Carboxyhemoglobin as a diagnostic and prognostic biomarker of hemolytic anemias in dogs.

BACKGROUND: Endogenous production of carbon monoxide during hemoglobin metabolism leads to the formation of carboxyhemoglobin. Carboxyhemoglobin concentration is abnormally high in humans with hemolytic anemia (HA). HYPOTHESIS: Measurement of carboxyhemoglobin concentration can discriminate HA from other forms of anemia. ANIMALS: Twenty-seven dogs with HA (immune-mediated HA, n = 22; microangiopathic HA, n = 5), 27 dogs with non-HA (kidney disease, n = 14; immune-mediated thrombocytopenia, [n = 6]; miscellaneous, n = 7) and 24 nonanemic control dogs. METHODS: Prospective cohort study. Carboxyhemoglobin quantification, a CBC and biochemistry profile were performed upon admission, and survival to hospital discharge and at 30 days were the measured outcomes. Groups were compared by the Mann-Whitney and Kruskal-Wallis tests. Receiver-operator characteristic (ROC) analyses were used to examine the predictive utility of carboxyhemoglobin for the diagnosis of HA in anemic dogs. RESULTS: Carboxyhemoglobin (median [interquartile range]) differed between dogs with HA (7.7% [2.5%]) and non-HA (3.6% [1.05]; P < .001) and dogs with HA and nonanemic dogs (3.5% [0.65%]; P < .001). No difference was detected between nonHA and nonanemic dogs. The area under the ROC curve for carboxyhemoglobin as predictor of HA in anemic dogs was 0.997 (95% CI, 0.99-1.00). Three optimal cut-off points were identified, including 5.05%, 4.55% and 4.85%, with corresponding sensitivity/specificity of 92.6%/100%, 100%/92.6% and 96.3%/96.3%, respectively. Neither carboxyhemoglobin nor any of the CBC or chemistry analytes were associated with survival. CONCLUSIONS AND CLINICAL IMPORTANCE: Carboxyhemoglobin proved an excellent predictor of HA in dogs and might constitute a useful, ancillary tool for diagnosing and monitoring hemolytic anemias.

[Evolution of the carboxyhemoglobinemia and methemoglobinemia during endoscopic resection: An observational study]. / Évolution de la carboxyhémoglobinémie et de la méthémoglobinémie lors de résections endoscopiques : une étude observationnelle.

AIM OF THE STUDY: Combustion of organic tissues due to endoscopic resection could induce methemoglobin (MetHb) and carboxyhemoglobin (COHb) formation. The aim of this study is to evaluate MetHb and COHb formation in patients undergoing prostatic or bladder endoscopic procedures. METHODS: COHb and MetHb measurements were performed in 44 patients at the beginning and end of the procedure. A third measurement was done in patients who stayed more than one hour in the recovery room. Means were compared using Student t-test, simple regressions were used for quantitative variables and ANOVA for categorical variables. Multiple linear regressions were used for multivariate analysis. RESULTS: COHb increased by 0.5±0.9 % (95 % CI: 0.2 to 0.7 % P=0.001). MetHb increase was 0.0±0.4 % (95 % CI: -0.1 to 0.2 % P=0.552). In univariate analysis, the variables associated with COHb increase are the length of surgery, the amount of irrigation fluid and location (prostate or bladder) of the procedure. In the multivariate model, COHb increase is associated with the amount of liquid and the location. CONCLUSION: MetHb did not increase during endoscopic surgery. In contrast, COHb increases, and can, in some patients, exceed 2-4 %. This could be responsible for a decreased angina threshold in patients with ischemic heart disease. LEVEL OF EVIDENCE: 4.

Endogenous carbon monoxide production: a rare and detrimental complication of extracorporeal membrane oxygenation.

Extracorporeal membrane oxygenation (ECMO) is a technique that can support gas-exchange and cardiac function in patients with acute respiratory or cardiac failure that is not responsive to conservative treatment. ECMO is a high-risk procedure in critically ill patients and both technical and patient-related complications frequently occur. We report on a patient with end-stage pulmonary fibrosis (histiocytosis x), in whom ECMO was used as bridge to urgent lung transplantation. Respiratory insufficiency necessitating ECMO therapy was due to spontaneous pneumothorax with bronchopleural fistula. Access was initially made by femoral veno-venous canulation. Due to right heart failure, access was switched to veno-arterial using the two existing canulae as efferent system and implanting a third canula on the femoral artery using a graft. Despite marked hemodynamic improvement after this intervention, high flow rates creating high premembrane pressures were required to ensure oxygenation. High levels of carboxyhemoglobin (COHb) occurred, most likely due to massive mechanical hemolysis in the ECMO circuit. This may have had detrimental effects by further complicating tissue oxygenation. We recommend that COHb should routinely be checked in ECMO patients.

Monóxido de carbono: dos caras de un mismo personaje / Carbon monoxide: two sides to the same coin

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Heme oxygenase-1 messenger RNA expression is induced in peripheral blood mononuclear cells of pediatric cancer patients with systemic inflammatory response syndrome.

OBJECTIVE: To determine whether heme oxygenase-1 messenger RNA expression in peripheral blood mononuclear cells is induced in pediatric cancer patients with the systemic inflammatory response syndrome (SIRS) and whether this expression correlates with the heme oxygenase-1 products, bilirubin and carboxyhemoglobin. DESIGN: Prospective, controlled study. SETTING: A tertiary care pediatric oncology hospital. PATIENTS: Fourteen patients admitted to the intensive care unit with a diagnosis of SIRS by American College of Chest Physicians/Society for Critical Care Medicine consensus criteria and 17 control patients (off therapy, no acute illness). INTERVENTIONS: Blood for bilirubin, carboxyhemoglobin, and heme oxygenase-1 messenger RNA expression was collected at study entry. SIRS patients continued to have samples collected every 12 hrs for 1 wk or until intensive care unit discharge. Heme oxygenase-1, bilirubin, and carboxyhemoglobin levels of SIRS patients were compared with controls, and correlation between heme oxygenase-1 and products was assessed. MEASUREMENTS AND MAIN RESULTS: Within 48 hrs of study entry, maximum heme oxygenase-1 expression for all SIRS patients compared with controls was 5.5 +/- 1.0 vs. 1.1 +/- 0.1 (p < .0006). Maximum expression was > or =2.3-fold in 13 of 14 SIRS patients. Maximum heme oxygenase-1 expression also differed from minimum (5.5 +/- 1.0 vs. 1.6 +/- 0.3, p < .003). Maximum bilirubin and carboxyhemoglobin levels within 48 hrs of study entry differed between SIRS patients and controls (3.0 +/- 0.8 vs. 0.3 +/- 0.1, p = .006; and 1.2 +/- 0.2 vs. 0.6 +/- 0.1, p = .001, respectively). Bilirubin, but not carboxyhemoglobin, correlated with heme oxygenase-1 expression (p = .0013). CONCLUSIONS: Heme oxygenase-1 messenger RNA, bilirubin, and carboxyhemoglobin levels were increased within 48 hrs of admission in pediatric cancer patients with SIRS. Heme oxygenase-1 expression correlated with serum bilirubin levels. The increase in heme oxygenase-1 expression may add to the understanding of the increase in serum bilirubin observed in patients with SIRS/sepsis. These findings support a role for heme oxygenase-1 in the physiologic response to inflammatory stress.

Acute effects of combined burn and smoke inhalation injury on carboxyhemoglobin formation, tissue oxygenation, and cardiac performance.

The objective of this study was to determine the relationship between carboxyhemoglobin (COHb) formation, global oxygen transport, and cardiac performance in the acute phase of combined burn and smoke inhalation injury. Following a third degree burn of 20% of the total body surface area, adult sheep were subjected to cotton smoke (4x12 breaths) according to an established protocol. Compared with baseline (BL), the burn injury led to an immediate and sustained COHb-independent depression in myocardial contractility. Despite a progressive increase in COHb formation, up to a maximum of 78+/-3% (P < 0.001 vs BL), smoke inhalation did not further impair these hemodynamic changes. This study demonstrated that in the early stage of combined burn and smoke inhalation injury, the depression in cardiac function is basically triggered by the burn injury, whereas COHb generation secondary to cotton smoke exposure primarily contributes to pulmonary shunting.

A physiological model for predicting carboxyhemoglobin formation from exposure to carbon monoxide in rats.

A time-dependent simulation model, based on the Coburn-Forster-Kane equation, was written in Advanced Continuous Simulation Language to predict carboxyhemoglobin (HbCO) formation and dissociation in F-344 rats during and after exposure to 500 parts/million CO for 1 h. Blood-gas analysis and CO-oximetry were performed on samples collected during exposure and off-gassing of CO. Volume displacement plethysmography was used to measure minute ventilation (VE) during exposure. CO diffusing capacity in the lung (DLCO) was also measured. Other model parameters measured in the animals included blood pH, total blood volume, and Hb concentration. Comparisons between model predictions using values for VE, DLCO, and the Haldane coefficient cited in the literature and predictions using measured VE, DLCO, and calculated Haldane coefficient for individual animals were made. General model predictions using values for model parameters derived from the literature agreed with published HbCO values by a factor of 0.987 but failed to simulate experimental data. On average, the general model overpredicted measured HbCO level by nearly 9%. A specific model using the means of measured variables predicted HbCO concentration within a factor of 0.993. When experimentally observed parameter fluctuations were included, the specific model predictions reflected experimental effects on HbCO formation.

Role of endogenous carbon monoxide in neointimal formation induced by balloon-injury in rat aorta.

OBJECTIVE: The present study investigated the role of endogenous carbon monoxide (CO) in the pathogenesis of neointimal formation induced by balloon injury in rat. METHOD: Endothelial denudation of the left common carotid artery of rat was carried out by three passages of a Fogarty 2F balloon catheter. DNA, collagen and elastin contents of each intima-media were estimated; and heme oxygenase (HO) activity and CO production in vascular smooth muscle cell (VSMC) were measured after administration of HO inhibitor. RESULT: Our data showed that neointima occurred in the rat on day 7 and day 21 after balloon injury, and at the same time HO activity and CO production in VSMC were markedly increased. Administration of HO inhibitor, zinc deuteroporphyrin 2,4-bisglycol (ZnDPBG), could effectively inhibit HO activity and CO production, significantly enhance neointimal formation (aortic intima/media ratio were 21.4+/-1.8% vs 17.6+/-2.0%, P<0.05 on day 7; and 30.5+/-2.4% vs 23.0+/-2.2%, P<0.01 on day 21, respectively, compared with balloon alone group). CONCLUSION: We concluded that 1) inhibition of CO production may enhance neointimal formation induced by endothelial denudation, implying endogenous CO play an protective role in response to vascular injury, and 2) induction of HO activity may be applied clinically for preventing restenosis after angioplasty.

[Biochemical mechanisms of protective action of enomelanin during hemic hypoxia caused by carbon monoxide]. / Biokhimicheskie mekhanizmy zashchitnogo deistviia énomelanina pri gemicheskoi gipoksii, vyzvannoi ugarnym gazom.

Prophylactic injection of enomelanine has been studied for its effect on hemic hypoxia and on different parts of breathing system. The enomelanine was shown to be effective for decreasing the level of carboxyhemoglobin and for protection from succinate dehydrogenase and cytochromoxidase. The authors think that these effects of enomelanine are conditioned not only by its anti-hypoxia abilities, but also by the capacity to activate the alternative protective mechanisms of the cell.

Rate of formation of carboxyhemoglobin in exercising humans exposed to carbon monoxide.

The purpose of this study was to test the CFK equation for its prediction of the rate of formation of carboxyhemoglobin (HbCO) in exercising humans by use of measured values of the respiratory variables and to characterize the rate of appearance of HbCO with frequent blood sampling. Ten nonsmoking male subjects were exposed to carbon monoxide (CO) on two separate occasions distinguished by the level of activity. Steady-state exercise was conducted on a cycle ergometer at either a low (approximately 45 W) or moderate (approximately 90 W) power output. Each experiment began with an exposure of 3,000 ppm CO for 3 min during a rest period followed by three intermittent exposures ranging from 3,000 ppm CO for 1 min at low exercise to 667 ppm CO for 3 min at moderate exercise. Increases in HbCO were normalized against predicted values to account for individual differences in the variables that govern CO uptake. No difference in the normalized uptake of CO was found between the low- and moderate-exercise trials. However, the CFK equation underpredicted the increase in HbCO for the exposures at rest and the first exposure at exercise, whereas it overpredicted for the latter two exposures at exercise. The net increase in HbCO after all exposures (approximately 10% HbCO) deviated by less than 1% HbCO between the measured and predicted values. The rate of appearance of HbCO fits a sigmoidal shape with considerable overshoot at the end of exposure. This can be explained by delays in the delivery of CO to the blood sampling point (dorsal hand vein) and by a relatively small blood circulation time compared with other regions of the body. A simple circulation model is used to demonstrate the overshoot phenomenon.

Influence of aromatic hydrocarbons on the metabolism of dichloromethane to carbon monoxide in rats.

The influence of prior or simultaneous oral administration of benzene, toluene, o-, m-, or p-xylene on the carboxyhemoglobin (COHb) level after a single dose of dichloromethane (DCM) was investigated in male rats. Six hours after administration of DCM, 6.2 mmol/kg, the mean maximum COHb level was 9.3 +/- 1.9%. This level was significantly enhanced by prior administration of benzene (16.9 mmol/kg) at 12-24 h, of toluene (18.8 mmol/kg) at 20-28 h, of o- (16.6 mmol/kg) and m-xylene (16.3 mmol/kg) at 20-32 h, and of p-xylene (16.2 mmol/kg) at 24-32 h. The corresponding maximum COHb levels were 20.7 +/- 1.3, 18.6 +/- 1.1, 18.9 +/- 1.1, 22.7 +/- 1.2, and 13.2 +/- 1.0%, respectively. After simultaneous administration of both DCM and the aromatic solvent, the COHb formation was inhibited: values of 1.3 +/- 0.3, 1.7 +/- 0.4, 3.6 +/- 0.2, 1.9 +/- 0.2, and 2.0 +/- 0.2% COHb, respectively, were found. The inhibition was also evident when DCM was administered 12 h after toluene or m-xylene and 12, 16 or 20 h after p-xylene. The inhibition was dose-related as seen after combined gavage of o-, m-, or p-xylene and DCM. The o- and m-, but not the p-methylhippuric acid (MHA) excretion in the urine was significantly reduced after simultaneous administration of equimolar doses of DCM and the corresponding xylenes. In conclusion, it seems that the stimulation or inhibition of the COHb formation after DCM caused by pretreatment with or by simultaneous administration of the aromatic solvents is due to the induction of cytochrome P-450 IIE1 or to competition between DCM and the aromatic solvent on this isozyme of cytochrome P-450.

[The effect of sodium nitrite, stable radical of 4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl and their mixture on methemoglobin formation]. / Vliianie nitrita natriia, stabil'nogo radikala 4-oksi-2,2,6,6-tetrametilpiperidin-1-oksila i ikh smesi na metgemoglobinoobrazovanie.

Sodium nitrite oxidizes the mice hemoglobin in vitro. The stable radical 4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl inhibits the process of oxidation. This effect is achieved when the radical is introduced into the system before sodium nitrite. The same effect is achieved in vivo. The level of methemoglobin is not influenced when mice get only the radical in comparison with the control group. We have not found the changes in the level of carboxyhemoglobin in the groups of mice that got the sodium nitrite, the radical and their mixture in comparison with the control group.

Derivative spectrophotometric studies on cytotoxic effects of carbon monoxide.

Characteristics of cytochrome oxidase prepared from hearts of Sprague-Dawley male rats were studied with the use of the fourth derivative spectrophotometry in respect to the cytotoxic effects of carbon monoxide (CO). CO-exposed rats tended to show lower specific activities of cytochrome oxidase than control and recovered rats. Moreover, there was a significant difference in the fourth derivative spectral features of the enzyme: CO-exposed groups indicated peaks at 412 nm in the spectra while controls at 408 nm. This spectral difference seemed to reflect specific effect of CO on cytochrome oxidase, though such trace remained for not more than a day after death.

Acute effect of cigarette smoking on physiologic response to graded exercise.

To assess the acute effect of cigarette smoking on physiologic response to graded exercise, eight physical education students were tested. The protocol included running on a treadmill for 5-min periods at the speed of 6, 8, 10, and 12 km/h. Each subject performed the exercise twice 1 week apart, once after abstaining from smoking for 24 h and once immediately after smoking two cigarettes. The following measurements were performed at each work load: HR, oxygen consumption, tidal volume, breathing frequency, pulmonary ventilation, and blood lactate. Running velocity corresponding to 4 mM lactate and to 170 HR were calculated. The average HR was higher after smoking at rest and at all work loads tested (P less than 0.05). The average VO2 was lower after smoking at all work loads above 6 km/h (P less than 0.05), and VE/VO2 was significantly higher (P less than 0.001) during smoking at all work loads above 6 km/h. No changes were found in the other parameters measured. No difference was found in the calculated work load corresponding to 4 mM blood lactate or 170 HR. It is concluded that although the acute effect of smoking two cigarettes by subjects accustomed to smoking does not dramatically affect their work capacity, it does significantly change their physiologic response, manifested by a higher HR, lower VO2, and lower breathing efficiency.

Metabolism of inhaled dihalomethanes in vivo: differentiation of kinetic constants for two independent pathways.

Dihalomethanes are metabolized by two major pathways: an oxidative, cytochrome P-450-mediated pathway that has been previously thought to yield only CO, and a glutathione (GSH)-dependent one that yields CO2. Both give 2 mol of halide ion. We studied the kinetic properties of the two pathways in vivo by exposing male rats to various inhaled concentrations of CH2Cl2,CH2F2, CH2FCl, CH2BrCl, and CH2Br2 and determining end-exposure carboxyhemoglobin (HbCO) and plasma bromide (where appropriate). Closed atmosphere gas uptake studies were employed for CH2F2, CH2FCl, CH2Cl2, and CH2BrCl metabolism. A physiologically based kinetic model was used to determine kinetic constants based on gas uptake or plasma bromide data and these constants were used to predict HbCO concentrations. Oxidation was high affinity, low capacity. The maximum metabolic rates for this pathway with CH2Br2, CH2BrCl, and CH2Cl2 were, respectively, 72, 54, and 47 mumol metabolized/kg/hr. CH2FCl did not undergo significant oxidative metabolism and appears more like CH3C1 than a dihalomethane in its metabolic reactivity. The GSH pathway was low affinity, but high capacity and could be described as a single first-order process at all accessible exposure concentrations. The rate constant for this first-order GSH-dependent pathway was related as CH2BrCl greater than CH2Cl2 congruent to CH2FCl greater than CH2Br2 greater than CH2F2. Presumably bromide is a preferred leaving group but steric hindrance in the initial reaction with GSH is important with CH2Br2. We also studied the effects of pyrazole (which inhibits microsomal oxidation) and 2,3-epoxypropanol (which depletes GSH) on dihalomethane metabolism. Pyrazole abolished CO production from CH2Br2, CH2BrCl, and CH2Cl2. GSH depletion did not change the yield of halide ion from the high-affinity pathway; it did increase the steady-state HbCO concentrations with CH2Cl2 and CH2ClBr, but not with CH2Br2. The putative formyl chloride (FC) intermediate from CH2Cl2 or CH2BrCl appears to have a longer life than the formyl bromide from CH2Br2 and a significant portion of the FC (congruent to 20-30%) may react with other cellular nucleophiles instead of spontaneously decomposing to CO. This portion of the oxidative pathway probably yields CO2.

Safety standards for occupational exposure to dichloromethane.

The toxic effects of dichloromethane (DCM) are reviewed. Human dose-response data, tolerance levels, and the effects of physical exercise and smoking on DCM toxicity are reported. Finally, occupational exposure, current NIOSH (1976) recommendations, and the consequences of ill-health as they pertain to DCM in the workplace are discussed.

Physiological and toxicological aspects of smoke produced during the combustion of polymeric materials.

Normally one expects that flame contact is the major cause of injury and death during fires. Analysis of the factors involved in numerous fires has revealed that most deaths were not due to flame contact, but were a consequence of the production of carbon monoxide, nitrogen oxides, and other combustion products, such as aldehydes, low molecular weight alcohols, hydrogen cyanide, and other noxious species. The major emphasis within the scope of this paper relates to the physiological and toxicological aspects of smoke produced during the combustion of materials. Special emphasis is directed toward laboratory procedures which have been developed to determine the qualitative and quantitative analysis of smoke, factors pertaining to smoke development, and to measure the response of laboratory animals exposed to smoke. The effects that fire retardants, incorporated into polymeric materials as a means of improving flammability characteristics, may have on smoke development, the mechanism of polymer degradation, and on the survival response of laboratory animals are also considered.