Sevoflurane preconditioning at 1 MAC only provides limited protection in patients undergoing coronary artery bypass surgery: a randomized bi-centre trial.

BACKGROUND: Volatile agents can mimic ischaemic preconditioning leading to a decrease in myocardial infarct size. The present study investigated if a 15 min sevoflurane administration before cardiopulmonary bypass (CPB) has a cardioprotective effect in patients undergoing coronary surgery. METHODS: Seventy-two patients were randomized in two centres. The intervention group (S) received 1 MAC sevoflurane administrated via the ventilator for 15 min followed by a 15 min washout before CPB, the control group did not. The primary outcome was the postoperative troponin Ic peak. A biopsy of the atrium was taken during canulation for enzyme dosages. Results are expressed as mean (SD). RESULTS: Neither troponin Ic nor tissular enzyme measurement exhibited any difference between the groups: peak of troponin Ic was 4.4 (5.6) in S group vs 5.2 (6.6) ng ml(-1) in control group (ns). Intratissular ecto-5'-nucleotidase activity was 7.1 (4.3) vs 8.5 (11.9), protein kinase C activity was 27.1 (15.7) vs 29.2 (28.7), tyrosine kinase activity was 101 (54.1) vs 98.5 (63.3), and P38 MAPKinase activity was 131.1 (76.1) vs 127.1 (86.8) nmol mg protein(-1) min(-1) in S group and control group, respectively (ns). However there were fewer patients with low postoperative cardiac index in S group (11% in S vs 35% in control group, P < 0.05) when considering the per protocol population. In S group, 25% of patients required an inotropic support during the postoperative period, vs 36% of patients in control group (ns). CONCLUSIONS: This study did not show a significant preconditioning signal after 15 min of sevoflurane administration. The 15 min duration might be too short or the concentration of sevoflurane too low to induce cardioprotection detected by troponin I levels.

Oesophagotracheal perforation after intraoperative transoesphageal echocardiography in cardiac surgery.

Although transoesophageal echocardiography (TOE) can be considered a safe procedure, severe complications may occur. We report an oesophagotracheal perforation diagnosed 7 days after a complex and very long four-valve replacement procedure in a patient with a poor preoperative condition. We believe that an ischaemic lesion of the oesophagotracheal wall caused by the TOE probe was the initial event leading to this perforation. This observation raises concerns about the safety of prolonged TOE monitoring and suggests that a combination of risk factors (i.e. a small stature, a very long procedure, congestive heart failure, and a low cardiac output before and after cardiopulmonary bypass) may warrant increased precautions while performing TOE during cardiac surgery.

Utility of cardiac troponin measurement after cardiac surgery.

Postoperative cardiac failure due to myocardial necrosis remains a major complication in cardiac surgical procedures and its diagnosis is still difficult. In fact, cardiac enzymes, electrocardiogram and echographic signs are often misleading. The prognostic valve of troponin I after coronary artery bypass or conventional value surgery has been evaluated in 500 adult patients. Postoperative troponin I concentrations after cardiac surgery represent an independent variable associated with mortality (in-hospital death) and morbidity (low cardiac output and acute renal failure).

Hyperprocalcitonemia in patients with perioperative myocardial infarction after cardiac surgery.

OBJECTIVE: To describe and compare procalcitonin (PCT) concentrations after cardiac surgery in uncomplicated patients and in patients with perioperative myocardial infarction (PMI). DESIGN: Retrospective comparative study. SETTING: One university hospital. PATIENTS: Fifty-eight adult patients undergoing cardiac surgery. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: In a first step, plasma PCT and C-reactive protein concentrations were measured preoperatively and until 72 hrs postoperatively in ten consecutive patients who underwent uncomplicated cardiac surgery. PCT concentrations increased progressively from the end of cardiopulmonary bypass (0.09 +/- 0.09 ng/mL), peaked at 24 hrs postoperatively (1.14 +/- 1.24 ng/mL), and began to decrease at 48 hrs. C-reactive protein appeared to peak at 48 hrs (from 5.8 +/- 11.7 mg/L preoperatively to 265.1 +/- 103.5 mg/L on the second postoperative day). In a second step, PCT concentrations were measured at day one in 23 patients (PMI group) who presented high postoperative plasma cardiac troponin I concentrations and were compared with PCT concentrations observed in 25 matched uncomplicated patients. All patients were free from infection. PCT in the PMI group was significantly higher than in the control group (27.1 +/- 63.2 vs. 2.0 +/- 2.4 ng/mL, respectively; p =.0053). CONCLUSION: Because high plasma concentrations of PCT were found in patients with PMI after cardiac surgery, it may be suggested that, in the early postoperative period, elevated plasma PCT concentrations should be interpreted with caution regarding infection diagnosis.

Halothane and isoflurane differentially affect the regulation of dopamine and gamma-aminobutyric acid release mediated by presynaptic acetylcholine receptors in the rat striatum.

BACKGROUND: General anesthetics are thought to produce their hypnotic effects mainly by acting at ligand-gated ionic channels in the central nervous system (CNS). Although it is well established that volatile anesthetics significantly modify the activity of the acetylcholine nicotinic receptors of the neuromuscular junction, little is known about their actions on the acetylcholine receptors in the CNS. In this study, the effects of halothane and isoflurane on the regulation of dopamine (DA) (gamma-aminobutyric acid [GABA]) depolarization-evoked release mediated by nicotinic (muscarinic) presynaptic receptors were studied in the rat striatum. METHODS: Assay for GABA (dopamine) release consisted of 3H-GABA (3H-DA)-preloaded synaptosomes with artificial cerebrospinal fluid (0.5 ml/min, 37 degrees C) and measuring the radioactivity obtained from 1-min fractions for 18 min, first in the absence of any treatment (spontaneous release, 8 min), then in the presence of depolarizing agents combined with vaporized halothane and isoflurane (0.5-5%, 5 min), and finally with no pharmacologic stimulation (5 min). The depolarizing agents were potassium chloride (KCl; 9 mM) alone or with acetylcholine (10(-6)-10(-4) M) and/or atropine (10(-5) M) for experiments with 3H-GABA, and KC1 (15 mM) and nicotine (10(-7) - 5 x 10(-4) M) alone or with mecamylamine (10(-5) M) for experiments with 3H-DA. RESULTS: Potassium chloride induced a significant, Ca(2+)-dependent release of both 3H-GABA and 3H-DA. Nicotine produced a concentration-related, mecamylamine-sensitive 3H-DA release that was significantly attenuated by nicotine (10(-7) M) preincubation. Acetylcholine elicited a dose-dependent, atropine-sensitive reduction of the KC1-evoked 3H-GABA release. Halothane and isoflurane significantly decreased the nicotine-evoked 3H-DA release but had only limited depressant effects on the KC1-stimulated 3H-DA and no action on the KC1-induced 3H-GABA release. The effects of acetylcholine on 3H-GABA release were reversed by halothane but not by isoflurane. CONCLUSIONS: Clinically relevant concentrations of halothane and isoflurane significantly, but differentially, alter the presynaptic cholinergic regulation of the release of inhibitory neurotransmitters in the striatum. These results suggest that the cholinergic transmission may represent an important and specific presynaptic target for volatile anesthetics in the CNS.

Is inhibition of dopamine uptake relevant to the hypnotic action of i.v. anaesthetics?

We have examined the effects of ketamine, etomidate, propofol and thiopentone on the uptake of [3H]-dopamine into rat striatal synaptosomes. [3H]-dopamine uptake (5 min, 37 degrees C) was potently inhibited by nomifensine, a classical inhibitor of the dopamine carrier. All anaesthetics induced concentration-related inhibition of the uptake process, values for IC50 being 4.6 x 10(-6), 5.5 x 10(-5), 1.5 x 10(-4) and 2.7 x 10(-4) mol litre-1 for ketamine, etomidate, propofol and thiopentone, respectively. For all anaesthetics, inhibition of [3H]-dopamine uptake was reversible with a non-competitive profile. These data suggest that inhibition of striatal dopamine uptake may represent a relevant target site for some, but not all, i.v. anaesthetics.

Anesthetics affect the uptake but not the depolarization-evoked release of GABA in rat striatal synaptosomes.

BACKGROUND: Numerous classes of anesthetic agents have been shown to enhance the effects mediated by the postsynaptic gamma-aminobutyric acid A (GABAA) receptor-coupled chloride channel in the mammalian central nervous system. However, presynaptic actions of anesthetics potentially relevant to clinical anesthesia remain to be clarified. Therefore, in this study, the effects of intravenous and volatile anesthetics on both the uptake and the depolarization-evoked release of GABA in the rat striatum were investigated. METHODS: Assay for specific GABA uptake was performed by measuring the radioactivity incorporated in purified striatal synaptosomes incubated with 3H-GABA (20 nM, 5 min, 37 degrees C) and increasing concentrations of anesthetics in either the presence or the absence of nipecotic acid (1 mM, a specific GABA uptake inhibitor). Assay for GABA release consisted of superfusing 3H-GABA preloaded synaptosomes with artificial cerebrospinal fluid (0.5 ml.min-1, 37 degrees C) and measuring the radioactivity obtained from 0.5 ml fractions over 18 min, first in the absence of any treatment (spontaneous release, 8 min), then in the presence of either KCl alone (9 mM, 15 mM) or with various concentrations of anesthetics (5 min), and finally, with no pharmacologic stimulation (5 min). The following anesthetic agents were tested: propofol, etomidate, thiopental, ketamine, halothane, enflurane, isoflurane, and clonidine. RESULTS: More than 95% of 3H-GABA uptake was blocked by a 10(-3)-M concentration of nipecotic acid. Propofol, etomidate, thiopental, and ketamine induced a dose-related, reversible, noncompetitive, inhibition of 3H-GABA uptake: IC50 = 4.6 +/- 0.3 x 10(-5) M, 5.8 +/- 0.3 x 10(-5) M, 2.1 +/- 0.4 x 10(-3) M, and 4.9 +/- 0.5 x 10(-4) M for propofol, etomidate, thiopental, and ketamine, respectively. Volatile agents and clonidine had no significant effect, even when used at concentrations greater than those used clinically. KCl application induced a significant, calcium-dependent, concentration-related, increase from basal 3H-GABA release, +34 +/- 10% (P < 0.01) and +61 +/- 13% (P < 0.001), respectively, for 9 mM and 15 mM KCl. The release of 3H-GABA elicited by KCl was not affected by any of the anesthetic agents tested. CONCLUSIONS: These results indicate that most of the intravenous but not the volatile anesthetics inhibit the specific high-affinity 3H-GABA uptake process in vitro in striatal nerve terminals. However, this action was observed at clinically relevant concentrations only for propofol and etomidate. In contrast, the depolarization-evoked 3H-GABA release was not affected by anesthetics. Together, these data suggest that inhibition of GABA uptake, which results in synaptic GABA accumulation, might contribute to propofol and etomidate anesthesia.

Effects of thiopental, halothane and isoflurane on the calcium-dependent and -independent release of GABA from striatal synaptosomes in the rat.

The effects of the anesthetic agents thiopental, halothane and isoflurane on the release of GABA induced by depolarization and/or reversal of the GABA carrier were investigated in a synaptosomal preparation obtained from the rat striatum. Veratridine (1 microM) and KCl (9 mM) elicited a significant, Ca(2+)-dependent release of [3H]GABA. The KCl-evoked release was not significantly modified in the presence of nipecotic acid (10(-5) M), a selective blocker of the neuronal GABA carrier. The [3H]GABA release was significantly decreased by omega-conotoxin (10(-7) M, a blocker of the N voltage-dependent Ca2+ channels, but was affected by neither nifedipine (10(-4) M) nor omega-Aga-IVA (10(-7) M which block the L and P Ca2+ channels, respectively. Thiopental application (10(-5) to 10(-3) M) was followed by a dose-related, significant, decrease in both the veratridine and KCl-induced releases, whether nipecotic acid was present or not. In contrast, halothane and isoflurane (1-3%) failed to alter [3H]GABA release. Altogether, these results suggest that reduction of the depolarization-evoked GABA release might contribute to thiopental anesthesia, but this seems unlikely for volatile anesthetics.

Riluzole, a novel antiglutamate, blocks GABA uptake by striatal synaptosomes.

The effect of riluzole (2-amino-6-trifluoro-methoxybenzothiazole, a novel antiglutamate agent) on the uptake of [3H]GABA (gamma-aminobutyric acid) by striatal synaptosomes was investigated in rats. Both nipecotic acid (a classical blocker of GABA uptake) and riluzole were found to inhibit [3H]GABA uptake in a dose-related fashion (IC50 = 3.6 x 10(-6) M and 4.3 x 10(-5) M for nipecotic acid and riluzole, respectively). These results indicate that, in addition to its antiglutamate properties, riluzole probably also promotes synaptic GABA accumulation, which might contribute to the anticonvulsant and/or anesthetic properties of this pharmacological agent.

Effects of volatile anesthetics, thiopental, and ketamine on spontaneous and depolarization-evoked dopamine release from striatal synaptosomes in the rat.

BACKGROUND: Recent experimental data indicate that anesthesia is often associated with significant changes in brain concentrations of dopamine (DA), an inhibitory neurotransmitter located in restricted, but functionally important, areas such as the striatum. Whether the presynaptic DA nerve endings represent potential targets for anesthetics remains unknown. Therefore, the current study was designed to investigate the effects of volatile anesthetics, thiopental, and ketamine on both spontaneous and depolarization-evoked DA release from striatal synaptosomes in the rat. METHODS: Purified striatal synaptosomes preloaded with 3H-DA were superfused with artificial cerebrospinal fluid (1 ml/min). Radioactivity obtained from 1-ml fractions was measured over 15 min; first, in the absence of any treatment (spontaneous release), then in either the absence (time-dependent control) or presence (evoked-release) of anesthetic and pharmacologic agents, and finally, again, without any pharmacologic stimulation. The compounds tested were: potassium chloride (15 and 50 mM), glutamate, N-methyl-D-aspartate (NMDA) and kainate (10(-4) M and 10(-3) M), MK-801 (10(-4) M, an antagonist of NMDA receptors) and 6-cyano-7-nitro-quinoxaline-2,3-dione (10(-4) M, an antagonist of D,L-alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate [AMPA] receptors), halothane, enflurane, isoflurane (1, 1.5, and 2 minimum alveolar concentrations), ketamine (10(-5) and 10(-4) M), and thiopental (10(-5) and 10(-4) M). RESULTS: Volatile anesthetics induced a significant, concentration-related increase in spontaneous 3H-DA release, but thiopental and ketamine were ineffective. The effect of 2 minimum alveolar concentration enflurane (but not halothane or isoflurane) was significantly enhanced when a Mg(2+)-free cerebrospinal fluid was used, and was reduced by MK-801 application. Nomifensine (10(-5) M, a blocker of monoamine transporter) did not affect the 3H-DA release evoked by volatile anesthetics. Glutamate, kainate, NMDA, and potassium chloride induced a significant, dose-related, Ca(2+)-dependent 3H-DA release. Halothane and isoflurane produced a significant and concentration-related decrease in the 3H-DA peaks evoked by glutamate, kainate, and NMDA; however, enflurane significantly attenuated the glutamate- and kainate-mediated release, but enhanced that evoked by NMDA. Thiopental and ketamine (10(-4), but not 10(-5) M) significantly reduced the glutamate- and NMDA-stimulated release, but only thiopental decreased the kainate-induced effect. Furthermore, the effect of potassium chloride (15 mM) was significantly reduced by all anesthetics examined, whereas that of potassium chloride (50 mM) was unaffected. CONCLUSION: The authors conclude that: (1) volatile anesthetics, thiopental, and ketamine exert significant changes in both spontaneous and depolarization-evoked 3H-DA release in the rat striatum; (2) enflurane uniquely enhances NMDA-receptor mediated dopamine release; and (3) the results obtained from these receptor-mediated effects (AMPA and NMDA) may apply to postsynaptic, as well as presynaptic, glutamate receptors.