Biomedical subjects
B H Johnson
Publications and source records attributed to B H Johnson.
I653 and isoflurane produce similar dose-related changes in the electroencephalogram of pigs.
I653 is a new volatile anesthetic structurally similar to enflurane and isoflurane. Since enflurane can induce convulsions, whereas isoflurane progressively depresses cortical electrical activity, the authors believed it important to assess the effect of I653 on the EEG (in both the "time" and "frequency" domain). The EEG was assessed visually and quantitatively, and a new EEG parameter was introduced. The burst-suppression ratio (percentage of time the EEG was isoelectric) quantified the extent of burst suppression phenomena. Eight swine were anesthetized with I653 or isoflurane in oxygen and in random sequence, exposed to approximately 0.8, 1.2, or 1.6 MAC with normocapnea and to 1.2 MAC with hypocapnea (PETCO2 of 25 mmHg). Four animals were also anesthetized with 3.2% (1.2 MAC) enflurane in oxygen. Both I653 and isoflurane produced a dose-related depression of cortical electrical activity. At 0.8 and 1.2 MAC of either agent, occasional sharp waves occurred singly, were apparently not related to external (auditory) stimuli, and probably represented normal variation in the EEG. No electrographic or gross motor seizures occurred with either I653 or isoflurane. In contrast, all pigs given enflurane developed seizures during hypocapnea. At equipotent concentrations, I653 and isoflurane had the same effect on EEG parameters. Increasing doses of either I653 or isoflurane caused decreasing amplitude and frequency and increasing suppression. Hypocapnea during either agent slightly increased high-frequency activity, and slightly decreased burst suppression.
Cardiovascular effects of I653 in swine.
I653 (difluoromethyl 1-fluoro 2,2,2-trifluoroethyl ether) is a new inhalation anesthetic with a low blood-gas partition coefficient and no demonstrable toxicity. The authors examined its cardiovascular effects at 0.8, 1.2, and 1.6 MAC in eight chronically instrumented domestic swine mechanically ventilated to maintain normocarbia. These data were compared with those obtained while the animals were conscious and while anesthetized with isoflurane at approximately equal MAC multiples. I653 caused dose-related decreases in mean arterial blood pressure (95 +/- 2 mmHg, mean +/- SE, conscious; 65 +/- 3 mmHg, 0.8 MAC; 55 +/- 3 mmHg, 1.2 MAC; and 48 +/- 2 mmHg, 1.6 MAC). At 0.8 MAC, systemic vascular resistance decreased 35% from the conscious condition value. Despite the decreases in blood pressure and systemic vascular resistance, and dose-dependent increases in right- and left-heart filling pressures, stroke volume fell in a dose-related fashion (2.11 +/- 0.10, 1.57 +/- 0.08, 1.37 +/- 0.06, and 1.10 +/- 0.06 ml/kg; conscious, 0.8, 1.2, and 1.6 MAC). At 0.8 MAC, cardiac output was unchanged (220 +/- 12 ml.min-1.kg-1) from the conscious condition (210 +/- 8 ml.min-1.kg-1), as heart rate increased (142 +/- 7 beats/min, at 0.8 MAC vs. 100 +/- 3 beats/min, conscious) and systemic vascular resistance decreased. At concentrations greater than 0.8 MAC, heart rate decreased towards but did not reach the conscious value (127 +/- 4 at 1.2 MAC, 120 +/- 4 at 1.6 MAC). Systemic vascular resistance increased slightly at 1.6 MAC compared to the values at 0.8 and 1.2 MAC, but was always less than in the conscious condition.(ABSTRACT TRUNCATED AT 250 WORDS)
Mechanism of age-related and nitrous oxide-associated anesthetic sensitivity: the role of brain catecholamines.
To provide a neurochemical basis for differences in their anesthetic requirements, the authors examined mice selectively bred for resistance (HI) and susceptibility (LO) to nitrous oxide anesthesia for brain levels of catecholamines. Concentrations of norepinephrine and dopamine in whole brain were 26% and 13% higher (P less than 0.001), respectively, in HI mice than in LO mice. Whole-brain levels of 3,4-dihydroxyphenylacetic acid, a major metabolite of dopamine, were the same for both HI and LO groups of mice. The authors then analyzed portions of the HI and LO mice brains for concentrations of norepinephrine and dopamine. A significant correlation was found between norepinephrine content in the medulla and nitrous oxide requirement. In other regions of the brain (cerebellum, cerebral cortex, hippocampus, pons, midbrain, hypothalamus), no significant differences in norepinephrine or dopamine levels could be detected. Differences in anesthetic requirements between resistant and susceptible mice decrease from 0.99 to 0.53 atm as they aged from 100 days to 600 days old, paralleling the decline in differences in norepinephrine levels in medulla oblongata between HI and LO mice from 1.6 to 0.73 ng/mg protein. Thus, the difference in anesthetic requirement between HI and LO mice may arise from alterations in catecholamine content in specific regions of the brain.
Minimum alveolar concentration of I-653 and isoflurane in pigs: definition of a supramaximal stimulus.
We determined the anesthetic potencies of a new fluorinated anesthetic, I-653, and isoflurane in pigs as a preliminary to a study of the relative cardiovascular and electroencephalographic effects of these agents. Clamps were sequentially applied to the dew claw and/or tail of each animal to determine the minimum alveolar concentration (MAC) that suppressed movement in response to each of these stimuli. MAC obtained by clamping the tail (8.28 +/- 1.34% [mean +/- standard deviation] for I-653 and 1.65 +/- 0.36% for isoflurane) was more variable and lower than MAC obtained by clamping the dew claw (10.00 +/- 0.94% for I-653 and 2.04 +/- 0.19% for isoflurane). We conclude that the type of stimulus applied affects the MAC value obtained for I-653 and isoflurane. Clamping the tail is not a supramaximal stimulus in pigs; a greater stimulus is provided by clamping the dew claw.
I-653 resists degradation in rats.
The ability of rats pretreated with phenobarbital to metabolize a new volatile anesthetic, I-653, was compared with the metabolism of halothane, isoflurane, and methoxyflurane. Each anesthetic was administered for 2 hours at 1.6 MAC (inspired). Control rats were given phenobarbital but not exposed to an anesthetic. In rats pretreated with phenobarbital and exposed to I-653, fluoride ion concentrations in serum and excretion of fluoride ion and organic fluoride in the urine were almost indistinguishable from values measured in control rats. In contrast, rats pretreated with phenobarbital metabolized small but significant amounts of isoflurane. In rats pretreated with ethanol and exposed to I-653, the 24-hour excretion of urinary organic fluoride was nearly ten times greater than that observed in control rats. Marked increases in organic fluoride (as high as 1000 times control values) and/or fluoride ion were found in serum and/or urine after anesthesia of phenobarbital-pretreated rats with halothane or methoxyflurane. The relative stability of I-653 indicates that it may possess minimal toxic properties.
Gene transfer in swine embryos by injection of cells infected with retrovirus vectors.
Key components for gene transfer to swine embryos using an avian retrovirus are described. A replication-defective reticuloendotheliosis (REV) viral vector can infect and be expressed in pig embryo fibroblasts (PEF). Infection with a replication-competent vector (REV-A) indicates a presumptive block to viral replication in PEF. Swine embryos obtained at the morula stage can be cultured in vitro to the blastocyst stage, injected with retrovirus helper cells or quail embryo fibroblasts producing REV, and transferred to recipient swine with survival to at least 6 wk of gestation.
Active immunization of boars against gonadotrop in releasing hormone. I. Effects on reproductive parameters.
Sexually mature boars were actively immunized against gonadotropin releasing hormone (GnRH) to characterize endocrine and gametogenic changes associated with immunoneutralization of endogenous GnRH. Injections of GnRH conjugated to bovine serum albumin (BSA) given five times over 24 wk induced production of antibodies against GnRH in all animals (n=5). Active immunization against GnRH reduced serum concentrations of testosterone (P<0.05) and luteinizing hormone (LH) (P<0.05), testes volume (P<0.01), paired testis weights (P<0.05), paired epididymis weights (P<0.05), sperm per testis (P<0.01) and seminiferous tubule diameters (P<0.001) when compared with controls (n=4). These results indicate that both steroidogenic and spermatogenic functions are impaired in testes of mature boars actively immunized against GnRH.
Active immunization of boars against gonadotropin releasing hormone. II. Effects on libido and response to testosterone propionate.
Of 20 sexually mature Duroc boars showing normal libido, 10 were actively immunized against gonadotropin releasing hormone (GnRH). After immunization against GnRH, boars showed minimal sexual interest in an estrous female, while untreated boars showed normal libido. Eight of the boars actively immunized against GnRH were randomly assigned to treatment (T) or control (C) groups. Boars in the T and C groups were given testosterone propionate or vehicle, respectively, on Days 0, 5, 10, and 15. Boars in both groups were observed for libido in the presence of an estrous female every 4 d for 28 d. Mean libido score for T boars increased gradually until all boars displayed maximum libido on Day 20, but libido returned to low levels on Day 28. In contrast, C boars remained sexually inactive throughout the study. The results of this study indicate that active immunization of sexually mature boars eliminates sexual behavior and that sexual behavior can be restored quickly by administering testosterone propionate.
Production of transgenic mice following deoxyribonucleic acid microinjection and embryo freezing.
Experiments with mouse embryos were designed to assess the feasibility of freezing embryos after DNA microinjection. One-cell pronuclear stage mouse embryos were microinjected with cloned deoxyribonucleic acid (DNA) and cultured in vitro to the late eight-cell stage. Microinjected and matched control embryos were frozen and stored in liquid nitrogen. Following thawing, embryos were cultured for 8 h and transferred to recipient females. In a separate set of experiments, embryos were transferred to recipients immediately following DNA microinjection. Control (uninjected) embryos developed to the late eight-cell stage significantly better than surviving microinjected embryos. Of the embryos thawed, 76% of the microinjected and 60% of the control embryos survived to be transferred to recipients. Progeny were obtained with similar survival rates from both groups following embryo transfer with transgenic mice identified among the progeny from microinjected embryos. Mouse embryos can be microinjected with DNA, cultured in vitro, frozen, thawed, transferred to recipients and transgenic progeny can be obtained.
Trustees and hospital staff: building bridges for better decisions.
Hospital trustees and employees often do not adequately understand each other's roles and the issues that they each face. This article discusses the composition of hospital boards, the ways in which they function, and their responsibilities. Further, it offers suggestions to encourage broader understanding and improved communication for both trustees and employees. New management approaches are presented that can build bridges for better communication, which in turn will lead to the formulation and implementation of more reasoned health care policies.
Stability of sevoflurane in soda lime.
Stability of halogenated volatile anesthetic is important because of the potential toxicity associated with the breakdown products. The authors enclosed 100 ml of gas containing sevoflurane with 100 g of soda lime in a 581-ml flask for periods up to 24 h. The rate of degradation of sevoflurane by soda lime was several-fold greater than previously reported, and the degradation was temperature-dependent. At 22 degrees C, soda lime degraded 6.5% of the sevoflurane per hour. The rate increased by 1.6% per hour per degree rise in temperature, reaching 57.4% degradation per hour at 54 degrees C. In contrast, isoflurane was not degraded by soda lime. Halothane did not degrade at 22 degrees C or 37 degrees C, but did degrade (2.2% per hour) at 54 degrees C.
A case report of a de novo tandem duplication (5p) (p14----pter).
The case described in this paper represents on the basis of cytogenetic evidence, the first reported example of a de novo tandem dup (5p)(p14----pter). Clinical changes were minimal, unlike previously described cases in which more complex structural chromosomal changes were involved and a phenotype was provisionally attributed to dup (5p)(p14----pter). The duplicated segment of minimal effect identified in this case involved more than five eighths of 5p. It is proposed that there is a localised critical segment elsewhere on the short arm of chromosome 5 (p11-p13), which when duplicated is of greater significance in terms of clinical effects.
Toxicity of sevoflurane in rats.
Sevoflurane, an experimental potent volatile anesthetic with a low blood/gas partition coefficient, degrades in the presence of soda lime to products the toxicity of which is unknown. We tested whether toxic products were produced by the passage of sevoflurane through soda lime, and a comparison was made of the toxicity of sevoflurane passed through soda lime with the toxicity of other potent volatile anesthetics in current clinical use. Halothane, isoflurane, sevoflurane (all in 1-MAC concentrations), or no anesthetic (control) were passed through soda lime for 4 hr with 12, 14, or 100% oxygen to groups of rats with hepatic microsomal enzyme induction. Separate groups of 12-13 rats were given 1 MAC of sevoflurane that had not passed through soda lime and either 14 or 100% oxygen. Sevoflurane was no more toxic than isoflurane and both of these anesthetics were less toxic than halothane. Soda lime was not a factor in any toxicity produced. Hepatic injury with all agents varied inversely with the oxygen concentration administered during anesthesia.
MAC of I-653 in rats, including a test of the effect of body temperature and anesthetic duration.
The anesthetic potency of a new fluorinated volatile anesthetic, I-653, was tested preliminary to testing its toxic and metabolic characteristics in rats. The minimum alveolar concentration (MAC) of I-653 at 37.9 +/- 0.2 degrees C (mean +/- SD) in eight rats was 5.72 +/- 0.40%. In five rats, we reduced the rectal temperature to 28 degrees C in two steps of 5 degrees C. MAC decreased by 0.238 +/- 0.036% I-653 per degree centigrade decrease in temperature. That is, MAC decreased 42% as temperature decreased 10 degrees C. We restored the temperature to 38 degrees C and redetermined MAC. This value (5.66 +/- 0.75%) did not differ from the average MAC obtained before hypothermia (5.84 +/- 0.36%).
Rates of awakening from anesthesia with I-653, halothane, isoflurane, and sevoflurane: a test of the effect of anesthetic concentration and duration in rats.
The low blood solubility of two new inhaled anesthetics, I-653 (human blood/gas partition coefficient, 0.42) and sevoflurane (0.69), suggested that awakening from these agents should be more rapid than awakening from currently available anesthetics such as isoflurane (1.4) and halothane (2.5). This prediction proved valid in a study of these four agents in rats given 0.4, 0.8, 1.2, or 1.6 MAC for 2.0 hr or 1.6 MAC for 0.5 or 1.0 hr. At a given dose and duration, awakening was most rapid with the least soluble agent and longest with the most soluble agent. For example, recovery of muscle coordination at 1.2 MAC administered for 2 hr required 4.7 +/- 3.0 min (mean +/- SD) with I-653, 14.2 +/- 8.1 min with sevoflurane, 23.2 +/- 7.6 min with isoflurane, and 47.2 +/- 4.7 min with halothane.
Studies of the toxicity of I-653, halothane, and isoflurane in enzyme-induced, hypoxic rats.
The physical stability and low blood solubility of the new inhaled anesthetic, I-653, imply that this agent produces limited or no toxic effects. To test this possibility, its effects were compared with those of other volatile agents on hepatic, renal, and pulmonary specimens taken from enzyme-induced, hypoxic rats. Male Sprague-Dawley rats were pretreated with phenobarbital and exposed for 1 hr to 12% O2 and no anesthesia (control) or to 1.2 MAC of one of three anesthetics: I-653, isoflurane, or halothane. Liver, kidney, and lung specimens were taken 24 hr after exposure concluded. The livers of all rats given halothane (n = 6) had swelling (20.5 +/- 5.7% of a lobule [mean +/- SD]) and centrilobular necrosis (6.7 +/- 2.1% of a lobule). Isoflurane produced only slight injury (6.7 +/- 3.5% swelling and 1.0 +/- 0.0% necrosis in 3 of 15 rats). No hepatic injury occurred in control rats (n = 20) or in those given I-653 (n = 16). Pulmonary and renal injury were not evident with any agent. Results suggest that I-653 has equivalent or less effect on hepatic, renal, and pulmonary integrity than currently available inhaled anesthetics.
Comparison of the toxicity of I-653 and isoflurane in rats: a test of the effect of repeated anesthesia and use of dry soda lime.
The low solubility and high stability of the new volatile anesthetic, I-653, suggest that this agent should have little or no toxic effect. This hypothesis was tested using repeated exposures to I-653, to isoflurane, or to no anesthetic. For 2 consecutive weeks, groups of 16 rats each were subjected to a total of six 2-hr exposures to 100% oxygen and 1.6 MAC I-653, isoflurane, or no anesthetic. Twenty-four hours after the last exposure, the rats were killed by administration of 100% carbon dioxide and then autopsied. Specimens were taken from brain, pituitary, lung, heart, duodenum, pancreas, kidney, and liver. No tissue damage attributable to either anesthetic was found nor was weight gain affected.