Anesthetics in blood

There are two separate requirements at present for measuring volatile anesthetics in blood. One is retrospect analysis of blood samples. The other is on-line monitoring of blood concentration during animal and clinical toxicity studies. Usually a method allowing analysis of samples within minutes is desired. 

Shen Y, Jdnsson jA, and Mathiasson L. On-line microporous membrane liquid-liquid extraction for sample pretreatment combined with capillary gas chromatography applied to local anesthetics in blood plasma. Anal. Chem. 1998 70 946-953. 

N.C. Yang, K.L. Hwang, C.H. Shen, H.F. Wang, W.M. Ho, Simultaneous determination of fluorinated inhalation anesthetics in blood by gas chromatography-mass spectrometry combined with a headspace autosampler, J. Chromatogr. B, 159, 307-318 (2001). 

The duration of infiltration anesthesia can be approximately doubled by the addition of epinephrine (5 pg/mL) to the injection solution epinephrine also decreases peak concentrations of local anesthetics in blood. Epinephrine-containing solutions should not, however, be injected into tissues supplied by end arteries- or exarrtple, fingers and toes, ears, the nose, and the penis. The resulting vasoconstriction may cause gangrene. 

Williams and Sweeley (1964) have given methods for the chromatographic separation of many urinary aromatic acids and have discussed diagnostic applications to (1) secreting tumors, e.g., malignant carcinoid, pheochromocytoma, and neuroblastoma, and (2) inborn errors of metabolism, e.g., tyrosinosis, phenylketonuria, Hartnup disease (involves aminoaciduria), and other inherited diseases. These authors referred to the use of infrared spectroscopy for verification of the identity of fractions of volatile organic anesthetics in blood. Chlorpromazine, pentobarbitone, and amphetamine, are examples of pharmacological substances that have been separated (Scott, 1966). 

Rapid Gas Chromatographic Assay for Volatile Anesthetics in Blood J. Pharmacol. Methods 1(2) 155-160... 

Preservation of Volatile Anesthetics in Blood and Tissues Anesthesiology 25 566-568 (1964) Biol. Abstr. 46 89539... 

Flame Ionization Detection of Volatile Organic Anesthetics in Blood, Gases and Tissues... 

Determination of All Volatile Organic Anesthetics in Blood, Gas and Tissue - With or Without Chromatography J. Gas Chromatogr. 2(11) 380-384 (1964) CA 62 9632c... 

Anesthetics in Blood Biomedical Applications of Gas Chromatography, edited by H. A. Szyman-ski. Plenum Press, New York, 1964, pp. 307-324 CA 62 4307h... 

Gas Chromatographic Method Using Surfactants for Analysis of Volatile Anesthetics in Blood Anesthesiology 37(6) 647-649 (1972) CA 78 52466m... 

Gas Chromatographic Determination of Volatile Anesthetics in Blood by Direct Injection Chung-hua I Hsueh Tsa Chih (Peking) 60(2) 68-69 (1980) CA 93 60853k... 

Isoflurane is a respiratory depressant (71). At concentrations which are associated with surgical levels of anesthesia, there is Htde or no depression of myocardial function. In experimental animals, isoflurane is the safest of the oral clinical agents (72). Cardiac output is maintained despite a decrease in stroke volume. This is usually because of an increase in heart rate. The decrease in blood pressure can be used to produce "deHberate hypotension" necessary for some intracranial procedures (73). This agent produces less sensitization of the human heart to epinephrine relative to the other inhaled anesthetics. Isoflurane potentiates the action of neuromuscular blockers and when used alone can produce sufficient muscle relaxation (74). Of all the inhaled agents currently in use, isoflurane is metabolized to the least extent (75). Unlike halothane, isoflurane does not appear to produce Hver injury and unlike methoxyflurane, isoflurane is not associated with renal toxicity. 

Desflurane is less potent than the other fluorinated anesthetics having MAC values of 5.7 to 8.9% in animals (76,85), and 6% to 7.25% in surgical patients. The respiratory effects are similar to isoflurane. Heart rate is somewhat increased and blood pressure decreased with increasing concentrations. Cardiac output remains fairly stable. Desflurane does not sensitize the myocardium to epinephrine relative to isoflurane (86). EEG effects are similar to isoflurane and muscle relaxation is satisfactory (87). Desflurane is not metabolized to any significant extent (88,89) as levels of fluoride ion in the semm and urine are not increased even after prolonged exposure. Desflurane appears to offer advantages over sevoflurane and other inhaled anesthetics because of its limited solubiHty in blood and other tissues. It is the least metabolized of current agents. 

The toxic effect depends both on lipid and blood solubility. I his will be illustrated with an example of anesthetic gases. The solubility of dinitrous oxide (N2O) in blood is very small therefore, it very quickly saturates in the blood, and its effect on the central nervous system is quick, but because N,0 is not highly lipid soluble, it does not cause deep anesthesia. Halothane and diethyl ether, in contrast, are very lipid soluble, and their solubility in the blood is also high. Thus, their saturation in the blood takes place slowly. For the same reason, the increase of tissue concentration is a slow process. On the other hand, the depression of the central nervous system may become deep, and may even cause death. During the elimination phase, the same processes occur in reverse order. N2O is rapidly eliminated whereas the elimination of halothane and diethyl ether is slow. In addition, only a small part of halothane and diethyl ether are eliminated via the lungs. They require first biotransformation and then elimination of the metabolites through the kidneys into the... 

They differ to some extent from signs and symptoms that occur during anaphylaxis not associated with anesthesia. Early subjective symptoms such as malaise, pruritus, sensation of heat, and dizziness are absent in the anesthetized patient. Cutaneous signs in a completely wrapped patient may escape the attention of the anesthetist. The increase in heart rate, a decrease in blood pressure and an increase in airway resistance may be initially misinterpreted as a result of a pharmacological dose-related effect of the drugs, or of excessively light anesthesia. Many differential diagnoses have to be considered (table 1). 

In an anesthetized, ventilated canine model of anaphylactic shock defined as hypotension with blood pressure maintained at 50% of baseline, epinephrine infusion produces an improvement in blood pressure, associated with positive inotropy [21]. 

A more complex cyclohexylamine, tiletamine (65), is a useful anesthetic in that injection leads to loss of consciousness without an untoward decrease in blood pressure or heart rate and without undue respiratory depression. Its synthesis15 begins with... 

The distribution of anesthetic throughout the entire body may be viewed as an equilibration process (Fig. 7.1.13), with tissues characterized by high blood flows reaching equilibration faster than muscle and fatJ4 Nevertheless, an anesthetic that is excessively soluble in blood will not partition substantially into brain and other tissues. The anesthetic properties of nitrous oxide and diethyl ether have been known since the 1840s. Zeneca Pharmaceuticals introduced the first modem inhalation anesthetic fluothane in 1957. Methoxyfluorane followed in 1960, enflurane 1973, isoflurane 1981, desflurane by Anaquest (Liberty Comer, NJ) in 1992, and sevoflurane by Abbott Laboratories in 1995J6 ... 

An effect on blood pressure was shown in the study by Clark and Litchfield (1969) in which subcutaneous injections of PGDN to anesthetized rats at 5, 10, 20, 40, 80, or 160 mg/kg resulted in a dose-related fall in mean arterial blood pressure (measured in the cannulized femoral artery) within 30 min with recovery over the next 12 h. The maximum drop in blood pressure correlated with the maximum concentration of PGDN in the blood. However, a drop in blood pressure did not occur in human volunteers who inhaled 0.5 ppm PGDN for 7.3 h. Rather, a mean elevation of diastolic blood pressure of 12 mm Hg was associated with severe and throbbing headaches (Stewart et al. 1974). A drop in blood pressure and decreasing stroke volume can result in brain ischemia, causing the dizziness and weakness reported by one subject after exposure at 0.5 ppm for 6 h in the Stewart et al. (1974) study as well as in occupationally exposed workers (Horvath et al. 1981). 

For gases and vapors, the amount absorbed is highly dependent on the partial pressure of the gas and the solubility of the gas in blood. Let s take the simple case of a gas that is not metabolized and is excreted by exhalation (e.g., an anesthetic gas or a Halon-type fire-extinguishing agent). At any given concentration (or partial pressure) in the atmosphere, the concentration in the blood will reach a steady state in the blood. Accordingly, prolonged exposure does not lead to continual buildup. 

Figure 9.15 presents an example of the in vivo measurements of the oxygen content in the arterial blood of dogs over a period of 10 h. The dots represent the batch gas analysis performed with a Nova Biomedical blood gas analyzer. The solid lines represent the analyses monitored by the instrument. Blood oxygen measurements were obtained continuously (not shown in the figure) about every 3 sec. Two different polymer solutions are shown. The measurements performed by the instrument are not affected by the presence of unmetabolized clots and/or anesthetics in the blood stream. Additionally, no deterioration of the signal was found after 10-h periods. 

Fish rapidly eliminate residues of MS-222 after exposure to the anesthetic (27). Blood, kidney, liver, and muscle show different rates of elimination, which probably reflect the form of the drug present and fluid turnover times in the tissues. The concentration of the anesthetic in these tissues decreased to the detection limit of their method within 5 h. 

Lappaconitine (2) this compound is 40 times less toxic than aconitine (1). In anesthetized rabbits it induced cardiac arrhythmias, preceded by bradycardia and fall in blood pressure [11]. 

Gases that do not react irreversibly with epithelial tissue, such as anesthetic gases, may diffuse into the bloodstream and will ultimately be eliminated from the body. A different and earlier model developed by DuBois and Rogers estimates the rate of uptake of inhaled gas from the tracheobronchial tree in terms of diffusion through the epithelial tissue, rate of blood flow, and solubility of the gas in blood. The rate of uptake from the airway lumen is determined by the equation ... 

The rates of onset and cessation of action vary widely between different inhalational anesthetics and also depend on the degree of lipophilicity. In the case of N2O, there is rapid elimination from the body when the patient is ventilated with normal air. Due to the high partial pressure in blood, the driving force for transfer of the drug into expired air is large and, since tissue uptake is minor, the body can be quickly cleared of N2O. 

In animal studies the 4-hour inhalation LCso was 17,000 ppm for hamsters and 13,300ppm for rats." Exposure to 5000ppm for 10 minutes produced a 50% decrease in respiration rate in mice in anesthetized rats significant increases in blood pressure were observed at 1700 ppm and concentrations above 6000 ppm significantly increased heart rate. ... 

Inhalation studies with chloropentafluoroethane in anesthetized dogs, rats, and monkeys showed that exposure to 100,000-2 5 0,000 ppm, under certain conditions, caused an increase in blood pressure, accelerated heart rate, depression of myocardial contractility and sensitized the heart to epinephrine.Compared with other chlorofluorocarbons, it is ranked among the least potent for cardiac sensitization." ... 

Blood pressure effects were recorded from cannulized femoral arteries in anesthetized rats after subcutaneous injection. Maximal falls in blood pressure occurred within 30 minutes of injection. Small responses were seen at the 5mg/kg level, but as the dose was increased marked hypotension occurred. 

The object of inhalation anesthetics is to obtain a concentration (partial pressure) of the drug in the brain sufficient to reach the desired level of anesthesia. In order to do this, anesthetic molecules must pass through the lungs into the brain through various biological phases. Therefore, inhalation anesthetics must be soluble in blood and interstitial tissue. 

Like many volatile halocarbons and other hydrocarbons, inhalation exposure to carbon tetrachloride leads to rapid depression of the central nervous system. Because of its narcotic properties, carbon tetrachloride was used briefly as an anesthetic in humans, but its use was discontinued because it was less efficacious and more toxic than other anesthetics available (Hardin 1954 Stevens and Forster 1953). Depending on exposure levels, common signs of central nervous system effects include headache, giddiness, weakness, lethargy, and stupor (Cohen 1957 Stevens and Forster 1953 Stewart and Witts 1944). Effects on vision (restricted peripheral vision, amblyopia) have been observed in some cases (e.g., Johnstone 1948 Smyth et al. 1936 Wrtschafter 1933), but not in others (e.g., Stewart and Wtts 1944). In several fatal cases, microscopic examination of brain tissue taken at autopsy revealed focal areas of fatty degeneration and necrosis, usually associated with congestion of cerebral blood vessels (Ashe and Sailer 1942 Cohen 1957 Stevens and Forster 1953). 

The initial unequal tissue-drug distribution cannot persist, however, because physicochemical forces tend to require an eventual establishment of concentration equilibria with other less well perfused organs. Therefore, as the drug continues to be removed from the blood by the less richly perfused tissues or eliminated by metabolism and excretion or both, plasma levels will fall, and the concentration of anesthetic in the brain will decline precipitously. 

---