* INSERM U26, Université Paris 7, Hôpital Fernand Widal, 200 rue du Faubourg Saint-Denis, 75010 Paris, France;
Laboratoire de Biochimie A, Hôpital Saint-Louis, 1 avenue Claude Vellefaux, 75010 Paris, France; and
Department of Emergency Medicine, George Washington University Hospital, 901 23rd Street NW, Washington, DC 20037
Received November 17, 2000; accepted February 23, 2001
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ABSTRACT |
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Key Words: cyanide; pharmacokinetics; respiratory acidosis; respiratory alkalosis; brain.
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INTRODUCTION |
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Inhalation of a high concentration of carbon dioxide induces a profound and immediate effect on the pattern of breathing. Carbon dioxide immediately increases minute ventilation (Read, 1967), contributing to the overall hazard of fire gas environment by causing accelerated lung absorption of gaseous toxicants (Hartzell, 1989
). However, the further contribution of carbon dioxide to the systemic toxicity of cyanide has not been addressed. Acute retention of carbon dioxide provokes respiratory acidosis, which dramatically augments cerebral blood flow (Feihl and Perret 1994
; Hossmann, 1990
; Hossmann and Blöink, 1981
; Kety and Schmidt, 1948
). Furthermore, respiratory acidosis can significantly modify the ratio of nonionized to ionized forms of xenobiotics, depending on the pH of the milieu and the pKa of the substance (Rowland and Tozer, 1995
). Accordingly, respiratory acidosis has been shown to increase the tissue distribution of weak acids such phenobarbital (Waddell and Butler, 1957
) and salicylate (Hill, 1973
).
Hydrocyanic acid is a weak acid with a pKa of 8.99 at 35°C (Izatt et al., 1962). The olive oil/water partition coefficient of cyanide is 0.15 and the brain uptake index is 41 ± 4% (Oldendorf, 1974
). Thus, hydrocyanic acid is considered a lipophilic substance (Oldendorf, 1974
). The movement of cyanide through membranes is complex. But accumulation of labeled cyanide by neuronal tissue is not an energy-dependent process (Borowitz et al., 1994
). These data led us to the hypothesis that respiratory acidosis might increase the distribution of cyanide into the brain by increasing the amount of toxicant delivered to the brain by the bloodstream and by increasing the nonionized fraction. Conversely, respiratory alkalosis might be expected to have opposite effects on the distribution of cyanide into the brain.
The effect of modulation of arterial pH by ventilation is also of importance when considering the supportive treatment of acute cyanide poisoning. Mechanical controlled ventilation is the basic standard of care of severe cyanide poisoning (Ellenhorn et al., 1997). Oxygen has been shown to significantly counteract the toxicity of cyanide in spontaneously breathing rats poisoned with cyanide (Burrows et al., 1973
; Isom and Way, 1974
). But to our knowledge, no study has addressed the effects of modulation of arterial pH through controlled ventilation on either the toxicokinetics or the toxicity of cyanide.
The question to be addressed is whether respiratory acidosis favors the cerebral distribution of cyanide, and conversely, if respiratory alkalosis limits its distribution. To answer this question, we first determined the pharmacokinetics of a nontoxic dose of cyanide in rats in order to determine the distribution phase. Then, we studied the effects of the modulation of arterial pH induced by controlled ventilation on the distribution of a nontoxic dose of cyanide administered intravenously into the brains of anaesthetized rats.
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MATERIALS AND METHODS |
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Preparation of the solution of radioactive cyanide.
One mCi of 14C-labeled potassium cyanide (New England Nuclear, Amersham, MA; specific activity: 56 mCi/mmol) was diluted in 40 ml of NaOH 0.1N and stored at 20°C. Cyanide salts autodegrade to carbonates (Christel et al., 1977), a process accelerated in the presence of water. Thus, in order to precipitate 14CO32, an aliquot of the parent solution was treated immediately before use, as follows (Christel et al., 1977
; McMillan and Svoboda, 1982
). Five hundred µl was thawed and then precipitated with 30 µl of BaCl2 3 M and 20 µl of NaHCO3 0.1 N. The mixture was vortexed, then centrifuged at 5000 rpm for 10 min. The supernatant was then decanted and used for the studies.
Kinetics of radiolabeled cyanide in whole blood.
Seven animals were anesthetized with Ketamine (Ketalar®, 70 mg/kg; Parke-Davis, France) and diazepam (Valium®, 7.5 mg/kg; Roche, France) ip, then placed on a warming blanket with a regulating thermostat. A rectal probe permitted feedback control of the temperature. The femoral artery and vein were catheterized, the venous catheter permitting systemic heparinization of the animal, as well as administration of the labeled cyanide. The arterial catheter permitted blood collection for the quantification of blood cyanide. Following catheterization, animals were heparinized with 500 µl/kg body weight of 10% heparinized saline. Five min after heparinization, 200 µl of purified 14C-labeled potassium cyanide, corresponding to 160 to 187 nmol CN/kg body weight, were administered as an intravenous bolus. These doses are dramatically below the reported toxic doses in the rat (Ballantyne, 1987). Three hundred µl of arterial blood were then collected at 30, 60, and 90 s and at 2, 6, 10, 30, 60, and 90 min.
An isotopic dosage of cyanide in whole blood was performed, based on a modification of the classic microdiffusion method in a Conway cell (Prieux, Joinville-le-Pont, France). This method is based on the liberation of blood cyanide in the form of hydrogen cyanide gas by the action of sulfuric acid in the outer chamber of the Conway cell. The HCN produced is captured by sodium hydroxide in the inner chamber (Rieders, 1975). Five hundred µl of 0.5 N sodium hydroxide were placed in the inner chamber of the Conway cell. Three hundred µl of normal saline and 500 µl of sulfuric acid 0.1 N were placed in the external chamber. A 200-µl blood sample was also placed in the outer chamber, remaining out of contact with the acid until the chamber was sealed hermetically. Microdiffusion was complete after 2 h at ambient temperature. The counting of radioactivity was performed on 20 µl of the sodium hydroxide phase contained in the internal chamber added to 10 ml of scintillation liquid (Pico-Fluor, Packard, France). A Tri-carb counter (Model 1900 TB, Packard) was used to measure the radioactivity. All results were corrected for background radiation.
As the method of measurement of blood cyanide concentrations is specific for cyanide and not affected by cyanide metabolites, the results of the radioactivity were transformed into nmol/l, taking into account the specific activity (56 mCi/mmol) of the radiolabeled cyanide. The modeling of the kinetics of nontoxic doses of cyanide in blood was performed using the Siphar software program (Simed, Créteil, France).
Effects of Respiratory Acidosis and Alkalosis on the Distribution of Cyanide into the Rat Brain
Development of a model of acidification and alkalinization.
This model of respiratory acidification and alkalinization is based on the ventilation of animals under neuromuscular blockade at various tidal volumes (Vt) and constant frequency. For realization of the model, 3 modes of ventilation were used:
The animals were anesthetized in a manner identical to that previously described, using ketamine and diazepam. The temperature of the animals was continuously monitored. The femoral artery and vein were catheterized and the animal subsequently tracheotomized and ventilated using a small animal ventilator (Harvard Biosciences, France). The animals in the acid pH group were ventilated with carbogen. Otherwise, animals received pure oxygen (Air Liquide). A preliminary study using repeated measures of blood gases of animals submitted to various ventilatory schemes demonstrated that alkalinization or acidification was achieved based on the Vt chosen. This modification of blood pH reached a plateau at 15 min, both for those animals with induced respiratory acidosis, as well as those placed in respiratory alkalosis. The modification of pH was stable for at least 15 min. Thus, a 500 µl blood specimen was collected for blood gas determination in a heparinized syringe (Bayer Diagnostics, France) 20 min after the start of mechanical ventilation.
Arterial blood gases were measured by means of a blood gas analyzer (Radiometer, Copenhagen, Denmark).
Determination of cyanide distribution by the method of Ohno.
This method, which studies the cerebral distribution of radioactive compounds, was undertaken using animals previously ventilated to obtain variable conditions of blood pH (alkaline, physiologic, or acid). The technique is composed of injecting the radioactive cyanide, along with tritiated sucrose, which permits the determination of the volume of the vascular space (Ohno et al., 1978).
We used the results of the previously performed pharmacokinetics study in order to determine the time for decapitation of the animal. The animals were prepared as previously stated. An aspirating pump was connected to the arterial catheter. Twenty min after the beginning of controlled ventilation an arterial blood gas was collected to verify the pH conditions, just before the administration of the radioactive cyanide and sucrose. The radioactive products were administered as a 200-µl iv bolus of normal saline containing 20 µCi of tritiated sucrose and 400 µl of purified 14C-cyanide equivalent to 6.25 µCi corresponding to 320 to 373 nmol CN/kg body weight. Arterial blood was drawn by the pump at a constant aspiration rate of 0.4 ml/min for a fixed time of 30 s from the end of injection of radioactive compounds until decapitation. Decapitation of the animal occurred 30 s after injection of the cyanide, as this represents 1.5 times the distribution half-life, as determined in the kinetic study. Two aliquots of the arterial blood were immediately centrifuged to separate plasma from erythrocytes. Five hundred µl of blood were obtained from the neck using a micropipette for determination of tritiated sucrose activity. The brain was immediately removed from the cranium and placed on crushed ice. The arachnoid and subarachnoid membranes were delicately removed. The brain was dissected into various parts, namely: pons-medulla, cerebellum, superior and inferior colliculi, hypothalamus, thalamus, hippocampus, striatum, frontal cortex, parietal cortex, and occipital cortex. These structures were placed in flasks and weighed, followed by addition of 1 ml of Soluene (Packard), then sealed. The tissues were digested in a water bath at 60°C for 2 h. The tubes were counted after addition of 9 ml of scintillation liquid. 14C and 3H activities were measured in all brain tissue specimens. Blood and plasma samples of 20 µl were placed in flasks and weighed, followed by addition of 1 ml of Soluene and then of 9 ml of scintillation liquid (Packard), sealed and counted. This treatment was performed in duplicate, on arterial blood for 14C and on blood collected at the neck immediately after decapitation for 3H. All results were corrected for background radiation.
Ohno's method permits the determination of cerebrovascular permeability of nonelectrolytes in rats. The method requires the determination of the amount of cyanide distributed into brain tissue. However, the amount of cyanide in whole brain (Qc) is the sum of the amount of cyanide in the brain tissue (QBr) and the amount of cyanide contained in the blood vessels within the brain structure (Qv). The amount of cyanide contained in the blood vessels within the brain structure can be calculated given the regional blood volume.
Regional blood volume.
In each brain structure, we measured the tritiated sucrose activity (dpm/mg). We also measured the tritiated sucrose activity in whole blood measured by means of the blood specimen collected at the neck after decapitation (dpm/mg of blood). The regional vascular volume (Vr), expressed as a percentage of the weight of the structure, is equal to the ratio of tritiated sucrose activity in the brain structure to the tritiated sucrose activity in blood.
Amount of radiolabeled cyanide in the regional blood volume (Qv).
The amount of radiolabeled cyanide in the regional blood volume is equal to the product of the regional blood volume and the activity of radiolabeled cyanide in blood (Qblood):
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Quantity of radiolabeled cyanide having penetrated into the brain (QBr).
In each brain structure we measured the whole 14C-cyanide activity (Qc, dpm/mg). The quantity of cyanide having penetrated into the brain is equal to:
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Calculation of the permeability-area product.
The calculation used in the method of Ohno is that of the permeability-area product (PA). The PA is the ratio between the quantity of the substance having penetrated into the brain (QBr) to the amount of drug delivered to the brain during the same time as assessed by the integral of the arterial radioactivity.
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where Cp = activity measured in the arterial plasma recovered by aspiration during the period of time (dt) after injection of the solution of the radiolabeled product, representing the integral of the blood concentrations during the 30 s. Results are expressed as s1.
Statistical analysis.
All comparisons were made using analysis of variance (ANOVA), followed by multiple comparisons using Bonferonni's correction (Prism 2.0 Software, GraphPad, Inc., San Diego, CA). Results are expressed as mean ± SE. A p value less than 0.05 was considered significant.
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RESULTS |
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The comparison of the mean arterial bicarbonate (Table 2) revealed significant differences between animals in the acidotic and physiologic groups (p < 0.05), the alkalotic and physiologic groups (p < 0.05), and the acidotic and alkalotic groups (p < 0.001).
There were no significant differences in the mean PaO2 between groups (Table 2).
Distribution of cyanide into rat blood, plasma, and brain.
Table 3 shows the mean regional blood volumes of the 10 structures in each group. There were no significant differences when comparing the mean regional blood volumes measured in each of the 10 brain structures in the acidotic, physiologic, and alkalotic groups. The mean global blood volumes (mean of the sum of regional blood volumes), expressed as a percentage of the weight of the structures in the acidotic, physiologic and alkalotic groups were 2.6 ± 0.3, 2.4 ± 0.1, and 2.5 ± 0.1%, respectively. There were no significant differences of the mean global blood volumes in the 3 groups (Fig. 2
).
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The mean plasma 14CN activities in arterial samples collected by aspiration during 30 s in the acidotic, physiologic, and alkalotic groups were 390.0 ± 77.9, 337.3 ± 96.2, and 477.1 ± 104.1 dpm/mg of blood, respectively. There were no significant differences among the 3 groups.
Table 4 and Figure 3
show the mean regional PAs of the 10 structures for each treatment group. The only significant difference found was in the physiologic group where the PA of the colliculi was significantly greater than in the hypothalamus (0.017 ± 0.003, 0.009 ± 0.001 s1, respectively; p < 0.05).
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DISCUSSION |
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Numerous methodological differences may explain the discrepancies between our results and those previously reported. While rats are frequently used to assess the toxicity of cyanide, the toxicokinetics have not been reported. The studied species may account for some discrepancies. Furthermore, in contrast with others, we performed repeated blood sampling in the early phase after the iv injection. A previous study performed in mice using a nontoxic dose of labeled cyanide showed that tissue distribution, assessed by means of whole-body autoradiography, was largely complete by as early as 5 min after iv administration (Clemedson et al., 1960). We observed a very rapid distribution of cyanide with a mean T1/2 in whole blood of about 22 s, which is consistent with the equally rapid onset of cyanide toxicity.
The reported apparent volume of distribution of cyanide varies according to species and among investigators: 0.075 l/kg in humans (Schulz et al., 1982), and 0.209 l/kg (Bright and Marrs, 1988
) or 0.498 l/kg in dogs (Sylvester et al., 1983
). However, these apparent volumes of distribution appear rather low, suggesting a very limited tissue penetration of cyanide. Indeed, the previous reported apparent volumes of distribution are consistent with a sequestration of cyanide partly in the intravascular space (Bright and Marrs, 1988
; Sylvester et al., 1983
) or extracellular compartment (Sylvester et al., 1983
). In contrast, we found a larger apparent volume of distribution (i.e., 0.83 l/kg) than previously reported. We believe that our data are more consistent with the lipophilic properties of cyanide (Oldendorf, 1974
), and with its intracellular action at a mitochondrial level in many tissues.
Variations in the pH of blood or urine influence the pharmacokinetics of numerous xenobiotics including salicylate (Cumming et al., 1964; Goldberg et al., 1961
; Hill, 1973
; Prescott et al., 1982
), barbital (Brodie et al., 1960
), phenobarbital (Goldberg et al., 1961
; Waddell and Butler, 1957
), acetazolamide (Goldberg et al., 1961
), pentachlorophenol (Uhl et al., 1986
), hexachlorophene (Flanagan et al., 1995
), and chlorophenoxy herbicides such as 2,4-dichlorophenoxyacetic acid, and 4-chloro-2-methylphenoxypropionic acid (Flanagan et al., 1990
; Prescott et al., 1979
).
Modulation of arterial pH alters not only the renal excretion but also the tissue distribution of weak acids, whether modified via metabolic (Brodie et al., 1960; Flanagan et al., 1995
; Waddell and Butler, 1957
) or respiratory (Goldberg et al., 1961
; Hill, 1973
; Waddell and Butler, 1957
) mechanisms. The effects of the modulation of arterial pH on the brain tissue distribution in these studies was assessed by measuring the ratio of brain to plasma concentrations. While the degree of modulation may vary with the mechanism of induction, the end result is predictable: an increase in arterial pH decreases brain tissue distribution while acidification has the opposite effect.
Toxic doses of cyanide are known to cause both intracellular acidosis (Lotito et al., 1989) and acidemia (Dodds et al., 1992
; Katsumata et al., 1980
; Salkowski and Penney, 1995
). Furthermore, a toxic dose of cyanide has been shown to significantly increase the blood-brain barrier permeability (Olesen, 1986
). Thus, in order to study the effects of respiratory acidosis/alkalosis per se, we chose to study the distribution of a nontoxic dose of cyanide.
We measured the permeability-area product of cyanide into the brain rather than the ratio of brain to blood 14CN activities for several reasons. The determination of a meaningful ratio of brain to blood concentrations requires that the distribution be at equilibrium. However, cyanide is rapidly metabolized to thiocyanate by a ubiquitous enzyme, rhodanese, which is present throughout the body, including the brain (Schulz, 1984; Way, 1984
). In this context, the measurement of 14C radioactivity does not permit the distinction of cyanide from its metabolite. Thus, measurement of the permeability-area product during the distribution phase permits the assessment of the effects of pH while minimizing the effect of metabolism. In order to respect the limits of Ohno's method, we performed a preliminary kinetic study demonstrating that blood and brain 14CN activities were measured during the phase of distribution.
Cyanide concentrations are usually measured in whole blood. However, cyanide rapidly accumulates into erythrocytes (McMillan and Svoboda, 1982; Vesey and Wilson, 1978
) while the plasma cyanide is the biochemically active fraction that determines tissue levels and toxic effects (Vesey, 1979
). There is considerable evidence that cyanide toxicity correlates better with plasma cyanide concentrations (Christel et al., 1977
; Marrs and Bright, 1987
; Marrs et al., 1982
, 1985
). Thus, in the distribution study, we studied plasma rather than whole blood 14CN activity.
We found no significant effect of respiratory acidosis-alkalosis on the regional blood volumes as measured by 3H sucrose activity. It should be noted that the regional blood volumes we measured in animals in the physiologic condition were in the same range as those previously reported by Ohno et al. (1978).
We found a low PA value at physiological pH for cyanide of 0.011 ± 0.001 s1. The in vivo kinetics of the penetration of cyanide into the brain have been poorly investigated. In a whole-body autoradiography study in mice, the central nervous system had the lowest activity of all the tissues examined (Clemedson et al., 1960). Postmortem findings showed that cyanide concentrations in both white and gray matter of sheep killed by an intramuscular injection of KCN were lower than the blood concentrations. The mean concentration of cyanide found in the brain was 2730% of the mean concentration in whole blood (Ballantyne, 1975
). Furthermore, in fatal human cases of acute cyanide poisoning, the brain concentrations were consistently very much lower than the blood concentrations (Ballantyne and Marrs, 1987
). In contrast, Oldendorff reported a high olive oil partition coefficient and a high brain uptake index for cyanide (Oldendorf, 1974
). These conflicting results require further studies to clarify the mechanisms and the in vivo kinetics of the penetration of cyanide into the brain at both nontoxic and toxic concentrations.
Our data show that respiratory acidification and alkalinization induce a significant effect on the rapidity of the distribution of intravenously administered cyanide into the brain. This result was unexpected as the pKa of cyanide of 8.99 at 35°C (Izatt et al., 1962) is well above the upper limit of pKa considered to be significantly influenced by alteration of physiologic pH (Rowland and Tozer, 1995
). Both respiratory acidosis (pH: 7.07 ± 0.01) and alkalosis (pH: 7.58 ± 0.01) significantly modified the permeability-area product in 7 of the 10 studied brain structures.
The same dose of labeled cyanide was administered to animals in the 3 treatment groups. Accordingly, there were no significant differences of the 14CN activities measured in the blood specimen collected at the neck after decapitation nor in the arterial plasma specimens. In contrast, the PAs in animals of the acidotic group were consistently greater than the PAs measured in the alkalotic group. Thus, respiratory acidosis increased the distribution of cyanide into rat brain in comparison with respiratory alkalosis. As the distribution of cyanide into neuronal tissue was shown to be a nonenergy-dependent process (Borowitz et al., 1994), the distribution of cyanide into the brain depends on the effect of respiratory acidosis/alkalosis on: (1) the binding of cyanide to plasma proteins, (2) the ratio of nonionized to ionized forms of cyanide, and (3) the cerebral blood flow (Goldberg et al., 1961
). At micromolar concentrations, 60% of cyanide is bound to plasma proteins (Christel et al., 1977
). However, we used an extremely low dose of cyanide. Such a low dose may modify the binding of cyanide to proteins and red blood cells, and consequently its tissue distribution pattern. Furthermore, we are not aware of any study dealing with the effect of modulation of blood pH on the binding of cyanide to plasma proteins. Unfortunately, we did not measure the cerebral blood flow in our study. Numerous factors may result in a modification of the cerebral blood flow in our study; these include not only the effects of respiratory acidosis/alkalosis (Hossmann and Blöink, 1981
; Kety and Schmidt, 1948
), but also ketamine (Hougaard et al., 1974
) and PaO2 (Kety and Schmidt, 1948
). However, there was no significant difference of the PaO2, and we used the same anesthetic agents in the 3 treatment groups. Respiratory acidosis dramatically increases the cerebral blood flow in rats, while respiratory alkalosis decreases it (Hossmann, 1990
). The pKa of cyanide is 8.99 at 35°C (Izatt et al., 1962
). According to the Henderson-Hasselbach equation, the nonionized to ionized ratio of cyanide would be 96.1 at a pH of 7.58, and 98.8 at a pH of 7.07. These data suggest that respiratory acidosis/alkalosis can significantly modify the nonionized to ionized ratio of cyanide.
Our study suffers several limitations. We studied the distribution of cyanide into the brain at only 30 s after its administration. Thus, we have no insight regarding the duration of the effect of the modulation of arterial pH on the brain distribution of cyanide. Furthermore, we cannot clarify the brain structure(s) in which 14CN activity accumulates. In the study of Clemedson et al. (1960), the central nervous system seemed to have the lowest activity of all the tissues examined. This may be due to a special process existing at the level of the blood-brain barrier. Thus, 14CN activity measured in whole brain may correspond to cyanide in the endothelial cells of the blood-brain barrier and not to cyanide in the brain tissue. Other methods such as brain microdialysis (Benveniste and Huttemeier, 1990) or capillary depletion (Triguero et al., 1990
), allowing access to the postcapillary compartment, would give meaningful results regarding the effect of modulation of arterial pH on the distribution of cyanide into the brain.
The range of arterial pH used in this study may be encountered in acute human poisonings. There was a 47% reduction of the permeability-area product of cyanide into the brain under alkaline conditions compared with acidosis. This fact may be of great importance in the clinical management of human cyanide poisoning, especially in the setting of smoke inhalation, where inhalation of high concentrations of carbon dioxide may cause acidosis and augment tissue distribution of cyanide. Furthermore, our data suggest that respiratory alkalosis may be protective with regard to the rapidity of cyanide distribution into the brain. However, we studied a nontoxic dose of cyanide. Thus, definitive conclusions about the role of respiratory acidosis/alkalosis in cyanide poisoning must await studies employing toxic doses.
In summary, the pharmacokinetics of a nontoxic dose of cyanide administered intravenously to rats follows a 3-compartment model. The distribution is very rapid (whole blood T1/2 = 21.6 ± 3.3 s) with an apparent volume of distribution of 0.83 l/kg. The modulation of arterial blood pH by variation of PaCO2 significantly modifies the cerebral distribution of a nontoxic dose of cyanide in rats. At a mean arterial pH of 7.58 ± 0.01, the rapidity of cyanide distribution into the brain assessed by the measurement of the permeability-area product was 43% of that measured at a pH of 7.07 ± 0.01. This effect of pH on cyanide distribution does not appear to be limited to specific areas of the brain, with 7 of 10 structures studied showing significant differences between acidotic and alkalotic conditions. Thus, modulation of arterial pH by altering PaCO2 may induce significant effects on the brain uptake of cyanide.
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NOTES |
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