In 1972, Takuo Aoyagi studied noninvasive cardiac output measurement using a dye dilution technique that inferred cardiac output based on how quickly the dye's concentration was diluted over time. He noted that arterial pulsations created “noise” which prevented accurate analysis of the down-sloping portion of the dye dilution curve. While attempting to cancel this noise, he realized that these pulsatile changes could be used to compute hemoglobin (Hb) oxygen saturation, ushering in the era of noninvasive pulse-oximetry.1 Since then, the pulse oximeter has become one of the most commonly used monitors, if not the most common. According to the American Society of Anesthesiologists' standards for basic monitoring, a quantitative method of assessing oxygen saturation, such as with a pulse oximeter, should be used during all anesthetics.2 Furthermore, many emergency departments measure arterial oxygen saturation with a pulse oximeter as a routine component of measuring vital signs.3
In addition to Hb oxygen saturation, additional variables can be monitored using a pulse oximeter, mainly pulse rate and heart rhythm. Indeed, the wide use of pulse-oximetry laid the groundwork for extensive research into the noninvasive measurement of many characteristics of circulating blood.4,5
Routine use of pulse-oximetry revealed numerous artifacts attributed to motion and low pulse amplitude as well as low accuracy and response delay. One solution found was to add adaptive filters to the 2-wavelength pulse oximeter.6,7 Another theoretical solution suggested in the mid-1990s was to increase the number of light wavelengths, initially 3 wavelengths (1996) and then 5 (2004) to support the development of the more accurate modern pulse -oximeters.8 The principal of using multiple wavelengths was never commercialized to help address artifacts, but did become the basis for noninvasive measurement of total Hb, methemoglobin, and carboxyhemoglobin concentrations.
LABORATORY HB CONCENTRATION MEASUREMENT
Conventional laboratory analysis of Hb concentration is performed using a spectrophotometer and is based on the Lambert-Beer law.9 The Lambert-Beer law states that when monochromatic light passes through any substance, some of the light is absorbed, thus reducing the intensity of the light. The amount of light intensity absorbed by the substance is called “absorbance” and is directly proportional to (1) the molar absorption coefficient, which is a unique physical property of the substance for a specific wavelength, (2) the optical path length (OPL), which is the distance the light must travel through the substance, and (3) the molar concentration, which is the concentration of absorbing material in the substance. This relationship may be expressed as:
where A = absorbance; [Latin Small Letter Open E] = molar absorption coefficient; d = OPL (in centimeters); and c = molar concentration.10,11
The common laboratory hemoglobinometer (known as a CO-oximeter) first creates a Hb suspension by hemolyzing a small sample of blood in a cuvette, thus eliminating erythrocyte membrane light absorption. Light of a known wavelength and intensity is then shone through the cuvette containing the Hb suspension. Finally, the intensity of the transmitted light is measured. Because all of the relevant physical properties of the cuvette and Hb are known, the only unknown variable is Hb concentration. Because different types of Hb have different molar absorption coefficients at different wavelengths, one would need to use multiple light wavelengths to both quantify and differentiate among different types of Hb. Common hemoglobinometers measure the concentration of 4 Hb types: oxyhemoglobin (O2Hb), deoxyhemoglobin, methemoglobin (MetHb), and carboxyhemoglobin (CO-Hb).9
NONINVASIVE Hb CONCENTRATION MEASUREMENT
A basic pulse oximeter transilluminates tissue with 2 light wavelengths (red, 660 nm; and near infrared, 940 nm) for the calculation of O2Hb fraction.10,12 It uses a spectrophotometer to measure light absorbance just as one would use a hemoglobinometer to measure light absorbance in blood samples in the laboratory. It was therefore very tempting to adapt this monitor for continuous noninvasive measurement of Hb concentration (SpHb). Several differences have made this development complicated: (1) The tissue through which light is transmitted is not homogeneous as it is in the laboratory Hb suspension. (2) The size of the finger changes from heart beat to heart beat, from finger to finger, and from person to person, thus making the OPL variable.10 Accordingly, the Lambert-Beer law cannot be applied directly and has to be modified.9 One modification is to replace OPL by “effective mean path length.” (3) Pulse oximeters are calibrated empirically by adding a correction factor derived from comparison with healthy volunteer blood samples. The calibration process incorporates the ratio of red and near-infrared values observed in these volunteers. An error range is inherent to this calibration.13 (4) Conventional pulse oximeters use only 2 light wavelengths that assume O2Hb and deoxyhemoglobin are the only 2 types of Hb that absorb light. Because there are in fact other types of Hb that absorb light (e.g., MetHb, CO-Hb), there is some error in the measurement.14 The solution to this last difficulty is incorporating additional light wavelengths that correlate with the other Hb types.
The year 2002 saw the first attempts to use oximetry technology to measure total Hb concentration noninvasively when Kinoshita et al.15 described the use of the Astrim™ (Sysmex, Kobe, Japan). Saigo et al.16 studied the Astrim and explained its mode of action. The Astrim emits light at 3 wavelengths (660, 805, and 880 nm) and uses a CCD camera to capture the transmitted light as a venous image. Because the concentration of Hb was higher, the contrast between the blood vessel and the surrounding tissue was higher. The study group consisted of healthy volunteers and patients with hematological disorders. The study failed to prove acceptable precision, although monitoring of sequential changes (trend) was satisfactory. Finger position and temperature were found to contribute to the poor performance of the Astrim.16,17 Currently, the Astrim is used to evaluate peripheral circulation and not Hb measurement.
In 2005, Noiri et al.12 used a 4-wavelength hemoglobinometer to measure hemoglobin noninvasively. Not only did they use one more wavelength to increase accuracy, they also changed one of the wavelengths used by the Astrim (660 nm for O2Hb, 805 nm for both O2Hb and deoxyhemoglobin, 940 nm for reduced Hb [the Astrim used 880 nm], and 1300 nm for water). The study compared noninvasive Hb with laboratory measurements in healthy volunteers, surgical patients, and chronic hemodialysis patients (enabling them to evaluate a wide range of Hb values: 6.8–17.0 g/dL). They found 84.3% sensitivity and 84.6% specificity in diagnosing anemia (defined as Hb ≤10.0 g/dL). Although these changes were an improvement over the accuracy of the Astrim, it was not yet clinically acceptable.12
Suzaki et al.18 made further progress in 2006 when they increased the number of wavelengths to 7. Their wavelengths ranged from 600 to 1300 nm and included the absorption spectra of O2Hb, reduced Hb, CO-Hb, MetHb, and water. Therefore, they were able to measure and differentiate all major Hb strands. They tested their prototype using an experimental model with good results.
In 1996, the SET (Signal Extraction Technology) was introduced by Masimo (Irvine, CA) to increase the accuracy of 2 wavelength pulse oximetry under motion and low perfusion conditions. It included arterial pulsation filters, light and radiofrequency shielded sensors, and digital processing algorithms.19,20 Masimo's Rainbow SET technology was later introduced (addition of numerous wavelengths) to measure total Hb, COHb, and MetHb concentrations: CO-Hb in 2005, MetHb in 2006, and noninvasive Hb (SpHb) in 2008.21 It measures SpHb using up to 12 wavelengths (Masimo does not include the exact wavelengths or their exact number in their publications).
Studies have been published evaluating the performance of the Rainbow SET in measuring SpHb relative to laboratory CO-oximeters (Table 1). The Bland-Altman bias and precision analyses are used to compare 2 technologies, such as with the Rainbow SET and a laboratory CO-oximeter. Bias is the mean of the measurement differences between methods, and describes systematic error between measurements (i.e., how closely do results of a new monitor compare to measurements in the laboratory.). Precision is 1.96 times the standard deviation of the differences between methods. Precision is a measure of consistency, i.e., are repeated measurements of the same sample close to each other (variance produced by the measurement device). The limits of agreement are defined as the differences between two methods approximately 95% of the time. The clinically acceptable limits of agreement depend on the variable of interest, the accuracy of the reference standard and what matters clinically.13
The first clinical study using this technology (Rainbow SET) evaluated the correlation between SpHb and laboratory CO-oximetry after hemodilution. After removing 1 U of blood, the subject's intravascular volume was replenished with 30 mL/kg of a crystalloid solution.22 Such hemodilution is a very good model of hemorrhage in humans, because the volume of blood taken is known.23 Bias and precision were found to be 0.03 and 1.12 g/dL, respectively.20 The same authors repeated this study using a similar protocol, except they targeted a 30% decrease in Hb concentration.21 The average difference between Hb and SpHb, that is the bias, was −0.15 g/dL. However, interpretation of the data using only bias may be misleading because the standard deviation of the difference between methods was 0.92 g/dL. Precision (1.96 × standard deviations) was 1.9 g/dL. The 95% limits of were almost 20% in each direction.
Hahn et al.24 compared the Rainbow SET SpHb measurement to venous blood sample measured in the laboratory and found the median deviation between the methods to be 1.6%.
Miller et al.25 studied patients undergoing posterior spine fusion, a surgery with significant blood loss potential. Their results suggested relatively low Hb measurement accuracy (22% of measurements were with a difference of >2 g/dL, bias was found to be 0.26 g/dL, and the 95% limits of agreement were −3.24 and 3.77). Three recently published manuscripts report the accuracy of the Rainbow SET non-invasive SpHb measurement.26–28 Lamhaut et al.26 studied patients undergoing urological surgeries. They used an old sensor (Version C). Their cutoff for clinical importance of the difference between SpHb and laboratory CO-oximeter was 1 g/dL. Accordingly 46% of the measurements fell outside the clinical acceptable range. The calculated bias was −0.02 and precision −1.1. The 95% limits of agreement were −2.75 and 2.7. The authors report that these limits of agreement are very similar to the one found by Gayat29 and are not acceptable. The most current Rainbow SET sensor is version G; the seventh since the introduction of Rainbow SET Hb measurement technology by Masimo. The direct implication is that every user must be familiar with the specific advantages and shortcomings of the sensor being used clinically.
Frasca studied the newest version E Rainbow SET sensor.27 In 65 ICU patients the bias ± the standard deviation between SpHb and laboratory CO-oximeter measurements was found to be 0.0 ± 1.0 g/dL. The Bland-Altman curve shows a tendency for the underestimation of the Hb values even though the bias was zero. This study gives us the opportunity to learn about the readings during low perfusion states. Frasca showed that when the perfusion index was less than 50% (the manufacturer's cut point for low signal) the bias ± the standard deviation increased to 0.4 ± 1.4 g/dL. Similar results were seen in patients receiving continuous infusion of noradrenalin; the bias ± standard deviation increased to −0.1 ± 1.4 g/dL. The meaning is that despite the improvements in sensor version E, it cannot be relied upon during peripheral vasoconstriction states.
Berkow28 used Version E sensors to study 29 patients undergoing spine surgery. Bias was found to be −0.3 g/dL and standard deviation was 1.0 g/dL. The 95% limits of agreement were wide: −2.4 and 1.5 g/dL. Trending of SpHb was also tested: while laboratory Hb decreased more than 1.5 g/dL in 6 patients the SpHb changed in the same magnitude only in 1 patient. Equally, SpHb increased in only 2 out of 5 patients in which laboratory Hb increased more than 1.5 g/dL. Therefore, this study failed to prove acceptable Hb trend.
It is also important to mention that in all of the above studies, the error was equally spread among clinically relevant Hb concentrations, meaning that the monitor error values were not influenced by Hb concentration. All 3 studies were reluctant to recommend transfusion based solely on the SpHb measurement.26–28
Beyond the accuracy of SpHb measurement, another concerning issue is the frequency of events where the SpHb monitor did not yield data at all or yielded data of low quality. In his study, Macknet21 reported the inability to measure SpHb in 2.4% of the SpHb measurements. A different study estimated failure rate to be about 9% (although the investigators of this study did not adhere to the manufacturer directions for use in the conduct of the study).29 Miller25 noticed reduced accuracy when the pulse oximeter indicated a low perfusion index. This finding is supported by Gayat et al.'s study29 where low blood pressure was associated with reduced accuracy. Frasca's study27 of ICU patients used version E sensors: in 3 out of the 65 ICU patients (4.6%), reading was not possible at the beginning of the study and 5 more patients lost the signal during the study. In between the spine surgery patients, 56 reading (out of 186, ∼30%) were excluded as they had a signal quality index that was lower than 50%.28 The association between monitor accuracy and peripheral perfusion should not be a surprise, because all pulse oximeters fail to some degree when the patient is peripherally vasoconstricted or hypotensive. All together, it may be inappropriate to rely on the availability of data from this monitor as signal quality index might change.
Patient benefit is an important issue for discussion: Would this new technology change clinical practice by allowing for fewer blood samples sent for laboratory Hb measurement or for fewer red blood cell (RBC) unit transfusions? In their study, Causey et al.19 provided SpHb trend data versus laboratory data for patients undergoing total hip arthroplasty (Fig. 1). A very similar figure is provided by Miller et al.25 In their discussion, Miller et al. elucidate the necessity to make 2 different decisions when blood loss occurs during surgery: when to send a sample to the laboratory and when to transfuse. When observing the trend graphs provided by Miller and Causey, one cannot avoid the impression that by following these graphs, one can substantially minimize the number of laboratory samples one sends. Because absolute Hb measurement value is in doubt (low Bland-Altman precision), we must correlate SpHb to the laboratory value at the beginning of surgery, much as one would correlate arterial CO2 measurement to end-tidal CO2. The ability to follow Hb concentration trend might be very helpful in procedures with substantial hemorrhage potential.18 Some support for the clinical benefit derives from a 2010 ASA annual meeting presentation by Ehrenfeld et al.30 of a study of 327 patients undergoing various orthopedic operations. Half of the patients were monitored according to current anesthetic standards whereas the other half was additionally monitored with a continuous noninvasive SpHb monitor. Their results showed a significant decrease in the number of patients receiving RBC transfusion. During standard care, 7 of 157 patients were transfused (4.5%) whereas only 1 of 170 (0.6%) who were monitored with SpHb was transfused. The authors stated that no patient received RBC transfusion within the first 12 hours postoperatively, suggesting that postponing transfusion did not bias the results.30
Another commercially available noninvasive multiwavelength hemoglobinometer is the NBM-200MP (OrSense, Nes Ziona, Israel). This monitor uses a unique technology consisting of a ring-shaped sensor fitted on the patient's finger. The ring intermittently compresses the finger with pressure greater than systolic pressure, thus preventing arterial pulsations and the errors those pulsations introduce. An optical system using an array of calibrated light sources measures light absorption and scatter to calculate Hb concentration.31 The monitor has Food and Drug Administration approval for pulse oximetry and European Community approval for Hb measurement; however, the authors of this review failed to find peer-reviewed literature assessing its accuracy.
An interesting and completely different technology, not yet commercially available, is optoacoustic imaging. In this technology, the tissue is exposed to a pulse laser. Absorption of photons by the tissue, e.g., erythrocytes, causes an increase in local temperature with subsequent increase in volume. This volume expansion raises the pressure within the object that then produces a pressure wave into the surrounding medium. An acoustic transducer senses the pressure wave, and the information is used to calculate Hb concentration. Preliminary in vitro and in vivo testing proved promising but it is still far from clinical use.32,33
NONINVASIVE CO-Hb CONCENTRATION MEASUREMENT
Carbon monoxide (CO) is a combustion product of organic material. CO intoxication can result from inhalation exposure to fires, warmers using carbon fuel (gasoline, charcoal, propane, butane, etc.) used in poorly ventilated spaces, and automobile exhaust. Also, anesthesia delivery systems set to low flow rates when using dry CO2 absorbents are associated with significant increases in inspired CO concentration in children older than 2 years. In some reports, blood CO-Hb concentrations reached 30%.34,35 In normal subjects, CO-Hb concentration can be up to 2% to 3%, whereas in smokers it can reach 10%, and in heavy smokers 20%. Symptoms (dyspnea, dizziness, headache, irritability, etc.) worsen as concentration increases. Confusion, coma, and convulsion are expected at concentrations of 50% to 60%, and death is expected when CO-Hb reaches 65%.36
CO's affinity to Hb is 260 times greater than oxygen's, and therefore exposure to CO can significantly decrease oxygenation, thus impairing cellular aerobic metabolism. CO-Hb concentration is measured by spectrophotometry using wavelengths of 546 and 578 nm.36
Early diagnosis of CO-Hb intoxication is important because early treatment may prevent hypoxic multiorgan damage and long-term cognitive disturbances. Signs and symptoms are nonspecific, so diagnosis is currently based on clinical suspicion confirmed by laboratory blood tests. The availability of a noninvasive screening tool, even in the prehospital period, would therefore be of great diagnostic value.
In 2005, Masimo introduced their Rad-57 pulse oximeter, based on their Rainbow SET technology. Using >8 wavelengths of light, this monitor was designed to noninvasively measure CO-Hb (SpCO), MetHb (SpMet), and arterial hemoglobin saturation (Spo2).14
Four prospective studies evaluated SpCO accuracy in the Masimo Rad-57 (Table 2). Common to all 4 studies is a relatively low bias but poor precision. It may be that bias is low because erroneous results occurring equally above and below the true value effectively cancel each other.
Barker et al.37 investigated the Rad-57 in healthy volunteers. Volunteers were exposed to an inspired gas mixture containing 500 ppm CO until SpCO reached 15%. Results of the noninvasive CO-Hb were compared with blood samples analyzed by a laboratory CO-oximeter. Results proved a bias of −1.22% and precision of ±2.19% (absolute range of error was −6 to +8%).37 Suner et al.38 and Chee et al.3 reported 1 study group in 2 reports. They used the Rad-57 to measure SpCO in every patient admitted to their emergency department (amounting to 10,856 SpCO measurements). Twenty-eight patients had abnormal CO levels, 11 with no apparent clinical suspicion. Their bias value was higher than in other studies, reaching −4.2% (95% CI −2.8% to 5.6%) for patients proved not to have CO toxicity. For patients with proven CO toxicity, bias was −1.1 (95% CI −4.7 to 2.5) demonstrating that the error is not linear along CO concentrations.38 Touger et al.39 studied the monitor in patients suspected of CO poisoning upon admission based on a history of exposure. Both SpCO and laboratory CO-Hb values were obtained for 120 patients. CO-Hb concentration ranged up to 38%. The mean difference between measurement methods was 1.4% (95% CI 0.2%–2.6%). This value by itself is acceptable, yet the CIs ranged from −11.6% to +14.4%. In this study, the Rad-57 demonstrated 48% sensitivity, 95% CI 27%–69% (i.e., high false-negative rate), in identifying patients with SpCO ≥15%. One of the alarming results presented in the article was from a patient whose laboratory CO-Hb was 35% whereas the SpCO was 0%. Conversely, specificity was very high (99%, 95% CI 94%–100%). In 35% of all measurements, the difference was >5%.39 O'Malley described in a letter to the editor 5 cases (out of 328) in which screening SpCO showed CO concentration >15%.40 In all of these cases, laboratory CO-oximeter measured <10%, that is, a false-positive rate of 100%. Some may argue that false-positive rates are not as important as false-negative rates; however, false positives may result in expending precious resources by referring patients to remote level 1 trauma hospitals and exposing patients to unnecessary tests.
Feiner et al.9 investigated whether concomitant methemoglobinemia influences SpCO readings in healthy volunteers. They found that increased concentrations of MetHb (≥2%) caused SpCO overestimation by the Rad-57. SpCO bias increased linearly until MetHb levels were approximately 7%, at which point bias stabilized at 50% of reading. It is important to note that CO concentrations were ≤1.3%, and therefore a bias of 50% of reading is not clinically significant.9 Another study checked the feasibility of using the Radical-7 as a prehospital screening tool.41 The study was able to demonstrate instances whereby the Rad-57 indicated high CO levels, but it did not assess accuracy or clinical benefit. Laboratory CO-Hb values were not provided.41
Roth et al.42 recently measured SpCO in 1578 patients admitted to their Emergency Department, 17 of them were diagnosed as suffering of CO intoxication. This small number of patients makes definitive conclusions about the clinical value of SpCO difficult. Their data showed bias of 2.32% and precision of 4.01%. The 95% limits of agreement were −5.7% and 10.37%. These values are rather high, implying significant overestimation. The Bland Altman plot shows that the error increases significantly with increasing CO-Hb concentration. As the authors failed to report which version of the Rainbow SET sensors they used together it is hard to draw significant conclusions from this study.
As discussed earlier, the clinically acceptable accuracy for SpCO measurements depends on what matters clinically. Therefore, we have to decide whether the differences cited above are clinically significant. An Editorial appearing with the study by Touger et al. claims that because of its low sensitivity, the Rad-57 cannot be used to exclude CO poisoning, that is, it cannot be used as a substitute for laboratory measurement in patients at risk.43
NONINVASIVE MetHb CONCENTRATION MEASUREMENT
Reduced Hb (deoxyhemoglobin) undergoes conversion to MetHb via oxidation of the ferrous (Fe2+) moiety to the ferric (Fe3+) moiety. The ferric moiety of MetHb impairs unloading of oxygen from the adjacent ferrous moiety, thus shifting the oxygen dissociation curve to the left. Healthy individuals without anemia have few symptoms at MetHb levels of 15%, but levels of 20% to 30% cause mental status changes, headache, fatigue, exercise intolerance, dizziness, and syncope. Levels of 50% result in dysrhythmias, seizures, coma, and death.44
A list of common medications that induce methemoglobinemia is presented in Table 3. Many of the more recent reports of methemoglobinemia focus on exposure to prilocaine, topical benzocaine, and celecoxib. Benzocaine spray has become an increasing problem, perhaps because it is directed to the mucosa where it can be rapidly absorbed by the blood and result in severely elevated levels of MetHb.44 Of special note is the use of nitrates to deliberately cause methemoglobinemia in cases of cyanide toxicity. The goal in rapid detoxification of cyanide is to prevent or reverse cyanide's inhibition of cytochrome oxidase. The basic strategy is to create inactive cyanide complexes by binding it with ferric iron, usually in the form of MetHb. Cyanide has higher affinity for MetHb than for cytochrome oxidase, thus the preferential formation of cyanmethemoglobin reverses the inhibition of cytochrome oxidase.45 Continuous noninvasive monitoring of MetHb levels may guide dosing by suggesting the largest safe dose of a local anesthetic that can be used during a medical procedure or by aiding in the titration of a treatment for cyanide poisoning.
Barker et al.37 assessed the Masimo Rad-57 for measurement of MetHb concentration. Healthy volunteers were given 300 mg sodium nitrite, which is 75% of the therapeutic dose for cyanide toxicity. Peak MetHb levels attained were 5% to 12%, which is a safe yet relatively low concentration. The results were compared with a laboratory CO-oximeter. Bland-Altman bias was found to be 0 whereas precision was 0.45%.37 Feiner et al.9 argued that Barker et al. did not evaluate MetHb concentration for subjects who were hypoxic, that is, there was a change in only the MetHb to CO-Hb ratio whereas O2Hb was constant. Feiner et al. therefore expanded the study by exposing healthy volunteers in 2 groups to concomitant hypoxia and methemoglobinemia. In 1 group, they targeted arterial oxygen saturation (SaO2) levels of 70% to 100% with a MetHb level of 7%, and in the other group an SaO2 level of 80% with a MetHb level of 15%. SpMet was most accurate when SaO2 was >95%. As SaO2 decreased, the error measuring SpMet increased, causing an overestimation up to a bias of 24.8% and precision of 15.6%. The authors postulated that increasing concentrations of deoxyhemoglobin are read by the Rad-57 as MetHb.9 Feiner and Bickler46 repeated their study with a revised probe and found bias to be 0.05%, increasing up to 0.36% when SaO2 was 85% to 90%. This increase is statistically (but not clinically) significant. They found confidence intervals to be 0.79% to 0.91%. The bias in reading SpMet was significantly influenced by increasing MetHb concentrations, to a highest bias of 3.1% when MetHb was 9.7%, but the magnitude was much smaller than in the previous study. Methemoglobinemia had a negative effect on SaO2, causing a −2.91% bias when MetHb was increased 4% to 15%. This bias seems clinically insignificant.46 Overall, the revised probe seems to be more reliable, although it has lost the ability to measure CO-Hb.
Continuing research has brought us closer to the ability to noninvasively measure the concentration of total Hb, COHb, and MetHb. Monitoring the trend in total Hb concentration using commercial hemoglobin meters may help to decide when and how frequently samples should be sent for laboratory blood count as well as helping to decide when to begin blood transfusion. Just like every pulse oximeter, measurements may not be accurate in the presence of peripheral vasoconstriction (severe hypovolemia, hypothermia, etc.).
MetHb measurements are accurate when a revised probe is used. Currently there is too much bias in noninvasive COHb measurement to warrant a recommendation for clinical use.
Name: Micha Y. Shamir, MD.
Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.
Attestation: Micha Y. Shamir approved the final manuscript.
Name: Aharon Avramovich, MD.
Contribution: This author helped design the study and write the manuscript.
Attestation: Avramovich Aharon approved the final manuscript.
Name: Todd Smaka, MD.
Contribution: This author helped design the study and write the manuscript.
Attestation: Todd Smaka approved the final manuscript.
This manuscript was handled by: Dwayne R. Westenskow, PhD.
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