Abstract  National Institute of Environmental Health Sciences.

Abstract  Historically, and at present, carbon monoxide is a major gaseous poison responsible for widespread morbidity and mortality. From threshold to maximal nonlethal levels, a variety of cardiovascular changes occur, both immediately and in the long term, whose homeostatic function it is to renormalize tissue oxygen delivery. However, notwithstanding numerous studies over the past century, the literature remains equivocal regarding the hemodynamic responses in animals and humans, although CO hypoxia is clearly different in several respects from hypoxic hypoxia. Factors complicating interpretation of experimental findings include species, CO dose level and rate, route of CO delivery, duration, level of exertion, state of consciousness, and anesthetic agent used. For example, tachycardia is commonly observed, although bradycardia also can result from myocardial and/or central nervous system (CNS) hypoxemia at high carboxyhemoglobin (COHb) saturations, as can electrocardiographic abnormalities. Augmented cardiac output usually observed with moderate COHb may be compromised in more severe poisoning for the same reasons, such that regional or global ischemia result. The hypotension usually seen in most animal studies is thought to be a primary cause of CNS damage resulting from acute CO poisoning, yet the exact mechanism(s) remains unproven in both animals and humans, as does the way in which CO produces hypotension. This review briefly summarizes the literature relevant to the short- and long-term hemodynamic responses reported in animals and humans. It concludes by presenting an overview using data from a single species in which the most complete work has been done to date.

Abstract  To assests the nature of the combined effect of the hypoxias of altitude (ALT) and CO exposure, 11 men and 12 women non-smokers served as subjects in a doubleblind experiment. The exposure conditions were four ambient CO levels (0, 50, 100, and 150 ppm) at each of four ALT (55, 1,524, 2,134, and 3,048 m). Each subject, after attaining the required ALT and ambient CO level, performed a maximal aerobic capacity test (VO zmax). Blood samples were obtained before, at 50-W, 100-W, 150-W, and maximum work loads and at the 5th min of recovery. Blood were analyzed for hemoglobin, hematocrit, plasma proteins, lactates, and carboxyhemoglobin (HbCO). VO zmax was similar at 55 and 1,524 m and decreased by 4 and 8% from the 55-m value at 2,134 and 3,048 m, respectively. On the basis of all statistical analyses, we concluded that VO2 max values measured in men were only slightly diminished due to increased ambient CO. HbCO attained at maximum was highest at 55 m and lowest at 3,048 m. Women?s HbCO concentrations were lower than men?s. At maximal work loads CO shifted into extravascular spaces and returned to the vascular space within 5 min after exercise stopped. The independence of altitude and CO hypoxias on parameters of the maximum aerobic capacity test and a decrease in the CO to HbCO uptake with increasing altitude were demonstrated and attributed in part to the decreasein driving pressure of CO at altitude.

Abstract  As observed with nitric oxide (NO), carbon monoxide (CO) binds and may activate soluble guanylate cyclase and increase cGMP levels in smooth muscle cells in vitro. Because inhaled NO (I(NO)) causes potent and sustained pulmonary vasodilation, we hypothesized that inhaled CO (I(CO)) may have similar effects on the perinatal lung. To determine whether I(CO) can lower pulmonary vascular resistance (PVR) during the perinatal period, we studied the effects of I(CO) on late-gestation fetal lambs. Catheters were placed in the main pulmonary artery, left pulmonary artery (LPA), aorta, and left atrium to measure pressure. An ultrasonic flow transducer was placed on the LPA to measure blood flow to the left lung. After baseline measurements, fetal lambs were mechanically ventilated with a hypoxic gas mixture (inspired O(2) fraction < 0.10) to maintain a constant fetal arterial PO(2). After 60 min (baseline), the lambs were treated with I(CO) [5-2,500 parts/million (ppm)]. Comparisons were made with I(NO) (5 and 20 ppm) and combined I(NO) (5 ppm) and I(CO) (100 and 2,500 ppm). We found that I(CO) did not alter left lung blood flow or PVR at any of the study doses. In contrast, low-dose I(NO) decreased PVR by 47% (P < 0.005). The combination of I(NO) and I(CO) did not enhance the vasodilator response to I(NO). To determine whether endogenous CO contributes to vascular tone in the fetal lung, zinc protoporphyrin IX, an inhibitor of heme oxygenase, was infused into the LPA in three lambs. Zinc protoporphyrin IX had no effect on baseline PVR, aortic pressure, or the pressure gradient across the ductus arteriosus. We conclude that I(CO) does not cause vasodilation in the near-term ovine transitional circulation, and endogenous CO does not contribute significantly to baseline pulmonary vascular tone or ductus arteriosus tone in the late-gestation ovine fetus.

Abstract  Pregnant rats (starting on E5) were exposed chronically to carbon monoxide (CO) from gestational days 5-20. In the postnatal period, rat pups were grouped as follows: group A: prenatal exposure to CO only; group B: prenatal exposure to CO then exposed to CO from postnatal day (P) 5 to P20; group C, control (air without CO). Groups A and B showed similar deleterious effects after CO exposure. At P3, rat pup cochlea from group A showed a normal organization of the organ of Corti. There was no morphological deterioration, or loss of inner or outer hair cells. At P20, animals from group A and B showed vacuolization on the afferent terminals at the basal portion of the cochlea. We found synapsin-1 immunoreactivity (IR) to be decreased in efferent nerve terminals in CO-exposed pups at P3. From P12 to P20, synapsin-1-IR is low in efferent terminals. At P20, type I spiral ganglia neurons and afferent nerve fibers showed decreased neurofilament-IR in CO-exposed groups when compared with controls. Heme oxygenase-1 and superoxide dismutase-1-IR were elevated in the stria vascularis and blood vessels from CO-exposed rat pups at P12 and P20 in group B; in contrast group A showed a comparable expression to controls. Inducible nitric oxide synthase (iNOS) and nitrotyrosine-IR were increased in blood vessels of the cochlea in CO-exposed groups, from P3 to P20. iNOS up-regulation and the presence of nitrotyrosine in blood vessels of the cochlea indicated that CO exposure activates the production of nitric oxide via increased iNOS activity. Prenatal chronic CO exposure promotes oxidative stress in the cochlea blood vessels that in turn is reflected in damage to spiral ganglia neurons and inner hair cells, suggesting for the first time that prenatal exposure to CO at concentrations expected in poorly ventilated environments impairs the development of the inner ear.

Abstract  Carbon monoxide causes a perivascular oxidative injury in animals, and we tested the hypothesis that endothelial cells could be a source of the injurious oxidants. Studies were undertaken to assess whether exposure to carbon monoxide would cause cultured bovine pulmonary artery endothelial cells to liberate reactive species. Concentrations of carbon monoxide between 11 and 110 nM caused progressively higher concentrations of nitric oxide to be released by endothelial cells based on measurements of nitrite and nitrate. Intracellular production of peroxynitrite was indicated by elevated concentrations of nitrotyrosine, and extracellular liberation of peroxynitrite was indicated by oxidation of p-hydroxyphenylacetic acid and dihydrorhodamine-123. Carbon monoxide did not disturb mitochondrial function based on the rate of oxygen consumption, intracellular production of hydrogen peroxide, and the ability of cells to reduce 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide. Carbon monoxide also did not alter arginine transport by cells or nitric oxide synthase activity, but it was found to increase steady state levels of nitric oxide by competing for intracellular binding sites. Acute cytotoxicity from carbon monoxide, assessed as radioactive chromium leakage, was due to nitric oxide-derived oxidants. A delayed cell death, whose mechanism is not entirely clear, was also demonstrated by chromium leakage and uptake of vital stain. These findings offer a possible mechanism for adverse health effects caused by carbon monoxide at concentrations ranging from the relatively low levels in polluted environments to levels typically encountered with life-threatening poisoning. Carbon monoxide causes oxidative stress by a novel mechanism involving a competition for intracellular binding sites which increases steady state levels of nitric oxide and allows for generation of peroxynitrite by endothelium.

Abstract  AIM: The aim of this study was to evaluate the frequency of carbon monoxide diffusing capacity (DLCO) impairment and microalbuminuria in patients with active ulcerative colitis (UC) and to assess whether these nonexpensive and noninvasive tests correlate with intestinal inflammation.

METHODS: A prospective observational study was set up at the Fiorenzuola Hospital and performed during a 4-year period. We enrolled 30 consecutive subjects with clinical and histological diagnosis of active UC and 20 healthy subjects matched for age and sex. After full colonscopic assessment with multiple mucosal biopsies, the clinical disease activity of each patient was quantified. A global spirometry and 24-h urine collection at rest to measure microalbuminuria were performed. Each biopsy specimen was assessed blindly by a histopathologist, who assigned a score according to the severity of enterocyte damage, cryptitis and acute and chronic inflammation of the lamina propria.

RESULTS: A latent pulmonary involvement with a reduction in DLCO was present in 20 patients (67%). A subclinical renal involvement with microalbuminuria was detected in 19 subjects (63%). The mean DLCO was 78.2+/-15.2 in Group 1 vs 94.7+/-13.1 in Group 2 (P<0.001). Microalbuminuria was 103.6+/-90.8 in Group 1 vs 57+/-31.7 in the control group (P=0.062). DLCO reduction correlated significantly with intestinal histopathological grading in Group 1 (r = -0.742, P< 0.001), although there was no correlation between microalbuminuria and histological grading (r = -0.273, P= 0.143).

CONCLUSION: Our data confirm that latent pulmonary involvement (DLCO impairment) and microalbuminuria are frequent in UC. The DLCO may provide a useful noninvasive indicator of colonic inflammation in subjects with UC and concomitant subclinical lung involvement.

Abstract  Objective. To assess whether severe gastroesophageal reflux (GER) is associated with abnormalities in lung function including measures of lung volume and gas diffusion.

Methods: Data from 147 patients with obesity (body mass index [BMI] range, 31.7 to 70 kg/m(2)) who presented for obesity surgery was analyzed retrospectively. A questionnaire was completed preoperatively that included a history of GER, frequency and severity of symptoms, investigations, and medications used. A history of lung disease, sleep-disordered breathing, and smoking also was obtained. A physician who was blinded to lung function graded GER severity prospectively by the results of pH monitoring and/or gastroscopy, and medication use. Spirometry, lung volumes, and gas transfer were measured preoperatively.

Results: Patients with severe GER had reduced levels of the diffusing capacity of the lung for carbon monoxide (DLCO) [21.1 mL/min/mm Hg; 95% confidence interval (CI), 18.9 to 23.2], as measured by CO transfer, compared with those patients without GER (26.3 mL/min/mm Hg; 95% CI, 24.4 to 28.2; p = 0.001). This remained significant after adjusting for age, gender, BMI, and smoking history. Gas transfer corrected for lung volume also was reduced in the group with severe GER (4.6 mL/min/mm Hg per L; 95% CI, 4.3 to 4.9) compared to the group without GER (5.3 mL/min/mm Hg per L; 95% CI, 5.1 to 5.5; p = 0.001). There was no significant difference in other measures of lung function.

Conclusions: Severe GER is associated with an impairment of gas exchange. This may be due to microaspiration of gastric acid or fluid into the airways.

Abstract  The authors conducted a case-control survey nested within a birth cohort and collected detailed risk factor information to assess the extent to which residual confounding and exposure misclassification may impact air pollution effect estimates. Using a survey of 2,543 of 6,374 women sampled from a cohort of 58,316 eligible births in 2003 in Los Angeles County, California, the authors estimated with logistic regression and two-phase models the effects of pregnancy period-specific air pollution exposure on the odds of preterm birth. For the first trimester, the odds of preterm birth consistently increased with increasing carbon monoxide exposures and also at high levels of exposure to particulate matter less than or equal to 2.5 µm in diameter (>21.4 µg/m3), regardless of type of data (cohort/sample) or covariate adjustment (carbon monoxide exposures of >1.25 ppm increased the odds by 21-25%). Women exposed to carbon monoxide above 0.91 ppm during the last 6 weeks of pregnancy experienced increased odds of preterm birth. Crude and birth certificate covariate-adjusted results for carbon monoxide differed from each other. However, further adjustment for risk factors assessed in the survey did not change effect estimates for short-term pollutant averages appreciably, except for time-activity patterns, which strengthened the observed associations. These results confirm the importance of reducing exposure misclassification when evaluating the effect of traffic-related pollutants that vary spatially.

Abstract  The endogenous production of carbon monoxide (V̇CO) has been followed with the aid of a rebreathing system for 3 hours in four healthy volunteers after i.v. injection of 50 mg nicotinic acid (NA). After an initial slight decrease for 15–30 min in the CO hemoglobin per cent saturation (COHb), a rapid increase was registered for 120 min, whereafter the V̇CO returned to the normal, preinjection level. The amount of “extra” CO produced varied between 4.1 and 2.2 ml, corresponding to 2.9 and 1.6 g Hb or 182 and 98 μmol heme, respectively. These figures are 3–5 times higher than those reported in the literature, calculated from increases in serum iron, bilirubin and COHb (without the use of a rebreathing system). When related to the total body heme (TBH) estimated with the CO dilution technique, the amount of “extra” heme metabolized after NA corresponded to 0.30% (range 0.26–0.32) of the TBH (a fourth of the total daily heme turnover or a third of the daily Hb heme catabolism).

Abstract  National Institutes of Health; Veterans Administration; American Heart Association.

Abstract  We have been investigating the hypothesis that the membrane-permeant molecules nitric oxide (NO) and carbon monoxide (CO) may act as retrograde messengers during long-term potentiation (LTP). Inhibitors of either NO synthase or heme oxygenase, the enzyme that produces CO, blocked induction of LTP in the CA1 region of hippocampal slices. Brief application of either NO or CO to slices produced a rapid and long-lasting increase in the size of synaptic potentials if, and only if, the application occurred at the same time as weak tetanic stimulation of the presynaptic fibers. The long-term enhancement by NO or CO was spatially restricted to synapses from active presynaptic fibers and appeared to involve mechanisms utilized by LTP, occluding the subsequent induction of LTP by strong tetanic stimulation. The enhancement by NO or CO was not blocked by the NMDA receptor blocker APV, suggesting that NO and CO act downstream from the NMDA receptor. In other systems, both NO and CO produce many of their effects by activation of soluble guanylyl cyclase and cGMP-dependent protein kinase. An inhibitor of soluble guanylyl cyclase blocked the induction of normal LTP. Conversely, the membrane-permeable analog 8-Br-cGMP produced a rapid onset and long-lasting synaptic enhancement if, and only if, it was applied at the same time as weak presynaptic stimulation. Similarly, two inhibitors of cGMP-dependent protein kinase blocked the induction of normal LTP, and a selective activator of cGMP-dependent protein kinase produced activity-dependent long-lasting synaptic enhancement. 8-Br-cGMP also produced an activity-dependent, long-lasting increase in the amplitude of evoked synaptic currents between pairs of hippocampal neurons in dissociated cell culture. In addition, 8-Br-cGMP, like NO, produced a long-lasting increase in the frequency of spontaneous miniature synaptic currents. These results are consistent with the hypothesis that NO and CO, either alone or in combination, serve as retrograde messengers that produce activity-dependent presynaptic enhancement, perhaps by stimulating soluble guanylyl cyclase and cGMP-dependent protein kinase, during LTP in hippocampus.

Abstract  U.S. Army, Medical Research and Development Command Project Order 1811; U.S. Environmental Protection Agency.

Abstract  There is conflicting evidence regarding the association between different size fractions of particulate matter (PM) and cardiac and respiratory morbidity and mortality. We investigated the short-term associations of four size fractions of particulate matter (PM1, PM2.5, PM10, and PM10-2.5) and carbon monoxide with hospital admissions and emergency room (ER) visits for respiratory and cardiac conditions and mortality in Spokane, Washington. We used a log-linear generalized linear model to compare daily averages of PM and carbon monoxide with daily counts of the morbidity and mortality outcomes from January 1995 to June 2001. We examined pollution lags ranging from 0 to 3 days and compared our results to a similar log-linear generalized additive model. Effect estimates tended to be smaller and have larger standard errors for the generalized linear model. Overall, we saw no association with respiratory ER visits and any size fraction of PM. However, there was a suggestion of greater respiratory effect from fine PM when compared to coarse fraction. Carbon monoxide was associated with both all respiratory ER visits and visits for asthma at the 3-day lag. We feel that carbon monoxide may be serving as a marker for combustion-derived pollutants, which is one large component of the diverse air pollutant mixture. We also found no association with any size fraction of PM or CO with cardiac hospital admissions or mortality at the 0- to 3-day lag. We found no consistent associations between any size fraction of PM and cardiac or respiratory ER visits or hospital admissions.

Abstract  The use of meta-analysis in environmental epidemiology can enhance the value of epidemiologic data in debates about environmental health risks. Meta-analysis may be particularly useful to formally examine sources of heterogeneity, to clarify the relationship between environmental exposures and health effects, and to generate information beyond that provided by individual studies or a narrative review. However, meta-analysis may not be useful when the relationship between exposure and disease is obvious, when there are only a few studies of the key health outcomes, or when there is substantial confounding or other biases which cannot be adjusted for in the analysis. Recent increases in the use of meta-analysis in environmental epidemiology have highlighted the need for guidelines for the application of the technique. Guidelines, in the form of desirable and undesirable attributes, are presented in this paper for various components of a meta- analysis including study identification and selection; data extraction and analysis; and interpretation, presentation, and communication of results. Also discussed are the appropriateness of the use of meta-analysis in environmental health studies and when meta-analysis should or should not be used.

Abstract  Ontario Heart and Stroke Foundation; Upjohn Company of Canada.

Abstract  OBJECTIVE: To assess the association between daily exposure to air pollution and lung function in school children. METHODS: Panel study with a random sample of 118 students (between 6 and 15 years of age), enrolled in a public school of the city of Rio de Janeiro, state of Rio de Janeiro, and living within 2 km of the study site. Data on students' characteristics were obtained with a questionnaire, including the International Study of Asthma and Allergies in Childhood - ISAAC. Daily peak expiratory flow measurements were taken to measure lung function. Daily data on PM10, SO2, O3, NO2 and CO levels, temperature and humidity were provided by a portable monitor. Repeated measurements of lung function were associated with pollutant levels with a multilevel model adjusted for time trend, temperature, air humidity, exposure to smoking at home, presence of asthma, height, sex, weight and age of children. RESULTS: Mean peak expiratory flow was 243.5 l/m (sd=58.9). The lowest mean peak expiratory flow was 124 l/m, and the highest, 450 l/m. For the 10 microg/m(3) increase in PM10, there was a 0.34 l/min decrease in mean peak flow on the third day. For the 10 microg/m(3) increase in NO2, there was a decrease between 0.23 l/min and 0.28 l/min in mean peak flow after exposure. CO and SO2 effects on students' peak flow were not statistically significant. O3 showed a protective result: an increase in 10 microg/m(3) of O3 would be associated, after a day of exposure, with a 0.2 l/min increase in mean lung function. CONCLUSIONS: Even within acceptable levels most of the time, air pollution, especially PM10 and NO2, was associated with a decrease in lung function in children living in the city of Rio de Janeiro.

Abstract  California Air Resources Board. #Seventeen men with stable-angina pectoris who resided at or near sea level performed cardiopulmonary exercise stress tests after they were exposed to either carbon monoxide (3.9%), carboxyhemoglobin, or clean air. Investigators conducted the tests at sea level, and they simulated 2.1-km altitudes (i.e., reduced arterial oxygen saturation by approximately 4%) in a randomized double-blind experiment in which each subject acted as his or her own control. The duration of symptom-limited exercise, heart rate, indicators of cardiac ischemia and arrhythmia, blood pressure, and respiratory gas exchange were measured. Analyses of variance showed that both independent variables-altitude and carbon monoxide-significantly (p

Abstract  Reactive gas emissions (CO, NOx, VOC) have indirect radiative forcing effects through their influences on tropospheric ozone and on the lifetimes of methane and hydrogenated halocarbons. These effects are quantified here for the full set of emissions scenarios developed in the Intergovernmental Panel on Climate Change Special Report on Emissions Scenarios. In most of these no-climate-policy scenarios, anthropogenic reactive gas emissions increase substantially over the twenty-first century. For the implied increases in tropospheric ozone, the maximum forcing exceeds 1 W m2 by 2100 (range 0.14 to +1.03 W m2). The changes are moderated somewhat through compensating influences from NOx versus CO and VOC. Reactive gas forcing influences through methane and halocarbons are much smaller; 2100 ranges are 0.20 to +0.23 W m2 for methane and 0.04 to +0.07 W m2 for the halocarbons. Future climate change might be reduced through policies limiting reactive gas emissions, but the potential for explicitly climate-motivated reductions depends critically on the extent of reductions that are likely to arise through air quality considerations and on the assumed baseline scenario.

Abstract  In this review an attempt is made to integrate our knowledge about sensory receptors lining the respiratory tract and the reflex reactions evoked following their stimulation by inhaled chemicals. The nature of the chemicals capable of eliciting sensory irritation and the mechanisms proposed for their interactions with nerve endings are reviewed. Methods proposed for evaluation of the effects of airborne chemicals in animals are reviewed and their usefulness for predicting the reactions to be expected in humans is evaluated. The application of these methods in industrial hygiene also discussecl. Articles reviewed Include mainly those concerned with acute exposures and the effects of the chemicals following stimulation of nervous structures in the respiratory tract. Other actions of inhaled chemicals such as their effect on ciliary motion, mucous secreting cells, etc. are excluded. Airborne chemicals can also impinge on the cornea and skin. Their action on nerve endings in these structures is compared with their action on nerve endings in the upper respiratory tract in an attempt to integrate the results obtained for chemicals capable of stimulating the "common chemical sense" receptor.

Abstract  We investigated the relationship between air pollution and incidence of cardiac arrhythmia in a study of patients with implantable cardioverter defibrillators (ICDs). Thirty-four patients (ages 15-85 yr, 80% male) with ICDs residing in the Vancouver, Canada, area were included in the analyses, representing all patients attending the 2 ICD clinics in the study region who had recorded at least 1 ICD discharge during the 14 February to 31 December 2000 study period. Air pollutant (PM2.5, PM10, SO42 -, elemental carbon [EC], organic carbon [OC], O3, SO2, NO2, and CO) concentrations on days for which ICD discharges were observed ("case days") were compared to concentrations on control days in case-crossover analyses. Control days were selected symmetrically, 7 days before and after each case day. ICD discharges occurring within 72 h of 1 another were grouped and considered as 1 discharge event. Temperature, relative humidity, barometric pressure, rainfall, and wind speed were included simultaneously as covariates. Sensitivity analyses examined the effect of grouping ICD discharges, of including meteorological variables, and of excluding discharges that were considered inappropriate by a cardiologist. As in previous studies, mean concentrations and interquartile ranges of air pollutants in Vancouver were low (e.g., PM2.5 mean = 8.2 ug/m3). Although in general there were no statistically significant results, there were trends that might indicate associations between pollutants and ICD discharges. Odds ratios (OR) were consistently higher in summer than in winter (e.g., lag 0 per interquartile range increase in EC: 1.09 [0.86-1.37] vs. 0.61 [0.31-1.18]) and, in general, the highest ORs were observed for same-day effects. The one major exception was the observation of high ORs for ozone in winter (e.g., lag 1: 2.27 [0.67-7.66]). While an OR of 1.55 (0.51-4.70) was observed in summer at lag 0 for PM10, no indications of positive associations were observed for PM2.5 or SO42 -. For indicators of local combustion-source pollution, EC, OC, CO, and SO2, ORs were elevated at all lags (0-3 days) in summer. In summary, this study provides little evidence that specific components of PM affect risk of cardiac arrhythmias, although power limited the ability of the study to detect small effects.

Abstract  OBJECTIVE: A comparison was made between the endogenous carbon monoxide (CO) production in mechanically ventilated critically ill adult patients with, and those without, severe sepsis. DESIGN: Prospective comparative study. SETTING: Medical ICU in a community hospital. PATIENTS: Twenty-four patients with severe sepsis of various etiologies and five control patients with varying diagnoses. INTERVENTION: CO concentration was determined with an infrared CO analyzer on exhaled breath collected at the outlet of the ventilator. Endogenous CO production was estimated by the lung CO excretion rate measured at steady state. MEASUREMENTS AND MAIN RESULTS:: Endogenous CO production was higher in the sepsis group during the first 3 days of treatment in comparison to the control group (10.9+/-5 (SD) microl/kg per h on day 1, 7.8+/-4.9 microl/kg per h on day 2 and 6.9+/-4.7 microl/kg per h on day 3 versus 2.1+/-0.5 microl/kg per h; p<0.01 for each comparison). Survivors of sepsis had a significantly higher endogenous CO production on day 1 compared to non-survivors (14.7+/-5.3 versus 8.5+/-3.3 microl/kg per h; p=0.02). CONCLUSION: Endogenous CO production was significantly higher in mechanically ventilated patients suffering from severe sepsis. Further studies are required in order to determine the mechanism(s) and the functional significance of this increase.

Abstract  Background: Many young children wheeze during viral respiratory infections, but the pathogenesis of these episodes and their relation to the development of asthma later in life are not well understood. Methods: In a prospective study, we investigated the factors affecting wheezing before the age of three years and their relation to wheezing at six years of age. Of 1246 newborns in the Tucson, Arizona, area enrolled between May 1980 and October 1984, follow-up data at both three and six years of age were available for 826. For these children, assessments in infancy included measurement of cord-serum IgE levels (measured in 750 children), pulmonary-function testing before any lower respiratory tract illness had occurred (125), measurement of serum IgE levels at nine months of age (672), and questionnaires completed by the children's parents when the children were one year old (800). Assessments at six years of age included measurement of serum IgE levels (in 460), pulmonary-function testing (526), and skin allergy testing (629). Results: At the age of six years, 425 children (51.5 percent) had never wheezed, 164 (19.9 percent) had had at least one lower respiratory tract illness with wheezing during the first three years of life but had no wheezing at six years of age, 124 (15.0 percent) had no wheezing before the age of three years but had wheezing at the age of six years, and 113 (13.7 percent) had wheezing both before three years of age and at six years of age. The children who had wheezing before three years of age but not at the age of six had diminished airway function (length-adjusted maximal expiratory flow at functional residual capacity [Vsub maxFRC]) both before the age of one year and at the age of six years, were more likely than the other children to have mothers who smoked but not mothers with asthma, and did not have elevated serum IgE levels or skin-test reactivity. Children who started wheezing in early life and continued to wheeze at the age of six were more likely than the children who never wheezed to have mothers with a history of asthma (P<0.001), to have elevated serum IgE levels (P<0.01) and normal lung function in the first year of life, and to have elevated serum IgE levels (P<0.001) and diminished values for VmaxFRC (P<0.01) at six years of age. Conclusions: The majority of infants with wheezing have transient conditions associated with diminished airway function at birth and do not have increased risks of asthma or allergies later in life. In a substantial minority of infants, however, wheezing episodes are probably related to a predisposition to asthma.

Abstract  Background: Exhaled carbon monoxide has been reported to increase in inflammatory pulmonary diseases and to be correlated with blood carboxyhaemoglobin (Hb-CO) concentration. A study was undertaken to determine whether arterial blood Hb-CO increases in patients with inflammatory pulmonary diseases. Methods: The Hb-CO concentration in arterial blood was measured with a spectrophotometer in 34 normal control subjects, 24 patients with bronchial asthma, 52 patients with pneumonia, and 21 patients with idiopathic pulmonary fibrosis (IPF). Results: The mean (SE) Hb-CO concentrations in patients with bronchial asthma during exacerbations (n=24, 1.05 (0.05)%), with pneumonia at the onset of illness (n=52, 1.08 (0.06)%), and with IPF (n=21, 1.03 (0.09)%) were significantly higher than those in control subjects (n=34, 0.60 (0.07)%) (mean difference 0.45% (95% confidence interval (CI) 0.23 to 0.67), p<0.01 in patients with bronchial asthma, mean difference 0.48% (95% CI 0.35 to 0.60), p<0.0001 in patients with pneumonia, and mean difference 0.43% (95% CI 0.26 to 0.61) p<0.001 in patients with IPF). In 20 patients with bronchial asthma the Hb-CO concentration decreased after 3 weeks of treatment with oral glucocorticoids (p<0.001). In 20 patients with pneumonia the Hb-CO concentration had decreased after 3 weeks when patients showed evidence of clinical improvement (p<0.001). The values of C-reactive protein (CRP), an acute phase protein, correlated with Hb-CO concentrations in patients with pneumonia (r=0.74, p<0.0001) and in those with IPF (r=0.46, p<0.01). In patients with bronchial asthma changes in Hb-CO concentrations were significantly correlated with those in forced expiratory volume in 1 second (FEV1) after 3 weeks (r=0.67, p<0.01). Exhaled carbon monoxide (CO) concentrations were correlated with Hb-CO concentrations (n=33, r=0.80, p<0.0001). Conclusions: Hb-CO concentrations are increased in inflammatory pulmonary diseases including bronchial asthma, pneumonia, and IPF. Measurement of arterial Hb-CO may be a useful means of monitoring pulmonary inflammation.