Ketamine and propofol have opposite effects on postanesthetic sleep architecture in rats: relevance to the endogenous sleep-wakefulness substances orexin and melanin-concentrating hormone.

BACKGROUND: Anesthesia and surgery disturb sleep. Disturbed sleep adversely affects postoperative complications involving the cardiovascular system, diabetes, and infection. General anesthetics share neuronal mechanisms involving endogenous sleep-wakefulness-related substances, such as orexin (OX) and melanin-concentrating hormone (MCH). We evaluated changes in sleep architecture and the concentration of OX and MCH during the peri-anesthetic period. METHODS: To examine sleep architecture, male Sprague-Dawley rats weighing 350-450 g received ketamine 100 mg/kg (n = 9) or propofol 80 mg/kg (n = 6) by intraperitoneal injection. Electroencephalography was recorded from 2 days pre- to 5 days postanesthesia. To quantify levels of OX and MCH, 144 similar rats received the same doses of ketamine (n = 80) or propofol (n = 64). Brain concentrations of these substances were determined at 0, 20, 60, and 120 min after anesthetic administration. RESULTS: Ketamine decreased OX content in the hypothalamus during the anesthesia period. OX content was restored to pre-anesthesia levels in the hypothalamus and pons. Both anesthetics increased brain MCH content in the postanesthetic period, with the degree of increase being greater with propofol. Ketamine enhanced wakefulness and inhibited non-rapid eye movement sleep (NREMS) immediately after anesthesia. Conversely, propofol inhibited wakefulness and enhanced NREMS in that period. Ketamine inhibited wakefulness and enhanced NREMS during the dark phase on the first postanesthesia day. CONCLUSIONS: Anesthetics affect various endogenous sleep-wakefulness-related substances; however, the modulation pattern may depend on the type of anesthetic. The process of postanesthetic sleep disturbance was agent specific. Our results provide fundamental evidence to treat anesthetic-related sleep disturbance.

Effects of adding epinephrine on the early systemic absorption kinetics of local anesthetics in abdominal truncal blocks.

We evaluated the pharmacokinetics of ropivacaine following rectus sheath block (RSB) and transversus abdominis plane (TAP) block with or without epinephrine. A total of 26 adult patients undergoing lower abdominal surgery with RSB (=RSB trial) and another 26 adult patients undergoing open prostatectomy with TAP block (=TAP trial) were enrolled. Patients were randomly assigned to receive either a mixture of 0.75 % ropivacaine 13.2 mL with 1 % plain lidocaine 6.8 mL (TAP-E(-) and RSB-E(-) groups) or a mixture of 0.75 % ropivacaine 13.2 mL and 1 % lidocaine containing adrenaline (1:100,000) 6.8 mL (TAP-E(+) and RSB-E(+) groups) under general anesthesia. The serum concentrations of ropivacaine were measured using gas chromatography with mass spectrometry. The peak concentration was significantly lower and time to peak concentration was significantly longer in the TAP-E(+) group than in the TAP-E(-) group (P < 0.05 and <0.01, respectively), while there were no significant differences in these parameters between the RSB-E(+) and RSB-E(-) groups. These results indicate that epinephrine attenuates the early phase of local anesthetic absorption from the injected site in TAP blocks, but not RSB.

Plasma ropivacaine concentrations after ultrasound-guided transversus abdominis plane block for open retropubic prostatectomy.

PURPOSE: Ropivacaine-induced vasoconstriction may affect the early absorption speed of ropivacaine; however, the effects of dose on pharmacokinetics following transversus abdominis plane (TAP) block have not been studied. In this study, we have examined plasma ropivacaine concentrations following TAP block with various ropivacaine concentrations (0.25, 0.5, and 0.75 %). METHODS: With the approval of our University ethics committee and informed consent, 39 adult patients undergoing open retropubic prostatectomy were enrolled. Patients were randomly assigned to three groups (n = 13 each) receiving TAP block with 20 ml (10 ml each side) of different concentrations of ropivacaine. To determine plasma concentrations, blood samples were drawn before and 15, 30, 45, 60, 90, 120, and 180 min after completion of bilateral TAP blocks. Plasma ropivacaine concentrations were analyzed by gas chromatography with mass spectrometry. RESULTS: We found that the peak plasma concentrations (C(max)) increased dose dependently (0.41 ± 0.14, 0.89 ± 0.55, and 1.56 ± 0.50 µg/ml), but the times to C(max) (23.0 ± 15.8, 23.1 ± 14.5, and 20.8 ± 11.5 min) were not different between 0.25, 0.5, and 0.75 % ropivacaine doses, respectively. Terminal elimination half-life (t(1/2)), total body clearance (CL), and distribution volume (V(d)) were also not different among the three groups. CONCLUSION: Ropivacaine concentration did not alter pharmacokinetic profile following TAP blocks.

[Analgesic efficacy and clinical safety of intraperitoneal instillation combined with rectus sheath block using ropivacaine for pain relief after laparoscopic gynecological surgery].

BACKGROUND: The aim of this study was to evaluate the analgesic efficacy and safety of rectus sheath block combined with intraperitoneal instillation using two doses of ropivacaine in patients undergoing laparoscopic gynecological surgery. METHODS: Altogether 53 consenting women were randomized to receive intraperitoneal infiltration with 0.25% ropivacaine or 0.5% ropivacaine followed by rectus sheath block with 0.375% ropivacaine. The outcomes of clinical safety were measured using plasma concentration of local anesthetics and occurrence of toxic symptoms. The analgesic efficacy was assessed using numerical rating scales for pain and morphine consumption up to 24 hours after surgery. RESULTS: Patients' baseline characteristics, surgical factors, and analgesic outcomes were comparable between the two groups. Although peak plasma concentration of ropivacaine was significantly higher in patients receiving 0.5% ropivacaine, none of analyzed concentrations was above the toxic ones. Besides, no patients showed any symptoms of local anesthetic toxicity. CONCLUSIONS: The present study showed that the combination of rectus sheath block with intraperitoneal instillation of ropivacaine was safe and potent enough to relieve pain after laparoscopic surgery.

Quantitative measurement of blood remifentanil concentration: development of a new method and clinical application.

We have developed a new detection method of blood remifentanil concentration using a gas chromatography-mass spectrometry(GC-MS) with fentanyl as the internal standard(IS). The detection was performed at m/z 168 and 245 for remifentanil and fentanyl, respectively. In addition, the retention times of remifentanil and fentanyl were 5 min 45 s and 6 min 51 s, respectively. The standard curve of relationship between remifentanil concentration and the ratio of the peak area of remifentanil to fentanyl was satisfactorily fitted as linear regression (R(2) = 0.998, p < 0.01). Intra- and inter-assay CV was 10.5 and 11.5 %, respectively. In the clinical setting, 21 adult patients undergoing elective surgery under propofol-remifentanil TIVA were enrolled. To determine blood remifentanil concentrations, arterial blood was obtained at 0-30 min after cessation of remifentanil infusion at 0.2 µg/kg/min. Blood samples were given into sample tubes(chilled on ice) containing citric acid 50 % 60 µl which inactivates all esterase, and then stored at -20 °C until assay. Measured blood remifentanil concentration was 3.59 ± 0.74 ng/ml at the end of remifentanil infusion, and the ime for a decrease in blood remifentanil concentration by half was ~2 min. Remifentanil concentration was below the detection limit 30 min after the cessation. Thus, we have confirmed that this new method is clinically applicable.

Brief reports: plasma ropivacaine concentrations after ultrasound-guided rectus sheath block in patients undergoing lower abdominal surgery.

A rectus sheath block can provide postoperative analgesia for midline incisions. However, information regarding the pharmacokinetics of local anesthetics used in this block is lacking. In this study, we detail the time course of ropivacaine concentrations after this block. Thirty-nine patients undergoing elective lower abdominal surgery were assigned to 3 groups receiving rectus sheath block with 20 mL of different concentrations of ropivacaine. Peak plasma concentrations were dose dependent, and there were no significant differences in the times to peak plasma concentrations. The present data also suggested a slower absorption kinetics profile for ropivacaine after rectus sheath block than other compartment blocks.

The effects of benzodiazepines on urotensin II-stimulated norepinephrine release from rat cerebrocortical slices.

BACKGROUND: Urotensin II (UII) and its receptor (UT) are implicated in mood disorders, such as stress and anxiety, and this may result, at least in part, from increased norepinephrine release from the cerebral cortex. Benzodiazepines have been widely used as hypnotics and anxiolytics, producing a decrease in cerebrocortical norepinephrine release. We hypothesized that there was some interaction between benzodiazepines and the UII system in the cerebral cortex. METHODS: In the present study, we have examined the effects of benzodiazepines on UII-increased norepinephrine release from rat cerebrocortical slices and intracellular Ca(2+) concentrations ([Ca(2+)]i) in HEK293 cells expressing rat UT receptor (HEK293-rUT cells). RESULTS: Midazolam, diazepam and flunitrazepam concentration-dependently inhibited UII-evoked norepinephrine release but did not affect [Ca(2+)]i. The IC(50) of midazolam for inhibition of UII-evoked norepinephrine release (0.32 microM, P < 0.01) was significantly lower than that of diazepam (187 microM) or flunitrazepam (40 microM). The inhibitory effects of midazolam on UII-evoked norepinephrine release were significantly attenuated by flumazenil, a benzodiazepine site antagonist. CONCLUSION: The present study suggests that midazolam, at clinically relevant concentration, significantly inhibited UII-evoked norepinephrine release. This inhibitory effect may be partially mediated via central benzodiazepine receptors.

Role of the orexinergic system in acute haemorrhage in the rat.

Orexins (OXs) stimulate sympathetic nerve activity to increase arterial pressure (AP) and heart rate (HR). We have previously reported that the OX(1)-receptor antagonist SB-334867 reversed the sympathomimetic actions of orexin A (OXA). In the present study we have investigated the role(s) of the orexinergic system in sympathetic activation during haemorrhage in rats. Sixteen Wistar rats, anaesthetised with pentobarbital, were assigned to 2 groups: saline i.p. (group S) and SB-334867 30 mg/kg i.p. (group SB) n=8 each. Haemorrhagic shock was established by acute withdrawal of 10 ml/kg of blood via an arterial catheter three times with a 30 min interval between each withdrawal. Haemodynamics were assessed 30 min after 10, 20, and 30 ml/kg of blood withdrawal. In addition, plasma orexin A and catecholamine concentrations in the shed blood were determined. In both groups, mean AP (MAP) and HR decreased significantly. Plasma catecholamine concentrations significantly increased following blood withdrawal. The reduction in MAP/HR and elevation of catecholamine levels were dependent on the total amount of shed blood. There were no differences between the groups. Plasma OXA concentrations increased to a greater extent in group SB than group S in response to haemorrhage. There was a significant correlation between plasma catecholamines and %change in MAP (epinephrine: r=0.553, p=0.0001, norepinephrine: r=0.374, p=0.0087) and HR (epinephrine: r=0.403, p=0.005, norepinephrine: r=0.436, p=0.002). There was no correlation with plasma orexin A levels. These data suggest that despite a weak activation the orexinergic system is unlikely to make a major contribution to the response to haemorrhage.

Urotensin II evokes neurotransmitter release from rat cerebrocortical slices.

Urotensin II (UII) has been reported to modulate rapid eye movement (REM) sleep via activation of brainstem cholinergic neurons and REM sleep is regulated by locus coerleus (LC)-cerebrocortical noradrenergic neurons. We hypothesized that UII may activate LC-cerebrocortical noradrenergic neurons. To test this hypothesis, we have examined the effects of UII on norepinephrine release from rat cerebrocortical slices. In addition, the effect of the putative UT receptor antagonist [Pen(5), DTrp(7), Dab(8)]UII(4-11) (UFP-803) was assessed. We have compared this with other wakefulness-promoting neurotransmitters such as dopamine, glutamate, serotonin and histamine. We also studied the effects of UII and UFP-803 on intracellular Ca(2+) ([Ca(2+)]i) in HEK293 cells stably expressing rat UT receptor (HEK293-rUT cells). UII produced a time- (peaking at approximately 10 min following stimulation with 10nM) and concentration-dependent increase in norepinephrine release with pEC(50) and E(max) (% of basal) values of 8.78+/-0.17 (1.65 nM) and 138+/-2%, respectively. UII also evoked dopamine, serotonin and histamine release with similar pEC(50) values. UII increased glutamate release but only at high concentrations (<100 nM) and this failed to saturate. UII markedly increased [Ca(2+)](i) in HEK293-rUT cells in a concentration-dependent manner with pEC(50) of 8.26+/-0.24. The UT antagonist UFP-803 reversed both UII-increased norepinephrine release from the cerebrocortical slices (pK(B)=8.98) and [Ca(2+)](i) (pK(B)=8.87) in HEK293-rUT cells. Collectively these data suggest that UII evokes the release of norepinephrine via UT receptor activation and produces similar effects on other wakefulness-promoting neurotransmitters: these neurochemical actions of UII may be important for the control of the sleep-wake cycle.

The effects of benzodiazepines on orexinergic systems in rat cerebrocortical slices.

BACKGROUND: As orexinergic (OXergic) neurons have been reported to mediate emotional changes, benzodiazepines might interact with OXergic neurons. METHODS: We examined the interactions between OXergic neurons and benzodiazepine receptors in orexin-A (100 nM) and K+ (25 mM)-evoked norepinephrine release from rat cerebrocortical slices. RESULTS: Midazolam, diazepam, and flunitrazepam concentration-dependently inhibited both OX-A- and K+-evoked norepinephrine release. The IC50 of midazolam for orexin-A-evoked release (0.87 microM, P < 0.01), which was insensitive to flumazenil, was significantly lower than that of diazepam and flunitrazepam (around 60 microM), whereas the IC50s for K+-evoked release were not different among the benzodiazepines. CONCLUSION: There may be no interaction between OXergic neurons and central benzodiazepine receptors.

Lack of interaction between orexinergic and alpha2-adrenergic neuronal systems in rat cerebrocortical slices.

Orexinergic and norepinephrinergic alpha2-adrenoceptor expressing neurons contribute to the regulation of the sleep-wakefulness cycle. In the present study, we have examined a possible interaction between orexinergic and alpha2-adrenergic systems in orexin-A (100 nM)- and K+ (25 mM)-evoked norepinephrine release from slices of rat cerebrocortex. In this tissue norepinephrinergic neurons are predominantly innervated via the locus coeruleus. Clonidine concentration-dependently inhibited K+-evoked norepinephrine release with pIC50 (Imax) of 6.44+/-0.38 (48.8+/-6.9%). A selective orexin-1 receptor antagonist, SB-334867 was ineffective. SB-334867 concentration-dependently inhibited orexin A-evoked norepinephrine release with pIC50 (Imax) of 6.05+/-0.14 (86.4+/-5.4%); clonidine (alpha2-agonist) was ineffective. In contrast, yohimbine reversed the inhibitory effects of clonidine (1 microM) on K+-evoked norepinephrine release with pIC50 (Imax) of 6.50+/-0.34 (77.6+/-10.9%); orexin A was ineffective. The present data suggest a lack of interaction between orexinergic and alpha2-adrenergic neurons in rat cerebral cortex.

Effects of central hypocretin-1 administration on hemodynamic responses in young-adult and middle-aged rats.

The prevalence of hypertension in middle age correlates with impaired autonomic regulation and as norepinephrinergic neurons decline with increasing age, and this reduction may contribute to this impairment. Central hypocretin-activated norepinephrinergic neurons contribute to sympathetic regulation. In the present study we compared sympathoadrenal effects of intracerebroventricular (i.c.v.) hypocretin-1(5 nmol) between young-adult (12-14 weeks) and middle-aged (12-14 months) rats. Arterial blood pressure, heart rate and plasma catecholamines were assessed under pentobarbital anesthesia. In addition, we compared hypocretin-1 and K(+)-evoked norepinephrine release from the cerebrocortical slices prepared from young-adult and middle-aged rats. We also examined whether the novel hypocretin receptor-1 antagonist (SB-334867) could reverse these hypocretin-1 effects both in vivo and in vitro. I.c.v. hypocretin-1 significantly increased blood pressure by some 7%, heart rate by 9% and plasma norepinephrine concentrations by 100% in young-adult rats. In middle-aged rats these parameters did not change. Plasma epinephrine did not increase in either group. There was a significant correlation between changes in mean arterial pressure and plasma norepinephrine. Similarly, hypocretin-1 evoked norepinephrine release from cerebrocortical slices prepared from young-adult rats was significantly higher than that of middle-aged rats whilst K(+)-evoked release did not differ between the groups. SB-334867 significantly attenuated hypocretin-1-increased blood pressure and both in vivo and in vitro norepinephrine release. The present data suggest that hypocretinergic neurons may contribute to the regulation of central but not adrenal sympathetic activity. Moreover, sympathetic regulation by hypocretinergic neurones may disappear in middle-age in rats.

Supraclinical concentrations of dexmedetomidine evoke norepinephrine release from rat cerebrocortical slices possible involvement of the orexin-1 receptor.

Dexmedetomidine is a highly selective alpha(2)-agonist and reduces norepinephrine release from several neuronal tissues. However, supraclinical concentrations of dexmedetomidine have been reported to increase norepinephrine release from cardiac stores. In addition, some report using microdialysis shows that intrathecal clonidine increased norepinephrine release from the dorsal horn in mid-thoracic spinal cord but dexmedetomidine did not. Thus, in the present study we have studied effects of dexmedetomidine on norepinephrine release from rat cerebrocortical slices and compared this with clonidine. We have also used a selective alpha(2)-antagonist yohimbine and an orexin-1 receptor antagonist SB-334867 to examine whether the effects of dexmedetomidine on norepinephrine release are mediated via alpha(2)-adrenergic or orexin (OX) receptors. In addition, concentrations of orexin A in the evoked sample were also measured. Dexmedetomidine significantly increased norepinephrine release (basal=100%) from rat cerebrocortical slices in a concentration-dependent manner with E(max) 377.3+/-8.6% and pEC(50) 6.12+/-0.07, whereas clonidine significantly reduced the release with E(max) 62.1+/-6.8% and pEC(50) 4.55+/-0.25. Yohimbine (10(-5)M) did not affect the concentration-response curve of dexmedetomidine for norepinephrine release. However, SB-334867 concentration-dependently antagonized dexmedetomidine-evoked norepinephrine release with I(max) 91.0+/-9.4% and pIC(50) 5.99+/-0.18. Orexin A concentrations did not differ between the samples. Thus, supraclinical concentrations of dexmedetomidine increase norepinephrine release from rat cerebrocortical slices, and this release may be mediated via OX(1) but not alpha(2)-adrenoceptors.

Lack of an interaction between orexinergic and opioid/nociceptinergic systems in rat cerebrocortical slices.

We have recently reported that orexins (OXs) selectively evoke norepinephrine release from rat cerebrocortical slices. In the present study, we have examined orexin-opioid interactions in OXA (100 nM) and K(+) (40 mM)-evoked norepinephrine release. OXA-evoked norepinephrine release was reversed approximately 90% by SB-334867 (OX(1)-receptor antagonist) (10 microM) but not naloxone (10 microM). [D-Pen(2),D-Pen(5)]-enkephalin (DPDPE) (DOP-agonist) and nociceptin/orphanin-FQ (N/OFQ) also failed to affect OXA-evoked release. [D-Ala(2),N-Me-Phe(4),Gly(5)-ol]-enkephalin (DAMGO) (MOP-agonist) and spiradoline (KOP-agonist) significantly reduced OXA-evoked release with the concentration producing 50% of the maximal inhibition (EC(50)) [maximal inhibition (E(max))] of 3.2 microM [41.8%] and 4.3 microM [54.9%] respectively. The effects of DAMGO and spiradoline were naloxone (10 microM)-insensitive. In contrast, naloxone significantly antagonized the inhibitory effects of DAMGO and spiradoline on K(+)-evoked release. We conclude that opioid receptors (DOP and KOP) are involved in K(+) but not OXA-evoked release. Moreover, we have failed to demonstrate an interaction between orexinergic and opioid/N/OFQ-ergic systems in this system.

Effects of nociceptin/orphanin FQ receptor ligands on blood pressure, heart rate, and plasma catecholamine concentrations in guinea pigs.

Nociceptin/orphanin FQ (N/OFQ) is the endogenous ligand for the N/OFQ peptide receptor (NOP) and has been shown previously to produce bradycardia and hypotension in rodents. In this study we have measured the effects of intravenous N/OFQ, and the NOP antagonists [Nphe(1)]N/OFQ(1-13)-NH(2) ([Nphe(1)]) and [Nphe(1),Arg(14),Lys(15)]N/OFQ-NH(2) (UFP-101) on cardiovascular parameters and plasma catecholamine concentrations. Female Hartley guinea pigs were anesthetized with pentobarbital and ventilated artificially. MAP and HR were measured via a femoral arterial catheter and ECG, respectively. Plasma catecholamine concentrations were measured by HPLC. Animals received saline, N/OFQ (0.25, 1.25, 6.25 and 25 nmol cumulatively at 10-min intervals), [Nphe(1)] (600 nmol) and UFP-101 (60 nmol) i.v. in various combinations. After establishing a stable baseline, MAP and HR measurements and blood sampling were performed at the beginning and 3 min following each drug administration. N/OFQ significantly decreased MAP, HR and the plasma noradrenaline concentrations in a dose dependent manner (maximally by 29.1+/-1.8%, 13.8+/-0.8% and 46.6+/-7.8%, respectively) To the contrary, N/OFQ tended to increase plasma adrenaline concentration but did not affect plasma dopamine concentrations. There was a significant correlation between percent change in MAP (0.69, P<0.01) or HR (0.84, P<0.01) and that in plasma noradrenaline. [Nphe(1)], but not UFP-101, alone significantly decreased MAP. [Nphe(1)] partially antagonized N/OFQ-induced hypotension, bradycardia and the decrease in plasma concentration of noradrenaline. UFP-101 fully prevented the effects of N/OFQ in this model. In conclusion, the present study shows that intravenous N/OFQ, via NOP receptors, elicits hypotension and bradycardia also in the anaesthetized guinea pig and that the decrease in MAP and HR are positively correlated with the decrease in the plasma noradrenaline level.

Inhibitory effects of intravenous anaesthetic agents on K(+)-evoked glutamate release from rat cerebrocortical slices. Involvement of voltage-sensitive Ca(2+) channels and GABA(A) receptors.

It is widely accepted that most general anaesthetic agents depress the central nervous system (CNS) by potentiation or activation of the GABA(A) receptor-mediated Cl(-) conductance. These agents also reportedly inhibit voltage-sensitive Ca(2+) channels (VSCCs), thus depressing excitatory transmission in the CNS. However, in this regard there are few functional data at the level of neurotransmitter release. In this study we examined the effects of VSCC antagonists and a range of intravenous anaesthetic agents on K(+)(40 mM)-evoked glutamate release from rat cerebrocortical slices in the absence and presence of the GABA(A) receptor antagonist bicuculline (100 microM). We employed both selective and non-selective VSCC antagonists, the anaesthetic barbiturates thiopental, pentobarbital and phenobarbital, the non-anaesthetic barbiturate barbituric acid, the non-barbiturate anaesthetics alphaxalone, propofol and ketamine and the GABA(A) receptor agonist, muscimol. Glutamate released into the incubation medium was determined by a glutamate dehydrogenase-coupled assay. Omega-agatoxin IV(A) (P-type VSCC), omega-conotoxin MVII(C) (P/Q-type VSCC) and Cd(2+) (non-selective) essentially abolished glutamate release whilst nifedipine (L-type VSCC) and omega-conotoxin GVI(A) (N-type VSCC) reduced release by less than 30%. The concentrations producing 50% of the maximum inhibition (IC(50)) for thiopental, pentobarbital, phenobarbital, alphaxalone, propofol and ketamine were (in microM) 8.3, 22, 112, 6.3, 83 and 120, respectively. Barbituric acid produced a small (about 20%) inhibition. With the exception of ketamine, the IC(50) values for these anaesthetic agents were increased threefold by bicuculline (100 microM). In addition, muscimol significantly inhibited release by 26% with an IC(50) of 1.1 microM. In summary, a range of anaesthetic agents at clinically achievable concentrations inhibit glutamate release and this inhibition of release appears to be due mainly to direct inhibition of P/Q-type VSCCs, although activation of the GABA(A) receptor plays a role in this response.

The interaction between fentanyl and propofol during emergence from anesthesia: monitoring with the EEG-Bispectral index.

STUDY OBJECTIVE: To investigate the effect of different plasma levels of fentanyl on the concentration of propofol and the Bispectral Index (BIS) required for patients to regain consciousness and orientation following surgery. DESIGN: Prospective, open-label study. SETTING: Operating room of a university hospital. PATIENTS: 28 patients, aging 20 to 50 years, scheduled for elective, 1- to 4-hour surgeries under general anesthesia. INTERVENTIONS: BIS was continuously monitored from bifrontal montage (At1-Fpz and At2-Fpz) using an Aspect A-1,050 EEG system (Aspect, Natick, MA). Anesthesia was induced with bolus injections of fentanyl 2 microg/kg and propofol 2 mg/kg, and maintained with intermittent injections of fentanyl and constant infusion of propofol. Propofol infusion was stopped at the end of surgery. MEASUREMENTS: Consciousness and orientation were assessed as clinical endpoints once every 2 minutes following the end of the surgery. Blood samples were extracted for plasma propofol and fentanyl concentrations (PCp and FCp, respectively), and BIS values were recorded when patients regained consciousness and orientation. Patients were allocated to one of three groups depending on FCp on awakening: Group 1, FCp > 1 microg/L (n = 8); Group 2, FCp < 1 microg/L and >0.45 microg/L (n = 9); and Group 3, FCp < 0.45 microg/L (n = 11). PCp, BIS, recovery time, and other data were compared between the three groups. MAIN RESULTS: Demographic values, duration of surgery, and consumption of propofol and fentanyl were not different between the three groups. Group 3 patients regained consciousness with significantly higher propofol concentration (mean PCp = 3.2 mg/L) compared with those in Groups 1 and 2 (p < 0.05). However, the BIS values at both recovery endpoints were not different among the three groups. CONCLUSIONS: The plasma levels of fentanyl affect the concentrations of propofol required for patients to regain consciousness. The BIS values for wakefulness are unaltered at the different combinations of propofol and fentanyl concentrations. Thus, the BIS appears to be a useful and consistent indicator for level of consciousness during emergence from propofol/fentanyl intravenous anesthesia.

Endocrine responses to total intravenous anesthesia with droperidol, fentanyl, and ketamine in cardiac patients.

Ketamine-induced sympathetic stimulation can be inhibited by administration of sedatives such as benzodiazepines, droperidol, or opioids. We have developed total intravenous anesthesia with ketamine in combination with droperidol and fentanyl (DFK) and have used this anesthetic method in more than 4000 surgical cases. In this study, we compared DFK in cardiac surgery with isoflurane-fentanyl anesthesia (AOI-F). Fourteen patients undergoing aortocoronary artery bypass graft surgery were randomly assigned to the DFK or AOI-F groups. The endocrine responses of the patients were evaluated from the plasma, levels of cortisol, antidiuretic hormone (ADH), atrial natriuretic peptide (ANP), and aldosterone. In both groups, anesthesia per se did not induced any significant changes in the hormones. Although cortisol and ADH increased during surgery, ANP and aldosterone did not change appreciably. All hormones were significantly elevated after the end of cardiopulmonary bypass. There were no significant differences in any of the hormones, blood pressure, and heart rate measured at different points in both groups. These results showed that DFK anesthesia as a total intravenous anesthesia deserves to be studied in more depth.

Pharmacokinetics of ketamine during hypothermic cardiopulmonary bypass in cardiac patients.

Cardiopulmonary bypass (CPB) makes prediction of any drug concentration diffcult because both hypothermia and hemodilution can alter the pharmacokinetics of the drug. Eleven patients undergoing cardiac surgery under CPB were anesthetized with continuous infusion of ketamine combined with intermittent administration of droperidol and fentanyl. The infusion rate of ketamine was 2 mg·kg-1·hr-1 following a bolus administration of 1.5 mg·kg-1 for the induction of anesthesia. Blood concentrations of ketamine and its main metabolite, norketamine, were measured at 0, 30, and 60 min after the start of and the end of CPB, and 0, 1, 2, and 24 h after the cessation of ketamine infusion. Hypothermia increased blood ketamine levels during CPB, but the norketamine levels did not change. Although acute hemodilution would decrease blood ketamine levels, their levels were already significantly increased at 30 min after CPB. Hypothermic factors have a more kinetically important role during CPB than hemodilution. Increases in blood norketamine levels following rewarming indicate that hypothermia could impair ketamine metabolism in the liver. Further increase in the plasma concentration of ketamine until 30 min after the end of CPB might be due to blood transfusion containing ketamine from the CPB reservoir.

[Comparison of setup accuracy between ExacTrac X-ray 6 dimensions and cone-beam computed tomography for intracranial and pelvic image-guided radiotherapy].

The aim of this study was to compare the setup difference measured with ExacTrac X-ray 6D (ETX6D) and cone-beam computed tomography (CBCT) for non-invasive fractionated radiotherapy. Setup data were collected on a Novalis Tx treatment unit for both a head phantom and patients with intracranial tumors and a pelvic phantom and patients with prostate cancer. Initially, setup was done for a phantom using ETX6D. Secondly, a treatment couch was shifted or rotated by each already known value. Thirdly, ETX6D and CBCT scans were obtained. Finally, setup difference was determined: the registrations of ETX6D images with the corresponding digitally reconstructed radiographs using ETX6D fusion, and registrations of CBCT images with the planning CT using online 6D fusion. The setup difference between ETX6D and CBCT was compared. The impact of shifts and rotations on the difference was evaluated. Patients' setup data was similarly analyzed. In phantom experiments, the root mean square (RMS) of difference of the shift and rotation was less than 0.45 mm for translations, and 0.17 degrees for rotations. In intracranial patients' data, the RMS of that was 0.55 mm and 0.44 degree, respectively. In prostate cancer patients' data, the RMS of that was 0.77 mm and 0.79 degree, respectively. In this study, we observed modest setup differences between ETX6D and CBCT. These differences were generally less than 1.00 mm for translations, and 1.00 degrees for rotations, respectively.