Cardiovascular, metabolic and neurologic effects of acute carbon monoxide poisoning in the rat

Acute severe carbon monoxide poisoning was investigated in a modified Levine preparation. The rats inhaled 2700 p.p.m. CO for 90 min (COHb = 80%). Body temperature, heart rate and carotid systemic and 'stump' blood pressure declined sharply during CO exposure. By 2 and 4 h post-CO, body temperature and blood pressure had not renormalized, while heart rate was elevated. Blood glucose was unchanged at termination of CO exposure, but increased from 115 mg/dl to 191 mg/dl by 2 h post-CO. Hematocrit increased significantly during CO exposure, but no change in plasma volume was observed. Many rats showed one-sided muscle weakness and unidirectional rotation. By 4 h post-CO, behaviorally-assessed neurologic deficit was strongly correlated with an increase in left cerebral hemisphere water content, demonstrating a direct relationship between brain edema and dysfunction resulting from CO poisoning.     

Cardiovascular, metabolic and neurologic effects of carbon monoxide and cyanide in the rat.

Levine-prepared, female Sprague-Dawley rats were used to investigate the effects of carbon monoxide (CO) and cyanide (CN) on heart rate, blood pressure, hematocrit, body temperature, blood glucose, lactate, and neurologic function. Rats were exposed to either 2400 ppm CO, 1500 ppm CO, 4 mg/kg NaCN, or both 1500 ppm CO and 4 mg/kg NaCN for 90 min, followed by 4 h of room air recovery. Following exposure to 2400 ppm CO, rats exhibited a significant bradycardia which normalized by 2 h of recovery. All groups exhibited an initial hypotension which was either maintained or exaggerated during exposure in all but the rats exposed to CN, and which returned to pre-exposure values by 90 min. All groups experienced a significant hypothermia during the exposure period, with those in the 1500 ppm CO or the CN returning to initial values over the recovery period. The only significant change in hematocrit was due to 2400 ppm CO (4.1% increase). During exposure, all groups experienced an initial surge in glucose concentration which was maintained in all but rats exposed to 2400 ppm CO. The greatest hyperglycemic response resulted from the combination of CO and CN, whereas 2400 ppm CO produced the smallest. CN alone produced no significant rise in lactate concentration. However, lactate concentration in all other groups was significantly elevated during the exposure period, returning to initial values by 4 h of recovery. Lactate concentrations and neurologic deficit in rats exposed to 1500 ppm CO, when added to those rats treated with CN, closely approximated the lactate and neurologic deficit of the combination treatment. Neurologic deficit was greatest in rats exposed to 2400 ppm CO. While in most cases the responses of the rats to CO and CN differed whether the substances were administered alone or in combination, a synergistic relationship is not suggested. An additive or less than additive relationship is more likely.     

Hypothermia protects brain function in acute carbon monoxide poisoning

The role of body temperature in the morbidity and mortality resulting from acute severe carbon monoxide (CO) poisoning (2400 ppm CO, 90 min) was investigated using an unanesthetized animal model. Modified Levine prepared female rats (left common carotid artery and jugular cannulated) displayed a lower rate of recovery period (4 hr) re-warming, and an increased mortality rate and behaviorally-assessed neurologic index (NI) compared to normal rats. This indicated their greater susceptibility to CO hypoxia, although the degree of CO-induced hypothermia was the same in both groups. The whole-body cooling of Levine rats to a similar extent prior to CO exposure increased somewhat the post-CO re-warming rate, and marginally decreased NI and mortality during CO exposure (in-CO). In contrast, maintenance of constant body temperature by external heating during CO exposure resulted in a negative post-CO re-warming rate and sharply increased NI and in-CO mortality. Normal euthermic rats were much less severely affected by CO. The results suggest that hypothermia, whether CO-induced or produced by prior cooling, provides measurable protection of brain function during acute severe CO poisoning, and that maintenance of body temperature increases in-CO mortality and interferes with ability to thermoregulate and increases NI in survivors.     

Effects of ethanol in acute carbon monoxide poisoning

The combined effects of ethyl alcohol (ETOH) intoxication and carbon monoxide (CO) poisoning were studied in the Levine-prepared rat. Infusion or injection of ETOH before and during 90 min of CO exposure to blood levels 2-4 times those considered legally drunk in humans, increased survival at 2400 ppm, and extended the tolerance time at 2400 ppm and 3000 ppm. CO exposure produced the usual hypothermia, hypotension and hemoconcentration; these responses were not altered by concurrent ETOH treatment. Blood ETOH concentration was increased in the presence of CO, and this was related to CO concentration. Although ETOH did not alter the average degree of hypoglycemia seen during the later stages of CO exposure, rats with the highest ETOH concentration tended to have the lowest blood glucose. ETOH increased the magnitude of the hyperglycemic rebound during recovery from exposure to both CO concentrations. Moreover, the magnitude of the recovery hyperglycemic rebound was directly related to the magnitude of the previous hypoglycemia, at both CO concentrations, with or without ETOH. Rats dying during exposure to both CO concentrations were severely hypoglycemic, whereas survivors maintained more or less normal blood glucose concentrations. The results suggest that the presence of ETOH during CO poisoning increases blood ETOH to higher than expected levels and provides a significant degree of survival protection.     

Magnetic resonance imaging of the rat brain following acute carbon monoxide poisoning.

Magnetic resonance (MR) may be used for repeatedly and non-invasively imaging the brain. Until now, no studies have used this approach to study the effects of carbon monoxide (CO) poisoning in a defined animal model. Conscious, Levine-prepared female rats (unilateral carotid artery and jugular vein occlusion) were exposed to 2400 ppm CO for 90 min, with or without the infusion of 50% glucose solution; CO-stimulated increases in blood glucose and lactate occurred in both groups, while blood pressure and body temperature fell. One to four hours following termination of CO exposure, increased cortical pixel intensity, cortical surface area and brain midline shift were observed on the operated side of the brain in some rats of both groups (i.e. responders = R), providing evidence of edema. At sacrifice, 5 h following termination of CO exposure, gross water content was increased on the left side in the corresponding cortical slices in R rats, providing another measure of edema. Significant positive correlations were found between left to right pixel intensity difference and water content difference, and between the extent of midline shift and water content difference. The elevations of blood glucose and lactate concentrations, and the magnitudes of CO-induced hypothermia and hypotension were similar to those in past studies, but appeared to exert no effect on the severity of cortical edema in terms of differences in pixel intensity, surface area, midline shift or gross tissue water content. Thus, the observed differences between the R rats is not explained by the available data.(ABSTRACT TRUNCATED AT 250 WORDS)     

Blood lactate and catecholamine levels in the carbon monoxide-exposed rat: the response to elevated glucose.

Previous studies have shown that elevated blood glucose is detrimental to the outcome in acute carbon monoxide (CO) poisoning. The present goals were to characterize the blood lactate and catecholamine changes and to determine whether elevated blood glucose results in increases in the levels of these substances. Two groups of adult Sprague-Dawley, Levine-prepared, female rats (n = 22 each) were exposed to 2400 ppm CO for 90 min: one group received nothing (CO alone), while the other group was infused with a 50% glucose solution (4 ml/kg) (CO + glucose). The usual hypothermia, hypotension, bradycardia and hemoconcentration associated with acute severe CO poisoning were observed. Survival rates were 68% and 54% in the CO alone and CO + glucose groups, respectively. Arterial blood pressure tended to decline more in rats that died; the difference was significant in the CO + glucose group. In the CO alone group, plasma glucose concentration was significantly lower after CO exposure in rats that died than in survivors (35 +/- 15 vs. 99 +/- 16 mg/dl). In the CO + glucose group, glucose concentration was significantly higher after 45 min in rats that died (d) than in survivors (s) (447 +/- 29 vs. 324 +/- 31 mg/dl). Elevated blood glucose in the CO + glucose group failed to significantly increase blood lactate; however, lactate tended to be higher in rats that died in both groups [CO alone group: 175 +/- 17 (d) vs. 138 +/- 9 (s); CO + glucose group: 154 +/- 10 (d) vs. 143 +/- 8 (s)]. Plasma epinephrine and norepinephrine increased significantly 6-10-fold and 2-6-fold in each of the two groups, respectively; however, catecholamine levels were not related to either the administration of glucose or survival. With regard to CO poisoning in this animal model, the results do not support the hypotheses that elevated blood glucose exacerbates the increase in blood lactate, that increased catecholamine increases glucose, or that greater CO-induced hypoglycemia results from increased lactate production. The results do show that death is related to abnormally high or low blood glucose, but that it is not due to higher blood lactate or catecholamine levels.     

Acute carbon monoxide poisoning in an animal model: the effects of altered glucose on morbidity and mortality

An animal in model which the common carotid artery and the jugular vein serving one side of the brain are occluded by indwelling catheters has been used during the past few years to investigate acute carbon monoxide (CO) poisoning. This article reviews the recent research examining the pattern of changes in blood glucose concentration which results from CO exposure, and the manner in which altered glucose concentration alters neurologic outcome and mortality. At present it appears that either greatly depressed glucose or greatly elevated glucose during and/or after CO exposure increases morbidity and mortality. Cyanide (CN) poisoning, in contrast to CO, produces a different pattern of changes in blood glucose and lactate, and unlike CO, fails to slow cardiac AV conduction and ventricular repolarization. Through the use of magnetic resonance imaging and spectroscopic techniques, cerebral cortical edema and the changes in brain phosphagens have been assessed following CO poisoning in the rat. The published results as well as data from recent pilot studies are discussed in the light of our current understanding of CO toxicology.     

The effect of exposure duration on the blood level of glucose, pyruvate and lactate in acute carbon monoxide intoxication in man

Blood glucose, pyruvate and lactate were examined during hospitalization of 13 cases of acute carbon monoxide poisoning developing from short (less than or equal to 1.5 h) or long (10-14 h) exposure. CO intoxication resulted in increased blood levels of all carbohydrate metabolites studied. Increased levels of pyruvate and lactate were much more pronounced and lasted for a longer time following long, compared with short, CO exposure despite similar blood COHb level (about 40% at the beginning of hospitalization). The results showed difference in biochemical effect of short and long single exposure to CO that could not be detected by the measurement of COHb.     

Effect of isoproterenol on glucose turnover and insulin secretion in the normal dog

Infusion of epinephrine in the dog causes a sustained hyperglycemia without increasing plasma insulin, whereas infusion of isoproterenol causes a transient hyperglecemia and increased plasma insulin. To investigate the basis for these differences, rates of hepatic glucose production and overall glucose uptake were determined using a primer-constant infusion of [3-³H]glucose in normal dogs, and these were correlated with plasma insulin levels. Infusion of epinephrine (0.2 μg/kg/min) for 3 hr caused a prompt and persistent hyperglycemia. Concomitantly glucose production was increased but returned to normal by 90 min. Plasma insulin and glucose uptake did not increase. Isoproterenol infusion (0.2 μg/kg/min) for 3 hr caused a transient hyperglycemia. Glucose production and uptake were increased during the entire period. Plasma insulin was also elevated. The transient hyperglycemic response to isoproterenol, therefore, is not due to inadequate glucose production. Infusion of the beta-adrenergic blocker, propranolol, prevented the hyperglycemia and increased hepatic glucose production normally produced by isoproterenol.     

Modulation of glucose homeostasis by doxepin.

Blood glucose level (BGL) was estimated up to 4 h (3 h in case of GTT) in 18-h fasted albino rabbits following acute and chronic (one month) feeding of doxepin and thereafter for another 8 days together with either insulin or glibenclamide or adrenaline. A single dose of doxepin produced significant hypoglycemia which peaked at 4 h and lasted up to 10 h. On chronic doxepin feeding there was complete attenuation of initial hypoglycemia on the 7th and 14th days, culminating into frank hyperglycemia on the 21st day. However, there was complete recovery on the 29th day exhibiting tolerance to initial hypo-as well as delayed hyperglycemia. Similarly, glucose intolerance was accentuated on the 8th day followed by a gradual recovery on the 15th and 22nd days, culminating in disappearance of glucose intolerance on the 30th day. The hypoglycemic effect of insulin was markedly potentiated in chronically doxepin fed animals which was further enhanced on continuing administration of both agents. Profound hypoglycemia was observed during GTT in such animals. The hyperglycemic effect of adrenaline was enhanced in chronically doxepin fed animals, which may be due to TCA induced enhancement of the response of exogenous adrenaline. Suppression of this hyperglycemia with continued administration of both drugs seems to be due to subsensitivity of alpha 2-adrenoceptors. Additive hyperglycemia was observed during GTT in such animals.     

The time-dependent protective effect of hyperbaric oxygen on neuronal cell apoptosis in carbon monoxide poisoning

Introduction:?The progressive clinical course with delayed neurological damage in carbon monoxide (CO) poisoning may be due to neuron apoptosis. The usefulness of hyperbaric oxygen (HBO) in different time periods after CO exposure in neuronal cell apoptosis reduction has not been evaluated thus far. The aim was to evaluate HBO efficacy in reducing neuronal apoptosis in different time periods after CO exposure.

Methods:?Wistar rats were exposed to 3000?ppm CO in air for 60?min and 100% oxygen at a pressure of three bar for 30?min 0–12?h after CO exposure. The apoptosis was evaluated by immunohistochemical analysis with antibodies against activated caspase-3 and the percentage of caspase-3 positive hippocampal ganglionic cells was reported.

Results:?It was shown that CO poisoning results in ganglionic cell apoptosis. The percentage of apoptotic cells in rats exposed to CO was the highest (32%), whereas the percentage of apoptotic cells in rats exposed to HBO 0 and 1?h after CO was similar with a lower percentage than rats exposed to CO. The percentage of apoptotic cells in rats exposed to HBO 3 and 5?h after CO was similar with a lower percentage than rats exposed to HBO 0 and 1?h after CO. The percentage of apoptotic cells in rats exposed to HBO 7–12?h after CO was similar with a higher percentage than rats exposed to HBO 5?h after CO.

Conclusion:?HBO has a time-dependent protective effect on CO-induced neuron apoptosis with the highest efficiency at 3 and 5?h after CO poisoning.     

Subacute inhalation exposure to ozone induces systemic inflammation but not insulin resistance in a diabetic mouse model

Epidemiological studies suggest that diabetics may be more susceptible to the adverse health effects from exposure to high ambient concentrations of ozone, the primary oxidant gas in photochemical smog. While increased morbidity and mortality from ozone inhalation has been linked to disruption of normal cardiovascular and airway functions, potential effects on glucose and insulin homeostasis are not understood. We tested the hypothesis that ozone exposure would worsen metabolic homeostasis in KKAy mice, a genetic diabetic animal model. Male KKAy mice were exposed to 0.5?ppm ozone for 13 consecutive weekdays, and then assessed for airway, adipose and systemic inflammation, glucose homeostasis, and insulin signaling. Ozone exposure increased plasma TNFα, as well as expression of VCAM-1, iNOS and IL-6 in both pulmonary and adipose tissues. Pro-inflammatory CD11b⁺Gr-1^lo7/4^hi macrophages were increased by 200% in adipose tissue, but unchanged in blood. Interestingly, glucose levels were not significantly different in the insulin tolerance test between air- and ozone-exposed mice, whereas fasting insulin levels and HOMA-IR in ozone-exposed animals were significantly reduced. These changes were accompanied by increased insulin signaling in skeletal muscle and liver, but not adipose tissues. Ozone also caused decrease in body weight and plasma leptin. Our results show that in addition to marked local and systemic inflammation, ozone increases insulin sensitivity that may be related to weight loss/leptin sensitization-dependent mechanisms in KKAy mice, warranting further study on the role of hyperglycemia in mediating cardiometabolic effects of ozone inhalation.     

Cardiovascular effects of subchronically low/high carbon monoxide exposure in rats

This study was designed to determine whether subchronic CO exposure ranging from 15 to 530 ppm induced modifications in the rat cardiovascular system. We investigated the degree of resistance to an in vitro transient ischemia in the hearts exposed in vivo to different CO concentrations for 1-4 weeks. Subchronic CO exposure induced dose and/or time-dependent increases (hematocrit, cardiomegaly and coronary flow). We showed an increase in the ventricular tachycardia (VT) incidence with the passing weeks of exposure, which demonstrated the proarrhythmic activity of CO even in low doses (15 ppm). The contractile recovery decreased owing to a low (50 ppm) or high (530ppm) CO exposure after a 25-min ischemia period. This diminution seems to be dependent on the increased amplitude of ischemic contracture. The present study supports the hypothesis that subchronic CO exposure, even at low levels of CO, can produce cardiovascular changes and could explain the increased risk of myocardial infarction.     

Influence of oral administration of sulfamethazine on thyroid hormone levels in Fischer 344 rats

Fischer 344 rats (810 of each sex) were divided into treatment groups and fed diets containing 0, 10, 40, 600, 1200, or 2400 ppm sulfamethazine. Serum samples were analyzed for levels of thyroid-stimulating hormone (TSH), total thyroxine (T4), total triiodothyronine (T3), and T3 uptake after 12, 18, or 24 mo of continuous dosing. There were no statistically significant differences in T3 levels or percent T3 uptake for either sex after any of the exposure periods. The serum T4 levels were lower (p less than 0.05) for females dosed at 1200 and 2400 ppm for 18 mo and for males dosed at 600, 1200, or 2400 ppm sulfamethazine for 24 mo than for those dosed at levels of 40 ppm or less. Serum TSH levels showed a general increasing trend (but not statistically significant) among animals receiving 600 ppm or more sulfamethazine. There was a significant dose-related reduction in (T3 + T4)/TSH ratio for both sexes (p less than 0.05) after 18 and 24 mo of exposure at dose levels of 600 ppm or more. A lack of response at 12 mo may have been due to the shorter treatment time. At each sacrifice period both sexes of rats fed sulfamethazine at 1200 and 2400 ppm had significantly heavier (p less than 0.05) thyroid weights than animals fed control diet. The heavier thyroid weights in the dosed animals may have resulted from increased TSH levels. The cause of reduction in serum T4 was not clearly evident. Therefore, the thyroid hormone to pituitary feedback mechanism apparently compensated for sulfamethazine effects in most animals. This would suggest that the thyroid gland was not irreversibly affected.     

Effects of toluene inhalation on behavior and expired carbon dioxide in macaque monkeys

Cynomolgus macaque monkeys received head-only exposure to 0, 100, 200, 500, 1000, 2000, 3000, and 4500 ppm toluene for 50 min while simultaneously tested for delayed matching-to-sample behavior, a test of cognitive functions. Response time increased and accuracy of matching decreased at 2000 ppm or more of toluene, indicating an attentional deficit but not specific memory effects. Behavioral indices exhibited monotonic concentration-related changes. Expired carbon dioxide (CO2), the most sensitive index, displayed an inverted U-shaped concentration-effect curve, which increased at 100 ppm (the TLV) and decreased at 4500 ppm toluene. Changes in expired CO2 provide new evidence of physiological changes at very low levels of toluene. These changes may indicate combined behavioral, respiratory, sensory, and metabolic effects. No behavioral measure exhibited either cumulative effects or tolerance to 4500 ppm during two 3-day exposures. However, both response time and expired CO2 exhibited an acute, within-session tolerance. The results indicate that brief inhalation exposure to toluene impairs cognitive and motor abilities at concentrations below those causing overt signs, such as ataxia and intention tremoring.     

Pharmacodynamics of glucose regulation by methylprednisolone. I. Adrenalectomized rats

Mechanisms related to the adverse effects of corticosteroids on glucose homeostasis were studied. Five groups of adrenalectomized (ADX) rats were given methylprednisolone (MPL) intravenously at 10 and 50 mg/kg, or a continuous 7 day infusion at rates of 0, 0.1, 0.3 mg/kg/h via subcutaneously implanted Alzet mini‐pumps. Plasma concentrations of MPL, glucose and insulin were determined at various time points up to 72 h after injection or 336 h after infusion. The pharmacokinetics of MPL was captured with a two‐compartment model. The Adapt II software was used in modeling. Injection of MPL caused a temporary glucose increase over 6 h by stimulating gluconeogenesis. The glucose changes stimulated pancreatic β‐cell secretion yielding a later insulin peak at around 10 h. In turn, insulin can stimulate glucose disposition. However, long‐term MPL treatment caused continuous hyperglycemia during and after infusion. Insulin was increased during infusion, and immediately returned to baseline after the infusion was terminated, despite the almost doubled glucose concentration. A disease progression model incorporating the reduced endogenous glucose disposition was included to capture glucose homeostasis under different treatments. The results exemplify the importance of the steroid dosing regimen in mediating pharmacological and adverse metabolic effects. This mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model quantitatively describes the induction of hyperglycemia and provides additional insights into metabolic disorders such as diabetes. Copyright © 2009 John Wiley & Sons, Ltd.     

Pulmonary biochemical effects of inhaled phosgene in rats

Three exposure regimens were used to study the time course of indicators of lung damage and recovery response to single or repeated exposures to phosgene (COCl2). Rats were sacrificed immediately or throughout a 38-d recovery period after inhalation of 1 ppm COCl2 for 4 h, at intervals during a 7-h exposure to 1 ppm phosgene, or at several time points throughout a 17-d exposure to 0.125 and 0.25 ppm COCl2 (4 h/d, 5 d/wk) and during a 21-d recovery period. Regimen 1 revealed significantly elevated lung wet weight, lung nonprotein sulfhydryl (NPSH) content, and glucose-6-phosphate dehydrogenase (G6PD) activity that stayed elevated for up to 14 d. A significant decrease in body weight and food intake was observed 1 d after exposure. Regimen 2 caused a slight depression in NPSH content but did not affect G6PD activity. Regimen 3 animals showed sustained elevations in lung wet weight, NPSH content, and G6PD activity after 7 d of exposure. No significant changes in these endpoints were observed for the 0.125 ppm COCl2 group. No consistent elevation in hydroxyproline content was seen at either exposure concentration. Light microscopic examination of lung tissue exposed to 0.25 ppm COCl2 for 17 d revealed moderate multifocal accumulation of mononuclear cells in the centriacinar region. In summary, exposure to COCl2 caused changes similar in most ways to those observed for other lower-respiratory-tract irritants.     

Changes in sleep and wakefulness following single and repeated exposures to toluene vapor in rats

Male rats with indwelling electrodes for electroencephalographic (EEG), electromyographic (EMG) and electrooculographic (EOG) recordings were exposed via inhalation to 900 ppm and 2700 ppm toluene vapor continuously for a 8-h period or repeatedly for 3 weeks at a rate of 8 h/day and 5 days/week. Rats exposed to a clean airstream under the same exposure schedules served as controls. Polygraphic recordings were made on 3 consecutive days after cessation of the single 8-h and repeated 3-week exposures to 900 ppm and 2700 ppm toluene vapor or clean airstream. Amounts of time spent in wakefulness (W), slow-wave sleep (SWS) and paradoxical sleep (PS) were quantified by visual inspection of the polygraphic records. Single exposure to toluene produced a prolonged PS latency and a long-lasting increase in SWS at the expense of depressed W, whereas repeated exposures prolonged both SWS and PS latencies, abolished the initial increase of SWS and increased the light-phase level of W on Days 1 and 2. The prolonged PS latency and the decreased light-phase PS on Day 2 induced by single exposure to toluene still persisted after repeated exposures. There were no statistically significant differences in attenuation of brain and blood toluene levels between single and repeated exposures to toluene vapor of 900 ppm and 2700 ppm.     

Consequences of brief exposure to high concentrations of carbon monoxide in conscious rats

Exposure to high-concentration carbon monoxide (CO) is of concern in military operations. Experimentally, the physiologic manifestations of a brief exposure to elevated levels of CO have not been fully described. This study investigated the development of acute CO poisoning in conscious male Sprague-Dawley rats (220-380 g). Animals were randomly grouped (n = 6) and exposed to either air or 1 of 6 CO concentrations (1000, 3000, 6000, 10,000, 12,000, or 24,000 ppm) in a continuous air/CO dynamic exposure chamber for 5 min. Respiration was recorded prior to and during exposures. Mixed blood carboxyhemoglobin (COHb) and pH were measured before and immediately after exposure. Before exposure the mean baselines of respiratory minute volumes (RMVs) were 312.6 +/- 43.9, 275.2 +/- 40.8, and 302.3 +/- 39.1 ml/min for the 10,000, 12,000 and 24,000 ppm groups, respectively. In the last minute of exposure RMVs were 118.9 +/- 23.7, 62.1 +/- 10.4, and 22.0 +/- 15.1% (p < .05) of their mean baselines in these 3 groups, respectively. Immediately after exposure, blood COHb saturations were elevated to 60.16, 63.42, and 69.37%, and blood pH levels were reduced to 7.43 +/- 0.09, 7.25 +/- 0.05, and 7.13 +/- 0.04 in the 3 groups, respectively. Mortality during exposure was 1/12 in the 12,000 ppm group and 4/12 in the 24,000 ppm group. Deaths occurred close to the end of 5 min exposure. In each animal that died by exposure, pH was <6.87 and COHb saturation was >82%. Blood pH was unaltered and no death occurred in rats exposed to CO at concentrations <6000 ppm, although COHb saturations were elevated to 14.52, 29.94, and 57.24% in the 1000, 3000, and 6000 ppm groups, respectively. These results suggest that brief exposure to CO at concentrations <10,000 ppm may produce some significant physiological changes. However, exposure to CO at concentrations >10,000 ppm for brief periods as short as 5 min may change RMV, resulting in acute respiratory failure, acidemia, and even death.