Combined effects of inspired oxygen, carbon dioxide, and carbon monoxide on oxygen transport and aerobic capacity.

We hypothesized that breathing hypoxic, hypercapnic, and CO-containing gases together reduces maximal aerobic capacity (Vo2max) as the sum of each gas' individual effect on Vo2max. To test this hypothesis, goats breathed combinations of inspired O2 fraction (FiO2) of 0.06-0.21 and inspired CO2 fraction of 0.00 or 0.05, with and without inspired CO that elevated carboxyhemoglobin fraction (FHbCO) to 0.02-0.45, while running on a treadmill at speeds eliciting Vo2max. Individually, hypoxia and elevated FHbCO decreased fractional Vo2max (FVo2max, fraction of a goat's Vo2max breathing air) in linear, dose-dependent manners; hypercapnia did not change Vo2max. Concomitant hypoxia and elevated FHbCO decreased Vo2max less than the individual gas effects summed, indicating their combined effects on Vo2max are attenuated, fitting the following regression: FVo2max = 4.24 FiO2 + 0.519 FHbCO - 8.22 (FiO2 × FHbCO) + 0.117, (R(2) = 0.965, P < 0.001). The FVo2max correlated highly with total cardiopulmonary O2 delivery, not peripheral diffusing capacity, and with arterial O2 concentration (CaO2), not cardiac output. Hypoxia and elevated FHbCO decreased CaO2 by different mechanisms: hypoxia decreased arterial O2 saturation (SaO2), whereas elevated FHbCO decreased O2 capacitance {concentration of hemoglobin (Hb) available to bind O2 ([Hbavail])}. When breathing hypoxic gas (FiO2 0.12), CaO2 did not change with increasing FHbCO up to 0.30 because higher SaO2 of Hbavail offset decreased [Hbavail] due to the following: 1) hyperventilation with hypoxia and/or elevated FHbCO; 2) increased Hb affinity for O2 due to both Bohr and direct carboxyhemoglobin effects; and 3) the sigmoid relationship between O2 saturation and partial pressure elevating SaO2 more with hypoxia than normoxia.

The enigma of the liganded hemoglobin end state: a novel quaternary structure of human carbonmonoxy hemoglobin.

The liganded hemoglobin (Hb) high-salt crystallization condition described by Max Perutz has generated three different crystals of human adult carbonmonoxy hemoglobin (COHbA). The first crystal is isomorphous with the "classical" liganded or R Hb structure. The second crystal reveals a new liganded Hb quaternary structure, RR2, that assumes an intermediate conformation between the R form and another liganded Hb quaternary structure, R2, which was discovered more than a decade ago. Like the R2 structure, the diagnostic R state hydrogen bond between beta2His97 and alpha1Thr38 is missing in the RR2 structure. The third crystal adopts a novel liganded Hb conformation, which we have termed R3, and it shows substantial quaternary structural differences from the R, RR2, and R2 structures. The quaternary structure differences between T and R3 are as large as those between T and R2; however, the T --> R3 and T --> R2 transitions are in different directions as defined by rigid-body screw rotation. Moreover, R3 represents an end state. Compared to all known liganded Hb structures, R3 shows remarkably reduced strain at the alpha-heme, reduced steric contact between the beta-heme ligand and the distal residues, smaller alpha- and beta-clefts, and reduced alpha1-alpha2 and beta1-beta2 iron-iron distances. Together, these unique structural features in R3 should make it the most relaxed and/or greatly enhance its affinity for oxygen compared to the other liganded Hbs. The current Hb structure-function relationships that are now based on T --> R, T -->R --> R2, or T --> R2 --> R transitions may have to be reexamined to take into account the RR2 and R3 liganded structures.

Neural circulatory responses to carbon monoxide in healthy humans.

The contribution of carbon monoxide (CO) to the acute cardiovascular effects of smoking is not clear. Using a double-blind, randomized, vehicle-controlled study design, we examined the sympathetic and vascular responses to modest increases in carboxyhemoglobin in 10 healthy humans. We measured muscle sympathetic nerve activity (microneurography), forearm blood flow (plethysmography), heart rate, blood pressure, and minute ventilation at baseline and during 60 minutes of CO inhalation (1000 ppm during the first 30 minutes and 100 ppm during the last 30 minutes). The same measurements were made in a vehicle session (room air inhalation) on a separate day. During the first 30 minutes of CO inhalation, carboxyhemoglobin levels increased progressively from 0.2 +/- 0.1% to 8.3 +/- 0.5% and were maintained at about this level for a further 30 minutes. Forearm vascular resistance did not change with CO but increased slightly with vehicle; the effects of CO on muscle sympathetic nerve activity, forearm blood flow, blood pressure, heart rate, and minute ventilation were not significantly different from the effects of vehicle. Modest increases in carboxyhemoglobin levels equivalent to those resulting from cigarette smoking are unlikely to contribute to the acute sympathetic and hemodynamic effects of smoking in healthy humans.

[The effect of hyperbilirubinemia on the measurement of oxygenated hemoglobin (O2Hb), carboxyhemoglobin (COHb) and methemoglobin (MetHb) using multiwavelength oximeters in mixed venous blood]. / Einfluss einer Hyperbilirubinämie auf die Messung von oxygeniertem Hämoglobin (O2Hb), Carboxyhämoglobin (COHb) und Methämoglobin (MetHb) mit Mehrwellenlängenoxymetern im gemischtvenösen Blut.

Oximetric measurements are influenced by several mechanisms. Severe jaundice is one of these mechanisms with some clinical interest. In the literature it is pointed out that a high bilirubin concentration may falsify oximetric measurements and is often accompanied by elevated COHb levels. The reason for this phenomenon is thought to be an interference in the absorption spectra of haemoglobin derivatives and bilirubin [2, 3, 4, 10]. In our investigation we attempted to answer the following questions: 1. How do multiwavelength oximeters measure haemoglobin derivatives in different bilirubin concentrations? 2. Do different multiwavelength oximeters give different concentrations of haemoglobin derivatives? METHODS. In 13 patients who developed postoperative jaundice on the intensive care unit, O2Hb, COHb and MetHb were measured in mixed venous blood with two multiwavelength oximeters (OSM3, Radiometer; CO 2500, Ciba-Corning). Bilirubin concentration was measured by the DPD (dichlorphenyldiazonium) method in the central laboratory of our hospital. RESULTS. With increasing bilirubin concentrations, both oximeters measured increasing O2Hb values; the OSM3 consistently showed higher O2Hb concentrations than the CO 2500, with a maximal difference of 2.8% (Fig. 3). Regarding COHb, we saw clear increases in the values with increasing bilirubin concentrations (Fig. 4). The CO 2500 showed higher COHb values than the OSM3 (average 1.54 +/- 0.3%). The findings regarding MetHb differed. The CO 2500 showed increasing MetHb values as the bilirubin concentration increased (Fig. 5). All measurements exceeded normal values above a bilirubin concentration of 17 mg/dl. The OSM3, however, measured constant MetHb values which did not depend on jaundice. CONCLUSIONS. 1. The in vitro measurement of haemoglobin derivates by multiwavelength oximeters is influenced by hyperbilirubinaemia. This is caused by an interference between the light absorption spectra of the haemoglobin derivates and of bilirubin and by the increasing development of endogenous CO in the haem metabolism during severe jaundice (Fig. 7). 2. With increasing bilirubin levels, a lower O2Hb is measured with the CO 2500 than with the OSM3. 3. We also see increasing COHb values with rising bilirubin concentrations. 4. With increasing bilirubin levels the MetHb concentration measured with the CO 2500 rises, while the OSM3 gives constant MetHb values. 5. In severe jaundice the O2Hb values measured with multiwavelength oximeters are not identical with the real blood concentration of this haemoglobin derivative. In this situation multiwavelength oximeters cannot be used as a reference method for in vivo oximetric systems such as pulse oximeters or fibreoptic pulmonary artery catheters.

Carboxyhemoglobin and brain blood flow in humans.

It has been shown that with increased carboxyhemoglobin (COHb) and associated decrease in blood oxygen-carrying capacity, a compensatory increase in brain-blood flow (BBF) develops. The BBF response in humans has been shown to be quite variable. Two experiments were conducted in which humans were exposed to sufficient carbon monoxide (CO) to produce COHb levels up to 18.4%. BBF was measured by the method of impedance plethysmography. The first was a pilot study in which BBF in 14 men was studied after transient exposure to various concentrations of CO in air. BBF increased as a function of COHb but not to the same extent (or at all) in some subjects. In a confirmatory experiment with 12 men, BBF was measured once per h during a 4-h experiment. All 12 subjects received CO. The variation of the BBF response among subjects was large and statistically significant whereas the variation over time was not significant. Thus it appears that the magnitude of the BBF response is unique for a given subject and differs across subjects. These results may help predict CO-induced behavioral decrements in future studies if subjects whose BBF response to COHb is small or absent are also more susceptible to impairment by acute CO exposure.

Effect of carboxyhemoglobin on tumor oxygen unloading capacity in patients with squamous cell carcinoma of the head and neck.

Hemoglobin and blood gas parameters, with special attention to the influence of carboxyhemoglobin, were studied in 115 head and neck cancer patients undergoing radiotherapy. In 712 weekly blood samples, the values of total hemoglobin, carboxyhemoglobin (CO-Hb), and p50 were measured and the total oxygen content in the arterial and tumor venous blood was estimated. The difference between these values express the tumor oxygen unloading capacity (t-OUC). CO-Hb ranged from 0-12% and showed a significant inverse relationship with t-OUC. This was caused by a reduced amount of effective hemoglobin combined with a left shift of the oxyhemoglobin dissociation curve (reduced p50). Overall, the tumor oxygen utilization decreased from 70% to 52% as a function of an increase in CO-Hb from 0 to 12%.

Influence of carboxyhemoglobin level on tumor growth, blood flow, and radiation response in an experimental model.

Carboxyhemoglobin (HbCO) is formed when carbon monoxide is bound to hemoglobin. High levels of HbCO are known to reduce the amount of oxygen that can be carried to the tissues. This experimental study focuses on the influence of HbCO on the growth, blood flow, and radiation response of an experimental mouse tumor. The study was designed to mimic the clinical situation where heavy smokers are undergoing radiotherapy while having a high HbCO level. The tumor was a C3H mammary carcinoma grown in the feet of CDF1 mice. Chronic exposure to carbon monoxide, resulting in 10% HbCO, increased the tumor volume doubling time from 2.5 to 3.5 days (p less than 0.05). The acute exposure to carbon monoxide prior to and during irradiation significantly raised the radiation dose required to control the tumor locally. The TCD50 increased from 54 Gy in air breathing mice (HbCO 0-2%) to 57 Gy (HbCO 7-9%) and 61 Gy (HbCO 20-23%). This increase corresponded to an increase in the fraction of clonogenic hypoxic tumor cells from 0.12 in air breathing animals to 0.21 and 0.41, respectively. The tumor blood flow, determined by the 86RbCl extraction technique, decreased to 63% (n.s.) and 50% (p less than 0.05) for low and high HbCO levels, respectively.

Effect of acute reduction in oxygen transport on parameters of aerobic function during exercise.

The binding of haemoglobin by carbon monoxide reversibly decreases the blood O2 carrying capacity, providing a useful model of impaired circulatory O2 transport. We evaluated noninvasive parameters of aerobic function during exercise to detect small changes in O2 transport, using carbon monoxide. Ten normal subjects performed both symptom-limited incremental and two levels of constant work rate on a cycle ergometer while breathing air and air with added carbon monoxide to cause carboxyhaemoglobin (COHb) to be approximately 11% (level of heavy cigarette smoker) and 20%. Maximal O2 uptake (VO2 max), the anaerobic threshold (AT) determined from the plot of CO2 output as a function VO2 (V-slope, the ratio of increase in VO2 to work rate increment (delta VO2/delta WR) and the upper slope of the V-slope analysis were measured while progressively increasing work rate. These changed in approximately the same percent as the increase in COHb. For the constant work rate tests, the time constant of VO2 and the difference in VO2 at six minutes as compared to three minutes of exercise (delta VO2 (6-3)) were significantly increased when COHb was increased. These noninvasive parameters of aerobic function, determined from the cardiopulmonary response to incremental and constant work rate exercise, particularly when used in combination, proved to be sufficiently sensitive to objectively detect small changes in O2 transport to the working muscles during exercise.

Effects of 4 percent and 6 percent carboxyhemoglobin on arrhythmia production in patients with coronary artery disease.

In this study, we assessed the effects of exposure to 4 percent and 6 percent carboxyhemoglobin on ventricular arrhythmias in 41 subjects (nonsmokers) with documented coronary artery disease. We used a randomized, double-blind, crossover design. On day 1, a training session with no exposure, the baseline carboxyhemoglobin level was measured, and a supine bicycle exercise test was done. On days 2 through 4, subjects were exposed to room air, 100 parts per million (ppm)2 carbon monoxide (target, 4 percent blood carboxyhemoglobin), or 200 ppm carbon monoxide (target, 6 percent blood carboxyhemoglobin), and they then did a supine bicycle exercise test. Radionuclide ventriculography was performed at rest and during exercise. Ambulatory electrocardiogram recordings were made during the four consecutive days to determine the frequency of premature ventricular contractions at various intervals. The frequency of single premature ventricular contractions per hour during exercise was significantly greater on the 6 percent carboxyhemoglobin day than on the room air day (167.72 +/- 37.99 for 6 percent carboxyhemoglobin compared with 127.32 +/- 28.22 for room air, p = 0.03). The frequency of multiple premature ventricular contractions per hour was also significantly greater during exercise on the 6 percent carboxyhemoglobin day compared with the room air day (9.59 +/- 3.70 for the 6 percent carboxyhemoglobin day compared with 3.18 +/- 1.67 for the room air day, p = 0.02). Patients who developed increased arrhythmias during exercise on the 6 percent carboxyhemoglobin day were significantly older than those who had no increased arrhythmia, and, in addition, exercised longer and had a higher peak workload during exercise. No effect of carbon monoxide exposure was seen on the 4 percent carboxyhemoglobin day.

Placental growth in rats exposed to carbon monoxide at selected stages of pregnancy.

Maternal hypoxemia has been associated with fetal-growth retardation and placental hypertrophy. Here, rats were exposed to carbon monoxide (CO), 100 ppm, at different stages of gestation to determine when during pregnancy placental hypertrophy can be elicited, whether hypertrophy is sustained when the stimulus is removed, and whether placental hypertrophy correlates with maintenance of normal fetal growth. Groups of rats (11-17 per group) were exposed to CO, throughout gestation, or over days 1-16, 4-12, 10-22 and 18-22, to cover significant periods of placental growth. Maternal carboxyhemoglobin levels were estimated to be in the order of 10-14%, but there was no effect on fetal survival. Fetal weights were significantly reduced by 8 and 6% in groups treated over days 1-22 and 10-22 of pregnancy, but not in those where treatment ceased before term, and surprisingly not in the group treated over days 18-22, the stage of maximal fetal growth. Placental weights were significantly increased by 11-13% in all groups in which carbon monoxide exposure was continued to term, but were unaffected in cases where treatment ceased before term. These results show that near term the placenta, when it is thought to normally reach the limit of its functional capacity, can hypertrophy in response to CO, and suggest that this response benefits the fetus presumably by improving oxygen transport.

Lack of effect of low levels of carboxyhemoglobin on cardiovascular function in patients with ischemic heart disease.

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.

Effects of thyroid and growth hormone deficiency, and food restriction on heart mass, with and without added stress (carboxyhemoglobinemia).

The roles of thyroid and growth hormone, and food restriction in maintenance of heart mass and in carbon monoxide-stimulated cardiac growth were examined. First, thyroidectomized and normal adult male rats inhaled up to 500 ppm CO in air for 42 days. Combined ventricular weights of thyroidectomized rats inhaling CO and air were 12 and 23% smaller than predicted, respectively, while the combined ventricular weight of normal rats inhaling CO was 29% larger than predicted. Thyroidectomy increased the mass of the left ventricle relative to the right ventricle; this was reversed by CO treatment. While the hematocrit increased in thyroidectomized-CO rats, it was lower than in normal-CO rats: likewise the hematocrit of thyroidectomized-AIR rats was lower than that of normal rats in air. Body weights of the thyroidectomized rats were 57% that of normals. As additional controls, two groups of normal rats (one AIR, one CO) were maintained at the same body weight as the thyroidectomized rats, by adjusting food intake. Combined ventricular weight was less than predicted in AIR rats and failed to increase in CO animals, while hematocrits were the same as normals in air and in CO. Serum thyroxine (T4) and growth hormone levels assayed in thyroidectomized rats were less than 15 and 25% of normal rats, respectively. Growth hormone levels were not altered by CO inhalation in thyroidectomized and in normal rats. Levels of both hormones were normal in food-restricted rats. While thyroidectomy produced cardiac atrophy, cardiac growth was stimulated by CO inhalation, although heart mass then only approached that of normals in air. Food restriction also produced cardiac atrophy, but CO inhalation failed to stimulate heart growth.

The health effects of involuntary smoking.

Involuntary smoking is defined as the exposure of nonsmokers to tobacco combustion products in the indoor environment. Involuntary smokers are exposed to a quantitatively smaller and qualitatively different smoke exposure than active smokers. Quantitation of exposure is particularly difficult in both physiologic and epidemiologic studies. Acute physiologic studies have documented minimal physiologic changes in healthy subjects. However, individuals with heart or lung disease may be differentially affected. A relatively large body of data relates parental (particularly maternal) cigarette smoking to the occurrence of both acute respiratory illnesses and chronic respiratory symptoms in children. The effect seems to be greatest early in life and cannot be separated from in utero exposure. Data linking parental smoking to lower levels of pulmonary function are all cross-sectional and less conclusive. What is apparent is that the magnitude of the direct effect of passive smoke exposure is likely to be relatively small (from 1 to 5% reduction in maximally obtained lung function level in exposed children). Data on adults are insufficient to allow for a quantitative estimate. The important effects of passive smoke exposure in childhood are twofold. The slight reduction in pulmonary function level may predispose individuals to increased risks from environmental agents later in life. In addition, having a parent who smokes substantially increases the likelihood that a child will become a smoker. Finally, two studies have linked lung cancer in nonsmokers to exposure to spouses' cigarette smoke. Further research is needed to confirm these findings. Involuntary smoking may have important health effects, either direct or indirect, which deserve further study.

Hemodynamic responses to acute carboxyhemoglobinemia in the rat.

The effects of carbon monoxide on the hemodynamics of the adult rat were investigated. A number of parameters were measured using an open-chest, chloralose-urethan anesthetized preparation. Our experiments showed this anesthetic agent to have several advantages over pentobarbital sodium. One group inhaled 150 ppm CO for 0.5-2 h, carboxyhemoglobin (HbCO) reaching 16%. Heart rate, cardiac output, cardiac index, dF/dtmax (aortic), and stroke volume rose significantly; mean arterial pressure, total peripheral resistance, and left ventricular systolic pressure fell, whereas stroke work, left ventricular dP/dtmax, and stroke power changed little. These effects were evident at a HbCO saturation as low as 7.5% (0.5 h). A second group inhaled 500 ppm CO for 5-48 h, HbCO reaching 35-38%. The same parameters changed in the same direction as in the first group, with mean arterial pressure and peripheral resistance remaining depressed, while heart rate, cardiac output, cardiac index, and stroke volume remained elevated. Heart rate and arterial systolic pressure were also monitored in conscious rats; rats in one group inhaled 500 ppm CO for 24 h, and rats in a second group were injected with a bubble of pure CO ip. In both cases heart rate was sharply elevated and blood pressure depressed as HbCO saturation increased. Both parameters recovered on CO washout. There was no significant difference between the response to inhaled vs. injected CO.