Trending, Accuracy, and Precision of Noninvasive Hemoglobin ...

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recorded every second from the pulse CO-oximeter and data extraction was performed using. TrendCom software (Masimo Corp.; Irvine, CA). The Perfusion ...
Shock, Publish Ahead of Print DOI: 10.1097/SHK.0000000000000310

Trending, Accuracy, and Precision of Noninvasive Hemoglobin Monitoring During Human Hemorrhage and Fixed Crystalloid Bolus

Nicole Ribeiro Marques*, George C. Kramer*, Richard Benjamin Voigt*†,

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Michael G. Salter*, Michael P. Kinsky*



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*Department of Anesthesiology, University of Texas Medical Branch, Galveston, TX/USA, Department of Electrical and Systems Engineering, University of Pennsylvania, Philadelphia,

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PA/USA.

Corresponding author: Nicole Ribeiro Marques. 301 University Boulevard, Galveston, TX/USA, 77550. Phone: (409) 747-0077. Fax: (409) 772-8895. Email: [email protected] Study Source of Funding: Office of Naval Research - Grant #: N000140811056 and

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N0001412C0556. US Army - Grant #: W23RYX0104N6050001. US AirForce - Grant #:

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FA86501126B08

Acknowledgement: This study was conducted with the support of the Institute for Translational

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Sciences – Clinical Research Center (ITS-CRC) at the University of Texas Medical Branch (UTMB) at Galveston, Texas. Supported in part by a Clinical Translational Science Award (#UL1TR000071) from the National Center for Research Resources and National Institutes of Health. The authors also thank volunteers and ITS-CRS staff of the research team for their contribution. Running head: SpHb trends during human hemorrhage

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Abstract Background: Automated critical care systems for enroute care will rely heavily on noninvasive continuous monitoring. It has been reported that noninvasive assessment of blood hemoglobin via CO-oximetry (SpHb) assessed by spot measurements lacks sufficient accuracy for clinical decision making in trauma patients. However the precision and utility of trending of continuous

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hemoglobin has not been evaluated in hemorrhaging humans. This study measured the trending and concordance of SpHb changes during dynamic variations resulting from controlled

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hemorrhage with concomitant fluid infusion.

Methods: With IRB approval and informed consent, 12 healthy volunteers under general anesthesia were subjected to hemorrhage (10 ml/kg over 15 minutes) accompanied by lactated

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Ringer`s infusion (30 ml/kg over 20 minutes). SpHb was measured continuously by the Masimo Radical-7, while total hemoglobin (tHb) was measured by arterial blood sampling. Results: Trend analysis, assessed by plots of SpHb over time of 12 subjects, shows consistent falls in SpHb during hemodilution without exception. Four-quadrant concordance analysis was

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95.4% with an exclusion zone of 1 g/dl. Spot comparisons of 106 data pairs (SpHb and tHb)

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showed that 50% exhibited error > 1g/dl with bias of 1.08 ± 0.82 g/dl, 95% LOA -0.5; 2.6. Conclusion: Both trend analysis and concordance analysis suggest high precision of pulse CO-

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oximetry during hemodilution by hemorrhage and fluid bolus in human volunteers. However, accuracy was similar to other studies and therefore the use of pulse CO-oximetry alone is likely insufficient to make transfusion decisions.

Keywords: Hemorrhage, Trauma, blood transfusion, noninvasive and continuous hemoglobin, pulse CO-oximetry, trend analysis

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Introduction Hemorrhage is the leading cause of trauma-related death in the military setting (1), with the majority of deaths occurring before reaching a medical treatment facility (2). Delays in beginning resuscitation and control of bleeding impact mortality. Assessment of acute and chronic anemia and estimation of blood’s oxygen carrying capacity are

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commonly performed by measuring total blood hemoglobin (tHb). Along with other parameters, tHb is a primary indicator for blood transfusion. Substantial benefit would be derived from the

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continuous and noninvasive monitoring of tHb to assess blood loss and hemodilution in trauma patients (3). Pulse CO-oximetry offers noninvasive, continuous hemoglobin (SpHb) monitoring with the potential to identify real time dynamic changes in tHb. Thus, SpHb would be an

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important input variable for decision support and it would help discern whether a patient needs fluid and/or blood replacement therapy. Further, trends in SpHb could be used in decisionsupport and closed-loop algorithms, which are programmed to titrate the rate and volume of blood or fluid administration.

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SpHb measured by pulse CO-oximetry has been evaluated in several clinical settings (4-13).

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Most clinical studies have compared spot measurement of SpHb versus tHb using linear regression and Bland-Altman plots (4-5, 10-11). Although SpHb and tHb show significant

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correlation, several studies suggest that the accuracy of a single SpHb measurement is insufficient to assess the need for perioperative (4-8) and trauma transfusion (9-11). Accuracy is most important when a specific value at a specific time is needed to make a decision. However, precision (or trending) is most important to assess a dynamic process e.g. ongoing blood loss. Few studies have evaluated the effectiveness of continuous SpHb measurements to assess their value in trend analysis-driven decision making (8, 12-15). Our goal was to define trending

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reliability of SpHb during simultaneous hemorrhage and fluid loading. Specifically, we measured the trend-accuracy and spot measurement accuracy during dynamic variation resulting from controlled hemorrhage with concomitant fluid infusion. Our analysis focused on the changes in SpHb and tHb in healthy volunteers during highly defined conditions of uniform hemorrhage (10 ml/kg ~ 15 minutes) and a fluid bolus (30 ml/kg of lactated Ringer’s in 20

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minutes). Materials and Methods

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Subject eligibility: The University of Texas Medical Branch Institutional Review Board (IRB) approved this study as part of a project evaluating autonomous fluid therapy of hemorrhage in humans. Healthy volunteers aged 21 to 35 years were recruited, and written informed consent

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was obtained.

Inclusion criteria: Male and non-pregnant female (confirmed by negative urine test) healthy volunteers, physical status 1 as defined by the American Society of Anesthesiologists (ASA), were eligible for the study.

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Exclusion criteria: Subjects with anemia (tHb male < 13 g/dl and tHb female < 11 g/dl), acute illness or chronic medically unstable illness, hypertension, cardiovascular disease (peripheral

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vascular disease, heart attack or stroke), weight > 100 kg or BMI > 30 kg/m2, metabolic diseases

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(DM type I or II, hypercholesterolemia, hyperlipidemia), bleeding disorders, anticoagulant use or aspirin use within 72 hours of the study, serum ferritin less than 25 ng/ml, liver or renal disease, glaucoma, reflux disease, fungal infections, cigarette smoking, sulfite or iodide allergies, subject personal history or family history of malignant hyperthermia or other complications with anesthesia and history or physical exam findings suggesting a difficult airway.

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Anesthesia and Monitoring: A dedicated staff anesthesiologist was present to monitor each subject’s clinical conditions and ensure safety throughout the entire study and during emergence. Subjects were monitored with ECG, invasive blood pressure, capnography, inspired oxygen, temperature, bispectral index (BIS - Aspect Medical Systems, Inc; Norwood, MA) and pulse CO-oximetry. Urinary output was estimated throughout the study by bladder ultrasound.

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A Masimo Radical-7 pulse CO-oximeter with pulse oximetry sensor (rainbow ReSposableTM adult sensor R2-25r) was placed on the volunteer’s left ring or middle finger and covered with an

rainbow ReSposableTM sensor.

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ambient shield accessory per manufacturer’s standard operating procedures for Masimo

Two peripheral intravenous catheters (right and left antecubital veins) and an arterial catheter

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under sterile technique (left radial artery) were placed. After monitors were placed and baseline measurements were obtained (T-30 to T0), a facemask was placed on the subjects for 3-5 minutes to achieve pre-oxygenation. Then, intravenous anesthetic (Propofol: 2-4 mg/kg) was

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used to induce general anesthesia. After achieving mask ventilation, an intubation dose of rocuronium was administered (1 mg/kg). Subjects were intubated and mechanically ventilated

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with a FiO2 of 0.4 (tidal volume 8 mL/kg and respiratory rate 10-15 breaths to achieve an endtidal CO2 of 35-40 mmHg). General anesthesia was maintained with Propofol (100-250

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mcg/kg/min) titrated to achieve a bispectral index between 40-60 throughout the study procedure.

Thirty minutes after induction of general anesthesia, each subject underwent a volume-controlled hemorrhage (10 ml/kg) over a 15 minute period, with onset defined as time point zero [T0], via left antecubital vein. Lactated Ringer’s (30ml/kg) was infused by pump over 20 minutes at T0.

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Hemoglobin Measurements: Measurements of tHb during the study were obtained from arterial blood samples and analyzed using a laboratory hematology analyzer (Sysmex XE2100/XT1800). The tHb samples were obtained at the start of hemorrhage (T0), every 5 minutes for the first 20 minutes (T5, T10, T15, T20), then at 30 minutes (T30) and every 30 minutes until 120 minutes (T60, T90, T120).

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Pulse CO-oximetry (Radical-7, Masimo Corp.; Irvine, CA) monitoring was performed continuously from the start of the study and continued 120 minutes after the start of controlled

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hemorrhage and fluid resuscitation. To obtain continuous data for trend graphs SpHb was recorded every second from the pulse CO-oximeter and data extraction was performed using TrendCom software (Masimo Corp.; Irvine, CA). The Perfusion Index (PI) was also recorded at

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each time point. PI indicates the ratio of pulsatile signal to non-pulsatile signal (pulse strength), and is an indicator of localized perfusion and analyzable signal. A percentage ≥ 1.0%, as defined by the manufacturer, represents an appropriate strength signal for SpHb determination. Each tHb

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value was paired with the SpHb spot measurement made at the time of the blood draw. Statistical Analysis: Statistical analysis was performed using computerized software (MedCalc;

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MedCalc Software version 12.7.0.0, Mariakerke, Belgium) and Microsoft Office Excel. Subject characteristics and descriptive statistics are displayed using mean, standard deviation (SD), and

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range. The comparison between means was performed using the Student’s t-test, in which P values were two-tailed, and a P value less than 0.05 was considered statistically significant. Evaluation of the trend in tHb over time was performed and represented by a plot of the SpHb changes against time during hemodilution. The time lag was defined as the delay of the SpHb value to reach its nadir compared with the time that the hemodilution was maximal, taken as the end of the bolus infusion.

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The ability to follow trends or concordance was assessed quantitatively as differences (∆) of SpHb and tHb values between consecutive time points as plotted in a scatter graph to determine whether a directional change of tHb corresponds with a comparable directional change of SpHb. An exclusion zone of ± 1 g/dl was set because small changes in hemoglobin are not a metric for trending ability (16).

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SpHb accuracy was assessed by Bland-Altman analysis for repeated measurements (17-19). Mean absolute difference (bias), standard deviation (SD) of the difference and 95% limits of

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agreement (LOA = 1.96 ± SD of the bias) were calculated. Results

The study included 12 subjects. One hundred and six blood samples were taken allowing for 106

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SpHb - tHb data pairs. The characteristics of the volunteers are summarized in Table 1. Strong PI signals were obtained with mean level equal to 8.3% ± 3.7% with a range of 2.6% to 17%. None of the SpHb measurements had a device-indicated PI of less than 1.0%. Trend analysis was assessed in two ways: plots of SpHb over time of all 12 subjects and four-

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quadrant analysis. Figures 1 shows continuous SpHb plots for each volunteer from the start (T0)

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to ten minutes after the end of the hemodilution (T30). Data are plotted as SpHb concentration (Figure 1A) and percentage of baseline value (Figure 1B) against time. Graphic representation

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shows a consistent and continuous decline of SpHb level in all subjects, without exception, during hemorrhage and simultaneous lactated Ringer’s infusion. The lowest level of SpHb was observed at 100 ± 102 seconds after the end of the infusion. Figure 2 shows a four-quadrant plot, which graphically depicts whether a change in both SpHb and tHb were in the same direction. The concordance rate was defined as the percentage of the number of data points that are in one of the two quadrants of agreement (upper right and lower

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left). A central exclusion zone of ±1 g/dl was applied because the data at the center of the plot correspond to small changes in hemoglobin and do not reflect the trending ability in a practical manner (8, 12-13). The concordance rate was 95.4%. The mean value of all tHb blood samples was 11.4 ± 1.7 g/dl with a corresponding value for SpHb of 12.5 ± 1.9 g/dl. The tHb ranged from 7.8 to 15.4 g/dl and SpHb from 8.3 to 16.9 g/dl

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(Table 2). The calculated bias was 1.08 ± 0.82 g/dl, 95% LOA -0.5; 2.6 (Figure 3).

The analysis was repeated with data grouped into low and normal tHb values. A low tHb group

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was arbitrarily defined as tHb less than 10 g/dl, which comprised 21% (n = 22) of the 106 blood samples. The group with tHb greater than or equal to 10 g/dl contained 79% (n = 84) of the blood samples (Figure 4). Applying modified Bland-Altman analysis, bias ± SD and 95% LOA for low

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tHb group were 1.03 ± 1.01, 95% LOA -1.0; 3.0 which were similar to the group with tHb ≥ 10 g/dl, 1.09 ± 0.79, 95% LOA -0.5; 2.7 (Table 3).

In our study, 75% of the absolute differences between paired measurements of tHb and SpHb

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Discussion

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were ≤ 1.5 g/dl. Differences greater than 2 g/dl were found in 11% of the measurements (Table

In the present study we performed an assessment of precision of trending using Masimo Radical-

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7 measurements. During the study protocol of hemorrhage with simultaneous 3:1 fluid infusion of lactated Ringer’s, clinical vital signs including blood pressure, heart rate, temperature, and oxygen saturation remained within normal limits. Trend analysis, assessed by plots of SpHb over time of 12 subjects, shows consistent falls in SpHb during hemodilution. Four-quadrant concordance analysis was 95.4% with an exclusion zone of 1 g/dl. Spot comparisons of 106 data

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pairs (SpHb and tHb) showed that 50% exhibited error > 1g/dl with bias of 1.08 ± 0.82 g/dl, 95% LOA -0.5; 2.6. Trending accuracy: The most compelling analysis on precision is Figure 1 with continuous SpHb plotted for each subject. Data, recorded every second, showed remarkably consistent decreases in SpHb particularly during the first 15 minutes when hemorrhage was occurring

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simultaneously with the crystalloid infusion. SpHb continued to decline during the subsequent 5 minutes of continued fluid infusion after hemorrhage stopped. There was a rebound in SpHb that

vascular to the interstitial space.

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began after the end of bolus infusion. This likely reflects the transfer of crystalloid from the

It has been established in human and animal studies using mass balance and volume kinetics that

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large bolus infusions of crystalloid results in an immediate fall and a steady decline in tHb that reaches its nadir at the end of the infusion (20, 21). In our study, lactated Ringer’s was infused over 20 minutes. Figure 1 shows that the initiation of the decrease in SpHb occurred within a 5 minute time period, while the nadir time varied over 7 minutes with the mean value after the end

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of infusion. The delay in the initial fall may reflect time for circulatory mixing and some level of

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transcapillary refill. An alternative explanation for the apparently delayed response of measured SpHb during hemodilution is time lag due to data processing by the Masimo CO-oximeter. Such

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delays appear to be uniform enough to allow for volume kinetic analysis using SpHb as shown by Sjöstran et al. (22) and Bergek et al. (23). The ability of volume kinetic analysis to be applied to human hemodilution speaks of the precision and the utility of continuous SpHb monitoring. Another approach to assess trending ability is the use of concordance analysis. Colquhoun et al. (12) were the first to calculate the concordance rate of Masimo SpHb using an approach developed by Critchley et al. (24). Colquhoun et al. (12) and Park et al. (8) showed concordances

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of 94% and 93%, respectively.

The measure of concordance in our study was similar and

showed that 95.4% of the time, the pulse CO-oximeter was able to follow the direction of hemoglobin changes during blood withdrawal and dilution. SpHb has proven to have low reliability in the emergency room in trauma patients, where there can be substantial physical movement associated with assessments and therapy (10-11).

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However, in these studies SpHb was assessed only by spot measurements. On the other hand, Sjöstran et al. (22) performed a study using volume kinetic analysis in the emergency room in

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which administered bolus volumes were analyzed successfully. Volume kinetic analysis requires precision in trending the percentage change in tHb, as opposed to the accuracy of any single spot value of SpHb.

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Spot Measurements and Accuracy: The positive bias seen in Figure 3 indicates that the Masimo Radical-7 overestimated hemoglobin compared with the laboratory analyzer. Despite conducting our study under ideal conditions, the results of the comparison between SpHb and tHb in our study were similar to other published clinical studies. We found that 75%

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of the absolute differences between paired measurements of tHb and SpHb were ≤ 1.5 g/dl

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(Table 4), which agrees well with 73% found by Park et al. (8), 61% by Miller et al. (4), and 67% by Butwick et al. (25). The fraction of outliers (absolute difference > 2.0 g/dl) in our data

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was 11%, smaller than shown in previous studies; 18% by Butwick et al. (25), 22% by Miller at el. (4) and Park et al. (8). Previous studies have suggested that tHb levels can influence the accuracy of SpHb (4, 6, 8). Our data do not establish a significance for the existence of a difference in device performance above and below tHb of 10 g/dl, P=0.7 (Table 3).

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However, the observed bias in spot measurements of SpHb versus tHb could result in delays of needed transfusions. If a transfusion trigger were set at a tHb threshold of 10 g/dl and used to determine a transfusion using the present data, then 36% (n=8) of needed transfusions would have been missed or delayed based on the spot SpHb measurement of the pulse CO-oximeter (Figure 4). On the other hand, no unnecessary potential transfusion would have been performed.

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Limitations: Our pool of data has 79% of measured tHb values over 10 g/dl. The bias calculated from this data might not reflect the bias affecting measurements in the range of values that are

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often associated with critical decisions on transfusion, and may not be representative of patients’ needs.

We studied only healthy volunteers, with a pre-defined hemorrhage and a fixed intervention. No

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hospitalized patients were enrolled, therefore clinical decision to transfuse was not influenced by the use of the device. All measurements were obtained in very controlled conditions and outcomes were not considered for data analysis. Elevated PI measurements indicated that subjects had sufficient peripheral perfusion to provide a robust photoplethysmogram. This may

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not occur in injured casualties where compensatory response triggers peripheral vasoconstriction

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and could limit the use of pulse CO-oximetry. Conclusion

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The accuracy and spot measurement ability of the Masimo Radical-7 to assess a specific transfusion trigger are only modest and a small delay in tracking hemoglobin changes was observed. On the other hand, pulse CO-oximetry does allow for the continuous and noninvasive monitoring of hemoglobin changes. Trend analysis, assessed by plots of SpHb against time of 12 subjects, shows consistent falls in SpHb during hemodilution. Trend graphs can visually provide the time course of SpHb changes with hemorrhage and hemodilution and may provide more

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confident and useful clinical decision-making. Four-quadrant concordance analysis was 95.4% with an exclusion zone of 1 g/dl. Spot comparisons of 106 data pairs (SpHb and tHb) showed bias of 1.08 ± 0.82 g/dl, 95% LOA -0.5; 2.6. Further evaluations are needed to assess how SpHb

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trending performs in patients.

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Figure Legends Figure 1: Trend plot of SpHb concentration [g/dl] (A) and SpHb normalized to percentage of baseline (B) in 12 volunteers during hemodilution. Data were recorded every second with the

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Masimo Radical-7 CO-Oximeter.

Figure 2: Four-quadrant trend plot of 94 paired changes in sequential measurements from SpHb

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and tHb. The 4-quadrant plot shows direction of the trend with a central exclusion zone of 1.0 g/dl hemoglobin. The concordance rate (a measure of the number of data points that fall into 1 of

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the 2 quadrants of agreement) is 95.4%.

Figure 3: Bland-Altman plot of 106 paired measures obtained in 12 subjects. Bias (dash line) was 1.08 ± 0.82 and 95% limits of agreement (dotted-dash lines) were -0.5 to 2.6 g/dl.

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and tHb.

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Figure 4: Scatter plot with shaded-in area indicating a transfusion trigger of 10 g/dl for SpHb

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Figure 1

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Figure 2

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Figure 3

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Figure 4

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Table 1: Characteristics of 12 subjects studied. N

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Data pairs

106

Gender (male/female)

8/4

28 ± 3.0

BMI (kg/m²)

27 ± 4.5

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Age (years)

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Mean ± SD

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Body mass index (BMI), standard deviation (SD).

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Table 2: Summary of tHb and SpHb mean ± SD and range per data group. T0

T30

All data points

Range

Mean ± SD

tHb (g/dl)

13.2 ± 1.7

10.9 ± 1.3

11.4 ± 1.5

7.8 – 15.4

SpHb (g/dl)

14.0 ± 1.9

11.6 ± 1.6

12.5 ± 1.9

8.3 – 16.9

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Mean ± SD Mean ± SD

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Total hemoglobin (tHb), continuous blood hemoglobin (SpHb), standard deviation (SD),

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hemodilution start time (T0), 30 minutes after starting hemodilution (T30).

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Table 3: Summary of Bland-Altman analysis per two tHb ranges. tHb range

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(g/dl)

Bias

SD

LOA

(g/dl) (g/dl)

(g/dl)

22 (21%)

1.03

1.01

-1.0; 3.0

tHb ≥ 10

84 (79%)

1.09

0.79

-0.5; 2.7

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tHb < 10

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P = 0.7. Total hemoglobin (tHb), standard deviation (SD), limits of agreement (LOA).

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Table 4: Distribution of the differences between tHb and SpHb (g/dl). tHb range

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28 (26%)

0.5 - 1.0

26 (24%)

1.1 - 1.5

27 (25%)

1.6- 2.0

14 (14%)

> 2.0

11 (11%)

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Total hemoglobin (tHb)

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< 0.5

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(g/dl)

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