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Biomedical subjects

M A Holmes

Publications and source records attributed to M A Holmes.

71 records · Page 4Linked to original sources
PubMed1989

Epinephrine-induced premature ventricular contractions and changes in arterial blood pressure and heart rate during I-653, isoflurane, and halothane anesthesia in swine.

I653 is a new inhalation anesthetic having especially desirable recovery characteristics because of its very low blood and tissue solubility. Investigations of its cardiovascular and electroencephalographic effects have revealed actions similar to those of isoflurane. However, these studies did not evaluate the potential of I653 to predispose the heart to epinephrine-induced arrhythmias. In this investigation, we studied eight domestic swine to compare the effects of I653 with those of other anesthetics on the cardiac arrhythmogenic actions of intravenously infused epinephrine. I653, isoflurane, and halothane each were given, on separate days, at 0.7-0.8 and at 1.1-1.2 MAC. The rate of infusion of epinephrine needed to produce premature ventricular contractions (PVCs) when the animals were anesthetized with I653 (6.9 +/- 0.7 and 6.6 +/- 0.9 micrograms.kg-1.min-1 at 0.8 and 1.2 MAC) did not differ from that during isoflurane anesthesia (5.7 +/- 1.1 and 6.0 +/- 1.0 micrograms.kg-1.min-1 at 0.7 and 1.1 MAC), but was greater than that required during halothane anesthesia (1.3 +/- 0.2 and 1.1 +/- 0.3 micrograms.kg-1.min-1 at 0.7 and 1.1 MAC). Similar mean arterial blood pressures and heart rates resulted from like infusions of epinephrine during I653 and isoflurane anesthesia. PVCs occurred at lesser infusion rates of epinephrine and at lower mean arterial blood pressures and heart rates with halothane than with I653 or isoflurane. Anesthetic concentration, over the range studied, did not alter the infusion rate of epinephrine required to produce arrhythmias with any anesthetic. The authors conclude that I-653 and isoflurane have similar properties with respect to epinephrine-induced arrhythmias and increases in heart rate and arterial blood pressure.

Anesthetics↗
PubMed1989

Cardiovascular safety and actions of high concentrations of I-653 and isoflurane in swine.

The ratio of lethal-to-anesthetic concentration can be used to define the margin of safety of an inhaled anesthetic. In mechanically ventilated swine the fatal concentration of I-653, a new inhaled anesthetic, was 23.9 +/- 0.06% (mean +/- SE), and of isoflurane, 6.22 +/- 0.23%. The ratio of fatal anesthetic concentration-to-MAC for I-653 (2.45 +/- 0.11) was less than that determined for isoflurane (3.02 +/- 0.13; P less than 0.01) but relatively greater than that reported previously for other inhaled anesthetics. As with other inhaled anesthetics, the concentration of I-653 causing cardiovascular collapse exceeds that producing apnea, making cardiovascular collapse during spontaneous ventilation unlikely. Mean aortic blood pressure and cardiac output decreased as linear functions of anesthetic concentration. Values for these variables for isoflurane were greater than those for I-653 at concentrations exceeding 1.5 MAC. Heart rate, blood lactate concentration, and base-deficit did not change with anesthetic depth. Mixed venous PO2, mixed venous oxyhemoglobin saturation, and the ratio of oxygen transport to oxygen consumption remained at or above values in conscious swine but decreased similarly with both anesthetics when anesthetic concentration increased to within 0.5 MAC of the fatal concentration. Thus, the latter three variables, reflecting the fraction of delivered oxygen that is consumed, and "mean" tissue PO2 appear to be useful indices of anesthetic concentrations approaching those producing cardiovascular collapse.(ABSTRACT TRUNCATED AT 250 WORDS)

Anesthetics↗
PubMed1989

Metabolism of I-653 and isoflurane in swine.

Fluoride ion concentrations were measured in plasma samples taken from chronically instrumented domestic swine before, immediately after, and 4 hours after exposure to either I-653 or isoflurane. Each anesthetic was administered at concentrations between 0.7 and 1.6 MAC and the total dose of anesthetic given was approximately 5.5 MAC hours for each agent. Plasma fluoride ion concentrations immediately after and 4 hours after exposure to isoflurane were approximately three times greater than values obtained in awake swine before anesthesia. In contrast, swine given I-653 had no detectable elevation in plasma fluoride concentration immediately after anesthesia, but a 17% (P less than 0.05) increase in plasma fluoride ion concentration 4 hours after anesthesia. These results imply that I-653 is metabolized less than is isoflurane in swine.

Anesthetics↗
PubMed1988

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.

Anesthesia, Inhalation↗
PubMed1988

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)

Anesthesia, Inhalation↗
PubMed1988

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.

Anesthetics↗
PubMed1987

Determination of plasma volume in swine by the enzyme-dilution method.

Plasma volume of six young swine was determined by simultaneous dilution in the plasma of two purified porcine enzymes, aspartate aminotransferase (AST) and alanine aminotransferase (ALT), and Evans blue dye. Ninety-minute time-activity and time-concentration curves were obtained, and the dilution spaces of each plasma indicator at the time of injection were estimated by extrapolation of data from the first 30 min after injection. Plasma volumes estimated using the two enzymes agreed closely with each other (AST, mean 50.2 ml/kg; ALT, mean 49.8 ml/kg) and were 11% smaller than those determined using Evans blue dye (mean 56.3 ml/kg). Plasma volumes calculated from the AST and ALT activities and Evans blue dye concentration in a sample drawn 5 min after injection very closely approximated those obtained by extrapolation. These values were comparable to previously published estimates of plasma volume for swine of equivalent weight. Endogenous plasma levels of AST and ALT activity were measured in samples drawn from five swine before and after a 40% blood loss. No significant change in AST or ALT activities occurred after hemorrhage.

Alanine Transaminase↗
PubMed1987

Effects of fentanyl on vasopressin secretion in human subjects.

To test the influence of an opioid on vasopressin (AVP) secretion, plasma AVP concentration was measured in five semirecumbent unmedicated volunteers before and during two continuous i.v. infusions of fentanyl. Infusion rates were adjusted to produce steady-state plasma fentanyl concentrations of 2.0 +/- 0.4 and 4.1 +/- 0.6 ng/ml; mild to moderate hypercarbia was induced during the control and infusion periods. Fentanyl increased plasma AVP concentration in a dose-dependent manner to 559 +/- 215 and 929 +/- 199% of the basal level of 1.9 +/- 0.7 pg/ml. Neither mild hypercarbia (PCO2 = 50 +/- 1 mm Hg) in the absence of fentanyl nor moderate hypercarbia (PCO2 = 66 +/- 3 mm Hg) in the presence of fentanyl changed plasma AVP concentration. Neither fentanyl nor hypercarbia, nor the combination of the two, altered plasma renin activity.

Adult↗
PubMed1983

Structural analysis of the inhibition of thermolysin by an active-site-directed irreversible inhibitor.

The mode of binding of the irreversible thermolysin inhibitor ClCH2CO-DL-(N-OH)Leu-OCH3 [Rasnick, D., & Powers, J.C. (1978) Biochemistry 17, 4363-4369] has been determined by X-ray crystallography at a resolution of 2.3 A and the structure of the covalent complex refined to give a crystallographic residual of 17.0%. This is the first such structural study of an active-site-directed covalent complex of a zinc protease. As anticipated by Rasnick and Powers, the inhibitor alkylates Glu-143 in the thermolysin active site, and the hydroxamic acid moiety coordinates the zinc ion. The formation of the covalent complex is associated with a significant shift in a segment of the polypeptide backbone in the vicinity of the active site. This conformational adjustment appears to be necessary to relieve steric hindrance which would otherwise prevent alkylation of Glu-143. It is suggested that this steric hindrance, which occurs for thermolysin but would not be expected for carboxypeptidase A, accounts for the previously inexplicable difference in reactivity of these two metalloproteases toward N-haloacetyl amino acids. The relevance of this steric hindrance to the mechanism of catalysis is discussed. In agreement with previous results [Kester, W. R., & Matthews, B. W. (1977) Biochemistry 16, 2506-2516], it appears that steric hindrance prevents the direct attack of Glu-143 on the carbonyl carbon of an extended substrate, therefore ruling out the anhydride pathway in thermolysin-catalyzed hydrolysis of polypeptide substrates and their ester analogues.

Binding Sites↗
PubMed1981

Can carbon monoxide be absorbed from the upper respiratory tract in man?

To investigate the possible absorption of carbon monoxide into the blood from tobacco smoke confined to the mouth and upper airways, an indirect study was made on 12 normal subjects of the recovery of CO from a bolus administered at various levels during a preceding inspiration. No measurable CO uptake was observed unless the bolus was inhaled early enough in inspiration to reach the alveolar region of the lung. Some movement of a tracer gas, argon, was however seen from the upper airways during breath-holding so that some CO might escape into the lungs this way. No detectable CO uptake occurred in one subject who inspired the bolus into his nasal cavities. We conclude that the elevated carboxyhaemoglobin levels seen in smokers, can only occur when smoke is inhaled into the lung, since no appreciable uptake can occur in the upper airways.

Absorption↗
PubMed1975

Pasteurella multocida. Infections after domestic animal bites and scratches.

Pasteurella multocida is a common cause of infection followingbites or scratches caused by dogs and cats. However, it is rarely reported and appar-ently often overlooked as a pathogen. It causes the typical clinical manifestationsof a rapidly developing cellulitis at the site of injury. The infection is potentiallydangerous and can cause a chronic local infection of deep tissues and septicemia. However, it responds well to several antimicrobials, with penicillin being the drug ofchoice

Adolescent↗