.41 (RLP) and 1.63 (LP) compared to FS controls. For drifting sleep patterns, they were 7.3 (RLP) and 6.0 (LP). MEDICATION USE: Zopiclone was the most frequently prescribed sleep medication. Melatonin was used by only 4% in the RLP group and 2% in the LP group. CONCLUSIONS: Extrapolations from the current study suggest that 3,000 blind and visually impaired New Zealanders may suffer from circadian-related sleep problems, and that of these, fewer than 15% have been prescribed melatonin. This may represent a therapeutic gap in the treatment of circadian-related sleep disorders in New Zealand, findings that may generalize to other countries.

Circadian rhythms and their development in children: implications for pharmacokinetics and pharmacodynamics in anesthesia.

The influence of time-of-day on the action and toxicity of drugs may be an important factor in the design of pharmacokinetic (PK) and pharmacodynamic (PD) studies, and the interpretation of data resulting from these studies. Time-of-day can have a profound influence on the action of drugs. In some settings (e.g. cancer chemotherapy), the timing of drug administration has been utilized to maximize therapeutic effect and minimize toxicity. Time-of-day variation in the action of anesthetic drugs has been clearly demonstrated in adults. For example, local anesthetic action is longest during the afternoon, and neuromuscular blockade by rocuronium lasts one-third longer in the morning than the afternoon. Circadian rhythms develop over the first months and years of life. Robust rhythms in hormone production (e.g. melatonin and cortisol) are seen at approximately 3 months of age, but it remains unclear as to when daily rhythms in drug PK and PD first appear. Here, we review the evidence for time-of-day effects in anesthetic drugs in adults and children and outline the potential influence this has on pediatric anesthesia.

Use of a new task-relevant test to assess the effects of shift work and drug labelling formats on anesthesia trainees' drug recognition and confirmation.

BACKGROUND: Drug administration errors occur in every aspect of clinical practice. Using a novel task-relevant Medication Recognition and Confirmation Test (MRCT), we investigated the effects on performance of working night and day shifts and labelling different drug formats. METHODS: Anesthesia trainees (n = 18) participated in one of two experiments during an 8-12 hr day shift and an 8-12 hr night shift. In Experiment-1 (n = 10), we compared standardized colour-coded labels with pictures of ampoules. In Experiment-2 (n = 8), we compared colour-coded labels with black and white labels. Sleep was measured with wrist actigraphy during both day and night shift runs over seven to eight days. The MRCT outcome measures were reaction times and drug errors. RESULTS: In the two experiments, colour-coded labels were recognized (and therefore selected) more quickly than pictures of conventional ampoules (mean difference 332 msec, 95% confidence interval (CI) 242-422 msec; P < 0.0001) and faster than black and white labels (mean difference 96 msec, 95% CI 46-146 msec; P < 0.0001). Participants obtained less sleep while working night shifts than while working day shifts (mean difference 57 min, 95% CI 0:15-1:39 hr; P = 0.013). Mean confirmation reaction times were slower during night shifts than during day shifts (mean difference 60 msec, 95% CI 1-120 msec; P = 0.048). No differences in error rates were observed between shifts or among drug label types. CONCLUSIONS: Label format influenced recognition and confirmation reaction times to representations of drugs in this study, and we found some evidence to suggest that performance is better during day shifts than during night shifts. The task-relevant test evaluated here may have further application in measuring performance in the wider clinical setting.

Why does insect RNA look degraded?

The integrity of extracted ribonucleic acid (RNA) is commonly assessed by gel electrophoresis and subsequent analysis of the ribosomal RNA (rRNA) bands. Using the honey bee, Apis mellifera (Hymenoptera: Apidae), as an example, the electrophoretic rRNA profile of insects is explained. This profile differs significantly from the standard benchmark since the 28S rRNA of most insects contains an endogenous "hidden break." Upon denaturation, the masking hydrogen bonds are disrupted, releasing two similar sized fragments that both migrate closely with 18S rRNA. The resulting rRNA profile thus reflects the endogenous composition of insect rRNA and should not be misinterpreted as degradation.

Dexmedetomidine hemodynamics in children after cardiac surgery.

BACKGROUND: Dexmedetomidine has opposing effects on the cardiovascular system. Action in the central nervous system produces sympatholysis and a reduction in blood pressure, while peripherally it causes vasoconstriction leading to an increase in blood pressure. The purpose of our study is to define the concentration-response profile for these hemodynamic effects in children after cardiac surgery. METHODS: A simultaneous pharmacokinetic-pharmacodynamic analysis of data from 29 children given a single bolus of dexmedetomidine 1-4 mcg.kg(-1) following cardiac surgery was undertaken using mixed effects modeling. There were four dexmedetomidine concentrations available from each patient, and mean arterial blood pressure (MAP) was recorded electronically every 5 min for 5 h after drug administration. A composite Emax model was used to relate mean arterial pressure changes to plasma dexmedetomidine concentration. RESULTS: Children had a mean age of 2.67 years (range 4 days-14 years) and a mean weight of 12.34 (range 3.4-48.4) kg. The peripheral vasopressor effect was directly related to plasma concentration with an Emax(pos) of 50.3 (CV 44.50%) mmHg, EC(50pos) 1.1 (48.27%) microg.l(-1) and a Hill(pos) coefficient of 1.65. The delayed central sympatholytic response was described with an Emax(neg) of -12.30 (CV 37.01%) mmHg, EC(50neg) 0.10 (104.40%) microg.l(-1) and a Hill(neg) coefficient of 2.35. The equilibration half-time (T(1/2)keo) was 9.66 (165.23%) min. CONCLUSIONS: Dexmedetomidine administered as a single bolus dose following cardiac surgery produces a biphasic effect on MAP. A plasma dexmedetomidine concentration of above 1.0 microg.l(-1) was associated with a 20% increase in MAP in this specific cohort. A dosage regimen involving a small bolus dose (0.5 microg.kg(-1)) followed by a continuous infusion should be used to avoid initial increases in MAP.

Dexmedetomidine pharmacokinetics in pediatric intensive care--a pooled analysis.

BACKGROUND: Published dexmedetomidine pharmacokinetic studies in children are limited by participant numbers and restricted pathology. Pooling the available studies allows investigation of covariate effects. METHODS: Data from four studies investigating dexmedetomidine pharmacokinetics after i.v. administration (n = 95) were combined to undertake a population pharmacokinetic analysis of dexmedetomidine time-concentration profiles (730 observations) using nonlinear mixed effects modeling (NONMEM). Estimates were standardized to a 70-kg adult using allometric size models. RESULTS: Children had a mean age of 3.8 (median 3 years, range 1 week-14 years) and weight of 16.0 kg (median 13.3 kg, range 3.1-58.9 kg). Population parameter estimates (between subject variability) for a two-compartment model were clearance (CL) 42.1 (CV 30.9%) lx h(-1) x 70 kg(-1), central volume of distribution (V1) 56.3 (61.3%) l.70 kg(-1), inter-compartment clearance (Q) 78.3 (37.0%) l x h(-1) x 70 kg(-1) and peripheral volume of distribution (V2) 69.0 (47.0%) l.70 kg(-1). Clearance maturation with age was described using the Hill equation. Clearance increases from 18.2 l x h(-1) x 70 kg(-1) at birth in a term neonate to reach 84.5% of the mature value by 1 year of age. Children given infusion after cardiac surgery had 27% reduced clearance compared to a population given bolus dose. Simulation of published infusion rates that provide adequate sedation for intensive care patients found a target therapeutic concentration of between 0.4 and 0.8 microg x l(-1). CONCLUSIONS: The sedation target concentration is similar to that described for adults. Immature clearance in the first year of life and a higher clearance (when expressed as l x h(-1) x kg(-1)) in small children dictate infusion rates that change with age. Extrapolation of dose from children given infusion in intensive care after cardiac surgery may not be applicable to those sedated for noninvasive procedures out of intensive care.

Dexmedetomidine disposition in children: a population analysis.

BACKGROUND: There are few data describing dexmedetomidine population pharmacokinetics (PK) in children (0-15 years) despite increasing use. METHODS: An open-label study was undertaken to examine the PK of i.v. dexmedetomidine 1-4 mug.kg(-1) bolus in children after cardiac surgery (n = 45). A population PK analysis of dexmedetomidine time-concentration profiles (148 observations) was undertaken using nonlinear mixed effects modeling. Estimates were standardized to a 70-kg adult using allometric size models. RESULTS: Children had a mean age of 3.38 years (range 4 days to 14 years) and weight 15.1 kg (range 3.1-58.9 kg). A two-compartment disposition model with first order elimination was superior to a one-compartment model. Population parameter estimates (between subject variability) were clearance (CL) 39.2 (CV 30.36%) l.h(-1) per 70 kg, central volume of distribution (V1) 36.9 (69.49%) l per 70 kg, inter-compartment clearance (Q) 68.2 (37.6%) l.h(-1) per 70 kg and peripheral volume of distribution (V2) 69.9 (48.6%) l per 70 kg. Clearance at birth was 15.55 l.h(-1) per 70 kg and matured with a half-time of 46.5 weeks to reach 87% adult rate by 1 year of age. Simulation of an infusion of 1 mug.kg(-1) over 10 min followed by an infusion of 0.7 mug.kg(-1).h(-1) for 50 min suggested that children arouse from sedation at a plasma concentration of 0.304 mug.l(-1). CONCLUSIONS: Clearance in neonates is approximately one-third of that described in adults, consistent with immature elimination pathways. Maintenance dosing, which is a function of clearance, should be reduced in neonates and infants when using a target concentration approach.