Acute high level carbon monoxide (CO) exposure can cause immediate cardio-respiratory arrest in anyone, but the effects of lower level exposures in susceptible persons are less well known. The percentage of CO-bound hemoglobin in blood (carboxyhemoglobin; COHb) is a marker of exposure and potential health outcomes. Indoor air quality guidelines developed by the World Health Organization and Health Canada, among others, are set so that CO exposure does not lead to COHb levels above 2.0%, a target based on experimental evidence on toxicodynamic relationships between COHb and cardiac performance among persons with cardiovascular disease (CVD). The guidelines do not consider the role of pathophysiological influences on toxicokinetic relationships. Physiological deficits that contribute to increased CO uptake, decreased CO elimination, and increased COHb formation can alter relationships between CO exposures and resulting COHb levels, and consequently, the severity of outcomes. Following three fatalities attributed to CO in a long-term care facility (LTCF), we queried whether pathologies other than CVD could alter CO-COHb relationships. Our primary objective was to inform susceptibility-specific modeling that accounts for physiological deficits that may alter CO-COHb relationships, ultimately to better inform CO management in LTCFs.

We reviewed experimental studies investigating relationships between CO, COHb, and outcomes related to health or physiological outcomes among healthy persons, persons with CVD, and six additional physiologically susceptible groups considered relevant to LTCF residents: persons with chronic obstructive pulmonary disease (COPD), anemia, cerebrovascular disease (CBD), heart failure, multiple co-morbidities, and persons of older age (≥ 60 years).

We identified 54 studies published since 1946. Six studies investigated toxicokinetics among healthy persons, and the remaining investigated toxicodynamics, mainly among healthy persons and persons with CVD. We identified one study each of CO dynamics in persons with COPD, anemia and persons of older age, and no studies of persons with CBD, heart failure, or multiple co-morbidities. Considerable heterogeneity existed for exposure scenarios and outcomes investigated.

Limited experimental human evidence on the effects of physiological deficits relevant to CO kinetics exists to support indoor air CO guidelines. Both experimentation and modeling are needed to assess how physiological deficits influence the CO-COHb relationship, particularly at sub-acute exposures relevant to indoor environments. Such evidence would better inform indoor air quality guidelines and CO management in indoor settings where susceptible groups are housed.

Acute carbon monoxide (CO) poisoning is the most common cause of poisoning and poisoning-related death in the United States. It manifests as broad spectrum of symptoms ranging from mild headache, nausea, and fatigue to dizziness, syncope, coma, seizures resulting in cardiovascular collapse, respiratory failure, and death. Cardiovascular complications of CO poisoning has been well reported and include myocardial stunning, left ventricular dysfunction, pulmonary edema, and arrhythmias. Acute myocardial ischemia has also been reported from increased thrombogenicity due to CO poisoning. Myocardial toxicity from CO exposure is associated with increased short-term and long-term mortality. Carboxyhemoglobin (COHb) levels do not correlate well with the clinical severity of CO poisoning. Supplemental oxygen remains the cornerstone of therapy for CO poisoning. Hyperbaric oxygen therapy increases CO elimination and has been used with wide variability in patients with evidence of neurological and myocardial injury from CO poisoning, but its benefit in limiting or reversing cardiac injury is unknown. We present a comprehensive review of literature on cardiovascular manifestations of CO poisoning and propose a diagnostic algorithm for managing patients with CO poisoning.

The heme oxygenase (HO)/carbon monoxide (CO) system is a physiological feedback loop orchestrating various cell-protective effects in response to cellular stress. The therapeutic use of CO is impeded by safety challenges as a result of high CO-Hemoglobin formation following non-targeted, systemic administration jeopardizing successful CO therapies as of this biological barrier. Another caveat is the use of CO-Releasing Molecules containing toxicologically critical transition metals. An emerging number of local delivery approaches addressing these issues have recently been introduced and provide exciting new starting points for translating the fascinating preclinical potential of CO into a clinical setting. This review will discuss these approaches and link to future delivery strategies aiming at establishing CO as a safe and effective medication of tomorrow.

Carbon monoxide (CO) is a colorless, odorless, nonirritant gas that accounts for numerous cases of CO poisoning every year from a variety of sources of incomplete combustion of hydrocarbons. These include poorly functioning heating systems, indoor propane-powered forklifts, indoor burning of charcoal burning briquettes, riding in the back of pick-up trucks, ice skating rinks using propane-powered resurfacing machines, and gasoline-powered generators that are not in correct locations. Once CO is inhaled it binds with hemoglobin to form carboxyhemoglobin (COHb) with an affinity 200 times greater than oxygen that leads to decreased oxygen-carrying capacity and decreased release of oxygen to tissues leading to tissue hypoxia. Ischemia occurs with CO poisoning when there is loss of consciousness that is accompanied by hypotension and ischemia in the arterial border zones of the brain. Besides binding to many heme-containing proteins, CO disrupts oxidative metabolism leading to the formation of free radicals. Once hypotension and unconsciousness occur with CO poisoning, lipid peroxidation and apoptosis follow. Because COHb has a short half-life, examination of other biomarkers of CO neurotoxicity that reflect inflammation or neuronal damage has not demonstrated consistent results. The initial symptoms with CO exposure when COHb is 15-30% are nonspecific, namely, headache, dizziness, nausea, fatigue, and impaired manual dexterity. However individuals with ischemic heart disease may experience chest pain and decreased exercise duration at COHb levels between 1% and 9%. COHb levels between 30% and 70% lead to loss of consciousness and eventually death. Following resolution of acute symptoms there may be a lucid interval of 2-40 days before the development of delayed neurologic sequelae (DNS), with diffuse demyelination in the brain accompanied by lethargy, behavior changes, forgetfulness, memory loss, and parkinsonian features. Seventy-five percent of patients with DNS recover within 1 year. Neuropsychologic abnormalities with chronic CO exposure are found even when magnetic resonance imaging (MRI) and magnetic resonance spectroscopy are normal. White-matter damage in the centrum semiovale and periventricular area and abnormalities in the globus pallidus are most commonly seen on MRI following CO exposure. Though not as common, toxic or ischemic peripheral neuropathies are associated with CO exposure in humans and animals. The cornerstone for treatment for CO poisoning is 100% oxygen using a tight-fitting mask for greater than 6 hours. The indications for treatment with hyperbaric oxygen to decrease the half-life of COHb remain controversial.

Measurement of biological indicators of physiological change may be useful in evaluating the effectiveness of stove models, which are intended to reduce indoor smoke exposure and potential health effects.

We examined changes in exhaled carbon monoxide (CO), percentage carboxy-hemoglobin, and total hemoglobin in response to the installation of a chimney stove model by the Juntos National Program in Huayatan, Peru in 2008.

Biomarkers were measured in a convenience sample comprising 35 women who met requirements for participation, and were measured before and three weeks after installation of a chimney stove. The relationships between exposure to indoor smoke and biomarker measurements were also analyzed using simple linear regression models.

Exhaled CO reduced from 6.71 ppm (95% CI 5.84-7.71) to 3.14 ppm (95% CI 2.77-3.66) three weeks after stove installation (P < 0.001) while % COHb reduced from 1.76% (95% CI 1.62-1.91) to 1.18% (95% CI 1.12-1.25; P < 0.001). Changes in exhaled CO and % COHb from pre- to post-chimney stove installation were not correlated with corresponding changes in exposure to CO and PM2.5 even though the exposures also reduced after stove installation.

Exhaled CO and % COHb both showed improvement with reduction in concentration after the installation of the chimney cook stoves, indicating a positive physiological response subsequent to the intervention.

This study was undertaken to determine whether there was an association between air pollutant levels and hospital admissions for congestive heart failure (CHF) in Kaohsiung, Taiwan. Hospital admissions for CHF and ambient air pollution data for Kaohsiung were obtained for the period 1996-2004. The relative risk of hospital admission was estimated using a case-crossover approach, controlling for weather variables, day of the week, seasonality, and long-term time trends. In the single-pollutant models, on warm days (> 25 degrees C) statistically significant positive associations were found in all pollutants except sulfur dioxide (SO(2)). On cool days (< 25 degrees C), all pollutants were significantly associated with CHF admissions. For the two-pollutant model, CO and O(3) were significant in combination with each of the other four pollutants on warm days. On cool days, NO(2) remained statistically significant in all the two-pollutant models. This study provides evidence that higher levels of ambient air pollutants increase the risk of hospital admissions for CHF and that the effects of air pollutants on hospital admissions for CHF were temperature dependent.

Carbon monoxide (CO) has recently been suggested to have anti-inflammatory properties, but data seem to be contradictory and species-specific. Thus, in studies on macrophages and mice, pretreatment with CO attenuated the inflammatory response after endotoxin exposure. On the other hand, human studies showed no effect of CO on the inflammatory response. Anti-inflammatory efficacy of CO has been shown at concentrations above 10% carboxyhaemoglobin. This study was undertaken to elucidate the possible anti-inflammatory effects of CO at lower CO concentrations.

Effects of CO administration on cytokine (TNF-alpha, IL-6, IL-1beta and IL-10) release were investigated in a porcine model in which a systemic inflammatory response syndrome was induced by endotoxin infusion. Endotoxin was infused in 20 anaesthetized and normoventilated pigs. Ten animals were targeted with inhaled CO to maintain 5% COHb, and 10 animals were controls.

In the control group, mean pulmonary artery pressure increased from a baseline value of 17 mmHg (mean, n = 10) to 42 mmHg (mean, n = 10) following 1 hour of endotoxin infusion. Similar mean pulmonary artery pressure values were found in animals exposed to carbon monoxide. Plasma levels of all of the measured cytokines increased in response to the endotoxin infusion. The largest increase was observed in TNF-alpha, which peaked after 1.5 hours at 9398 pg/ml in the control group and at 13395 pg/ml in the carbon monoxide-exposed group. A similar peak was found for IL-10 while the IL-6 concentration was maximal after 2.5 hours. IL-1beta concentrations increased continuously during the experiment. There were no significant differences between carbon monoxide-exposed animals and controls in any of the measured cytokines.

Our conclusion is that 5% COHb does not modify the cytokine response following endotoxin infusion in pigs.

This study was undertaken to determine whether there was an association between air pollutant levels and hospital admissions for congestive heart failure (CHF) in Taipei, Taiwan. Hospital admissions for CHF and ambient air pollution data for Taipei were obtained for the period from 1996 to 2004. The relative risk of hospital admission was estimated using a case-crossover approach, controlling for weather variables, day of the week, seasonality, and long-term time trends. In the single-pollutant model, the number of CHF admissions was significantly associated with the environmental presence of the contaminants particulate matter (PM(10)), nitrogen dioxide (NO(2)), carbon monoxide (CO), and ozone (O(3)) on warm days (>20 degrees C). However, statistically significant positive effects on increased CHF admissions on cool days (<20 degrees C) was observed only for CO levels. For the two-pollutant model, NO(2) and O(3) were significant in combination with each of the other four pollutants on warm days for enhanced CHF admissions. This study provides evidence that higher levels of ambient air pollutants increase the risk of hospital admissions for CHF.

Eclipse, produced by R. J. Reynolds Tobacco Company, is a potential reduced exposure product (PREP) that heats rather than burns tobacco. We hypothesized that switching to Eclipse would result in relative normalization of pulmonary epithelial permeability, airway inflammation, and blood leukocyte activation in current smokers. We assessed 10 healthy smokers (aged 21-50 years, 19+/-8 pack-years) at baseline and after 2 and 4 weeks of switching to Eclipse, for symptoms, pulmonary function, airway inflammation, lung clearance of (99m)technicium-diethylenetriaminepentaacetic acid, and blood leukocyte activation and production of reactive oxygen species. Values were compared before and after Eclipse use and with those of healthy, lifetime nonsmokers (aged 18-53 years). Compared with baseline values before switching to Eclipse, lung permeability half-time increased from 33+/-3 to 43+/-6 min (p = .017) after 2 weeks and to 44+/-7 min (p = .10) after 4 weeks of Eclipse use. Carboxyhemoglobin levels increased from 5%+/-2% to 7%+/-2% (p<.01) at 4 weeks. Compared with smoking the usual brand of cigarettes, after smoking Eclipse the percentage of natural killer cells, the expression of intercellular adhesion molecule-1 on monocytes, and the expression of CD45RO on T cells showed significant improvement. However, expression of other surface markers, notably CD23 on monocytes, became more abnormal. Production of reactive oxygen species by smokers' neutrophils and monocytes increased further with Eclipse use. We found no significant effects on pulmonary function, cells in induced sputum, or exhaled nitric oxide. Switching to Eclipse reduces alveolar epithelial injury in some smokers but may increase carboxyhemoglobin levels and oxidative stress.

This study was undertaken to determine whether there is an association between air pollutants levels and hospital admissions for cardiovascular diseases (CVD) in Taipei, Taiwan. Hospital admissions for CVD and ambient air pollution data for Taipei were obtained for the period 1997-2001. The relative risk of hospital admission was estimated using a case-crossover approach, controlling for weather variables, day of the week, seasonality, and long-term time trends. For the one-pollutant models, on warm days (>or=20 degrees C) statistically significant positive associations were found between levels of particulate matter <10-microm aerodynamic diameter (PM10), nitrogen dioxide (NO2), carbon monoxide (CO), and ozone (O3). On cool days (<20 degrees C), all pollutants except O3 and SO2 were significantly associated with CVD admissions. For the two-pollutant models, CO, NO2, and O3 were significant in combination with each of the other four pollutants on warm days. On cool days, PM10 remained statistically significant in all the two-pollutant models. This study provides evidence that higher levels of ambient pollutants increase the risk of hospital admissions for CVD.

This study was undertaken to determine whether there is an association between air pollutants levels and increased number of hospital admissions for cardiovascular diseases (CVD) in Kaohsiung, Taiwan. Hospital admissions records for CVD and ambient air contaminant data collected from monitoring station in Kaohsiung were obtained for the period 1997-2000. The relative risk of hospital admission for CVD was estimated using a case-crossover approach, controlling for weather variables, day of the week, seasonality, and long-term time trends. In the single-pollutant model, on warm days (> or =25 degrees C) statistically significant positive associations were found between levels of particular matter of < 10 microm aerodynamic diameter (PM10), nitrogen dioxide (NO2), carbon monoxide (CO), and ozone (O3). On cool days (< 25 degrees C), all pollutants except O3 were significantly associated with increased CVD admissions. For the two-pollutant model, CO and O3 were both significant in combination with each of the other four contaminants on warm days. PM10 and NO2 remained significantly associated with elevated CVD admissions on warm days. On cool days, CO and NO2 remained statistically significant in all the two-pollutant models. This study provides evidence that higher levels of ambient contaminants, particularly CO, increase the risk of increased hospital admissions for CVD.

Preexisting data sets were used to investigate the association between hospital admissions for congestive heart failure and air pollutants.

Medicare hospital admissions data, ambient air pollution monitoring data, and meteorological data were used to create daily values of hospital admissions for congestive heart failure, maximum hourly temperature, and maximum hourly levels of carbon monoxide, nitrogen dioxide, sulfur dioxide, and ozone. Data were compiled for each of seven cities (Chicago, Detroit, Houston, Los Angeles, Milwaukee, New York, and Philadelphia) for 1986 through 1989. Single-pollutant and multipollutant models with adjustments for temperature, seasonal effects, and weekly cycles were used in conducting negative binomial regression analyses.

Ambient carbon monoxide levels were positively associated with hospital admissions for congestive heart failure in the single-pollutant and multipollutant models for each of the seven cities. The relative risk of hospital admission for congestive heart failure associated with an increase of 10 ppm in carbon monoxide ranged from 1.10 in New York to 1.37 in Los Angeles.

Hospital admissions for congestive heart failure exhibited a consistent association with daily variations in ambient carbon monoxide. This association was independent of season, temperature, and other major gaseous pollutants.

Inhalation of small amounts of carbon monoxide diminishes the pain threshold in patients with stable angina pectoris. The aim of this study was to identify and describe patients who had been exposed unknowingly to toxic inhalations of this gas and subsequently presented to hospital with a clinical picture of unstable angina. Blood carboxyhaemoglobin levels of 104 patients referred with unstable angina to a coronary care unit were determined on admission. The likely source of carbon monoxide was identified in all patients. Three patients had definite carbon monoxide intoxication. Another five patients had evidence of minor exposure. When the three cases with carbon monoxide poisoning were excluded, the mean carboxyhaemoglobin level was 2.5% (+/- 1.3) for smokers (n = 30) and 0.6% (+/- 0.5) for non-smokers (n = 71). Use of fossil fuel combustion in an enclosed environment was responsible for the three most serious intoxications and one of the minor cases. We suggest that a number of patients admitted for coronary care with unstable angina may have significant carbon monoxide poisoning. This intoxication is often overlooked by attending physicians with the result that high concentration oxygen therapy is not administered, when it is in fact a necessary part of treatment.

The effects of carbon monoxide (CO) on blood carboxyhemoglobin (COHb) levels, though well studied at sea level, have not been investigated in populations at altitude. COHb levels were measured in laboratory rats following 6 wk exposure to either clean air or air containing 9 ppm CO at ambient altitude (3300 ft), 10,000 ft, or 15,000 ft simulated high altitude. In animals breathing clean air, COHb levels increased with increasing altitude from 0.68 +/- 0.09% at 3300 ft to 1.16 +/- 0.28% and 1.68 +/- 0.14%, respectively, at 10,000 and 15,000 ft. The relationship between COHb levels and increasing altitude is linear with a correlation coefficient of 0.90 (p less than .001). In animals breathing 9 ppm CO, COHb levels also increased with increasing altitude from 0.99 +/- 0.06% at 3300 ft to 1.77 +/- 0.17% and 2.10 +/- 0.08%, respectively, at 10,000 and 15,000 ft. The relationship between COHb levels and increasing altitude in animals breathing CO is also linear with a correlation coefficient of .92 (p less than .001). These data indicate that, compared with animals at sea level, animals at altitude have an increased body burden of COHb and will attain the COHb level associated with the National Ambient Air Quality Standard for CO more quickly when breathing CO.

The importance of smoking as a possible factor in coronary heart disease (CHD) may be related to the effect of carbon monoxide (CO) on oxygen exchange at the hemoglobin molecule (Hb). We examined the kinetics of this process in vitro and ex vivo using a fast-reaction technique (stopped-flow) whereby the dissociation-rate constant of oxygen was determined in the blood of smokers and non-smokers and at fixed HbCO-concentrations in non-smokers blood. In non-smokers, carbon monoxide saturated blood was obtained by gassing with carbon monoxide and mixing the samples with appropriate carbon monoxide free blood to achieve HbCO-concentration in the range of 10-60%. The reaction time course for the oxygen-dissociation was divided into a non-linear-initial phase (loss of the first oxygen molecule) and a subsequent linear phase. The oxygen-dissociation velocity decreased from 96.5 x 10(3) ms-1 to 42.7 x 10(3) ms-1 in the linear phase at pH 7.4 and decreased from 29.2 x 10(3) ms-1 to 20.9 x 10(3) ms-1 at pH 9.2 when the HbCO-concentration was increased to 63%. For the initial phase at pH 7.4, the dissociation velocity decreased depending on the HbCO-concentration. In non-smokers 50% of the bound oxygen was released in 17.5 +/- 2.3 ms (n = 13) whereas in smokers 19.4 +/- 1.8 ms (n = 14) (p less than 0.05) was required.(ABSTRACT TRUNCATED AT 250 WORDS)

The purpose of this study was to determine whether low doses of carbon monoxide (CO) exacerbate myocardial ischemia during a progressive exercise test. The effect of CO exposure was evaluated using the objective measure of time to development of electrocardiographic changes indicative of ischemia and the subjective measure of time to onset of angina. Sixty-three male subjects (41-75 years) with well-documented coronary artery disease, who had exertional angina pectoris and ischemic ST-segment changes in their electrocardiograms, were studied. Results from three randomized, double-blind test visits (room air, low and high CO) were compared. The effect of CO exposure was determined from the percent difference in the end points obtained on exercise tests performed before and after a 1-hr exposure to room air or CO. The exposures resulted in postexercise carboxyhemoglobin (COHb) levels of 0.6% +/- 0.3%, 2.0% +/- 0.1%, and 3.9% +/- 0.1%. The results obtained on the 2%-COHb day and 3.9%-COHb day were compared to those on the room air day. There were 5.1% (p = 0.01) and 12.1% (p less than or equal to 0.0001) decreases in the time to development of ischemic ST-segment changes after exposures producing 2.0 and 3.9% COHb, respectively, compared to the control day. In addition, there were 4.2% (p = 0.027) and 7.1% (p = 0.002) decreases in time to the onset of angina after exposures producing 2.0 and 3.9% COHb, respectively, compared to the control day. A significant dose-response relationship was found for the individual differences in the time to ST end point and angina for the pre- versus postexposure exercise tests at the three carboxyhemoglobin levels. These findings demonstrate that low doses of CO produce significant effects on cardiac function during exercise in subjects with coronary artery disease.

We evaluated alveolar carbon monoxide (CO) levels of 122 male, adult hockey players active in recreational leagues of the Quebec City region (Canada), before and after 10 weekly 90-minute games in 10 different rinks. We also determined exposure by quantifying the average CO level in the rink during the games. Other variables documented included age, pulmonary function, aerobic capacity, and smoking status. Environmental concentrations varied from 1.6 to 131.5 parts per million (ppm). We examined the absorption/exposure relationship using a simple linear regression model. In low CO exposure levels, physical exercise lowered the alveolar CO concentration. However, we noted that for each 10 ppm of CO in the ambient air, the players had adsorbed enough CO to raise their carboxyhemoglobin (COHb) levels by 1 percent. This relationship was true both for smokers and non-smokers. We suggest that an average environmental concentration of 20 ppm of CO for the duration of a hockey game (90 minutes) should be reference limit not to be exceeded in indoor skating rinks.

Patients with atherosclerotic cardiovascular disease may be adversely affected by the presence of carboxyhemoglobin, even at low concentrations. We investigated the effects of carbon monoxide exposure on myocardial ischemia during exercise in 63 men with documented coronary artery disease. On each test day, subjects performed two symptom-limited incremental exercise tests on a treadmill; the tests were separated by a recovery period and 50 to 70 minutes of exposure to either room air or air containing one of two concentrations of carbon monoxide (117 +/- 4.4 ppm or 253 +/- 6.1 ppm). The order of exposure was assigned randomly. On each occasion, neither the subjects nor the study personnel knew whether the subjects had been exposed to room air or to one of the concentrations of carbon monoxide. Exposure to room air resulted in a mean carboxyhemoglobin level of 0.6 percent, exposure to the lower level of carbon monoxide resulted in a carboxyhemoglobin level of 2.0 percent, and exposure to the higher level of carbon monoxide resulted in a level of 3.9 percent. An effect of carbon monoxide on myocardial ischemia was demonstrated objectively by electrocardiographic changes during exercise. We observed a decrease of 5.1 percent (90 percent confidence interval, 1.5 to 8.7 percent; P = 0.02) and a decrease of 12.1 percent (90 percent confidence interval, 9.0 to 15.3 percent; P less than or equal to 0.0001) in the length of time to a threshold ischemic ST-segment change (ST end point) after carbon monoxide exposures that produced carboxyhemoglobin levels of 2.0 percent and 3.9 percent, respectively. The length of time to the onset of angina decreased by 4.2 percent (90 percent confidence interval, 0.7 to 7.9 percent; P = 0.054) at the 2.0 percent carboxyhemoglobin level and by 7.1 percent (90 percent confidence interval, 3.1 to 10.9 percent; P = 0.004) at the 3.9 percent carboxyhemoglobin level. Significant dose-response relations were found in both the change in the length of time to the ST end point (P less than or equal to 0.0001) and the change in the length of time to the onset of angina (P = 0.02). We conclude that low levels of carboxyhemoglobin exacerbate myocardial ischemia during graded exercise in subjects with coronary artery disease.

The effects of acute elevation of carboxyhemoglobin (COHb) concentrations on resting and exercise-induced ventricular arrhythmias were evaluated in 10 patients who had ischemic heart disease and in whom no ectopy during baseline monitoring was noted. After an initial training session, patients were exposed to air, 100 ppm carbon monoxide (CO), or 200 ppm CO on successive days in a randomized, double-blind, cross-over fashion. After exposure to 100 and 200 ppm CO, venous COHb levels averaged 4% and 6%, respectively. Symptom-limited supine exercise was performed after exposure. Eight of the 10 patients had evidence of exercise-induced ischemia--either angina, 1.0 mm ST depression, or abnormal ejection fraction response--during 1 or more exposure days. Ambulatory electrocardiograms were obtained on each day and analyzed for arrhythmia frequency and severity. On air and CO exposure days, each patient had only 0-1 ventricular premature beat/h in the 2 h prior to exposure, during the exposure period, during the subsequent exercise test, and in the 5 h following exercise. In conclusion, low-level CO exposure is not arrhythmogenic in patients with coronary artery disease and no ventricular ectopy at baseline.

Acute exposure to carbon monoxide has the potential to impair exercise capacity in patients with ischemic heart disease. The effect of sufficient inhalation of this compound to gradually produce a level of 6% carboxyhemoglobin was studied in 30 nonsmoking patients with obstructive coronary artery disease and evidence of exercise-induced ischemia. After an initial training session, subjects were exposed to air or carbon monoxide on successive days in a randomized double-blind crossover fashion. Cardiac function and exercise capacity were assessed during symptom-limited supine radionuclide ventriculography. On the carbon monoxide day, mean postexposure carboxyhemoglobin was 5.9 +/- 0.1% compared with 1.6 +/- 0.1% (p less than 0.01) after air exposure. The mean duration of exercise was significantly longer after air compared with carbon monoxide exposure (626 +/- 50 s for air versus 585 +/- 49 s for carbon monoxide, p less than 0.05). Actuarial methods suggested that subjects were likely to experience angina earlier during exercise on the day of carbon monoxide exposure (p less than 0.05). Both the level (62 +/- 2.4 versus 60 +/- 2.4%, p = 0.05) and change in left ventricular ejection fraction at submaximal exercise (1.6 +/- 1.6 versus -1.2 +/- 1.6%, p = 0.05) were greater on the air exposure day compared with the carbon monoxide day. The peak exercise left ventricular ejection fraction was not different for the two exposures (57 +/- 2.5% for both). These results demonstrate earlier onset of ventricular dysfunction, angina and poorer exercise performance in patients with ischemic heart disease after acute carbon monoxide exposure sufficient to increase blood carboxyhemoglobin to 6%.

We studied 30 patients 38-75 yr of age who had ischemic heart disease to assess the effect of acute elevation of carboxyhemoglobin (COHb) concentration. Patients were nonsmokers with ischemia defined by exercise-induced ST depression (ST decreases)--25/30, angina--23/30, or abnormal ejection fraction (EF) response--18/30. After an initial familiarization and exercise session patients were exposed to air (carboxyhemoglobin [COHb] = 1.5 +/- 0.05%) and to carbon monoxide (CO) (100 ppm-COHb-average = 3.8 +/- 0.1%) on successive days in a double blind, randomized fashion. There was no significant difference in time to onset of angina (air = 312 sec, CO = 306 sec), maximal exercise time (air = 711 sec, CO = 702 sec), maximal ST decreases (1.5 mm for both), or time to significant ST decreases (air = 474 sec, CO = 475 sec). Double product at ST decreases and maximal double products were similar for both conditions. Resting ejection fraction was slightly but nonsignificantly higher after CO exposure (air = 53.9%, CO = 55.2%). Maximal ejection fraction was similar for both conditions (air = 57.4%, CO = 57.1%). Change in ejection fraction was slightly lower for CO exposure (air = 3.5%, CO = 2%), p = .049. In conclusion, there is no clinically significant effect of 3.8% COHb (representing a 2.2% increase from resting values) on the cardiovascular system in this study.

From January 1978 through March 1984, 115 cases of acute carbon monoxide poisoning were treated with hyperbaric oxygen. Exposure resulted from accidental sources (n = 39), attempted suicide (n = 47), and smoke inhalation (n = 29). Forty-one victims were never unconscious, 30 victims were unconscious at the scene but awoke before arriving at the hospital, and 44 victims were unconscious in the ED. Eleven patients (9.6%) died, and two victims (1.9% of the survivors) experienced major sequelae. All these patients were comatose on arrival. The remaining 102 patients recovered fully. Carboxyhemoglobin levels did not correlate with clinical findings, thereby demonstrating the variability between carbon monoxide exposure and impairment of the cellular cytochrome system. Hyperbaric oxygen therapy facilitates the rapid removal of carbon monoxide from the hemoglobin and cytochrome systems while reoxygenating compromised tissues, and it can be an effective treatment in reducing mortality and morbidity.

The recent deaths of two workers with coronary artery disease (CAD) following exposure to carbon monoxide (CO) at work reinforced our appreciation of the hazard of this exposure to individuals with preexisting heart disease. Carbon monoxide acts to precipitate ischemia by reducing oxygen delivery to the myocardium. Animal and in vitro experiments suggest that CO may accelerate the development of atherosclerosis, particularly if exposure is in association with other risk factors. Thus, persons with known CAD who are exposed to CO at work are at risk for both the acceleration of the course of the underlying disease and for precipitation of acute ischemia or infarction following excessive exposure. Particular attention should be given to control of CO exposures in light of this hazard. For various reasons, preplacement evaluations or other job selection procedures do not adequately address his hazard. In view of the high prevalence of CAD in the U.S. and the high frequency of workplace exposure to CO, particular attention should be given to control of CO exposure through industrial hygiene measures.

To evaluate the effect of breathing 50 ppm carbon monoxide (CO) on exercise capacity in persons with anemia, 10 nonsmoking subjects with chronic anemia (mean hemoglobin 8.9 g%) were studied. No subject had heart or lung disease. By double-blind, randomized, crossover design, duration of fatigue-limited exercise after breathing CO and purified air for 1 hr was compared. Mean carboxyhemoglobin levels increased from 2.14 to 3.38% after breathing CO and decreased from 2.15 to 1.86% after breathing purified air, P less than 0.004. Mean exercise duration decreased from 270.8 to 221.0 sec after breathing CO in contrast to an increase from 267.9 to 271.6 sec after breathing purified air, P less than 0.0001. Hence, in the absence of clinical heart or lung disease, increasing carboxyhemoglobin concentrations aggravate exercise performance in nonsmokers with chronic anemia.

Cardiovascular effects of tobacco smoke have been studied in passive smokers far less extensively than in active smokers. Under real-life conditions, passive smokers inhale approximately 0.02 to 0.01 of the amount of particulate matter taken up by active smokers. Their nicotine concentration in serum is within a range that is barely distinguishable from the background level. The increase in carboxyhemoglobin rarely exceeds 1%. In healthy subjects heavily exposed to tobacco smoke, no or only slightly acute effects on the cardiovascular system are found. Whether or not passive smoking is likely to aggravate symptoms in patients with advanced coronary heart disease has not yet been unequivocally established and requires further investigation. From a few studies on occupational groups exposed to carbon monoxide (CO) and from experiments with animals chronically treated with CO or nicotine, the conclusion can be drawn that neither CO nor nicotine is likely to play a role in the development and progression of coronary heart disease in those concentrations normally found in passive smokers.

To determine the prevalence of carboxyhemoglobin levels in banked blood exceeding Air Quality Standards (level of carboxyhemoglobin greater than 1.5 percent), we analyzed banked blood for the level of carboxyhemoglobin from 101 randomly selected samples. Of 101 units of banked blood, 49 (49 percent) had carboxyhemoglobin levels greater than 1.5 percent, and 36 (36 percent) had levels of 2.0 percent or more. We suggest that it may be undesirable to use blood with increased carboxyhemoglobin content when multiple transfusions are necessary, particularly in patients with cardiac or pulmonary disease. Labeling banked blood for carboxyhemoglobin content would be useful in order to help avoid multiple or consecutive transfusions of blood with high levels of carboxyhemoglobin.

In the metabolism of isosorbide dinitrate (ISDN), fast denitration with the formation of nitrite ions and a mononitrate plays an important role. In contrast, the denitration of isosorbide-5-mononitrate (IS-5-MN) to isosorbide is very slow. Accordingly po administration of high doses of ISDN (92.5 and 236 mg/kg) in conscious dogs led to maximum nitrite concentrations in the blood of 0.9 and 3.3 mg/liter, respectively. In contrast, with equimolar doses of IS-5-MN (75 and 191 mg/kg) we were able to detect nitrite ions reliably only at the higher dose and this gave a maximum blood concentration of 0.4 mg/liter. The rise in nitrite ion concentration is followed by the formation of methemoglobin. As is known from the literature, there is a rise in the activity of alkaline phosphatase in the serum of rabbits in addition to methemoglobin formation following repeated administration of sodium nitrite. So we have specifically investigated whether this is also the case following ISDN and IS-5-MN administration. On po administration of 236 mg/kg ISDN/day to dogs, there was a continuous rise in alkaline phosphatase from about the 20th day onward which we did not observe after the equimolar dose of IS-5-MN (191 mg/kg). NaNO2, 35 mg/kg po, led to a comparable maximal rise in methemoglobin to that obtained with 236 mg/kg ISDN. Repeated po administration of 35 mg/kg NaNO2/day also caused a rise in alkaline phosphatase. It is concluded that the formation of nitrite ions from ISDN is the reason for the rise in methemoglobin and alkaline phosphatase. The lower formation of nitrite ions from IS-5-MN can also be of clinical importance, at least in certain cases.

Although official efforts to control air pollution have traditionally focused on outdoor air, it is now apparent that elevated contaminant concentrations are common inside some private and public buildings. Concerns about potential public health problems due to indoor air pollution are based on evidence that urban residents typically spend more than 90 percent of their time indoors, concentrations of some contaminants are higher indoors than outdoors, and for some pollutants personal exposures are not characterized adequately by outdoor measurements. Among the more important indoor contaminants associated with health or irritation effects are passive tobacco smoke, radon decay products, carbon monoxide, nitrogen dioxide, formaldehyde, asbestos fibers, microorganisms, and aeroallergens. Efforts to assess health risks associated with indoor air pollution are limited by insufficient information about the number of people exposed, the pattern and severity of exposures, and the health consequences of exposures. An overall strategy should be developed to investigate indoor exposures, health effects, control options, and public policy alternatives.