Biomedical subjects

M J Laster

Publications and source records attributed to M J Laster.

At least 55 records · Page 3Linked to original sources

PubMed1995

Nephrotoxicity in rats undergoing a one-hour exposure to compound A.

We previously demonstrated that rats experienced renal injury when exposed for 3-12 h to 50 ppm or more of a vinyl ether called Compound A [CF2 = C(CF3)OCH2F], a compound produced by CO2 absorbents acting on sevoflurane. These durations of exposure exceed the average duration of clinical anesthesia. We now report the effect of a 1-h exposure to 0, 100, 150, 200, 400, 600, or 800 ppm of Compound A in oxygen in 145 Wistar rats. Twenty-four hours after exposure, we obtained kidney and liver specimens for microscopic examination, applying hematoxylin and eosin, and (separately) an immunochemical marker (PCNA) for cell proliferation (regeneration). Compared with results from control rats (those breathing oxygen for 1 h), renal injury (defined as necrosis of the outer strip of the outer medullary layer or "corticomedullary junction necrosis") occurred at and above 200 ppm. Exposure to 150 ppm produced cell regeneration (i.e., stimulated cell proliferation). We conclude that the threshold concentrations for nephrotoxicity (i.e., minimal toxicity) for a 1-h exposure to Compound A exceed the maximum concentrations (particularly those at low inflow rates) reported in clinical practice by a factor of 2-3. If these threshold effects in rats apply to humans, one 1-h exposure to sevoflurane probably would not alter usual measures of renal function.

Animals↗

PubMed1994

Toxicity of compound A in rats. Effect of a 3-hour administration.

BACKGROUND: Soda lime converts sevoflurane to CF2 = C(CF3)OCH2F, an olefin called compound A, whose toxicity raises concerns regarding the safe administration of sevoflurane via rebreathing circuits. The present report extends the findings of a previous investigation by others of the toxicity of this olefin, and establishes concentration-response relationships for such toxicity. METHODS: Eighteen groups of ten Wistar rats breathed 0, 25, 50, 100, 200, 300, 350, and 400 ppm of the olefin in oxygen for 3 h. The olefin concentrations were developed in a square-wave manner by injection of saturated vapor followed by a continuous delivery of dilute vapor. The lethal concentration in 50% (LC50) of animals was estimated by logistic regression. Rats were killed on day 1 or day 4 after breathing the olefin, and specimens of brain, kidney, lung, liver, and small intestine were obtained from all rats for examination using light microscopy. RESULTS: The LC50 equaled 331 ppm (95% confidence limits +/- 13 ppm). No injury resulted to lung or small intestine in either the experimental or the control group (those breathing only oxygen for 3 h). Renal injury (necrosis of the outer strip of the outer medulla, defined in this report as corticomedullary tubular necrosis) occurred at 50 ppm and greater; hepatic injury at 350 ppm and greater; and cerebral injury only at 400 ppm. CONCLUSIONS: The lethal concentration and the threshold for toxicity of the olefin are less than previously reported. The threshold for nephrotoxicity reaches the range of values for the olefin that have been attained in clinical practice. Further studies are required to determine whether these results in rats can be extrapolated to patients.

Anesthetics↗

PubMed1994

Toxicity of compound A in rats. Effect of increasing duration of administration.

BACKGROUND: An olefin called compound A (CF2 = C(CF3)OCH2F) results from the action of soda lime or Baralyme on sevoflurane. We have demonstrated that rats exposed to the olefin for 3 h died at or were injured by olefin concentrations lower than those previously reported to produce these effects. The present report examines the impact of duration of exposure to the olefin on such effects. METHODS: Twenty-three groups of ten Wistar rats breathed 0, 12.5, 25, 50, 75, 100, 125, 150, 175, 200, 225, and 250 ppm of the olefin in oxygen for 6 or 12 h. Rats that survived were killed on day 1 or day 4 after breathing the olefin, and specimens of brain, kidney, lung, liver, and small intestine were obtained from all rats for examination by microscopy using hematoxylin and eosin stain and a stain (proliferating cell nuclear antigen) for cell growth (regeneration). RESULTS: The lethal concentrations in 50% of rats equaled 203 +/- 4 ppm (mean +/- SE) for a 6-h exposure period and 127 +/- 9 ppm for a 12-h exposure period, and both values were less than the previously determined value of 331 +/- 7 ppm for a 3-h exposure period. Compared with results from control rats (those breathing oxygen for 6 h or 12 h), only renal and pulmonary injury were found. Pulmonary injury only occurred at near-lethal concentrations. Renal injury (defined as necrosis of the outer stripe of the outer medullary layer or corticomedullary junction necrosis) occurred at and above 25-50 ppm for 6-h and 12-h exposures, respectively, a result similar to that previously obtained with a 3-h exposure. Exposure to 25-50 ppm stimulated cell regeneration in a dose-related manner. CONCLUSIONS: In rats, lethal concentrations of the olefin and concentrations producing severe renal injury are inversely related to the duration of exposure to the olefin, exceeding by two- to fourfold peak concentrations that can be obtained in clinical practice. The threshold concentrations for nephrotoxicity (i.e., minimal toxicity) equal concentrations that can be produced in clinical practice. However, even if these threshold effects in rats apply to humans, they probably would not alter renal function. Although dose-related, neither the lethal nor the toxic effects are simply a function of cumulative dose (concentration-time).

Anesthetics↗

PubMed1994

Specific gravities of desflurane, enflurane, halothane, isoflurane, and sevoflurane.

We determined the specific gravities of presently available volatile anesthetics in order to supply a consistent quantitative basis for calibration standards. Using four 50-mL volumetric flasks, we obtained the following values at 20 degrees C: desflurane 1.4651 +/- 0.0004 g/mL (mean +/- SD); enflurane 1.5230 +/- 0.0003 g/mL; halothane 1.8680 +/- 0.0007 g/mL; isoflurane 1.5019 +/- 0.0006 g/mL; and sevoflurane 1.5203 +/- 0.0008 g/mL. Measurements made at 0 degree C, 10 degrees C, 20 degrees C, and 25 degrees C (not for desflurane at 25 degrees C) revealed a decrease in specific gravity of 0.00250 +/- 0.00014 g/mL for each degree of increase in temperature. These data bear on the issue of cost for anesthetics that are stored as liquids, but used as gases.

Anesthesia, Inhalation↗

PubMed1994

Pharmacokinetics do not explain the absence of an anesthetic effect of perfluoropropane or perfluoropentane.

In conflict with the prediction of the Meyer-Overton hypothesis, perfluoropropane (C3F8) and perfluoropentane (C5F12) have no anesthetic effect in rats. To test whether this resulted from a failure of the inspired drugs to reach the brain, we determined the increase in partial pressures of C3F8 and C5F12 in the blood and brains of rats exposed to 0.65 ata of each drug. C3F8 and C5F12 blood/gas partition coefficients equaled 0.00125 +/- 0.00037 (mean +/- SD, n = 9) and 0.00277 +/- 0.00082 (n = 4), and brain/gas partition coefficients equaled 0.0119 +/- 0.0002 (n = 4) and 0.0229 +/- 0.0055 (n = 7), respectively. As a fraction of the inspired value (Pa/PI), the partial pressures of C3F8 and C5F12 in blood (Pa) were 0.99 +/- 0.12 and 0.69 +/- 0.19, respectively, 30 min after administration. The increases in cerebral (Pb) partial pressures of both drugs paralleled the arterial increases (Pb/PI = 0.85 +/- 0.02, and 1.05 +/- 0.03, respectively at 30 min), with C3F8 reaching a plateau at 2 h of 96% +/- 4% of the partial pressure of inspired gas. We conclude that failure of C3F8 and C5F12 to reach the brain does not account for the absence of an anesthetic effect of these compounds.

Anesthesia, Inhalation↗

PubMed1994

A cutoff in potency exists in the perfluoroalkanes.

Anesthetic potencies (minimum alveolar anesthetic concentration [MAC]) of perfluoroalkanes from perfluoromethane to perfluorooctane were assessed in male rats to determine whether a cutoff in anesthetic effect (i.e., an absence of any anesthetic effect) exists for the larger compounds in this series. Although hyperbaric measurements suggested a MAC of 38.9 +/- 6 atm (mean +/- SD) for CF4, this pressure was nearly identical to the lethal pressure of 41.1 +/- 5.8 atm. Hyperbaric studies of C2F6 caused death without causing anesthesia, the lethal pressure being 23.8 +/- 2.6 atm. Results from studies of additivity with desflurane suggested that the MAC of CF4 was 66.5 +/- 13.4 atm at an average CF4 test partial pressure of 17.7 +/- 4.0 atm (i.e., 17.7 atm of CF4 decreased the MAC of desflurane by 26.6%). Studies of additivity with desflurane, isoflurane, or halothane did not reveal an anesthetic effect of C2F6 at a pressure of 7.2 +/- 0.4 atm, or of larger perfluoroalkanes near to or at their saturated vapor pressures. We conclude that a cutoff in anesthetic potency for perfluoroalkanes exists between perfluoromethane and perfluoroethane.

Alkanes↗

PubMed1994

Molecular properties of the "ideal" inhaled anesthetic: studies of fluorinated methanes, ethanes, propanes, and butanes.

We examined 35 unfluorinated, partially fluorinated, and perfluorinated methanes, ethanes, propanes, and butanes to define those molecular properties that best correlated with optimum solubility (low) and potency (high). Limited additional data were obtained on longer-chained alkanes. Using standard techniques, we assessed anesthetic potency (minimum alveolar anesthetic concentration [MAC] in rats); vapor pressure; stability in soda lime; and solubility in saline, human blood, and oil. If nonflammability, stability, low solubility in blood, clinically useful vapor pressures, and potency permitting delivery of high concentrations of oxygen are essential components of an anesthetic that might supplant those presently available, our data indicate that such a drug would have three or four carbon atoms with single or dual hydrogenation of two carbons, especially terminal carbons. We conclude that: 1) smaller and larger molecules and lesser hydrogenation provide insufficient potency; 2) high vapor pressures of smaller molecules do not permit the use of variable bypass vaporizers; 3) greater hydrogenation enhances flammability, and complete hydrogenation decreases potency; 4) internal hydrogenation decreases stability; and 5) greater hydrogenation increases blood solubility.

Alkanes↗

PubMed1994

Polyhalogenated and perfluorinated compounds that disobey the Meyer-Overton hypothesis.

Fourteen polyhalogenated, completely halogenated (perhalogenated), or perfluorinated compounds were examined for their anesthetic effects in rats. Anesthetic potency or minimum alveolar anesthetic concentration (MAC) was quantified using response/nonresponse to electrical stimulation of the tail as the end-point. For compounds that produced excitable behavior, and/or did not produce anesthesia when given alone, we determined MAC by additivity studies with desflurane. Nine of 14 compounds had measurable MAC values with products of MAC x oil/gas partition coefficient ranging from 3.7 to 24.8 atm. Because these products exceed that for conventional inhaled anesthetics (1.8 atm), they demonstrate a deviation from the Meyer-Overton hypothesis. Five compounds (CF3CCIFCF3, CF3CCIFCCIFCF3, perfluorocyclobutane, 1,2-dichloroperfluorocyclobutane, and 1,2-dimethylperfluorocyclobutane) had no anesthetic effect when given alone, had excitatory effects when given alone, and tended to increase the MAC for desflurane. These five compounds had no anesthetic properties in spite of their abilities to dissolve in lipids and tissues, to penetrate into the central nervous system, and to be administered at high enough partial pressures so that they should have an anesthetic effect as predicted by the Meyer-Overton hypothesis. Such compounds will be useful in identifying and differentiating anesthetic sites and mechanisms of action. Any physiologic or biophysical/biochemical change produced by conventional anesthetics and deemed important for the anesthetic state should not be produced by nonanesthetics.

Anesthetics↗

PubMed1994

Effect of n-alkane kinetics in rats on potency estimations and the Meyer-Overton hypothesis.

Neither lipophilicity nor vapor pressure of larger n-alkanes appear to correlate with their anesthetizing partial pressures in inspired gas. Such results suggest that the Meyer-Overton hypothesis and Ferguson's rule may not apply to these compounds. An alternative explanation might be that a large difference in inspired-to-arterial partial pressure exists, i.e., that the inspired partial pressure misrepresents the effective partial pressure. To test this explanation, we investigated the kinetics of five consecutive even-numbered n-alkanes (C2H6 to C10H22) in rats. The ratio of end-tidal-to-inspired (PA/PI), arterial-to-end-tidal (Pa/PA), and arterial-to-inspired (Pa/PI) partial pressures decreased with increasing carbon chain length, consistent with our separate finding that blood solubility increased. Using Pa/PI and the minimum inspired concentration (MIC) obtained previously, we calculated the true effective potency, minimum alveolar anesthetic concentration (MAC); of these n-alkanes as (Pa/PI)(MIC). This markedly improved, but did not perfectly correct, the correlation of MAC with lipid solubility (the Meyer-Overton hypothesis) and vapor pressure (Ferguson's rule). A coefficient of variation of 76.7% was found for the product of MAC and the olive oil/gas partition coefficient. More importantly, the correlation of the logarithm of MAC and oil solubility had a slope of -0.724 (i.e., deviated from -1.0), whereas the slope for eight conventional anesthetics was -1.046 (approached-1.0). These data imply that olive oil does not adequately mimic the nature of the anesthetic site of action of n-alkanes.

Alkanes↗

PubMed1993

Anaesthetic properties of dimethylthiourea.

We have examined dimethylthiourea, a potent scavenger of free radicals, for its anaesthetic properties in mice and rats. In mice, dimethylthiourea abolished the righting reflex at intraperitoneal doses greater than 1.5 mg g-1 bodyweight; in rats, it decreased the MAC value for isoflurane in a dose-dependent fashion. Dimethylthiourea 0.5 g kg-1 decreased isoflurane MAC by 23%; at a dose of 2.0-4.0 g kg-1, it abolished the response to tail clamp. Doses of 4.0 g kg-1 were lethal in the presence of isoflurane. A serum concentration of dimethylthiourea approximately 1 mg ml-1 produced a 50% reduction in isoflurane MAC. These anaesthetic properties of dimethylthiourea may influence experimental studies that examine the biochemical and physiological properties of this agent.

Anesthesia, General↗

PubMed1993

Anesthesia by n-alkanes not consistent with the Meyer-Overton hypothesis: determinations of the solubilities of alkanes in saline and various lipids.

Because deviations from the Meyer-Overton rule may provide insights into the attributes of the anesthetic site of action, we characterized the solubility of the n-alkanes in various hydrophobic solvents (n-tetradecane, olive oil, n-octanol, and lecithin) as well as saline using variations on standard techniques. Increasing alkane chain length correlated with a decrease in solubility in saline and an increase in solubility in the hydrophobic solvents. The product of solubility in the hydrophobic solvents x the partial pressure (in atmospheres) required to produce anesthesia (i.e., the Meyer-Overton rule) did not produce a constant for any one of these solvents. The means and standard deviations for the products were: tetradecane, 65 +/- 103; olive oil, 33 +/- 63; n-octanol, 64 +/- 129; and lecithin, 16 +/- 26. Thus, our data suggest that the n-alkanes (especially those longer than n-heptane) do not follow the Meyer-Overton rule.

Alkanes↗

PubMed1993

Is there a cutoff in anesthetic potency for the normal alkanes?

Vapor pressures and anesthetizing partial pressures in rats were measured for 10 consecutive normal alkanes, methane through decane. All produced anesthesia as defined by the absence of movement in response to either the application of a tail-clamp or electrical stimulation of the tail. The anesthetizing partial pressure was calculated as the average between the concentrations just permitting and preventing movement. Although nonane and decane did not provide anesthesia when given alone at their saturated vapor pressures, their anesthetic properties could be demonstrated by their ability to decrease the anesthetic requirement for isoflurane (i.e., their anesthetic potencies could be defined by studies of additivity). Anesthetic potency increased (from 9.9 atm for methane to 0.0142 atm for decane) and vapor pressure decreased (from 38.2 atm for ethane to 0.0028 atm for decane) with increasing chain length. The decrease in vapor pressure far exceeded the increase in potency. For nonane and decane, the ratio of the partial pressure required for anesthesia to the saturated vapor pressure was less than 1, being 0.48 and 0.19, respectively. We conclude that no cutoff phenomenon (i.e., no absence of anesthetic effect with longer chain alkanes) exists from n-methane to n-decane, but that larger alkanes have vapor pressures too low to permit their potency to be evident when given alone.

Alkanes↗

PubMed1993

Electrical stimulation as a substitute for the tail clamp in the determination of minimum alveolar concentration.

Circumstances may preclude the use of standard stimuli, namely tail clamp or surgical incision, to determine minimum alveolar concentration. In rats anesthesized with isoflurane, an alternative stimulus, electrical currents (10, 15, 20, or 40 V; biphasic pulses of 6.5 ms duration; 50 Hz), gave results comparable to those obtained with the tail clamp and the results did not change with repeated measurements if care was taken to avoid desensitization by exhaustion of a particular set of electrodes. The 40 V stimulation gave slightly higher values (4%; P < 0.006) than tail clamp, but the difference was too small to be of experimental significance. More importantly, the higher voltages produced desensitization after fewer attempts at stimulation. In addition to these results with isoflurane, we found that 15 V stimulation and tail clamp produced comparable minimum alveolar concentration values for halothane and for desflurane.

Anesthesia, Inhalation↗

PubMed1992

No correlation between quantitative electroencephalographic measurements and movement response to noxious stimuli during isoflurane anesthesia in rats.

A meaningful use of the electroencephalogram (EEG) for monitoring depth of anesthesia has proven elusive. Although changes in the EEG with changing anesthetic dose or concentration have been noted for 60 yr, it has been difficult to demonstrate reliable, quantitative correlation between the EEG and other physiologic measures of anesthetic depth. We attempted to correlate several quantitative EEG measurements in rats, including average amplitude, spectral edge frequency, and burst suppression ratio, with the movement response to supramaximal noxious stimulation. We anesthetized 21 Sprague-Dawley rats with isoflurane 1.5% and allowed them to breathe spontaneously. After equilibration, EEG was recorded for off-line analysis; then a noxious stimulation was delivered with a tail clamp and the somatic response noted. Isoflurane concentration was adjusted up and down, and the EEG and movement response to tail clamp were assessed at each level until the minimum alveolar concentration was determined in each rat. We found no EEG dose response to increasing inspired concentrations of isoflurane, except for an increasing degree of burst suppression. We found no difference in any parameter between rats that responded and those that did not respond to stimuli at a given concentration of isoflurane. Finally, we found that the presence of burst suppression did not predict lack of response.

Anesthesia, Inhalation↗

PubMed1991

The neuromuscular effects of desflurane, alone and combined with pancuronium or succinylcholine in humans.

The neuromuscular effects of desflurane administered alone were studied in ten healthy human volunteers aged 20-27 yr. Also, the dose-response relationships of pancuronium and succinylcholine in surgical patients during anesthesia with desflurane (n = 13) were compared to those during isoflurane anesthesia (n = 14). In the volunteers, we measured the mechanical response of the adductor pollicis muscle to stimulation of the ulnar nerve in a train-of-four (TOF) sequence at 2 Hz and at tetanic frequencies of 50, 100, and 200 Hz, each administered for 5 s. Amplitudes of the first response (T1) in each TOF sequence and the ratios of the fourth TOF response (T4) to the first were similar at 3, 6, and 9% desflurane and decreased significantly only at 12% (P less than 0.05). Desflurane concentrations of 3-12% caused tetanic fade (greater than 10% decrement in amplitude) at 50, 100, and 200 Hz. The addition of N2O and the duration of anesthetic exposure did not alter desflurane's neuromuscular effects. The only neuromuscular variable influenced by CO2 was T1 amplitude, which decreased as arterial CO2 tension (PaCO2) increased. The doses of pancuronium that depressed T1 amplitude by 50% (ED50) were similar during anesthesia with 1.25 MAC desflurane, 10.5 +/- 2.8 micrograms/kg (mean +/- SD) and 1.25 MAC isoflurane, 12.3 +/- 5.0 micrograms/kg. The ED50 doses of succinylcholine were similar during anesthesia with desflurane 132 +/- 76 micrograms/kg and isoflurane 123 +/- 36 micrograms/kg. We conclude that desflurane significantly depresses neuromuscular function and augments the action of pancuronium and succinylcholine to a degree similar to that of isoflurane.

Adult↗

PubMed1991

What solvent best represents the site of action of inhaled anesthetics in humans, rats, and dogs?

The correlation between the potency of inhaled anesthetics and their solubility in a hydrophobic phase provides an opportunity to define better the characteristics of the anesthetic site of action. The correlation implies that inhaled anesthetics act in a hydrophobic site and that the solvent used has properties representative of the true site of anesthetic action. We sought to characterize this site more accurately by testing for the solvent that provided the best correlation for a diverse group of anesthetics. We determined the solubility of halothane, enflurane, cyclopropane, fluroxene, isoflurane, sevoflurane, and desflurane in benzene, olive oil, Intralipid, n-octanol, and lecithin. We used established MAC values for rats, dogs, and humans for all but sevoflurane and desflurane, for which we determined MAC in rats to be 2.80% +/- 0.24% (mean +/- standard deviation) and 7.71% +/- 0.65%, respectively. Lecithin gave the lowest coefficient of variation for the product of potency (MAC) x solubility, but the difference was statistically significant only for a comparison of the products for lecithin and olive oil. The values for lecithin were within the range of values produced by biological variation. More important, the correlation of log MAC and log solubility had an average slope of unity (-1.04 +/- 0.07) for lecithin, but a slope differing from unity for benzene (-0.82 +/- 0.05) and olive oil (-0.87 +/- 0.05). We conclude that lecithin is probably more representative of the site of action of these anesthetics than the other solvents.

Anesthesia, Inhalation↗

PubMed1991

Absorption and degradation of sevoflurane and isoflurane in a conventional anesthetic circuit.

Soda lime and Baralyme degrade sevoflurane, the rate of degradation being a direct function of temperature. We tested whether this degradation would impede the development of an anesthetizing concentration of sevoflurane (compared with isoflurane, a compound that is not degraded) in a circle-absorption system having an increased temperature consequent to (a) carbon dioxide production (200 mL/min) and absorption; and (b) a low inflow rate (70 mL/min). We also measured the temperatures reached in various parts of the absorption system when used in clinical practice, finding that peak temperatures usually reached 37 degrees - 46 degrees C when low inflow rates (500 mL/min) were applied. The tests in the model system demonstrated that soda lime and Baralyme absorbed both sevoflurane and isoflurane, and that both absorbants degraded sevoflurane but not isoflurane. Baralyme produced a fourfold greater degradation of sevoflurane vapor than did soda lime (0.66 mL/min compared with 0.17 mL/min). However, except for a slight delay at the start of anesthesia, neither absorption nor degradation should noticeably affect the requirement for anesthetic delivery in clinical practice, even in low-flow systems.

Absorption↗

PubMed1991

Visceral losses of desflurane, isoflurane, and halothane in swine.

Percutaneous loss of inhaled anesthetics is small relative to their uptake. The minor nature of this loss results in part from the substantial barrier to diffusion posed by the skin. Pleural and peritoneal surfaces pose less effective barriers because diffusion distances are smaller than in the skin. Accordingly, we measured visceral loss to air of desflurane, isoflurane, and halothane from pleural and peritoneal surfaces in five juvenile swine. Pleural and peritoneal losses per percent end-tidal anesthetic correlated directly with the solubility of the anesthetic in blood or tissues. The total pleural losses for the first 30 min of anesthetic administration were desflurane, 1.22 +/- 0.22 mL (mean +/- standard deviation for the 30-min period); isoflurane, 2.34 +/- 0.52 mL; and halothane, 4.69 +/- 0.98 mL; respective peritoneal losses were 0.64 +/- 0.12 mL, 1.23 +/- 0.25 mL, and 2.69 +/- 0.57 mL. Pleural loss per unit time did not change with increasing duration of anesthesia, whereas peritoneal loss increased for all anesthetics. These visceral losses are greater than total percutaneous losses in humans given these anesthetics for the same period of time, but the loss of anesthetic by either route is too small to affect measurements of anesthetic kinetics or recovery.

Administration, Inhalation↗