End-tidal Breath Carbon Monoxide Research Articles

Perinatal Hemolytic Disorders and Identification Using End Tidal Breath Carbon Monoxide.

Hemolytic disorders can cause severe morbidity or can be life-threatening. Before the re-cent development of practical and inexpensive testing for hemolysis by quantifying carbon monox-ide in end-tidal breath, some hemolytic disorders in perinatal patients were not detected until se-verely problematic hyperbilirubinemia and/or anemia occurred. Here we review studies aimed at es-tablishing the normal reference intervals for end tidal breath carbon monoxide (ETCO) in various perinatal populations. We also review reports, and new theories, about using this methodology to diagnose and quantify hemolytic disorders in term and premature neonates, anemic pregnant wom-en, and fetuses in utero. The purposes of making these measurements are to; (1) identify patients who have hemolytic disorders, (2) characterize the severity of the hemolysis in each hemolytic pa-tient, and (3) predict and prevent co-morbidities, thereby improving outcomes.

Inhaled carbon monoxide increases vasodilation in the microvascular circulation

Preeclampsia (PE) is characterized by systemic maternal endothelial dysfunction. Changes in endothelial reactivity have been reported before the onset of clinical signs of PE, and continuing into the post-partum period. Women who smoke during pregnancy have a 33% reduced risk of developing PE. This reduced risk is hypothesized to be, in part, attributed to carbon monoxide (CO), a by-product of cigarette combustion and a known endogenous vasodilator. Determining the vascular effects of CO in healthy women, may inform how CO can improve endothelial function and have promise as a novel therapeutic for PE. As part of a pilot study to determine the vascular effects of CO, the aim of this study was to measure microvascular vasodilation following low-dose CO inhalation. Non-pregnant women inhaled ambient room air or 250 ppm CO for 24 min during microvascular assessment using laser speckle contrast imaging. Changes in vascular flux were measured in the forearm before, during, and following a three-minute arterial occlusion. CO inhalation increased end-tidal breath CO (EtCO) (9.1 ± 1.9 vs. 1.8 ± 0.7 ppm, p < 0.05) and increased microvascular vasodilation, measured as difference of maximum level/resting level ratio (mean difference 0.476, 95% confidence interval (CI) = 0.149–0.802 vs. 0.118, 95% CI = −0.425–0.662, p < 0.05). Women who inhaled CO had a longer time to half recovery of endothelial function following arterial occlusion, compared to controls (hazard ratio 0.29, 95% CI = 0.10–0.91, p = 0.033). Inhalation of CO moderately increased EtCO and resulted in an increased microvascular response, suggesting that CO may have potential as a therapeutic for PE.

Identification of risk for neonatal haemolysis.

To identify neonates at risk of haemolytic hyperbilirubinaemia through near-concurrent measurements of total serum/plasma bilirubin (TB) or transcutaneous bilirubin (TcB) and end-tidal breath carbon monoxide (CO), corrected for ambient CO (ETCOc), an index of bilirubin production and haemolysis. Paired TB/TcB (mg/dL) and ETCOc (ppm) measurements were obtained in newborns (n = 283) at 20 to <60 hours of age in five nurseries. TB/TcB values were assigned TB/TcB percentile risk values using the Bhutani hour-specific nomogram. In infants having two serial TB/TcB measurements (n = 76), TB rate of rise (ROR, mg/dL/h) was calculated. For the entire cohort (n = 283), 67.1% and 32.9% had TB/TcB<75th and ≥75th percentile, respectively. TB/TcB (5.79 ± 1.84 vs 9.14 ± 2.25 mg/dL) and ETCOc (1.61 ± 0.45 vs 2.02 ± 1.35 ppm, p = 0.0002) were different between the groups. About 36.6% of infants with TB/TcB ≥75th percentile had ETCOc ≥ 2.0 ppm. In the subcohort of infants with serial TB/TcB measurements (n = 76), 44.7% and 55.3% had TB/TcB<75th and ≥75th percentile, respectively. TB/TcB (5.28 ± 1.97 vs 9.53 ± 2.78 mg/dL), ETCOc (1.72 ± 0.48 vs 2.38 ± 1.89 ppm, p = 0.05) and TB ROR (0.011 ± 0.440 vs 0.172 ± 0.471 mg/dL/h) were different between the groups. The combined use of TB/TcB percentile risk assessments and ETCOc measurements can identify infants with haemolytic hyperbilirubinaemia. The addition of TB ROR can identify those infants with elimination disorders.

Erythrocyte aging as a mechanism of anemia and a biomarker of device thrombosis in continuous-flow left ventricular assist devices

Blood trauma caused by continuous-flow left ventricular assist devices (CF-LVADs) has been associated with device thrombosis and anemia. Accurate in vivo quantification of erythrocyte turnover and its contribution to CF-LVAD complications have yet to be elucidated. We investigated the age (lifespan) of circulating erythrocytes in subjects with CF-LVAD. Erythrocyte lifespan is a quantitative indicator of in vivo erythrocyte turnover that can be accurately derived from measurement of the exhaled carbon monoxide (CO) level. Sixty non-smoking subjects were prospectively enrolled: 25 had a CF-LVAD without thrombosis; 10 had a CF-LVAD with thrombosis; and 25 were normal controls. End-tidal breath CO levels were measured and used to calculate erythrocyte lifespan. The mean erythrocyte lifespan was significantly shorter in CF-LVAD subjects with (29.7 ± 14.9 days) compared to those without (65.0 ± 17.3 days) device thrombosis (p < 0.0001). The lifespans in these 2 groups were significantly shorter compared with normal controls (96.0 ± 24.9 days, both p < 0.0001). A receiver operator curve demonstrated high sensitivity-specificity for use of erythrocyte lifespan to detect device thrombosis (AUC = 0.94). In addition, all CF-LVAD subjects had low hemoglobin (11.8 ± 2.0 g/dl), and their anemia was normochromic normocytic with elevated mean reticulocyte counts. Erythrocyte lifespan correlated significantly with mean corpuscular hemoglobin concentration (r = 0.56, p = 0.0005) and red cell distribution width (r = -0.65, p < 0.001), but not with reticulocyte count (r = 0.27, p = 0.32). Erythrocyte lifespan is substantially reduced in subjects with a CF-LVAD, which was more pronounced in the presence of device thrombosis. The etiology of anemia in CF-LVAD was primarily due to accelerated erythrocyte aging. Further studies are needed to determine whether erythrocyte lifespan could provide a practical means of detecting subtle pre-clinical thrombosis.

Measuring End-Tidal Carbon Monoxide of Jaundiced Neonates in the Birth Hospital to Identify Those with Hemolysis

Background: End-tidal breath carbon monoxide (ETCOc) levels correlate with catabolism of heme, but until recently, this measurement was not readily available for application to neonatology practice. Objectives: We performed a prospective, multihospital, test-of-concept study where ETCOc was measured during the birth hospitalization of neonates with a total bilirubin (TB) value >75th percentile on the Bhutani bilirubin nomogram. This was done to test the feasibility and ease of use of this new device. Methods: Neonates with an elevated ETCOc (with a >95th percentile reference interval previously established) were labeled as having ‘hemolytic jaundice'. We recommended a follow-up TB check <24 h after hospital discharge to these families. Results: One hundred and fifteen neonates were eligible for the study, the parents of 103 provided consent, and measurements were obtained for 100. Sixty-three had normal and 37 had elevated ETCOc values. By means of a direct antiglobulin test (DAT; Coombs), 11 of these 37 were found positive for ABO hemolytic disease; the remaining 26 had other etiologies. Thirty-six of the 37 with an elevated ETCOc had repeat TB monitoring <24 h after discharge home. None of the 100 were rehospitalized for jaundice treatment compared with a rate of 2.99 rehospitalizations per 100 control neonates who had a TB value >75th percentile (p = 0.079). Conclusion: ETCOc measurement is a feasible means of assessing hemolysis in jaundiced neonates during the birth hospitalization. When hemolysis is identified, parents are likely to comply with instructions to bring the infant for a TB checkup <24 h after discharge home.

End-tidal carbon monoxide and hemolysis.

Hemolytic disease in newborns can result from a number of conditions, which can place such infants at an increased risk for the development of severe hyperbilirubinemia. Because the catabolism of heme produces equimolar amounts of carbon monoxide (CO) and bilirubin, measurements of end-tidal breath CO (corrected for ambient CO) or ETCOc can serve as an index of hemolysis as well as of bilirubin production from any cause. Elevated levels of ETCOc have been correlated with blood carboxyhemoglobin levels and thus hemolysis. However, the detection of hemolysis can be a clinically challenging problem in newborns. Here, we describe the importance of determining ETCOc levels and their application in identifying infants at risk for developing hyperbilirubinemia associated with hemolysis and other causes of increased bilirubin production.

Chronic carbon monoxide inhalation during pregnancy augments uterine artery blood flow and uteroplacental vascular growth in mice

End-tidal breath carbon monoxide (CO) is abnormally low in women with preeclampsia (PE), while women smoking during pregnancy have shown an increase in CO levels and a 33% lower incidence of PE. This effect may be, in part, due to lowered sFLT1 plasma levels in smokers, and perhaps low-level CO inhalation can attenuate the development of PE in high-risk women. Our previous work showed maternal chronic CO exposure (<300 ppm) throughout gestation had no maternal or fetal deleterious effects in mice. Our current study evaluated the uteroplacental vascular effects in CD-1 maternal mice that inhaled CO (250 ppm) both chronically, gestation day (GD) 0.5 to 18.5, and acutely, 2.5 h on each of GD 10.5 and 14.5. We demonstrated, using microultrasound measurements of blood velocity and microcomputed tomography imaging of the uteroplacental vasculature, that chronic maternal exposure to CO doubled uterine artery blood flow and augmented uteroplacental vascular diameters and branching. This finding may be of benefit to women with PE, as they exhibit uteroplacental vascular compromise. The ratio of VEGF protein to its FLT1 receptor was increased in the placenta, suggesting a shift to a more angiogenic state; however, maternal circulating levels of VEGF, sFLT1, and their ratio were not significantly changed. Doppler blood velocities in the maternal uterine artery and fetal umbilical artery and vein were unaltered. This study provides in vivo evidence that chronic inhalation of 250 ppm CO throughout gestation augments uterine blood flow and uteroplacental vascular growth, changes that may protect against the subsequent development of preeclampsia.

End-Tidal Breath Carbon Monoxide Measurements: Current Directions

Because heme catabolism leads to the formation of equimolar amounts of carbon monoxide (CO) and bilirubin, a variety of techniques have been developed to correlate CO production rates as indices of bilirubin production. The use of end-tidal breath CO measurements for estimating rates of bilirubin production in infants has been well documented and validated in a number of clinical studies for its use and predictive value in identifying infants who are high producers of bilirubin and hence at risk for developing pathologic neonatal hyperbilirubinemia. Recently, end-tidal breath CO has been suggested as a marker for chronic lung disease and developmental problems. Trace gas analysis remains an area for interesting investigation in the future.

Self-reported cigarette smoking status imprecisely quantifies exposure in pregnancy

Objective: We sought to determine the validity of self-reported smoking activity versus two quantitative measurements of tobacco exposure in pregnancy. We hypothesized that pregnant women would under-report their daily smoking amounts, due to the negative social stigmas associated with such a behavior. Methods: Cigarette-smoking and non-smoking pregnant women were recruited as part of a larger research study. Pregnant women with a singleton baby (>24 weeks) were recruited at a clinical appointment or prior to an elective caesarian section. Self-reported smoking status, including time since last cigarette, was recorded. End-tidal breath carbon monoxide (ETCO) levels and urine cotinine levels were measured and compared. Results: Both normotensive non-smoking (NTN) (n = 44) and normotensive smoking (NTS) (n = 24) pregnant women were recruited. A strong correlation was found between ETCO levels and urine cotinine measurements (r = 0.6566, p 0.05). Conclusion: Self-reported smoking status accurately identifies women who smoke in pregnancy, but not their level of tobacco exposure. Urine cotinine or ETCO are much better quantitative measurements of nicotine and carbon monoxide, respectively, and should be measured for a more precise indicator of smoking activity. These devices will allow for better counseling and monitoring of women who are trying to quit smoking and/or who enter into smoking cessation programs.

End tidal carbon monoxide levels are lower in women with gestational hypertension and pre-eclampsia.

The possible role of heme oxygenase and its byproduct carbon monoxide (CO) in the regulation of blood pressure is under investigation. The aim of this study was to compare end tidal breath CO (ETCO) levels in women with gestational hypertension (GH) or pre-eclampsia to the levels in healthy pregnant and nonpregnant women. We prospectively performed ETCO measurements corrected for ambient CO (ETCOc) in two medical centers (Stanford, CA and Cleveland, OH). A Natus CO-Stat End Tidal Breath Analyzer (Natus Medical Inc., San Carlos, CA) was used. The study group included a convenience sample of 31 women with GH/pre-eclampsia (PE). Control groups included 46 nonpregnant healthy women, 44 first-trimester and 48 third-trimester pregnant healthy women. Mean+/-SD ETCOc measurements were significantly lower in the GH/PE group compared to first-trimester (p=0.004) and third-trimester (p=0.001) normotensive pregnant and nonpregnant women (p=0.002) (1.36+/-0.30 vs 1.76+/-0.47, 1.72+/-0.42 and 1.78+/-0.54 ppm, respectively). The ETCOc values were < or =1.6 ppm in 89% of GH/PE women compared with, respectively, only 45, 54, and 46% of nonpregnant, first- and third-trimester normotensive pregnant women (p<0.05). ETCO measurements were not influenced by maternal age, parity, ethnicity, body mass index, gestational age or presence of household smokers. In the two centers, the controls had a similar mean ETCOc and the differences found remained significant when results for each center were analyzed separately. ETCOc levels were found to be significantly lower in women with GH/PE. Further investigation is required to determine if the lower CO levels reflect a deficient compensatory response to the increase in blood pressure or whether these are primary changes of significance to our understanding of the pathogenesis of GH/PE.

Isoimmunization is unlikely to be the cause of hemolysis in ABO-incompatible but direct antiglobulin test-negative neonates.

It is stated that the direct antiglobulin (Coombs') test (DAT) may be negative in ABO hemolytic disease of the newborn. Thus, significant jaundice in neonates who are A-B incompatible with their mothers but DAT test negative is often attributed to isoimmunization and another diagnosis is not sought. We wished to determine the rate of bilirubin production, as an objective measure of hemolysis, in 2 groups of DAT-negative neonates--ABO-compatible and ABO-incompatible--and in DAT-positive ABO-incompatible neonates. In consecutive, term, healthy newborns who were admitted to the general care nursery, we measured the level in parts per million (ppm) of end-tidal breath carbon monoxide (CO), corrected for inspired CO (ETCOc), an index of the rate of bilirubin production. We compared the levels in DAT-negative ABO-incompatible neonates with those in ABO-compatible neonates and with the levels in DAT-positive ABO-incompatible neonates. Statistical analysis was performed using 2-sample t and chi(2) tests. There was no significant difference between the mean 12-hour ETCOc levels in DAT-negative ABO-incompatible neonates (n = 60, 2.2 +/- 0.6 ppm) versus DAT-negative ABO-compatible neonates (n = 171, 2.1 +/- 0.6 ppm), although there was a difference between the mean levels in DAT-positive ABO-incompatible neonates (n = 14, 3.4 +/- 1.8 ppm) and the DAT-negative groups. Four DAT-negative ABO-incompatible neonates had elevated ETCOc levels; in 2, we diagnosed a specific hematologic abnormality, namely, glucose-6-phosphate dehydrogenase deficiency in 1 and elliptocytosis in the other. In DAT-negative newborns with significant jaundice or increased bilirubin production, even if ABO-incompatible, a cause other than isoimmunization should be sought.

Ethnic Origin Should Be Considered When End-Tidal Breath Carbon Monoxide Measurements Are Used to Predict the Development of Hyperbilirubinemia in Healthy Term Infants

Ethnic Origin Should Be Considered When End-Tidal Breath Carbon Monoxide Measurements Are Used to Predict the Development of Hyperbilirubinemia in Healthy Term Infants