Noninvasive hematocrit assessment for cardiovascular magnetic resonance extracellular volume quantification using a point-of-care device and synthetic derivation

Myocardial extracellular volume (ECV) fraction derived from cardiovascular magnetic resonance (CMR) T1 mapping has been validated based on histology [1‐3], with demonstrated prognostic significance in several conditions [4‐6]. Calculation of ECV requires accurate and timely assessment of hematocrit, to correct for the blood contrast volume of distribution [7]. Traditional laboratory determination of hematocrit via venipuncture in the setting of ECV evaluation is costly, mildly uncomfortable for the patient, and often inconvenient. Therefore, rapid noninvasive determination of hematocrit would be beneficial in the setting of ECV analysis.

Noninvasive point-of-care (POC) devices have recently become commercially available, providing immediate hemoglobin and hematocrit results without the need for blood sampling by venipuncture or finger prick [8‐10]. Additionally, synthetic derivation of hematocrit has recently been described based on the relationship between hematocrit and non-contrast blood pool T1 values [11]. However, there are important limitations to synthetic analysis, as each specific acquisition scheme requires derivation and validation [12]. A recent study suggests that synthetic ECV may result in miscategorization of individual patients [13].

The purpose of this study was to evaluate the diagnostic accuracy of CMR ECV calculated using noninvasive measures of hematocrit (determined with a POC device and synthetic derivation) compared to ECV calculated with input of laboratory hematocrit as the reference standard. We hypothesized that there would be no significant difference in myocardial ECV calculated using noninvasive measures of hematocrit as compared with ECV derived from laboratory hematocrit.

Baseline characteristics and clinical details are summarized in Table 1. CMR findings are summarized in Table 2.

The results of this prospective study demonstrate that accurate and reproducible CMR ECV values can be calculated with input of hematocrit measured using a noninvasive POC device, potentially eliminating the need for blood collection by venipuncture for the purpose of ECV analysis. POC-ECV values correlate strongly with conventionally calculated ECV using laboratory hematocrit as the reference standard, with good diagnostic test performance, minimal bias and good agreement with Lab-ECV in both genders. Synthetic-ECV has slightly larger bias, wider limits of agreement and is less robust on sensitivity analyses when compared to POC-ECV.

There is growing interest in quantifying myocardial ECV as a marker of diffuse interstitial myocardial changes including fibrosis [22]. Myocardial ECV correlates with histologic measures of diffuse myocardial fibrosis [23, 24], and is independently associated with adverse outcomes including mortality [4]. However, clinical implementation of myocardial ECV may be limited by the requirement for timely hematocrit assessment [25]. Hematocrit is conventionally assessed by a peripheral blood sample obtained by venipuncture which is often inconvenient and uncomfortable for the patient. Several methods of noninvasive hematocrit evaluation have recently become commercially available which could be implemented to streamline CMR ECV evaluation.

Noninvasive POC devices provide rapid on the spot measures of hemoglobin without the need for blood sampling [15, 26]. Most noninvasive POC devices rely on a spectrophotometer finger probe sensor to analyze light absorption characteristics of different hemoglobin species [27]. Prior studies utilizing earlier POC devices reported conflicting results [28, 29]. However, comparison of earlier results to current POC device performance is limited given ongoing software and hardware revisions [30]. More recent generations of POC devices (including the device used in this study), have been evaluated in subjects in a variety of clinical settings [9, 31, 32] and in healthy volunteers [33, 34], with good correlation between POC hemoglobin and laboratory reference measures. A recent large meta-analysis evaluating the accuracy and precision of current POC devices against central laboratory hemoglobin measurements reported a pooled random-effects mean difference of POC minus central laboratory hemoglobin values of 0.10 ± 1.37 g/dL (limits of agreement − 2.59 to 2.80 g/dL) [15]. Similarly, the results of our study demonstrate a small mean difference between POC-ECV and Lab-ECV of − 0.18% with relatively narrow limits of agreement (− 2.85 to 2.49%). Notably, previous publications have not evaluated the diagnostic performance of POC derived ECV values, which is an important strength of the current study.

We evaluated POC device performance in the calculation of myocardial ECV in a relatively diverse cohort of subjects, and therefore results are applicable in a relatively broad range of clinical and research settings. POC analysis was quick, with most measurements acquired with a single analysis attempt. This noninvasive measure of hematocrit was easily incorporated into the CMR workflow and can be implemented in myocardial ECV calculation with the following caveats. POC analysis was not possible in a small subset of subjects, including subjects with applied gel nail polish, marked hand tremor and poor peripheral perfusion, which are recognized limitations of POC device analysis [28, 35]. Additionally, in the subset of subjects with anemia, there was a significant difference between laboratory and POC ECV values. This may be explained by the fact that low hemoglobin levels have been shown to impair perfusion analysis [36]. Given this finding, POC derived hematocrit is not recommended for CMR ECV calculation in subjects with anemia. This finding can be further explored in future studies that include a larger number of subjects with anemia.

A few recent studies have reported synthetic derivation of hematocrit and ECV based on the linear relationship between hematocrit and non-contrast R1 of blood [11, 13]. Automated inline derivation of synthetic hematocrit with subsequent calculation of myocardial ECV could potentially improve workflow, eliminating the need to acquire an invasive hematocrit value at the time of CMR. Treibel et al. demonstrated moderate correlation between synthetic and laboratory hematocrit (r² = 0.51–0.45, p < 0.001) and strong correlation between synthetic and laboratory derived ECV (r² = 0.97, p < 0.001) [11]. Our study similarly demonstrates excellent correlation between synthetic and laboratory ECV, although the mean difference between synthetic-ECV and Lab-ECV was slightly greater and the limits of agreement were slightly wider when compared to POC-ECV. A recent study investigating synthetic ECV in a pediatric population reported 41 (25%) false negatives and 4 (2%) false positives for mid-septal synthetic ECV using a published model and cut-off value of 28.5% [13]. The authors conclude that use of synthetic hematocrit for the calculation of ECV results in miscategorization of individual patients. Similarly, the results of the current study demonstrate that synthetic-ECV values are less robust on sensitivity analysis compared to POC-ECV, with significant differences between laboratory and synthetic ECV values when restricted to females, patients and those with anemia. Synthetic hematocrit and ECV values are affected by factors that affect non-contrast blood pool T1 values, such as changes in oxygen and iron concentration and body temperature [37‐40]. There are also important practical limitations to synthetic analysis, as formulas to calculate synthetic hematocrit should be derived at each institution in a large sample of patients imaged on each individual scanner and with each specific acquisition scheme to which the results will be applied [12]. We conclude that synthetic-ECV is less robust compared to POC-ECV, and requires further evaluation prior to clinical implementation.

Our study has a number of limitations. First, the non-invasive POC device used in this study became commercially unavailable after this study was completed. However, multiple other non-invasive hemoglobin monitoring devices are currently available, including Pronto^® Pulse CO-Oximeter^® (Masimo Personal Health), Radical-7^® Pulse CO-Oximeter^® (Masimo Personal Health), NBM-200 (OrSense, Petah-Tikva, Israel) and Haemospect^® (MRB Optical Systems GmbH & Co. KG, Wuppertal, Germany). Several prior studies have compared hemoglobin results from the Pronto-7^® device used in this study and NBM-200 device, with similar accuracy and bias reported between devices [26, 41‐43]. A recent meta-analysis evaluating the accuracy of non-invasive hemoglobin monitoring devices reported that pooled mean differences and standard deviations were similar among three devices included in the analysis (Radical-7^®, Pronto-7^®, and NBM-200 devices) [15]. We demonstrate no significant difference in hematocrit or ECV assessed using the Pronto^® Pulse CO-Oximeter^® compared to the Pronto-7^® Pulse CO-Oximeter^® and to laboratory values. These results suggest that currently available non-invasive hemoglobin monitoring devices will most likely lead to similar findings as reported in this study. Second, diurnal and monthly within-subject fluctuations in hematocrit are a recognized phenomenon, estimated at 3% [44, 45], with additional variations in hematocrit values linked to season, age, hydration and physical activity [46‐49]. Our study used a single laboratory hematocrit measure within 24 h of CMR as the reference standard. It is possible that slight fluctuations in hematocrit between the time of CMR, POC device acquisition and peripheral blood sampling for laboratory analysis could have influenced the results. The median interval between laboratory hematocrit analysis and CMR was only 1.3 h and therefore the impact of potential variations in hematocrit between analysis methods is likely minimal. Third, non-invasive hemoglobin measurements may vary between POC devices and settings. However, a recent meta-analysis has demonstrated good agreement in hemoglobin between various POC devices [15]. The presence of an arrhythmia, including atrial fibrillation, was not recorded at the time of CMR. Therefore, the accuracy of POC devices in the setting of an arrhythmia has not been evaluated. Finally, the sample size was modest and all data were acquired at a single institution. Further multi-center studies including a larger number of patients with anemia should be performed to validate these results.

CMR ECV calculated with input of hematocrit measured using a noninvasive POC device is accurate and reproducible compared to conventionally calculated ECV using laboratory hematocrit, potentially overcoming an important barrier to clinical implementation of ECV measurements. Further evaluation of synthetic ECV is required prior to clinical implementation.