Feiner, John R. MD; Rollins, Mark D. MD, PhD; Sall, Jeffrey W. MD, PhD; Eilers, Helge MD; Au, Paul BS; Bickler, Philip E. MD, PhD
Carbon monoxide (CO) is a leading cause of unintentional poisoning deaths in the United States. Accidental, nonfire-related CO poisoning is responsible for approximately 15,000 emergency department visits and nearly 500 deaths annually,1 with as many as 50,000 total emergency department visits for all causes of CO poisoning.2 Until the introduction of pulse CO-oximetry (e.g., Masimo Rainbow® pulse oximeters; Masimo Corp., Irvine CA), the detection of CO poisoning required laboratory analysis of a blood sample. Therefore, significant CO poisoning can be missed if not suspected,3–5 with diagnosis and treatment delayed while awaiting laboratory measurement.3 Standard pulse oximetry (SpO2) does not detect carboxyhemoglobin (COHb), and SpO2 readings may remain within normal ranges despite severely decreased oxygen-carrying capacity, decreasing only at very high COHb levels.6
The Masimo Rainbow SET® Radical-7 Pulse CO-Oximeter (Masimo Corp.) uses 7 wavelengths of light to measure levels of both methemoglobin (SpMet) and carboxyhemoglobin (SpCO). In a prior study on healthy volunteers, an early version of the Radical-7 oximeter yielded inaccurate results when hypoxemia was combined with increased methemoglobin (MetHb), producing errors in both MetHb accuracy and false indications of highly elevated COHb levels.7 The errors in MetHb detection during hypoxia were subsequently corrected.8
Studies on healthy volunteers have demonstrated acceptable accuracy of the Masimo pulse CO-oximeter for detecting COHb during normoxia,9,10 although observations in patients revealed limits of agreement exceeding 10%.11–13 No study has examined the effect of hypoxia on COHb measurements with pulse CO-oximetry. Because hypoxemia may occur simultaneously with CO poisoning, particularly in fires with smoke inhalation,14 this issue is clinically important. Currently, the United States Food and Drug Administration (FDA) does not have standards of accuracy for detection of elevated COHb during simultaneous hypoxemia, although the current device is approved clinically for continuous noninvasive monitoring of SpO2, SpCO, and SpMet. Therefore, we studied the accuracy of Masimo pulse CO-oximeter detection of COHb during both normoxia and hypoxemia.
The University of California at San Francisco Committee on Human Research approved the study, and all subjects gave informed written consent. The pool of subjects was healthy, nonsmoking men and women, from 18 to 49 years of age, willing to volunteer for the study for a nominal payment. The selected group of subjects was gender and ethnically balanced, following the FDA requirements for standard studies of pulse-oximeter accuracy. The final group included 12 healthy adult subjects, 7 men and 5 women, with a range of skin pigmentation (Table 1). The study size was based on prior studies,7,8,15,16 and the size of standard studies of pulse-oximeter accuracy for the FDA.
Oximeter probes and instruments were supplied by Masimo Corporation. Rainbow DCI Sensor System oximeter probes (reusable, clip-on probes), Revision H, were used to measure SpCO and SpO2. The standard Masimo oximeter probes were the “red DCI” type. Both probe types were connected to Radical-7 oximeters (SET software version 188.8.131.52). One probe of each type was placed on the middle and ring fingers of each hand of each subject. The probe locations were randomized for each subject. The probes were covered with black plastic to shield them from ambient light and prevent interference from other oximeter probes. Both forearms and hands were kept warm with electric heating pads. The oximeter box and probe combination were kept together and considered as a single “device.”
A 22-gauge radial arterial cannula was placed in either the left or right wrist of each subject. Arterial blood was analyzed with a multiwavelength optical blood analyzer (ABL800 FLEX; Radiometer Medical A/S, Copenhagen, Denmark) to determine arterial oxygen saturation (SaO2), COHb concentration (%COHb), and MetHb concentration (%MetHb).
Studies on each subject began with 1 arterial blood sample drawn while breathing room air. Hypoxemia was then induced to 4 to 5 different targeted plateaus from 100% to 80% by having subjects breathe mixtures of nitrogen, air, and carbon dioxide according to a protocol previously detailed.16 Oxygen saturation is calculated from end-tidal PO2 and CO2 breath-by-breath, which guides the gas mixtures, because pulse-oximeter values lag behind. Each saturation plateau level was maintained for at least 60 seconds with pulse-oximeter stabilization, then 2 arterial blood samples were obtained approximately 30 seconds apart. After the final SaO2 plateau, the subject received 100% O2 and then returned to breathing room air. Elevated COHb was induced by breathing CO gas to produce a target %COHb level of ≈10% to 12% based on the volunteer study by Barker et al.9 and accumulated experience in volunteers in our laboratory. To do this, CO (15–30 mL) was added to a 1-L bag prefilled with approximately 500 mL of oxygen. Subjects then briefly rebreathed this mixture from a mouthpiece, allowing us to produce approximately 2% step-wise changes in %COHb. Blood samples were obtained 5 minutes after each administration of CO. When %COHb reached target levels (10%–12%), hypoxemia was induced in steps and blood samples were taken using the prior protocol. Data output from the oximeters was recorded at 1 Hz using custom software developed with LabVIEW 2009 (National Instruments, Austin, TX).
There is no current FDA standard of accuracy for SpCO. We did not establish acceptable limits of agreement ahead of time. For SpO2, root-mean-square error (Arms) <3% is the acceptable accuracy standard established by the FDA. We considered that the SpO2 accuracy would be degraded if elevated %COHb increased Arms to >3%. Arms <3% would certainly represent acceptably accurate performance for determining SpCO, although it may not be reasonable to expect the same accuracy and precision as for determining SpO2.
Pulse-oximeter performance was analyzed by calculating mean bias (SpO2 − SaO2 or SpCO − %COHb), precision (standard deviation of the bias) and Arms over different ranges of %COHb and SaO2. The Shapiro-Wilk test was used to confirm the normality of the distribution of the SpCO bias (individual and pooled devices all >0.07). Bias was compared with analysis of variance, and Tukey-Kramer honestly significant difference was used for any multiple comparison testing. A 2-sided F test compared the variances for SpCO bias at SaO2 <95% or ≥95%.
Bias was plotted against %COHb, which was treated as a gold standard. Limits of agreement were calculated according to Bland and Altman with adjustments for multiple measurement for each individual.17 Bias, precision, and Arms were determined and analyzed separately for both SpO2 and SpMet.
To examine the effects of other variables on bias, a mixed-effects model was used to analyze within-subjects factors (SaO2 or %COHb) and between-subjects factors (gender and skin color). The effects of SaO2 and %COHb were examined by both univariate analysis, and with both variables, either as an analysis of variance (5% SaO2 range intervals) or as linear regression.
SpCO performance was also analyzed by observing the incidence of excessive reading bias at the various levels of SaO2. Sensitivity, specificity, and positive and negative predictive values for detecting COHb were calculated from the observed data using different cutoff values. Receiver operating characteristics (ROC) were analyzed by setting %COHb ≥10% and ≥5% as positive tests. The distribution of true and false positives and negatives in different SaO2 ranges was tested with χ2.
Data are reported as mean ± SD or mean (95% confidence interval [CI]) as indicated. For all statistical tests, P < 0.05 was considered significant. Data were analyzed with JMP 10.0 (SAS Institute, Cary, NC) and Prism 6.0 (GraphPad Software, La Jolla, CA).
Demographic data and summary information for each individual’s instrument reading bias and perfusion index (PI) are provided in Table 1.
Accuracy of Detecting Hypoxemia
The devices read higher values of SpO2 at lower SaO2 (P < 0.0001), as demonstrated by a positive bias in SpO2 reading. This effect was small, 0.04% for each 1% of desaturation for the Rainbow oximeters (Fig. 1A). For the standard pulse oximeters, the bias also increased with desaturation, 0.07% for each 1% change, P < 0.0001 (Fig. 1B). The Arms was 1.70% for the Rainbow oximeters, and 2.05% for the standard device for SaO2 70% to 100%.
For the Rainbow probes, SpO2 bias at low saturation was also more positive at lower COHb levels (P < 0.0001, Fig. 2A). For standard oximeter probes, SpO2 bias was also more positive at lower COHb levels (P < 0.0001, Fig. 2B). The Arms was 1.67% at elevated %COHb (≥4%) for the Rainbow devices and 1.79% for the standard devices.
Accuracy of Detecting Elevated COHb During Normoxia (Room-Air Breathing)
Higher COHb levels lead to an increasingly negative SpCO bias (P < 0.0001), shown in Figure 3A and summarized in Table 2.
Individual mean bias is shown in Table 1. The range of individual bias was from −3.3 to +3.4. Skin color was not a significant predictor of SpCO bias for either device (Table 1).
COHb Combined with Hypoxia
Below SaO2 of 85%, both COHb devices reported low signal errors and read blank values for SpCO. At %COHb values near zero, the devices sometimes displayed blank SpCO readings rather than zero. Details of missing values at various ranges of SaO2 and COHb are shown in Table 3.
SaO2 had no significant effect on SpCO bias for the pooled device data (P = 0.66, Fig. 3B). In Table 4, data are shown within SaO2 ranges of 5% increments. The standard deviation of the SpCO bias was significantly higher (precision lower) with hypoxemia (SaO2 <95%), 4.0 vs 2.6 (P < 0.0001).
Sensitivity, Specificity, and Predictive Values for Detecting Elevated COHb in the Presence of Hypoxia
Sensitivity, specificity, and positive and negative predictive values are summarized in Table 5 for different ranges of elevated %COHb. The distribution of true and false positives and negatives for the 10% COHb cutoff (shown graphically in Fig. 4) was different among the different SaO2 ranges (P = 0.0004). For the 5% cutoff, the distribution was not different (P = 0.20).
A ROC curve analyzed for %COHb ≥10% as significant carboxyhemoglobinemia maximized sensitivity and specificity at an SpCO of 6.6%, with an area under the curve (AUC) of 0.84 (95% CI, 0.79–0.89) (Fig. 5A). Sensitivity, specificity, and predictive values for this cutoff are summarized in Table 5. The ROC curve for %COHb ≥5% as “positive” carboxyhemoglobinemia had an AUC of 0.88 (95% CI, 0.84–0.92) (Fig. 5B).
MetHb levels were in the low range of normal for all subjects during the study. SaO2 had a slight effect on SpMet bias (P = 0.008) with a slightly more positive bias as lower SaO2, but this was only 0.006% for every 1% of desaturation (Fig. 6A). COHb produced a small but statistically significant effect on SpMet bias (P = 0.018, Fig. 6B).
Women had significantly lower PI than men, with a mean (95% CI) of 1.7% (0.4%–3.0%) vs 5.5% (3.9%–7.1%) (P = 0.0014). Despite efforts to warm hands, 1 female subject had a PI <1%. Overall, PI had no significant effect on the Rainbow SpO2 bias (P = 0.086, Fig. 7A) or SpCO bias (P = 0.95, Fig. 7B). SpO2 bias had lower precision (higher SD) at PI <2% (P < 0.0001), although SpCO bias did not (P = 0.93).
The primary purpose of this study was to assess the accuracy of pulse CO-oximetry measurement of COHb in the presence of mild to moderate hypoxemia. We found that, in the presence of 10% to 12% COHb, accuracy for detecting hypoxemia was not degraded, with an Arms still <3%. Mild to moderate hypoxemia did not appreciably degrade the accuracy of COHb measurement as indicated by the bias, but slightly degraded the precision and Arms. However, when the SaO2 was <85%, the devices read “low signal IQ” and would not report SpCO values.
The usefulness of a noninvasive measurement of COHb has been demonstrated in numerous case reports,18–20 and studies of occult CO poisoning.4,5 The ability to diagnose suspected cases of CO exposure in a timely manner and to avoid unnecessary invasive testing requires good positive and negative predictive values. Detecting elevated COHb levels to enable rapid initiation of appropriate treatment, including normobaric and hyperbaric oxygen, may improve outcomes.21 Detecting elevated COHb levels, even at levels that may not be clinically important, may identify sources of CO exposure at home or at work that could cause more serious harm in the future or lead to testing of others exposed to the event. Determining whether COHb levels are improving in patients requires more frequent measurements.
No prior studies involving pulse CO-oximetry in patients mention simultaneous evaluation in the presence of hypoxemia. Previous reports of pulse CO-oximetry in emergency room patients probably involved supplemental oxygen administration.5,12 Simultaneous hypoxemia would be likely in cases of smoke inhalation and loss of consciousness. However, studies comparing SpCO and blood values did not include such data in the field because of the lack of blood analyzers. The manufacturer reports that the Rainbow Radical-7 is not accurate with simultaneous methemoglobinemia. We reported erroneous SpCO reading in an earlier study with induced methemoglobinemia,7 but we did not test the combination of MetHb and COHb in the current study.
Our results concerning the detection of COHb during normoxia were similar to 2 studies in normal volunteers in laboratory settings at normal levels of oxygen that found good accuracy and precision.9,10 In contrast, studies in emergency room patients have shown larger bias, from −3% to +4%, and wider limits of agreement, spanning from lower to upper limits of agreement of 15% to 25%.4,11–13,22 A study of 139 patients in a pulmonary function laboratory found a low bias, but fairly wide limits of agreement.23 In some studies, significant delays occurred between the SpCO reading and blood sampling for COHb measurements, making accurate assessment of bias difficult.4,12
Skin color and gender alter pulse-oximeter performance.15,16 Many studies have not reported the gender and skin pigmentation of study subjects, making direct comparison of the results difficult, although Touger et al.13 attempted some analysis excluding dark-skinned patients. Our subjects were intentionally of different genders, ethnicities, and skin color because it is important that the results apply broadly and is also required by the FDA for studies of pulse-oximeter accuracy. Our study did not have the power to resolve differences in performance related to skin pigmentation.
The sensitivity, specificity, and positive and negative predictive values for detecting COHb in the presence of mild hypoxia were acceptable (Table 5 and Fig. 5). However, our study was not optimally designed to measure these variables because most of our data were clustered around subjects’ baseline values and at the target of 10% to 12% COHb. Testing in volunteers at these higher levels would not be appropriate, especially if combined with hypoxia. ROC analysis of our data (Fig. 5 and Table 5) indicated that maximal sensitivity and specificity for detecting COHb levels ≥10% was an SpCO of 6.6%. Similarly, Roth et al.12 found that an SpCO of 6.6% was 94% sensitive in identifying the 17 patients with CO poisoning, with 77% specificity. Decreasing the SpCO thresholds to maximize sensitivity in order to prevent missing anyone with potential serious CO poisoning might be better for initial screening. For our data, a threshold of 5% SpCO is >90% sensitive in detecting all subjects with COHb ≥10%. While lowering the threshold decreases specificity, this may be desirable as a screening test for the presence of COHb. In a study of emergency room patients, Suner et al.4 reported 94% sensitivity and 54% specificity for the Rad-57 from 64 data points. However, Touger et al.13 found lower sensitivity (48%) but good specificity and positive and negative predictive values for a 15% COHb cutoff. The exact clinical threshold indicating treatment necessity is not clear, although a level of COHb of 25% has been suggested for hyperbaric oxygen treatment.22
We studied 2 devices of each type, randomly placing them on different hands and different fingers. This increased the total number of data points for analysis. The oximeters behaved similarly, although slight differences, typically only 1% to 2%, were apparent at times. We have previously found small difference in probes types.16 Limitations on the reasonable number of probes we can study in volunteers mean that we do not have data on all probe types in this study.
Defining acceptable performance and accuracy is somewhat arbitrary, but depends on the clinical purpose of the device. Clearly, measurement of SpCO is less accurate than for SpO2 and SpMet, being reported only to a whole number. Piatkowski et al.11 concluded that the bias of 3.15% (precision 2.36%) represented acceptable accuracy. Roth et al.12 concluded that accuracy was acceptable at a bias of 2.32 ± 4.01. Touger et al.13 defined ±5% as acceptable accuracy, reporting that 33% of data was outside this range, which was discussed in an editorial by Maisel and Lewis24 in the Annals of Emergency Medicine.
MetHb readings from the Rad-7 CO-oximeters showed excellent stability with changes in COHb and SaO2. Although a repeated-measures analysis is extremely robust in detecting small changes in bias with a large number of measurements, the changes in SpMet bias as shown in Figure 6 are not clinically important. Changes in SpMet bias might not be expected from induced carboxyhemoglobinemia and hypoxemia; however, early versions of the pulse CO-oximeter could not discriminate multiple different hemoglobin species.7 This was corrected in subsequent versions.8 Cyanide toxicity can occur in fires because of combustion of nitrogen-containing compounds. Treatment is with sodium nitrite, which produces methemoglobinemia.25 This creates a clinical scenario in which MetHb and COHb would be present concurrently.
Within the range of carboxyhemoglobinemia studied, both the Rainbow and the conventional pulse oximeters were able to detect hypoxemia even in the presence of elevated COHb, with an Arms of 1.70% and 2.05% being well below the acceptable FDA threshold of 3%. Confusion of COHb and oxyhemoglobin might lead the oximeters to read a higher SpO2 (positive bias) even at low oxygen saturation. Data on standard pulse-oximeter accuracy with carboxyhemoglobinemia have shown a slightly negative bias at high COHb levels, with an obvious “gap” in measuring “fractional” oxygen saturation.6,26
Because of the similarity of the absorption spectra of oxyhemoglobin and COHb, measurement may be intrinsically more difficult than for MetHb, which has greater spectral separation from oxyhemoglobin. The “pulse-oximeter gap” describes the difference between SpO2 and fractional oxygen saturation with elevated %COHb, and implied that pulse oximeters were reading COHb as if it were oxyhemoglobin.26–28 Current pulse oximeters are calibrated with functional oxygen saturation, so accuracy should properly be considered only for functional SaO2. The ability of the pulse oximeters to detect oxygen desaturation in the presence of elevated COHb suggests there is no clinically relevant “confusion.”
Similar to findings with other parameters from pulse oximetry,29–31 accuracy and precision were degraded slightly at lower PI. The effect was not dramatic, and it should be noted that we were actively warming subjects’ hands.
A volunteer study has both limitations and advantages over other study designs. In volunteers, we are limited as to the degree of carboxyhemoglobinemia and hypoxemia that we can safely produce. We have set the upper limit to 15%, with a target of 12% COHb in the setting of hypoxemia. Twelve subjects may not be adequate to produce robust data on sensitivity, specificity, and predictive performance, although the study provided a total >150 data points for SpCO and nearly 300 data points for SpMet and SpO2 with simultaneous arterial blood measurements. However, the repeated-measures design is very robust for determining interaction between low SaO2 and elevated COHb. A laboratory setting also provides excellent coordination of blood draws and noninvasive measurement. Our step changes in COHb, rather than continuous breathing of CO, provides better stability for the coordination of SpCO and blood measurements. Continued updates and changes to hardware and software make comparisons between our studies and other past or future studies difficult. We treated laboratory measurements as a gold standard, although even such devices may have inaccuracies. Our population of study subjects may not represent all patient populations, but did have intentional variability of gender and ethnicity. Performance in a controlled laboratory environment may still differ from the clinical setting in patients with multiple comorbidities.
Accuracy of the Masimo pulse CO-oximeter for measuring COHb was not affected by hypoxemia to a clinically significant degree. However, hypoxemia did result in a significant increase in device-reported low signal errors and blank COHb readings. COHb increases up to 12% minimally affected measurements of SpO2 and SpMet. Sensitivity, specificity, and predictive value at up to 12% COHb were good (AUC of the ROC curve >0.8), but more data at higher COHb levels would be useful in helping clinicians define appropriate thresholds for optimizing screening for potential CO poisoning. Given the history of pulse-oximeter development, further investments in multiwavelength pulse-oximeter technology are likely to improve accuracy and performance.
Name: John R. Feiner, MD.
Contribution: This author helped design the study, conduct the study, record the data, analyze the data, and prepare the manuscript.
Attestation: John Feiner approved the final manuscript. John Feiner attests to the integrity of the original data and the analysis reported. John Feiner is the archival author.
Name: Mark D. Rollins, MD, PhD.
Contribution: This author helped perform the study and revise the manuscript.
Attestation: Mark Rollins read and approved the final manuscript.
Name: Jeffrey Sall, MD, PhD.
Contribution: This author helped perform the study and revise the manuscript.
Attestation: Jeffrey W. Sall read and approved the final manuscript.
Name: Helge Eilers, MD.
Contribution: This author helped perform the study and revise the manuscript.
Attestation: Helge Eilers read and approved the final manuscript.
Name: Paul Au, BS.
Contribution: This author helped recruit the study patients and collect the data.
Attestation: Paul Au read and approved the final manuscript.
Name: Philip E. Bickler, MD, PhD.
Contribution: This author helped design the study, conduct the study, and revise the manuscript.
Attestation: Philip Bickler read and approved the final manuscript. Philip Bickler attests to the integrity of the original data and the analysis reported.
This manuscript was handled by: Dwayne R. Westenskow, PhD.
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