Thomas E. Dahms

Short-Term Effects of Carbon Monoxide Exposure on the Exercise Performance of Subjects with Coronary Artery Disease

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.

Hypercarbia during carbon dioxide pneumoperitoneum

Patients with cardiopulmonary insufficiency undergoing laparoscopic surgery with carbon dioxide (CO2) pneumoperitoneum may retain CO2 resulting in clinically significant respiratory acidosis. A canine model of pulmonary emphysema induced by papain inhalation was utilized to evaluate the respiratory effects of both CO2 and helium pneumoperitoneum. Prior to papain inhalation and 5 and 8 weeks after initial treatment under general anesthesia, mechanical ventilation was adjusted to maintain the end-tidal CO2 (ETCO2) at 40 mm Hg during baseline and pneumoperitoneum physiologic monitoring periods. Utilizing an analysis of variance, hemodynamic and respiratory physiologic parameters were compared. In this canine model, all dogs demonstrated consistent hypercarbia during CO2 pneumoperitoneum prior to papain treatments, but CO2 retention was significantly increased in the emphysematous state. The occurrence of hypercarbia during CO2 pneumoperitoneum may be underestimated by ETCO2 monitoring as was revealed by an increased PaCO2 (arterial carbon dioxide pressure)-ETCO2 gradient with an increasing time interval between papain exposure and period of physiologic monitoring. Irrespective of the pulmonary condition of the dog, helium pneumoperitoneum did not produce any hypercarbic or acidic changes when compared with the concomitant baseline period of dogs prior to the induction of pneumoperitoneum, thus suggesting that helium pneumoperitoneum may be a reasonable alternative in patients at risk for CO2 retention.

CARBON MONOXIDE AND HUMAN VIGILANCE. A DELETERIOUS EFFECT OF PRESENT URBAN CONCENTRATIONS.

This study was conducted to determine whether carbon monoxide gas is a factor responsible for deterioration of vigilance in men breathing polluted air. Ten subjects were exposed for slightly longer than two hours, on separate occasions, to CO levels approximating the average (26 ppm) and peak (111 ppm) levels found while driving in urban traffic. During the last hour of each exposure the subjects undertook a, standard test of visual vigilance. They also undertook the test while breathing air without CO. Blood carboxyhemoglobin levels were measured prior to exposure, before and after the tests. Heart rates and minute ventilatory volumes were also measured The results showed that vigilance was impaired by breathing 111 ppm CO which raised the average COHb level to 6.6.% Heart rates and minute ventilatory volumes were not affected.

Effects of carbon monoxide exposure in patients with documented cardiac arrhythmias

OBJECTIVE This study was designed to determine whether carbon monoxide has proarrhythmic effects at rest and during upright exercise in patients with myocardial ischemia and moderate baseline ectopic activity. BACKGROUND Exposure of patients with documented myocardial ischemia to low levels of carboxyhemoglobin (COHb) alters the myocardial response to exercise. Anecdotal reports from patients with myocardial ischemia have noted the development of arrhythmias related to carbon monoxide exposure. Increased frequency of arrhythmias related to carbon monoxide exposure in patients performing supine bicycle exercise has been recently reported. METHODS Twenty-eight nonsmoking men and five nonsmoking women with documented coronary artery disease and a minimum of 30 ventricular ectopic beats/h over a 20-h period were studied. Subjects were exposed in a randomized double-blind fashion to either room air or sufficient carbon monoxide to elevate their COHb concentration to 3% or 5% in 1 h, followed by a maintenance exposure to carbon monoxide. The subjects then left the laboratory and resumed their normal daily activity to determine changes in ventricular ectopic beats after carbon monoxide exposure. RESULTS There was no significant change in the frequency of single ventricular ectopic beats at rest from 115 +/- 28 (in room air) to 121 +/- 31 at 3% COHb to 94 +/- 23 at 5% COHb. Exercise itself increased the frequency of ventricular ectopic beats, but there was no additional effect of carbon monoxide exposure on the exercise-induced increase in isolated ectopic beats or complex ectopic waveforms. Analysis of the data based on grouping of the subjects by the severity of disease (ventricular ectopic beat frequency, ejection fraction, presence of exercise-induced ischemia) indicated no proarrhythmic effect of carbon monoxide. CONCLUSIONS In patients with frequent ventricular ectopic activity (> or = 30 ectopic beats/h), exposure to carbon monoxide producing either 3% or 5% COHb does not increase arrhythmia frequency of single or multiple beats during rest or exercise.

β-Adrenergic blockade does not prevent polycythemia or decrease in plasma volume in men at 4300 m altitude

Abstract When humans ascend to high altitude (ALT) their plasma volume (PV) and total blood volume (BV) decrease during the first few days. With continued residence over several weeks, the hypoxia-induced stimulation of erythropoietin increases red cell production which tends to restore BV. Because hypoxia also activates the β-adrenergic system, which stimulates red blood cell production, we investigated the effect of adrenergic β-receptor inhibition with propranolol on fluid volumes and the polycythemic response in 11 healthy unacclimatized men (21–33 years old exposed to an ALT of 4300 m (barometric pressure 460 Torr) for 3 weeks on Pikes Peak, Colorado. PV was determined by the Evans blue dye method (PVEB), BV by the carbon monoxide method (BVCO), red cell volume (RCV) was calculated from hematocrit (Hct) and BVCO, and serum erythropoietin concentration ([EPO]) and reticulocyte count, were also determined. All determinations were made at sea level and after 9–11 (ALT-10) and 19–20 (ALT-20) days at ALT. At sea level and ALT, six men received propranolol (pro, 240 mg · day−1), and five received a placebo (pla). Effective β-blockade did not modify the mean (SE) maximal values of [EPO] [pla: 24.9 (3.5) vs pro: 24.5 (1.5) mU · ml−1] or reticulocyte count [pla: 2.7 (0.7) vs pro: 2.2 (0.5)%]; nor changes in PVEB [pla: −15.8 (3.8) vs pro: −19.9 (2.8)%], RCVCO [pla: +7.0 (6.7) vs pro: +10.1 (6.1)%], or BVCO [pla: −7.3 (2.3) vs pro: −7.1 (3.9)%]. In the absence of weight loss, a redistribution of body water with no net loss is implied. Hence, activation of the β-adrenergic system did not appear to affect the hypovolemic or polycythemic responses that occurred during 3 weeks at 4300 m ALT in these subjects.

Early biochemical markers of inflammation in a swine model of endotracheal intubation.

Background:A common complaint after endotracheal tube use is sore throat, which may be due to abrasion, ischemia–reperfusion injury, or an inflammatory reaction. Few studies have evaluated localized tracheal inflammation as part of the response to intubation. Methods:Inflammation of the trachea due to intubation was assessed in a swine model by following indicators of inflammation over time in the tracheal lumen. Repeated tracheal lavages proximal to the endotracheal tube cuff were performed, and recovered lavage was analyzed for cells, protein, lactate dehydrogenase, and cytokines. Results:The baseline tracheal lavage samples contained 18% polymorphonuclear cells. These cells increased rapidly to 43% by 1 h. The polymorphonuclear cell increase from baseline was significant at 1, 2, and 4 h (P < 0.01) after intubation. Tumor necrosis factor &agr;, interleukin 1&bgr;, interleukin 6, and interleukin 8 increased over time, but only interleukin 6 increased significantly (P < 0.01). Interleukin 6 was not detected at baseline or 1 h, but was detected at 2 h and increased significantly by 4 h. Neither lavage protein concentration nor lactate dehydrogenase activity increased over time. Conclusions:These results demonstrate that inflammation does occur during tracheal intubation, even when markers suggest minimal tracheal damage. The dramatic elevation in polymorphonuclear cells, along with the increase in interleukin 6, suggests an inflammatory response to the endotracheal tube itself or to some aspect of the intubation process. A more complete understanding of the response of the tracheal tissues is important in improving the treatment of intubated patients.

Carbon monoxide elimination

The elimination rates of carbon monoxide in anesthetized, spontaneously breathing dogs were determined following acute inhalation of varying amounts of this gas. Blood levels of carboxyhemoglobin (COHb) induced ranged between 5 and 43%. Following the administration of carbon monoxide, the decline in arterial blood %COHb was biphasic. The decline in the blood %COHb level could be described as an initial distribution curve which was exponential in nature, followed by an elimination curve which was linear for 90 min. Prediction equations for elimination of CO from blood according to the initial levels of COHb are presented. Animals having low (5-16%) and high (20-43%) COHb levels eliminated 50% of their total load in 190 plus or minus 6.4 and 134 plus or minus 5.3 min, respectively.

Innate Immunity Mediating Inflammation Secondary to Endotracheal Intubation

OBJECTIVE To investigate the inflammatory markers associated with short-term endotracheal intubation in healthy surgical patients. DESIGN An observational and prospective study of subjects scheduled for same-day surgery procedures. SETTING Level I trauma center. PATIENTS Fourteen healthy patients intubated for same-day surgery procedures. The median duration of surgery was 3 hours. INTERVENTIONS Serial lavages above the tracheal cuff were obtained at the beginning of surgery, at 1 hour, and at the end of surgery; samples were assayed for cellular counts and levels of cytokines and complement 5a (C5a). RESULTS The total number of polymorphonuclear cells (PMNs) increased almost 10-fold from intubation to extubation (P < .01). The levels of 3 of the cytokines measured in tracheal lavage supernatants were significantly elevated over the time of intubation: tumor necrosis factor (TNF) (P < .01), interleukin 6 (IL-6) (P < .01), and IL-1β (P < .025). Levels of IL-8 showed an upward trend over time but were not significantly increased; C5a levels were significantly elevated over time (P < .05). CONCLUSIONS Short-term intubation in healthy patients resulted in significant tracheal inflammation. Involvement of the innate immune system as documented in the present study provides information that may help to better understand the pathophysiologic characteristics of subglottic stenosis and other endotracheal injuries secondary to endotracheal intubation.

C-reactive protein increases F-actin assembly and cortical distribution with resultant loss of lamellipod formation in human neutrophils

C‐reactive protein (CRP) inhibits neutrophil movement through a p38 MAP kinase pathway. We hypothesized that CRP altered F‐actin content and distribution on human neutrophils as a means of inhibiting movement. CRP produced simultaneous increased F‐actin and decreased G‐actin levels. CRP increased F‐actin levels in a concentration‐dependent manner once a threshold (>100 μg/ml) was reached, and transiently increased F‐actin (peak levels at 2.5 and 10 min) that returned to baseline by 30 min. Confocal microscopy of neutrophils revealed that fMLP provoked acquisition of a migratory phenotype as evidenced by the appearance of F‐actin rich lamellipods. In contrast, CRP caused neutrophil rounding, prevented lamellipod formation and shifted F‐actin from the cytoskeleton to the cortex. The p38 MAP kinase inhibitor, SB203580, produced a similar effect on neutrophil shape. Concentrations of SB203580 that dramatically decreased p38 activity in neutrophils also caused round cell morphology and cortical F‐actin distribution. Since CRP inhibits p38 MAP kinase and p38 blockade leads to actin polymerization and prevention of lamellipod formation, it is concluded that round morphology and loss of lamellipod formation result from CRP inhibition of p38 MAP kinase. Understanding the signal transduction of CRP prevention of lamellipod formation will aid in the development of therapeutic agents against neutrophil‐associated inflammatory disease.

Triolein Increases Microvascular Permeability in Isolated Perfused Rabbit Lungs: Role of Neutrophils

BACKGROUND Pathophysiologic mechanisms of the fat embolism syndrome are poorly understood. Neutrophils are thought to play a role in the development of many forms of acute lung injury. The objective of this study was to examine the role of intrapulmonary neutrophils in lung injury resulting from fat infusion. METHODS Triolein (0.08 mL/kg) was infused into isolated rabbit lungs perfused with Krebs-Henseleit buffer. Pulmonary arterial pressure was monitored, and pulmonary vascular resistance and microvascular permeability (Kf) were measured at baseline and 60 minutes after triolein infusion. RESULTS Triolein produced increases in pulmonary arterial pressure, pulmonary vascular resistance, and Kf. Neutrophil depletion or inhibition of neutrophil elastase prevented the increase in Kf after triolein, and catalase partially blocked this Kf increase. CONCLUSION These results suggest that activated intrapulmonary neutrophils play a major role in developing triolein-induced lung injury, intrapulmonary neutrophils act chiefly via neutrophil elastase release, and reactive oxygen species are involved in the lung injury.