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In each of 14 patients, two small but comparable psoriatic lesions were infused for 2 weeks with either saline or a saline solution of peptide T (as its analog D-ala1-peptide T amide) at 10(-7) mol/L with Alzet osmotic pumps worn extracorporeally. During infusion, lesions were photographed and scored for clinical features of psoriasis on a 9-point scale. After another 7 days, biopsy specimens were taken from the infused sites, and sections were scored for features of psoriasis on a 19-point scale. The differences between means for data from saline- and peptide T-infused lesions were evaluated statistically. Peptide T-infused lesions improved clinically; scores decreased from a mean of 4.35 initially to 1.57 at biopsy, whereas control lesions changed from 4.43 to 3.57 (p less than 0.01 for 1.57 vs 3.57). Histologic scores were also significantly different (5.28 for peptide T vs 10.00 for controls, 0.05 greater than p greater than 0.02). This study provides evidence that intralesionally infused peptide T demonstrates some clearing effect in psoriasis.

A multiple logistic regression analysis of 12,914 pregnancies and 10,523 live births, based on a mail survey of professional women in medicine, was carried out to determine the relationship between maternal cigarette smoking, and spontaneous abortion and congenital abnormality. After controlling for interfering variables (age, exposure to trace anesthetic gases, pregnancy history, and mailing response), a statistically significant increase in risk associated with maternal cigarette smoking was found for spontaneous abortions and congenital abnormalities. The risk of spontaneous abortion for the heavy smoker is estimated to be as much as 1.7 times that of the nonsmoker in certain risk groups. The risk for congenital abnormality for babies born of smoking mothers is estimated to be as much as 2.3 times that of the nonsmoker, depending on age, pregnancy history, and other factors.In an effort to determine the relationship between maternal cigarette smoking, and spontaneous abortion and congenital abnormality, a multiple logistic regression analysis of 12,914 pregnancies and 10,523 live births, based on a mail survey of professional women in medicine, was conducted. The multiple logistic regression model, with certain interactions, appears to fit the spontaneous abortion and abnormality data well. The model provides an efficient method for adjusting for many variables, and on the basis of this approach, the following conclusions are drawn: 1) the survey data provide statistically significant indication that the risk of spontaneous abortion is substantially higher for women who smoke during pregnancy; 2) an analysis of the congenital abnormality data shows a statistically significant risk associated with maternal smoking - the relative risk ranges from 0.8 to 2.3 times that of the non-smoker, depending on age, previous pregnancy history, and exposure to the operating room. Despite the fact that the findings are retrospective survey data, obtained by mail and subject to variation in response due to the experience and background of the participant, the study confirms previous reports indicating that smoking is positively correlated with spontaneous abortion and provides evidence of a large increase in the risk of congenital abnormalities for the child born of a smoking mother.

The application of 136 atm of helium pressure to suspensions of mixed dipalmitoyl-dimyristoylphosphatidylcholine bilayers caused a 3–5°C elevation of points on the envelope of the binary phase diagram. Membrane bilayers containing lateral phase separations are able to respond to external pressure by converting fluid phase phospholipids to the more compact gel phase.

Previous studies have shown that high pressures increase the twitch tension of directly or indirectly stimulated mammalian muscle, while depressing transmission at the neuromuscular junction. The present paper explores the interaction between high pressures and muscle relaxants on the indirectly stimulated rat phrenic nerve--diaphragm preparation. Two muscle relaxants, d-tubocurarine and succinylcholine, were studied. Measurements of the electromyogram and twitch tension amplitudes were made before and after application of the muscle relaxants and compared with results of measurements of those two variables under hyperbaric conditions. High pressures tended to enhance neuromuscular blockade by d-tubocurarine more than that by succinylcholine, as indicated by electromyographic suppression, and high pressures tended to antagonize the succinylcholine effect on twitch tension more than that of d-tubocurarine. The findings are in agreement with previous observations that high pressures increase muscular twitch tension and depress excitatory synapses. They further demonstrate a complex interaction between hyperbaric pressures and neuromuscular blocking drugs.

Inert gases at high pressure may compress and dissolve in tissue of intact organism to result in narcosis, reversal of the effects of anesthetic agents or hyperexcitability. The effects of 51 and 102 atm of helium, hydrogen, nitrogen, argon, xenon and nitrous oxide on the molecular motion of nitroxide spin-labeled phospholipid-cholesterol bilayers were measured by electron paramagnetic resonance (EPR) techniques. Immediately, application of high pressures of all gases decreased the molecular motion of the fatty acid chains of the membrane phospholipids; the magnitude of ordering was linearly related to the amount of pressure applied. The second effect was an increase in molecular motion of the fatty acid chains which appeared more slowly due to the slow gas diffusion through the column of lipid dispersion. The magnitude of disorder of the phospholipid membrane at equilibrium correlated with the known lipid solubilities of the gases in olive oil as well as with the anesthetic potency of all the gases except xenon. The environment of the spin label became less polar as the gases diffused into the bilayer. The present studies in the phospholipid model membrane show that the net effects of high pressure gases in the lipid phase consist of an initial ordering of the membrane by compression opposed by the ability of the gas molecules to diffuse and dissolve in the lipid bilayers and disorder them. It is thus suggested that the resultant perturbations of the membrane lipid fluidity by high pressure gases may subsequently be transmitted to membrane-bound protein to result in changes that may be associated, in part, with the diverse effects of anesthesia and of the high pressure nervous syndrome (HPNS) observed in deep-sea divers. The model system may be useful in developing gas mixtures which minimize HPNS.

The depth of local anesthetic-induced conduction block is modified by the frequency of impulse traffic in the nerve (frequency-dependent conduction block). The present study was designed to compare the frequency-dependent characteristics of a number of local anesthetics of different lipid solubiliti

The presence of two volatile halothane metabolites, 2-chloro-1,1,1-trifluoroethane (CF3CH2Cl) and 2-chloro-1,1-difluoroethylene (CF2CHCl), and a metabolite-decomposition product, 2-bromo-2-chloro-1,1-difluoroethylene (CF2CBrCl), were identified by gas chromatography-mass spectrometry in exhaled gases of 16 patients anesthetized with halothane in nonrebreathing, semiclosed and totally closed anesthesia circuits. No significant differences in concentrations of CF3CH2Cl and CF2CHCl were found relative to the anesthesia circuits used. CF2CBrCl could not be identified in the expired gases of patients anesthetized with a nonrebreathing circuit (Bain), but was present in gases recovered from both semiclosed and totally closed circuits. Under totally closed-circuit rebreathing conditions, the concentration of CF2CBrCl increased to 4-5 ppm, indicating significant breakdown of halothane by the soda lime. Possible pathways for formation of the two metabolites and the metabolite-decomposition product are presented, as well as clinical implications of these findings.

A mail survey of 30,650 dentists and 30,547 chairside assistants grouped according to occupational exposure to inhalation anesthetic and sedatives in the dental operatory indicated increased general health problems and reproductive difficulties among respondents exposed to anesthetics. For male dentists who were heavily exposed to anesthetics, the increase in liver disease was 1.7-fold, kidney disease was 1.2-fold, and neurological disease was 1.9-fold. For wives of male dentists who were heavily exposed to anesthetics, the increase in spontaneous abortion rate was 1.5-fold. Among female chairside assistants who were heavily exposed to anesthetics, the increase in liver disease was 1.6-fold, kidney disease was 1.7-fold, and neurological disease was 2.8-fold. The increase in spontaneous abortion rate among assistants who were heavily exposed was 2.3-fold. Cancer rates in women heavily exposed to inhalation anesthetics were increased 1.5-fold but this finding was not statistically significant (P = .06). Separate analysis of the data for disease rates and birth difficulties by type of inhalation anesthetic indicates that in both dentists and chairside assistants chronic exposure to nitrous oxide alone is associated with an increase rate of adverse response.

The order parameter (S′n) of spin-labeled phosphatidylcholine vesicles has been shown to decrease in a concentration-dependent manner with two inhalation anesthetics, halothane and methoxyfluorane. Similar decreases ofS′n are observed in vesicles labeled adjacent to the polar head group and those labeled near the bilayer center. This suggests that inhalation anesthetics cause a generalized fluidization of the membrane rather than a disorder localized in a particular region of the bilayer. Measurements of the isotropic nitrogen hyperfine coupling constant (a′N) show a decrease in polarity of the environment with increasing anesthetic concentrations. The experimental approach of plottingS′n versus anesthetic concentration provides a test of whether anesthetics produce their effects on a per molecule or per volume basis.

Summary The effects of anesthetics in luminous bacteria, newts, tadpoles. and mice are reversed by application of 150-200 atm of helium or hydrostatic pressure. The disorder induced by the inhalation anesthetic halothane in spin-labeled phospholipid vesicles is also reversed by similar pressures of helium. If pressure reversal of anesthesia occurs in intact nerve systems. then all theories of anesthesia must accommodate the phenomenon and nerve membrane model systems demonstrate it as well. The occurrence of pressure reversal in spin-labeled phospholipid vesicles supports their use as models for the hydrophobic region of nerve membranes and suggests that the primary site of pressure reversal is in the lipid phase of the nerve membrane. This finding is in agreement with the theory that anesthetics act by disordering the lipid region of the membranes.

The distribution of volatile anesthetics in the monkey brain was studied with the technique of low-temperature autoradiography, using 14C-labeled halothane, chloroform, diethyl ether, and ethylene. Animals were sacrificed 2, 5, and 20 minutes after administration of the anesthetic. Autoradiographs were prepared from coronal sections of the brain. Results indicate that the early distribution of anesthetics to the gray matter and nuclei is determined primarily by circulatory factors, while the later distribution to the white matter more closely correlates with lipid content, although many exceptions were found. Of particular interest is the high concentration of anesthetic within the reticular formation.

Autoradiographic studies of the spinal cord in the dog indicate a specific uptake of C-Iabelled lidocaine and procaine by the neuraxis. The highest concentrations of the intrathecally-adminis-tered drug were found in the posterior and lateral columns, with only small concentrations noted in the anterior columns. Uptake of drug was higher in the grey matter than in the white matter of the cord, and posterior nerve roots had a higher concentration than anterior roots. Biopsies of the cord and scintillation counting of the weighed specimens provided confirmation of the autoradiographic studies. The significance of these findings is discussed, and possible explanations arc considered.

Evidence for tachyphylaxis to the local anesthetic agents lidocaine and mepivacaine has been found in a study of continuous caudal anesthesia in obstetrical patients. Seduced response to these drugs is shown to be independent of the increasing pain of labor. An experimental study of tachyphylaxis in the dog was undertaken, utilizing 14C-lidocaine and 24C-procaine administered by a continuous spinal technique. Repeated injections of the acid anesthetic salt were associated with continued decreases in pH of the cerebrospinal fluid and proportionate increases in the concentration of local anesthetic- Calculations of the percentages of the free base form (lipid-soluble) indicated significant shifts with minor changes in pH. It is suggested that tachyphylaxis to local anesthetic agents may be associated with changes in pH and shifts in the amounts of ionized and nonionized forms. The limited buffer reserve available in the cerebrospinal fluid (and presumably, the extradural space) makes these areas especially vulnerable.

A study of the chemistry, uptake and distribution, and toxicology of dichlorohexafluorobutene (DCHFB) was undertaken in the experimental animal with additional studies of uptake being carried out in man. DCHFB is a trace contaminant in halothane manufactured by high thermal synthesis and can develop significant increases in concentration during the clinical administration of halothane. Toxicity studies in the rat, dog, and monkey show variable pathologic change with primary involvement of the central nervous system, lungs, and liver. In the former species the LD50 is only five to ten fold that concentration of DCHFB vaporized during the clinical administration of halothane. Studies in man demonstrate alveolar uptake and indicate its presumed metabolism. Studies in the monkey incriminate the liver as a site of metabolism. Recommendations for its removal are made.

As many as 2% of all pregnant women undergo surgery during gestation, but there are few reports of the effects of anesthesia and surgery on fetal outcome. The present paper presents information on 287 women who had surgery during pregnancy. Surgery during early pregnancy was associated with a significant increase in the rate of spontaneous abortion compared to the rate in a control group that did not have surgery. There were no differences in the incidence of congenital abnormalities in this offspring of women who had surgery during early pregnancy. The data suggest that elective surgery be deferred during early pregnancy to minimize potential fetal loss.

Semen samples were collected from 46 anesthesiologists each of whom had worked a minimum of one year in hospital operating rooms ventilated with modern gas-scavenging devices. Samples collected from 26 beginning residents in anesthesiology served as controls. Concentrations of sperm and percentages of sperm having abnormal head shapes were determined for each sample. No significant differences were found between anesthesiologists and beginning residents. Limiting the analyses to men having no confounding factors (varicocele, recent illness, medications, heavy smoking, frequent sauna use) did not change the results. The sperm concentration and morphology in 13 men did not change significantly after one year of exposure to anesthetic gases. However, the group of mean who had one or more confounding factors (excluding exposure to anesthetic gases) showed significantly higher percentages of sperm abnormalities than did the group of men without such factors. These results suggest that limited exposure to anesthetic gases does not significantly affect sperm production as judged by changes in sperm concentration and morphology. These data are reassuring, but since the hospitals surveyed used modern gas-scavenging devices, men who are occupationally exposed to anesthetic gases without this protection should be studied for fuller assessment of the possible human spermatotoxic effects.

Although once considered completely devoid of complications, it is now recognised that the misuse or inappropriate use of nitrous oxide (N2O) often results in adverse side effects. Hypoxia, particularly the entity 'diffusion hypoxia', can occur with the administration of inadequate amounts of oxygen during or immediately after a N2O anaesthetic. N2O will diffuse into air-containing cavities within the body faster than nitrogen diffuses out. This results in a temporary increase in either the pressure and/or volume of the cavity depending upon the distensibility of its walls. The magnitude of the effect is proportional to the blood supply of the cavity, the concentration of N2O inhaled and the length of time the patient is exposed to N2O. Significant morbidity or even death can result from this phenomenon. A property unique to N2O is its ability to oxidise and inactivate the vitamin B12 components of certain enzymes in both animals and man. One such enzyme, methionine synthetase is essential for normal DNA production. Animal and human studies have demonstrated that the haematological, immune, neurological and reproductive systems are each affected. These adverse effects of N2O can occur after both acute (surgical) or long term (occupational) exposure to the gas. Because of its effects on the pressure and volume characteristics of air-containing spaces, N2O should not be used for patients with bowel obstruction, pneumothorax, middle ear and sinus disease, and following cerebral air-contrast studies. Many anaesthesiologists feel that use of N2O should be restricted during the first two trimesters of pregnancy because of its effects on DNA production and the experimental and epidemiological evidence that N2O causes undesirable reproductive outcomes. Since N2O affects white blood cell production and function, it has been recommended that N2O not be administered to immunosuppressed patients or to patients requiring multiple general anaesthetics. Many anaesthesiologists believe that the potential dangers of N2O are so great that it should no longer be used at all for routine clinical anaesthesia. However, the continued use of N2O remains a controversial topic since, at present, a suitable substitute gas is not available.

The urinary metabolites of halothane (2-bromo-2-chloro-1,1,1-trifluoroethane) were investigated in five individuals given trace doses (25 muCi), and in three individuals given large doses (1 mCi) of radioactively labeled 14C-halothane. The latter were donor subjects for heart transplant operations. Separation of the nonvolatile urinary metabolites of halothane was accomplished by chemical extraction, electrophoresis, ion-exchange and high-pressure liquid chromatography, and gas chromatography. Identification of the individual metabolites was by nuclear magnetic resonance and mass spectrometry. Three major metabolites were identified: trifluoroacetic acid, N-trifluoroacetyl-2-aminoethanol, and N-acetyl-S-(2-bromo-2-chloro-1,1-difluoroethyl)-L-cysteine. Smaller unidentified radioactive peaks were also found. The presence of both ethanolamide and cysteine conjugates of halothane is of concern. These urinary products imply the presence of reactive intermediates. The conjugation of such intermediates to proteins and phospholipids may give rise to the high-molecular-weight covalently bound metabolites demonstrated to be present in the liver following halothane anesthesia. Elucidation of the structures of the urinary metabolites provides information important to an understanding of halothane metabolism and its potential hepatotoxicity.

Reactions of N-acetylcysteine with the halothane metabolite, 2-chloro-1,1-difluoroethylene (CF2CHCl), and two related probable metabolites, 2-bromo-1,1-difluoroethylene (CF2CHBr) and 2-bromo-2-chloro-1,1difluoroethylene (CF2CBrCl), afforded the saturated conjugates, RSCF2CH2Cl, RSCF2CH2Br, and RSCF2CHBrCl, as well as the unsaturated analogs, RSCFCHCl and RSCFCHBr; R = −CH2CH(COOH)NHCOCH3. The mutagenic and genotoxic potential of these conjugates was evaluated in the Salmonella/microsome system described by Ames and a “rec” DNA repair system developed by Kada employing recombination proficient and deficient strains of Bacillus subtilis. When screened for mutagenicity with Salmonella typhimurium strains TA1535 and TA100, the saturated and the unsaturated conjugates were found to be nonmutagenic. However, in a preliminary test using strain TA100 in logarithmic growth, compounds RSCF2CHBrCl and RSCFCHCl were mutagenic. Furthermore, screening for DNA-damaging ability in the B. subtilis “rec” assay with strains H17 and M45 revealed that the urinary halothane metabolite, RSCF2CHBrCl, and the unsaturated analogs, RSCFCHCl and RSCFCHBr, preferentially inhibited the growth of strain M45, which is deficient in its ability to repair DNA. In view of the reported correlation between known mutagens and their differential lethal action on rec− versus rec+ bacteria, the present findings of the DNA-damaging effects of the nonvolatile halothane metabolites and related probable metabolites suggest a possible relationship between halothane metabolism and reported toxic effects associated with occupational anesthetic exposure.

Binary mixtures of helium with nitrogen, xenon or nitrous oxide were applied to suspensions of phosphatidylcholine-cholesterol vesicles to determine those mixtures of lipid soluble gases which would exactly antagonize the membrane rigidifying effect of 100 ATA compression. A previous study has shown that the initial application of 100 ATA compression by gas produces a significant reduction in the fluidity of the phospholipid bilayer. However, as the high pressure gas dissolves into the lipid region it creates disorder and increases fluidity. Fluidity of the bilayer at equilibrium represents the sum of the compression-ordering and dissolved-gas disordering effects and is dependent on the gas/lipid partition coefficient of the particular gas. The beneficial effect of a narcotic gas added to Trimix mixtures to ameliorate HPNS in deep divers may be due to a balance of compression-ordering and solubility-disordering effects achieved within the nerve membrane. It is therefore valuable to determine those gas mixtures which achieve balance of these two effects and result in zero net change in phospholipid bilayer fluidity at an established pressure of 100 ATA. Binary mixtures of helium with 88% nitrogen, 3.8% xenon or 2.8% nitrous oxide resulted in zero net change in bilayer fluidity with our model system at 100 ATA. A graph of the percent of narcotic gas needed to produce zero net effect as a function of pressure, however, was nonlinear. This would suggest the ratio of gases in Trimix must be varied as a function of pressure. While the phosphatidylcholine-cholesterol bilayer is a good model for certain components of the nerve membrane, it does not allow for study of protein-lipid or gas-protein interactions. The data presented thus aid in our understanding of HPNS but are yet incomplete for precise use in predicting diving mixtures.

Several workers have shown that phase transition-related changes in membrane lipids have a profound effect on membrane-solvated protein function. This phase transition temperature dependence has been explained as resulting from the formation of lateral phase separations within the membrane bilayer. The present study demonstrates that a clinical concentration of an inhalation anesthetic produces changes in both the phase transition temperature of pure lipid bilayers and the lateral phase separation temperature of mixed dipalmitoyl- and dimyristoylphosphatidylcholine bilayers of a magnitude sufficient to influence protein function. It is further shown that pressure is able to antagonize the effect of the anesthetic on these transition temperatures. It is proposed that anesthetic action within nerve membranes may be the result of changes in the lateral phase separation-controlled environment of the membrane-solvated proteins essential to nerve function.

A nine compartment analog computer model was constructed to simulate and study the uptake and distribution of d-tubocurarine. By varying model parameters, six compartments were simulated using directly obtained experimental data. Drug distribution in the experimentally inaccessible compartments was obtained indirectly from the analog model. The model proved predictive and close agreement was observed with the experimentally observed data.

1. 1. A carefully controlled study of 200 normal obstetrical patients alternately given a placebo or an injection of repository curare showed no significant differences between the two groupings. An exception is noted in that there was a significant reduction in the number of episiotomies in the multiparous patients, when the Tubadil series is compared with the control series. 2. 2. There were no harmful effects on mother or child with the preparation used. 3. 3. The further use of repository curare in routine obstetrics is not justified from this report.

Present day manufacturers evidence considerable awareness in the problem of toxic impurities in anesthetic drugs. Rigid standards are set by the Food and Drug Administration and are carefully followed by the manufacturer. Fortunately, most impurities are harmless contaminants, or represent specific additives to the anesthetic, whose only disadvantage is to slightly dilute the agent. On the other hand, occasional toxic impurities are formed as by-products of the manufacturing process, and these may be difficult to remove. In addition, hazardous impurities may form during storage of the anesthetic, or appear after the container is opened and exposed to light, heat, moisture, or air. A recent report by Chenoweth and Brewer (1968) calls attention to a number of important toxic impurities and breakdown products found in anesthetics.

Halothane present in the ambient atmosphere was continuously measured in each of two operating rooms during the conduct of surgical anesthesia. Concentrations were determined on-line with a mass spectrometer and found to vary with sampling site, breathing system used, and the scavenging system employed to remove overflow anesthetic gases. Concentrations of halothane measured within a 3-foot radius of the anesthesia equipment averaged 8.7 ppm when a nonrebreathing circuit was used (flow 10 l/min), and 4.9 ppm with a semiclosed circle system (flow 4–5 l/min). End-tidal concentrations of halothane averaged 0.21 ppm in 81 samplings from operating room nurses and 0.46 ppm in 36 samplings from anesthetists. Residual concentrations were present in many individuals 16 hours after exposure. A significant reduction in atmospheric contamination of the operating room was obtained by use of appropriate scavenging equipment. The implications of these findings are discussed.

The intravenous injection of halothane-2 14C into the mouse was followed by an accumulation of labeled nonvolatile metabolites, with the highest concentrations present in the liver. These materials remained in the body for at least 12 days, although in decreasing amounts. Comparative studies using other 14C-labeled anesthetics indicated decreasing ratios of liver-lo-whole-body radioactivity for diethyl ether and chloroform, but an increasing ratio for halothane. Repeated injection of halothane at weekly intervals for five weeks yielded a rapidly-increasing concentration of radioactivity in the liver, suggesting the stimulation of enzyme-induction systems. Implications of these findings arc discussed.

The use of a narcotic to support patients about to undergo anesthesia and surgery has a very long history; nonetheless, there are adequate reasons for examining the practice objectively. Such an examination begins logically with questions as to the purposes of the practice, its undesirable effects, and whether or not there are better ways to attain the desired results. The beginning of this use of a narcotic was probably in 1850, when Lorenzo Bruno of Turin first mentioned the use of morphine as a hypnotic agent prior to the induction of anesthesia.1He used "the injection of morphine an hour before surgery... to lessen psychic trauma." In 1869 Claude Bernard, working in Bruno's clinic, described how the injection into animals of small amounts of morphine one hour before the administration of chloroform reduced by half the quantity of chloroform necessary for deep anesthesia.2Since that time many others

(1957). Premedication for the Obstetric Patient. Postgraduate Medicine: Vol. 22, No. 5, pp. 485-488.

A questionnaire was mailed to dentists and dental assistants requesting information about work, health, and reproductive history. Statistical analysis of the data indicated that there were no increased rates of spontaneous abortions or congenital abnormalities in the children of men and women who were exposed to low versus high levels of mercury in a dental environment.