Thiopental Concentrations Research Articles

Drug Interaction between Dexamethasone and Ketoprofen with Thiopental in Male Dogs: Effect on the Recovery from Anesthesia and Pharmacokinetics Parameters.

Drug-drug interactions (DDIs) are an important part of clinical veterinary pharmacology. Forty-two healthy mixed breed male dogs were randomly divided into three groups. The control group (C) received normal saline (1 mg/kg) 5 minutes before intravenous administration of thiopental (17 mg/kg), the T1 group received ketoprofen (2.2 mg/kg), and the T2 group received dexamethasone (0.2 mg/kg) 5 minutes before thiopental, respectively. Clinical parameters of anesthesia, heart rate, respiration rate, and electrocardiography were measured. Serum samples were also used to assay thiopental concentration using the high-performance liquid chromatography (HPLC) method, and then, thiopental pharmacokinetic parameters were calculated. Changes in the heart rate and respiration were significant intragroup differences 5 and 10 minutes after anesthesia, respectively. Recovery time parameters showed a significant increase between T1 and control groups (P < 0.05). Elimination rate and half-life of thiopental in the T1 group compared to the control and T2 groups showed a significant decrease and increase, respectively. In addition, the distribution of thiopental in T1 showed a significant increase compared to other groups. However, thiopental clearance in T1 and T2 groups had no significant difference with control (P > 0.05). It can be concluded that drug interaction between ketoprofen and thiopental causes to change in the pharmacokinetics parameters and recovery time from anesthesia in comparison with dexamethasone.

High-throughput assay for quantification of the plasma concentrations of thiopental using automated solid phase extraction (SPE) directly coupled to LC-MS/MS instrumentation.

Most previous assays for thiopental are time-consuming due to laborious sample extraction steps prior to analysis using gas chromatography or high pressure liquid chromatography. Here, we describe the first high-throughput liquid chromatography - tandem mass spectrometry (LC-MS/MS) method for quantification of thiopental concentrations in samples of human plasma. Robotic on-line solid phase extraction (SPE) was used to elute the analytes of interest from samples of human plasma (50μL) loaded onto C18 SPE cartridges to which were added aliquots (50μL) of internal standard solution (thiopental-d5 100ng/mL) and 0.5% formic acid in water (100μL). Cartridges were washed using 10% methanol in ammonium acetate buffer (50mM, pH 7) before elution with mobile phase comprising 0.1% formic acid in water and acetonitrile with a flow rate of 0.55mL/min using a 7.2min run time. The analytes were separated on a C18 XTerra® analytical column. Mass spectrometry detection was performed using a QTrap 5500 mass spectrometer (AB Sciex) with negative ionisation. The multiple reaction monitoring (MRM) transitions for thiopental and the internal standard were 241→58, and 246→58, respectively. The calibration curve was linear over a range of 6-600ng/mL. Thiopental was stable in human plasma samples for at least 36h in the autosampler, as well as after three cycles of freeze and thaw, and after 3h storage at room temperature. The absolute recovery and matrix effect were 102% and 6.9%, respectively, and the within-run and between-run precision and accuracy were ≤15%. Our method is fully-validated and satisfies the requirements of the 2012 European Medicines Agency (EMEA) guideline for Bioanalytical Method Validation.

Sevoflurane and thiopental preconditioning attenuates the migration and activity of MMP-2 in U87MG glioma cells

BackgroundTumor cell migration and diffuse infiltration into brain parenchyma are known causes of recurrence after treatment in glioblastoma (GBM), mediated in part by the interaction of glioma cells with the extracellular matrix, followed by degradation of matrix by tumor cell derived proteases, particularly the matrix metalloproteinases (MMP). Sevoflurane and thiopental are anesthetics commonly used in cancer surgery. However, their effect on the progression of glioma cells remains unclear. The aim of this study was to explore the role of these anesthetics on the migration and activity of MMP-2 in glioma cells. MethodologyCultured U87MG cells were pretreated with sevoflurane or thiopental and in vitro wound healing scratch assay was carried out to analyze their effect on migration of these cells. Gelatin zymography was carried out to examine the effect of these anesthetics on tumor cell MMP-2 activity using the conditioned media 24 h after pretreatment. Cell viability was analyzed using 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) assay. ResultsU87MG cells exposed to 2.5% sevoflurane or different concentrations of thiopental significantly decreased migration and activity of MMP-2 compared to control. No effect was seen on the viability of these cells after pretreatment with sevoflurane or thiopental. Conclusion/significanceThese results suggest that both sevoflurane and thiopental have inhibitory effect on the migration and MMP-2 activity in glioma cells. Thus, it is important that the choice of anesthetics to be used during glioma surgery takes into account their inhibitory properties against the tumor cells.

Anesthetic actions of thiopental remain largely unaffected during cholinergic overstimulation in cultured cortical networks.

In case of military or terrorist use of organophosphorus (OP) compounds victims are likely to suffer from not only intoxication but physical trauma as well. Appropriate emergency care may therefore include general anesthesia to allow life-saving surgical intervention. Since there is evidence that drug potency and efficacy of several anesthetics are attenuated by high concentrations of acetylcholine in the CNS, this study was designed to evaluate the anesthetic actions of thiopental during cholinergic overstimulation. Making use of organotypic slice cultures derived from the mouse neocortex, drug effects were assessed by extracellular voltage recordings of network activity at basal cholinergic tone and during simulated cholinergic crisis (high cholinergic tone). The latter was achieved by inhibition of acetylcholinesterases via soman and an ambient acetylcholine concentration of 10μM. The induction of cholinergic crisis in vitro increased the network activity of cortical neurons significantly. Surprisingly, differences in network activity between basal and high cholinergic tone became less pronounced with rising concentrations of thiopental and drug potency and efficacy were almost equivalent. These results clearly distinguish thiopental from previously tested general anesthetics and make it a promising candidate for in vivo studies to identify suitable anesthetics for victims of OP intoxication.

Execution by Lethal Injection: Illegal Research?

AbstractSeveral states systematically collect data to assess whether the anesthesia administered was sufficient—the same data used by researchers to show that the concentration of sodium thiopental in the blood of executed prisoners was not enough to ensure loss of consciousness and that these inadequate levels of anesthesia were not the result of pharmacokinetic changes after death. This activity could constitute human subjects research under existing law.

HPTLC method for the assay of thiopental in post-mortem blood in a fatal case of suicide

Thiopental is an ultra-short-acting barbiturate, used as an induction agent during general anesthesia and to manage intra cranial pressure in traumatic brain injuries. Because of its rapid onset of action, the potential for accidental or intentional abuse of thiopental is high. In this paper, a case is presented in which a 25-year-old female deliberately injected a fatal dose of thiopental.A method is developed for the evaluation of thiopental levels in the post-mortem blood (PMB) by simple and rapid HPTLC. Three different extraction procedures were compared for optimum recovery of thiopental from spiked blood samples. The effect of pH on the extraction yield of thiopental over a pH range of 5–6.5 was examined. An average analytical recovery of 90.5% was achieved from an ethyl acetate extract at pH 5.5. Chromatographic separation was achieved on silica gel 60F254 plates with an optimized mobile phase consisted of hexane–dichloromethane–ethyl acetate in the ratio 7.5:2:0.5 (v/v). Densitometric detection was carried out at 290nm in absorbance mode. No significant chromatographic interference was observed from other drugs used to diagnose the brain death. Calibration curve for thiopental in blood were linear from 1 to 100μgml−1 with r2=0.994. The detection limit was 0.5μgml−1 and its lower limit of quantification was 1.5μgml−1. The method showed excellent intra-assay precision (R.S.D. 1.07–6.28%) and inter-assay precision (R.S.D. 0.39–1.43%) for spiked blood samples at concentration of 1, 10, and 50μgml−1.The toxicological analysis revealed high concentrations of thiopental in PMB (204.75μgml−1 ±0.34), which is of immense help to conclude that the death occurred due to fatal doses of thiopental.

Propofol Preferentially Relaxes Neurokinin Receptor-2-induced Airway Smooth Muscle Contraction in Guinea Pig Trachea

Propofol is the anesthetic of choice for patients with reactive airway disease and is thought to reduce intubation- or irritant-induced bronchoconstriction by decreasing the cholinergic component of vagal nerve activation. However, additional neurotransmitters, including neurokinins, play a role in irritant-induced bronchoconstriction. We questioned the mechanistic assumption that the clinically recognized protective effect of propofol against irritant-induced bronchoconstriction during intubation was due to attenuation of airway cholinergic reflexes. Muscle force was continuously recorded from isolated guinea pig tracheal rings in organ baths. Rings were subjected to exogenous contractile agonists (acetylcholine, histamine, endothelin-1, substance P, acetyl-substance P, and neurokinin A) or to electrical field stimulation (EFS) to differentiate cholinergic or nonadrenergic, noncholinergic nerve-mediated contraction with or without cumulatively increasing concentrations of propofol, thiopental, etomidate, or ketamine. Propofol did not attenuate the cholinergic component of EFS-induced contraction at clinically relevant concentrations. In contrast, propofol relaxed nonadrenergic, noncholinergic-mediated EFS contraction at concentrations within the clinical range (20-100 mum, n = 9; P < 0.05), and propofol was more potent against an exogenous selective neurokinin-2 receptor versus neurokinin-1 receptor agonist contraction (n = 6, P < 0.001). Propofol, at clinically relevant concentrations, relaxes airway smooth muscle contracted by nonadrenergic, noncholinergic-mediated EFS and exogenous neurokinins but not contractions elicited by the cholinergic component of EFS. These findings suggest that the mechanism of protective effects of propofol against irritant-induced bronchoconstriction involves attenuation of tachykinins released from nonadrenergic, noncholinergic nerves acting at neurokinin-2 receptors on airway smooth muscle.

Cardioprotection Via Modulation of Calcium Homeostasis by Thiopental in Hypoxia-Reoxygenated Neonatal Rat Cardiomyocytes

PurposeCa2+ homeostasis plays an important role in myocardial cell injury induced by hypoxia-reoxygenation, and prevention of intracellular Ca2+ overload is key to cardioprotection. Even though thiopental is a frequently used anesthetic agent, little is known about its cardioprotective effects, particulary in association with Ca2+ homeostasis. We investigated whether thiopental protects cardiomyocytes against hypoxia-reoxygenation injury by regulating Ca2+ homeostasis.Materials and MethodsNeonatal rat cardiomyocytes were isolated. Cardiomyocytes were exposed to different concentrations of thiopental and immediately replaced in the hypoxic chamber to maintain hypoxia. After 1 hour of exposure, a culture dish was transferred to the CO2 incubator and cells were incubated at 37℃ for 5 hours. At the end of the experiments, the authors assessed cell protection using immunoblot analysis and caspase activity. The mRNA of genes involved in Ca2+ homeostasis, mitochondrial membrane potential, and cellular Ca2+ levels were examined.ResultsIn thiopental-treated cardiomyocytes, there was a decrease in expression of the proapoptotic protein Bax, caspase-3 activation, and intracellular Ca2+ content. In addition, both enhancement of anti-apoptotic protein Bcl-2 and activation of Erk concerned with survival were shown. Furthermore, thiopental attenuated alterations of genes involving Ca2+ regulation and significantly modulated abnormal changes of NCX and SERCA2a genes in hypoxia-reoxygenated neonatal cardiomyocytes. Thiopental suppressed disruption of mitochondrial membrane potential (ΔΨm) induced by hypoxia-reoxygenation.ConclusionThiopental is likely to modulate expression of genes that regulate Ca2+ homeostasis, which reduces apoptotic cell death and results in cardioprotection.

Thiopental pharmacokinetics in newborn infants: a case report of overdose

Thiopental may be used for sedation before intubation in newborn infants. A boy, born at 33 weeks of gestation (gw); birth weight 2435 g, was prescribed thiopental 3 mg/kg before intubation. He developed temporary hypotension and oxygen desaturation, and remained unconscious for longer than expected with a suppressed electroencephalography for 48 h. Serum thiopental concentration was 82, 59, 42 and 32 micromol/L after 20 min and 6, 24 and 68 h respectively. Serum concentrations from five newborn infants at the same time points after intubation with the same thiopental dose were used as reference values, and indicated a 10-fold overdose in the index case. The cause of the overdose could not be identified. The infant recovered; cerebral magnetic resonance imaging at the age of 42 gw and psychomotor development at 2 years were normal. These results show that thiopental concentrations are variable in neonates and there is a high risk of dosage error as no specific paediatric formulation is available. Well-designed procedures and continuous education are required to prevent errors and adverse events during drug delivery to newborn infants. To develop a safe method of administration for thiopental, an extended pharmacokinetic and pharmacodynamic study in neonates is warranted.

A Critical Review: Does Thiopental Continuous Infusion Warrant Therapeutic Drug Monitoring in the Critical Care Population?

Thiopental is a barbiturate used in traumatic brain injuries (TBIs) to reduce intracranial pressure (ICP) and to manage cerebral ischemia. As thiopental follows Michaelis-Menten kinetics, therapeutic drug monitoring (TDM) has been used in practice to improve efficacy and reduce adverse effects. However, its role is still debatable, and TDM is not widely practiced. Current evidence suggests that thiopental therapy may improve mortality and functional outcome in a subpopulation of patients with severe TBI with elevated ICP refractory to conventional medical therapy. Several analytical methods are available to quantify thiopental concentrations. This review uses a previously published 9-step decision-making algorithm to determine whether TDM of thiopental in TBI is warranted. There seems to be poor correlation between thiopental concentration and pharmacological response in terms of neurological response, ICP, electroencephalography, and drug toxicity. There is no established therapeutic range for thiopental continuous infusion due to a wide range of plasma concentrations corresponding to efficacy (25-50 mg/L) and toxicity (30-70 mg/L) and the resulting overlap between the 2. Thiopental exhibits intrapatient and interpatient variability due to age, obesity, renal and hepatic dysfunction, Michaelis-Menten kinetics, and hepatic enzyme autoinduction. Available evidence suggests that TDM of thiopental continuous infusion is not beneficial in improving efficacy or avoiding toxicity. There are however 2 possible scenarios in which TDM may provide additional information to sound clinical judgment. The first is providing patient-specific plasma target concentration to guide titration of therapy. The second scenario is differentiating between brain death and barbiturate-induced coma.

Anesthetics Discriminate Between Tonic and Phasic γ-Aminobutyric Acid Receptors on Hippocampal CA1 Neurons

Anesthesia is produced by a depression of neuronal signaling in the central nervous system (CNS); however, the mechanism(s) of action underlying this depression remain unclear. Recent studies have indicated that anesthetics can enhance inhibition of CNS neurons by increasing current flow through tonic gamma-aminobutyric acid (GABA(A)) receptor gated chloride channels in their membranes. Enhanced tonic inhibition would contribute to CNS depression produced by anesthetics, but it remains to be determined to what extent anesthetic actions at these receptors contribute to CNS depression. In the present study, we compared and contrasted the involvement of tonic versus synaptic GABA(A) receptors in the functional depression of CNS neurons produced by isoflurane and thiopental. In rat hippocampal slices, whole cell patch clamp recordings were used to study anesthetic effects on CA1 neuron intrinsic excitability, and population spike recordings were used to investigate effects on synaptically evoked discharge. These responses were chosen to test whether anesthetic effects on GABA receptors alter single neuron discharge and/or circuit level synaptic functioning. Phasic (synaptic) GABA receptors were selectively blocked using the GABA(A) antagonist gabazine and tonic responses were blocked using the chloride channel blocker picrotoxin. Clinically relevant and equi-effective concentrations of thiopental and isoflurane depressed CA1 neuron synaptically evoked discharge. This depression was partially reversed by blocking synaptic GABA(A) receptors with gabazine (20 microM). The thiopental-induced depression was reversed by approximately 60%, but the isoflurane-induced depression was reversed by only approximately 20%. Blocking tonic GABA(A) receptors with the addition of 100 microM picrotoxin produced an additional 40% reversal of the thiopental-induced depression, but no additional reversal was seen for isoflurane-depressed responses. In response to direct DC current injection, CA1 neuron discharge was depressed by thiopental and membrane conductance was increased. Both of these effects were reversed by picrotoxin, but not by gabazine. Isoflurane, in contrast, neither depressed current-evoked discharge, nor altered the membrane conductance of CA1 neurons. These results indicate that general anesthetics discriminate between synaptic and tonic GABA(A) receptors. Effects on both phasic and tonic receptors combined to depress circuit responses produced by thiopental, whereas only effects on synaptic GABA receptors appeared to play an important role for isoflurane. Together with the other known sites of action for these two anesthetics, our results support a multisite, agent-specific mechanism for anesthetic actions.

Depression of spinal network activity by thiopental: Shift from phasic to tonic GABA A receptor-mediated inhibition

Interneuronal networks in the spinal ventral horn are plausible substrates for mediating anesthetic-induced immobility. Here, we investigated how their activity is affected by clinically relevant concentrations of thiopental, a barbiturate in clinical use. In cultured spinal cord slices from mice, thiopental reduced action potential activity with an EC 50 of 16.6 ± 2.4 μM. Recordings of GABA A and glycine receptor-mediated inhibitory currents indicated that the effect was largely mediated by GABA A receptors and that glycine receptors were not relevant targets. Specifically, 20 μM thiopental prolonged the decay time of spontaneous GABAergic inhibitory postsynaptic currents (sIPSCs) more than twofold. Although this prolongation of decay time increased the inhibitory charge per sIPSC the concomitant strong reduction of sIPSC frequency resulted in less inhibitory current entering the neurons via this route. However, 20 μM thiopental also induced a tonic current of 30 ± 10 pA, mediated by GABA A receptors; 50 μM thiopental nearly abolished sIPSC activity but augmented tonic currents to 69 ± 14 pA. Furthermore, at this concentration, activity-depressing mechanisms independent of GABA A receptors came into play. The results suggest that in the spinal ventral horn thiopental acts mostly, but not exclusively, via GABA A receptors. With increasing concentrations of the drug, inhibition via sIPSCs is limited by negative feedback on interneuronal firing whereas action potential-independent GABAergic inhibition due to tonic currents gains progressively in impact.

Monocyte Phagocytosis of Viable Staphylococcus aureus is Impaired by Barbiturates, but not by Propofol

Barbiturates and propofol are used for deep sedation of patients with elevated intracranial pressure refractory to standard therapeutic regimens. Such patients often suffer from bacterial infections, which are most commonly caused by Staphylococcus aureus. Various interactions of anesthetics with components of the host defense have been documented, but very little is known about the influence on monocytes, which are a first-line defense against bacterial invasion. Therefore, we studied the effects of thiopental, methohexital, and propofol on monocyte phagocytosis using an in vitro whole blood model of viable S. aureus. Whole blood samples were preincubated with different concentrations of thiopental, methohexital, and propofol. Phagocytosis was stopped at different time points after addition of viable S. aureus. Monocytes then were stained with monoclonal antibodies for flow cytometric analysis of monocyte recruitment (ratio of ingesting monocytes). Furthermore, the fluorescence intensity of ingested bacteria served as semiquantitative measurement of phagocytosis activity. Both barbiturates inhibited monocyte recruitment and phagocytosis activity concentration-dependently, whereas propofol did not affect any of the investigated parameters. At concentrations of 7.6 x10(-3) M thiopental or 1.1 x 10(-3) M methohexital and greater, monocyte recruitment and phagocytosis activity were significantly inhibited. The calculated half-maximum inhibitory concentration (IC50) of thiopental was 8.4 x 10(-3) M for monocyte recruitment and 8.6 x 10(-3) M for phagocytosis activity. The corresponding values for methohexital were 4.1 x 10(-3) M and 1.1 x 10(-3) M, respectively. The two barbiturates induce concentration-dependent inhibition of monocyte phagocytosis, whereas propofol is without effect. In combination with previously described effects on granulocyte function, these findings suggest that defense against bacterial infection might be reduced by barbiturates.

Thiopental‐Induced Neutropenia in Two Patients with Severe Head Trauma

Thiopental has been used for decades in the treatment of refractory intracranial hypertension in patients with traumatic and nontraumatic head injuries. Commonly reported adverse effects include hypotension, hypokalemia, respiratory complications, and hepatic dysfunction. Neutropenia has rarely been reported as an adverse effect of thiopental. We witnessed probable thiopental-induced neutropenia in two patients with traumatic brain injuries who developed increased intracranial hypertension that was refractory to standard therapy. Based on a MEDLINE search of published case reports and literature, we propose two mechanisms by which thiopental-related neutropenia might be explained. The first is inhibition of inflammatory mediator nuclear factor-kappa B (NF-kappa B), leading to granulocyte apoptosis. The second mechanism involves inhibition of calcineurin. Although the precise link between these two mechanisms has not been elucidated, calcineurin is known to regulate NF-kappa B activity. Development of neutropenia does not appear to be correlated with time but may correlate with plasma concentrations of thiopental. The optimum management of drug-induced neutropenia is unclear. The decision to discontinue thiopental in patients who develop neutropenia should be made by weighing the risks versus benefits. Broad-spectrum antibiotics may be required in the presence of fever. The role of hematopoietic growth factors such as granulocyte colony-stimulating factor is not yet defined. Given the adverse infectious consequences of neutropenia, it is essential to closely monitor neutrophil counts in patients receiving thiopental.

General Anesthetics Inhibit Gap Junction Communication in Cultured Organotypic Hippocampal Slices

Gap junctions are protein channels that directly connect the cytosol of neighboring cells, thus forming electrical synapses and promoting synchronous neuronal activities. Such activities lead to the initiation and propagation of electroencephalogram oscillations implicated in cognition and consciousness. In this study, we investigated the effects of propofol, thiopental, and halothane on gap junction communication in cultured organotypic hippocampal slices by recovery of fluorescence after photo bleaching (FRAP) technique and electrophysiological recordings. Propofol 15 microM and thiopental 10 microM attenuated gap junction communication in slice cultures by 46.7% +/- 4.5% and 48.8% +/- 5.5%, respectively, as measured by FRAP. Smaller concentrations of propofol 5 microM and thiopental 2 microM did not change gap junction coupling. Accompanying the decreased gap junction communication, hippocampus slice cultures exposed to propofol 15 microM and thiopental 10 microM were found to have reduced electrophysiologic spontaneous discharges and primary after discharges evoked by a tetanic train of 50 Hz for 2 s. On the other hand, halothane 0.64 mM, a concentration slightly larger than twice its minimum alveolar concentration had no effect on gap junction coupling while halothane 2.8 mM blocked FRAP by 70%. The current study illustrates that anesthetic concentrations of propofol and thiopental, but not halothane, attenuate gap junction communication in cultured hippocampal slices. Suppression of gap junction function could compound the mechanisms of anesthetic actions.

Effects of Intravenous Anesthetics on the Human Radial Artery Used as a Coronary Artery Bypass Graft

Intravenous anesthetics are often used for anesthesia, sedation, and analgesia in the intraoperative and postoperative periods of coronary artery bypass graft (CABG) surgery. This study was designed to investigate the direct effects of intravenous anesthetics on the human radial artery (RA). In vitro, prospective with repeated measures. University research laboratory. RA segments (n = 20) were obtained from CABG surgery patients and were divided into 3- to 4-mm vascular rings. Using the organ bath technique, the endothelium-independent vasodilatation function was tested in vitro by the addition of cumulative concentrations of thiopental, ketamine, etomidate, and propofol after vasocontraction by phenylephrine in the presence of N(G)-nitro-L-arginine methyl ester (L-NAME) and indomethacin. Thiopental (10(-8) to 10(-4) mol/L), ketamine(10(-8) to 10(-4) mol/L), propofol (10(-8) to 3 x 10(-4) mol/L), and etomidate (10(-8) to 3 x 10(-4) mol/L) caused concentration-dependent vasorelaxation in human RA rings precontracted with phenylephrine in the presence of L-NAME and indomethacin (n = 20, for each drug). The pEC(50) and maximum relaxant effect values of thiopental and ketamine were significantly higher than for etomidate and propofol (p < 0.05). These findings indicate that thiopental, ketamine, etomidate, and propofol produce concentration-dependent relaxation on RA rings from humans. Thiopental and ketamine are more potent relaxant agents than etomidate and propofol. Intravenous anesthetics may be effective as alternative vasodilators for treatment of intraoperative and postoperative spasm of coronary artery grafts.

Effects of anesthetics on ATP-sensitive K channels in rat substantia nigra

ATP-sensitive K (KATP) channels are widely expressed in cytoplasmic membranes of neurons and they couple cell metabolism to excitability. They are known to play important roles in neuroprotection during ischemia and excitotoxicity. We studied the effects of three anesthetics on surface KATP channels in principal neurons of rat substantia nigra pars compacta. Whole cell voltage- and current-clamp recordings were made using rat midbrain slices. When neurons were dialyzed with an ATP-free pipette solution during perfusion with a glucose-free external solution, a hyperpolarization and an outward current developed slowly in a tolbutamide-inhibitable manner. Ketamine and thiopental did not affect the membrane potential or current when intracellular ATP was preserved, however, isoflurane slightly depolarized the neurons and increased frequency of spontaneous firings. The hyperpolarization and outward current induced by intracellular ATP depletion were reversibly inhibited by ketamine and thiopental at 100 and 300 μM but not by 704 μM isoflurane. These results suggest that surface KATP channels in these neurons are inhibited by high concentrations of ketamine and thiopental but not by isoflurane when the channels are activated. Our findings do not support the idea that KATP channel activation is important for previously reported neuroprotective actions of isoflurane.

Ionic mechanisms of thiopental on prolongation of action potential duration in rat ventricular myocytes

Isolated rat ventricular myocytes were used to examine the effects of thiopental on various currents relating to the repolarization phase of action potential. The clinically relevant concentrations of thiopental modestly, but significantly, reduced the transient outward K+ current and inwardly rectifying K+ current. Thiopental moderately reduced the Ca2+ current (ICa, L).

Effects of different anaesthetic agents on immune cell function in vitro

Anaesthesia may affect the regulatory balance of postoperative immune response. The aim of this study was to investigate the effects of different volatile and non-volatile anaesthetic agents and particularly of clinically used agent combinations on the proliferation capacity and cytokine production of immune cells. Peripheral blood mononuclear cells from healthy donors were PHA-activated in the presence or absence of various concentrations of thiopental, propofol, fentanyl, sufentanil, sevoflurane, nitrous oxide and combinations of these anaesthetics. Cell proliferation was assessed by tritiated thymidine uptake. Interleukin-2 production and release of the soluble IL-2 receptor were determined by enzyme immunoassays and used as measures of lymphocyte activation. Thiopental inhibited cell proliferation in a dose dependent manner (P < 0.001) and reduced sIL-2R release (2090-970 microg mL(-1); P < 0.05). Propofol reduced sIL-2R release at the high concentration of 10 microg mL(-1) (2220 pg mL(-1) 1780 microg mL(-1); p < 0.05). Fentanyl and sufentanil did not compensate for or enhance the inhibitory effects of thiopental. Nitrous oxide, but not sevoflurane, reduced the proliferation of human peripheral blood mononuclear cells (P < 0.05). In combinations with thiopental or nitrous oxide, sevoflurane compensated the inhibitory effects of these two agents. Fentanyl, sufentanil, sevoflurane and nitrous oxide did not affect PHA-induced IL-2 and sIL-2 receptor release by human peripheral blood mononuclear cells. Thiopental and nitrous oxide have immunosuppressive activity. In contrast, sevoflurane may have a beneficial effect by alleviating the immunosuppressive effects of both substances.

Inadequate anaesthesia in lethal injection for execution

Anaesthesia during lethal injection is essential to minimise suffering and to maintain public acceptance of the practice. Lethal injection is usually done by sequential administration of thiopental, pancuronium, and potassium chloride. Protocol information from Texas and Virginia showed that executioners had no anaesthesia training, drugs were administered remotely with no monitoring for anaesthesia, data were not recorded and no peer-review was done. Toxicology reports from Arizona, Georgia, North Carolina, and South Carolina showed that post-mortem concentrations of thiopental in the blood were lower than that required for surgery in 43 of 49 executed inmates (88%); 21 (43%) inmates had concentrations consistent with awareness. Methods of lethal injection anaesthesia are flawed and some inmates might experience awareness and suffering during execution.