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Thiopental combination treatments for cerebral resuscitation after prolonged cardiac arrest in dogs. Exploratory outcome study.

We postulate that mitigating the multifactorial pathogenesis of postischemic encephalopathy requires multifaceted treatments. In preparation for expensive definitive studies, we are reporting here the results of small exploratory series, compared with historic controls with the same model. We hypothesized that the brain damage mitigating effect of mild hypothermia after cardiac arrest can be enhanced with thiopental loading, and even more so with the further addition of phenytoin and methylprednisolone. Twenty-four dogs (four groups of six dogs each) received VF 12.5 min no-flow, reversed with brief cardiopulmonary bypass (CPB), controlled ventilation to 20 h, and intensive care to 96 h. Group 1 with normothermia throughout and randomized group 2 with mild hypothermia (from reperfusion to 2 h) were controls. Then, group 3 received in addition, thiopental 90 mg/kg i.v. over the first 6 h. Then, group 4 received, in addition to group 2 treatment, thiopental 30 mg/kg i.v. over the first 90 min (because the larger dose had produced cardiopulmonary complications), plus phenytoin 15 mg/kg i.v. at 15 min after reperfusion, and methylprednisolone 130 mg/kg i.v. over 20 h. All dogs survived. Best overall performance categories (OPC) achieved (OPC 1 = normal, OPC 5 = brain death) were better in group 2 than group 1 (< 0.05) and numerically better in groups 3 or 4 than in groups 1 or 2. Good cerebral outcome (OPC 1 or 2) was achieved by all six dogs only in group 4 (P < 0.05 group 4 vs. 2). Best NDS were 44 +/- 3% in group 1; 20 +/- 14% in group 2 (P = 0.002); 21 +/- 15% in group 3 (NS vs. group 2); and 7 +/- 8% in group 4 (P = 0.08 vs. group 2). Total brain histologic damage scores (HDS) at 96 h were 156 +/- 38 in group 1; 81 +/- 12 in group 2 (P < 0.001 vs. group 1); 53 +/- 25 in group 3 (P = 0.02 vs. group 2); and 48 +/- 5 in group 4 (P = 0.02 vs. group 2). We conclude that after prolonged cardiac arrest, the already established brain damage mitigating effect of mild immediate postarrest hypothermia might be enhanced by thiopental, and perhaps then further enhanced by adding phenytoin and methylprednisolone.

Animals↗

Influence of thiopental anaesthesia on fetal motor behaviour in early pregnancy.

Real-time ultrasonography has shown fetal motor activity to be present long before the mother is able to perceive any movements. The development of fetal movement patterns reflects neuromotor maturation of the fetal central nervous system. Drugs given to the mother may affect fetal neuromotor behaviour. In 20 first trimester pregnant women, applicants for legal abortion, fetal movements were objectively recorded before and after thiopental anaesthesia, using a semi-automatic method for quantitative recording of fetal movements displayed in real-time ultrasound image of the uterus. In ten patients randomly selected for premedication with morphine-scopolamine 1 h before surgery, fetal motor activity was practically abolished after the thiopental injection. In the other ten patients not so premedicated, the abolishment of fetal movements was delayed by 3 min. During the second minute after the thiopental injection, there was an increase both in the number and incidence of movements, as compared with the control period. In the latter group there was a positive correlation between the number of fetal movements and thiopental concentrations both in maternal plasma and placental tissue. The present method might be used for description of the pharmacodynamic effect of a drug distributed to the mother and traversing the placenta.

Adolescent↗

High-performance liquid chromatographic method for determining thiopental concentrations in twelve rat tissues: application to physiologic modeling of disposition of barbiturate.

A sensitive, selective and reproducible high-performance liquid chromatographic assay of thiopental concentrations in twelve rat tissues was developed using thiamylal as the internal standard. Samples were homogenized in phosphate buffer, extracted into pentane and chromatographed on a microparticulate octadecyl reversed-phase column using ultraviolet detection at 290 nm. A simple digestive step with collagenase prior to homogenization facilitated analysis of thiobarbiturate in skin. Thiopental extraction recovery from fat exceeded 90%. Assay sensitivity was greater than 1 microgram/ml for tissue and plasma samples as small as 50 microliters. This assay has been applied to physiologic pharmacokinetic studies. The paper also presents typical concentration-time profiles of thiopental in four tissues taken from 74 rats given 20 mg/kg thiopental.

Adipose Tissue↗

Effects of thiopental on bispectral index and heart rate variability.

BACKGROUND AND OBJECTIVE: Thiopental has been reported to reduce sympathetic tone, however, it is not clear whether change in heart rate variability is associated with depth of anaesthesia. The purpose of the present study was to evaluate changes in heart rate variability at different depths of hypnosis during induction of anaesthesia with thiopental. METHODS: We studied 17 ASA I patients scheduled for minor surgery. The depth of hypnosis was monitored by the BIS. Spectral analysis of heart rate variability using a maximum entropy method resulted in a characteristic power spectrum with two main regions, a high frequency and a low frequency. Haemodynamics, entropy, low frequency, high frequency and low frequency/high frequency were monitored in an awake state and after the induction of anaesthesia. RESULTS: Heart rate increased in a BIS-dependent manner, whereas blood pressure showed no significant changes during the study period. High frequency, entropy and low frequency decreased with a reduction in the BIS value. Low frequency/high frequency showed no significant change during the study period. CONCLUSIONS: Induction of anaesthesia with thiopental increased heart rate and decreased high frequency, entropy and low frequency in a BIS-dependent manner, indicating that thiopental reduces cardiac parasympathetic tone depending on the depth of hypnosis.

Adult↗

Time-dependent pharmacokinetics of high dose thiopental infusion in intensive care patients.

PURPOSE: In patients with severe head injuries receiving long-term infusion for reducing intracranial pressure, a decline in concentrations was apparent following attainment of an initial steady state. This could be explained by an increased rate of elimination. An adequate modeling of the plasma disposition curves was used to demonstrate clearly the metabolic induction. METHODS: The concentration-time data of 17 patients were fit by a one compartment pharmacokinetic model in which the decline of plasma concentration during infusion was due to an increase in the clearance rate of thiopental following a latency period. This time-dependent clearance model provided estimates of initial and final clearance rates. RESULTS: This study demonstrated that large interindividual variations were observed during the course of the thiopental time-dependent pharmacokinetics. Depending on the patient, one or two steps of induction occurred. The mean initial and final clearance rates were 1.22 +/- 0.82 mL/min/kg and 10.5 +/- 23 mL/min/kg. The latency period for the first induction averaged 69 +/- 56 h. For 6 subjects, the rate of thiopental metabolism continued to change with time and there was a second step of induction. CONCLUSIONS: Induction of thiopental metabolism occur within therapeutic ranges, but it was not established that attainment of individual limits in dosing rate, total dose, or treatment duration occur in the process. Thus, monitoring is needed for achievement of a target plasma concentration.

Adolescent↗

Effect of thiopental, propofol, and etomidate on vincristine toxicity in PC12 cells.

Neurotoxicity is the dose-limiting side-effect of vincristine in cancer therapy. Using the nerve growth factor (NGF)-dependent neurite outgrowth and cell proliferation of the PC12 pheochromocytoma cell line as an in vitro assay, the protective effect of different intravenous anesthetics was assessed. Vincristine (1 nmol/L) significantly decreased the percentage of neurite-forming cells from 68% +/- 9% to 27% +/- 7% within a 3-day incubation period. The longer neurites (> 2 x cell body) in particular proved to be extremely sensitive to vincristine (from 17% +/- 4% to 0% of total neurite-expressing cells). Flow cytometry results revealed an S-phase percentage of 15.85% +/- 3.25% after NGF induction, with vincristine reducing this percentage to 0.68% +/- 0.38%. Reversal of the inhibitory effect of vincristine was noted in the cells treated with thiopental or propofol but not etomidate. Bicuculline partially antagonized the protective effect of thiopental and propofol in both studies. We conclude that thiopental and propofol, but not etomidate, have a protective effect in vincristine-induced neurotoxicity. The protective effect produced by thiopental and propofol is probably secondary to activation of GABAA receptors.

Animals↗

Haemodynamic effects of intravenous clonidine on propofol or thiopental induction.

The study evaluated the effects of premedication with intravenous clonidine on thiopental or propofol requirements for induction and haemodynamic changes associated with both induction and endotracheal intubation. Clonidine administered intravenously before induction of anaesthesia reduced propofol or thiopental requirements. The association of clonidine and propofol caused, after injection of the induction drug, a decrease in mean arterial pressure which was significantly greater than with thiopental. Moreover, a major haemodynamic stability was registered before and after laryngoscopy in the clonidine-thiopental group. These findings might contraindicate the clonidine-propofol combination in patients with cardiovascular disease.

Adrenergic alpha-Agonists↗

Physicochemical compatibility of propofol with thiopental sodium.

The physicochemical compatibility of propofol and thiopental sodium when mixed together in various ratios and stored was studied. Mixtures of propofol and thiopental sodium in five volume ratios from 1:3 to 3:1 were refrigerated (4 degrees C) for up to seven days and then centrifuged at 2000g for two hours. Droplet sizes were determined at intervals by optical microscopy and laser diffraction, and chemical stability of the 1:1 mixture was evaluated by high-performance liquid chromatography (HPLC). Optical microscopy and laser diffraction indicated negligible changes in droplet size within 48 hours of mixing. A small increase in the width of the frequency distribution of droplet sizes occurred 24-48 hours after mixing for the two mixtures with the lowest propofol concentration. Some coalescence of droplets occurred on centrifugation. These results indicated negligible formation of droplets that might cause embolism after i.v. injection of fresh mixtures (not more than six hours old). A yellow color appearing after 24-48 hours indicated anticipated chemical changes. HPLC of samples stored at 25 degrees C indicated clinically unimportant drug loss after six hours. The mixtures were considered physically stable for not more than 48 hours. Droplet size in mixtures of propofol and thiopental sodium did not increase until at least 24 hours. Drug loss from mixtures containing propofol 5 mg/mL and thiopental sodium 12.5 mg/mL was insignificant for up to eight hours.

Anesthetics, Intravenous↗

A model of the kinetics and dynamics of induction of anaesthesia in sheep: variable estimation for thiopental and comparison with propofol.

We describe a six-compartment kinetic and dynamic physiological model of induction of anaesthesia with thiopental. The model included an accurate account of initial drug distribution by representing the inter-relationships between initial vascular mixing, lung kinetics and cardiac output, and the use of the brain as the target organ for anaesthesia (two-compartment sub-model with slight membrane limitation). It also accounted for thiopental-induced reductions in cerebral blood flow and cardiac output. Parameters for the model were estimated using hybrid modelling from an extensive in vivo data set collected in sheep. Simulations were used to compare the properties of the thiopental model with an analogous previously published model of propofol. Differences in the blood:brain equilibrium half-lives of thiopental (1.22 min) and propofol (4.32 min) contributed to significant differences in the predicted optimal rate of bolus injection of each agent for inducing anaesthesia in sheep.

Anesthesia↗

Anoxic depolarization of rat hippocampal slices is prevented by thiopental but not by propofol or isoflurane.

BACKGROUND: There is strong evidence to suggest that anoxic depolarization (AD) is an important factor in hypoxia/ischaemia-induced neural damage. Treatments that prevent the occurrence of AD may be useful in providing neuronal protection against hypoxia. The current study was designed to determine whether general anaesthetics which have been suggested to 'induce prophylaxis' against hypoxia can attenuate the incidence of AD. METHODS: The effects of anoxia (3 min) on evoked extracellularly recorded field potentials of CA1 neurons in rat hippocampal slices were assessed in the absence and presence of the i.v. general anaesthetics thiopental and propofol and the volatile anaesthetic isoflurane. RESULTS: In the absence of anaesthetics, AD occurred in 81% of the preparations tested. Thiopental (2 x 10(-4) M) significantly reduced the incidence of AD (16%, P=0.0006). In comparison, propofol (2 x 10(-4) M) and isoflurane (1.5 vol%) were ineffective (69% and 60%, respectively). Furthermore, in the presence of thiopental, the population spike amplitude recovered with and without AD (90% and 94% of pre-anoxic value, respectively) following 3 min anoxia. CONCLUSION: The prophylactic effect of thiopental against hypoxia might be induced, in part, by preventing the generation of AD.

Anesthetics, Inhalation↗

A simple method for determining thiopental in plasma.

A simple rapid HPLC method for the measurement of thiopental is described. Plasma was deproteinised with 50% (v/v) acetonitrile in methanol containing flufenamic acid as an internal standard. Chromatography was carried out on a C-18 mu Bondapak reverse phase column using 220 mL of buffer (1.79 g of ammonium dihydrogen phosphate and 1.75 g of sodium sulfate adjusted to pH 7.9 with ammonium hydroxide) in 300 mL of methanol. Detection at 280 nm was near the absorption maxima of both thiopental and flufenamic acid. The method is linear up to 75 micrograms/mL and is therefore suitable for the measurement of thiopental in plasma from patients sedated by thiopental infusion. The sensitivity can be increased such that single dose studies can be investigated.

Chromatography, High Pressure Liquid↗

Propofol, but not thiopental, supports the growth of Candida albicans.

We determined whether propofol, thiopental, or 0.9% saline would serve as a growth medium for Candida albicans. In Part I, we investigated whether opening 20 propofol ampules would cause glass particles from the exterior of the ampule to fall into the emulsion and contaminate it. Each ampule was painted with red fingernail polish and its contents were passed through filter paper after it was opened in a routine manner. In Part II, a sample from a colony of C albicans was added to sterile vials containing 20 mL of either 0.9% saline, 1% propofol, or 2.5% thiopental. A 1-microL sample from each vial was then plated onto Sabaroud's dextrose plus brain-heart infusion (SABHI) agar at the following times after inoculation: 0, 3, 6, 16, and 24 h. The plates were incubated at 35 degrees C for 24 h and the number of colony-forming units counted. The filtration of two of the painted ampules in Part I revealed red glass fragments. In Part II, the saline and thiopental solutions did not increase the number of colonies of C. albicans by 24 h. However, the propofol, after a latent period between 6 and 16 h, supported the growth of C. albicans at a rapid rate. Our investigation shows that glass particles from the exterior of a propofol ampule can contaminate its contents when the ampule is opened in a routine manner. Furthermore, propofol provides an excellent growth medium for C. albicans. Thiopental and saline showed no growth. We conclude that the ability of propofol to grow C. albicans necessitates rigorous standards of sterility in its handling.

Candida albicans↗

Thiopental-rocuronium versus ketamine-rocuronium for rapid-sequence intubation in parturients undergoing cesarean section.

We investigated the neuromuscular effects and conditions of tracheal intubation after administration of rocuronium in 40 parturients undergoing elective cesarean section. After preoxygenation, anesthesia was induced in 20 patients by thiopental 4 mg/kg and, in the other 20 patients, by ketamine 1.5 mg/kg. Rocuronium 0.6 mg/kg was then administered, and neuromuscular transmission was assessed using electromyographic response to train-of-four stimulation of the ulnar nerve at the wrist every 10 s. The time to T1/control ratio of 50% neuromuscular block (NMB) as well as the time to maximum NMB (onset time) were compared in the two groups. The time to 50% block was 45 +/- 10 s in the thiopental group and 42 +/- 14 s in the ketamine group, while the onset time was 105 +/- 35 s in the thiopental group and 101 +/- 35 s in the ketamine group. Neither the time to 50% NMB nor the onset time were significantly different between the two groups. Tracheal intubation at 50% NMB was easily performed in all patients in the ketamine-rocuronium group but was difficult in 75% of the thiopental-rocuronium group. We concluded that ketamine 1.5 mg/kg followed by rocuronium 0.6 mg/kg may be suitable for rapid-sequence induction of anesthesia in parturients undergoing cesarean section.

Adult↗

Part I: propofol, thiopental, sevoflurane, and isoflurane-A randomized, controlled trial of effectiveness.

UNLABELLED: When compared with thiopental and isoflurane, propofol and sevoflurane are associated with a faster return to wakefulness after anesthesia. Yet their wider usage in inpatient surgery has been restrained by concerns regarding their acquisition costs and by lack of studies demonstrating improved patient outcome. We randomly allocated 453 adult surgical inpatients to one of four anesthetic regimens (thiopental-isoflurane, propofol-isoflurane, propofol induction and maintenance, or sevoflurane induction and maintenance) and measured their rate and quality of recovery. We found no significant differences in the rate and quality of recovery between groups. Propofol was associated with more pain on injection (P: < 0. 0005), but less cough during induction (P: = 0.003), and less early postoperative nausea and vomiting (P: = 0.003). We could not detect any significant advantages with propofol and sevoflurane, when compared with thiopental and isoflurane in adults undergoing elective inpatient surgery. IMPLICATIONS: Propofol and sevoflurane do not offer any significant advantages over thiopental and isoflurane in adults undergoing elective inpatient surgery.

Adult↗

Limbic neuronal firing rates in man during administration of nitrous oxide--oxygen or sodium thiopental.

Electroencephalographic activity and extracellular discharges from neurons in deep temporal lobe structures were recorded from fine wire microelectrodes chronically implanted in seven psychomotor epileptic patients for diagnostic localization of seizure foci. In four patients, inhalation of 80 per cent nitrous oxide resulted in loss of consciousness without change in firing rates of temporal lobe neurons (n = 22). In all seven patients, thiopental (400 or 200 mg, iv) decreased limbic neuronal firing rates (n = 38) until the return of wakefulness. In only three of these patients, however, did the firing rates of the neurons (n = 19) decrease significantly (P less than .05). Thiopental suppression of unit activity was not related to systemic hypoxia. This study demonstrates that anesthetic induction with nitrous oxide-oxygen does not significantly affect the firing of neurons in various regions of the human limbic system, which may explain the incidence of patient awareness reported when nitrous oxide-oxygen is administered alone. Thiopental depresses the firing of limbic neurons, and this may account in part for the temporary confusion and amnesia often manifested by patients recovering from the effects of thiopental.

Adolescent↗

Hypoxic ventilatory drive in dogs during thiopental, ketamine, or pentobarbital anesthesia.

The ventilatory responses to isocapnic hypoxia and hypercapnia were studied in seven chronically tracheostomized dogs awake and during anesthesia with pentobarbital (30 mg/kg, iv), ketamine, or thiopental (10 and 15 mg/kg, respectively, followed by infusion). Isocapnic hypoxic ventilatory drive (HVD) was expressed as the parameter A such that the higher the A, the greater the hypoxic drive. HVD(A) was significantly reduced from 259 +/- 28 (mean +/- SEM) in awake dogs, to 96 +/- 14 after pentobarbital, 161 +/- 27 after thiopental, and 213 +/- 23 after ketamine. Hypercapnic ventilatory drive (HCVD) as measured by S (slope of the VE-PACO2 response curve) was significantly reduced from 1.3 +/- .32 in awake dogs to 0.4 +/- .13 after pentobarbital, 0.5 +/- .12 after thiopental, and 0.6 +/- .11 after ketamine. In addition, hypercapnia-induced augmentation of hypoxic drive was markedly diminished by the two barbiturates but was unaffected by ketamine. Therefore, ketamine at this dose level afforded greater protection during exposure to hypoxia than did barbiturates. (Key words: Ventilation, hypoxic response; Hypoxia, ventilation; Oxygen, ventilatory response; Carbon dioxide, ventilatory response; Anesthetics, intravenous, ketamine; Anesthetics, intravenous, thiopental; Hypnotics, barbiturates, pentobarbital.)

Anesthesia, Intravenous↗

Effects of halothane, thiopental, and lidocaine on fluidity of synaptic plasma membranes and artificial phospholipid membranes.

The effects of halothane, thiopental, and lidocaine were studied with spin-labeling methods in synaptic plasma membranes (order parameter) and artificial phospholipid membranes (lateral diffusion). Halothane had a biphasic action, low concentrations (0.64 mM) ordering and high concentrations (2.9 mM) fluidizing both types of membranes. A biphasic effect in phospholipid membranes was also seen with thiopental, 0.1 mM ordering and 10 mM fluidizing, whereas in synaptic plasma membranes both low and high concentrations caused an increased order in the lipid bilayer region. At high thiopental concentrations, a considerable number of molecules may have reacted with membrane proteins or accumulated in the highly fluidic hydrophobic interior region of the membrane without affecting the rotational movement of the labeled fatty acid. Lidocaine alone, or together with calcium chloride, at various concentrations to 10 mM had no significant effect, and a fluidizing effect of 1 mM calcium chloride was possibly a result of interaction of calcium chloride with the label. The results indicate that the three lipid-soluble anesthetics interact differently with the lipid part of membranes. Lidocaine did not seem to affect bilyer lipids, while thiopental and halothane in phospholipid vesicles and halothane alone in synaptic membranes caused a dose-dependent biphasic effect.

Anesthesia, Inhalation↗

Time course of ventilatory depression after thiopental and midazolam in normal subjects and in patients with chronic obstructive pulmonary disease.

Using a dual isohypercapnic technique, the authors compared the effect on ventilatory control of midazolam (0.2 mg/kg) and thiopental (3.5 mg/kg) in normal volunteers and in subjects with chronic obstructive pulmonary disease (COPD). In normal volunteers the slope of the CO2 response curve decreased from 1.77 +/- 0.16 l . min-1 . mmHg-1 (mean +/- SEM) to a minimum of 1.14 +/- 0.17 l . min-1 . mmHg-1 3.5 min after midazolam, returning to 1.32 +/- 0.21 l . min-1 . mmHg-1 15 min after injection. In the same subjects, the slope of the CO2 response curve fell from 1.89 +/- 0.18 l . min-1 . mmHg-1 to a minimum of 1.37 +/- 0.29 l . min-1 . mmHg-1 one minute after injection of thiopental, returning to 1.69 +/- 0.22 l . min-1 . mmHg-1 15 min after injection. These changes were not statistically significant. In subjects with clinical COPD, the slope of the CO2 response curve decreased from 1.89 +/- 0.63 l . min-1 . mmHg-1 to a minimum of 0.39 +/- 0.19 l . min-1 . mmHg-1 two minutes after injection of midazolam (P less than 0.05 compared with control), while 15 min after injection, the slope recovered to only 0.62 +/- 0.40 l . min-1 . mmHg-1 (P less than 0.05 compared with control). In the same subjects, the slope of the CO2 response curve decreased from 1.53 +/- 0.17 to a minimum of 0.69 +/- 0.25 l . min-1 . mmHg-1 0.5 min after injection of thiopental, recovering to 1.47 +/- 0.28 l . min-1 . mmHg-1 15 min after injection. This was significantly greater than the corresponding slope after midazolam (P less than 0.05). The authors conclude that while the time course of ventilatory depression after thiopental is similar in normal volunteers and in patients with COPD, the ventilatory depression 15 minutes after midazolam is more profound in patients with COPD than in normal subjects.

Anesthetics↗