In this study, we used a carefully controlled laboratory procedure, LBNP, to induce, then resolve, a standardized circulatory disturbance, and we then directly compared the diagnostic capabilities and limitations of four non-invasive CO and SV measurement modalities. LTI and EBI, based on the waveform analysis and thoracic bioimpedance, respectively, yielded CO and SV ROC AUCs which were similar and diagnostically promising. Throughout progressive hypovolaemia, the third investigative modality, MF, was diagnostically similar to both LTI and EBI. During progressive hypovolaemia, PP also declined, but not as reliably, and it trended towards lower AUCs than the other metrics. The reduction in PP underestimated the reduction in SV; this was evidenced by the finding that CO-PP*HR yielded a paradoxical increase throughout progressive LBNP. After simulated resuscitation, (i.e. termination of LBNP), both MF and PP remained reduced, with inferior ability to discriminate between ongoing hypovolaemia (e.g. −30 or −45 mm Hg of LBNP, as in Table ) and euvolaemia.
It appears that two of the investigational methods, CO-EBI and CO-LTI, would be preferable for monitoring subjects who receive resuscitation for their hypovolaemia. In terms of practical requirements, CO-EBI measurement involves electrode placement on the neck and chest, which is sometimes precluded by surgical wounds, injury, or both (e.g. burns), and CO-EBI may not perform as well in critically ill patients vs
healthy research subjects, because of errors associated with abnormal thoracic anatomy (e.g. post-pneumonectomy) or intrathoracic fluid (e.g. pleural effusions, pulmonary oedema, acute respiratory distress syndrome).12,13,14
LTI requires an ABP waveform, which can be measured via an indwelling arterial catheter and can also be measured using a non-invasive finger-cuff apparatus, for example, the Finometer (used in this study), which uses the volume-clamp method of Penaz.
Clinically, it would be most useful to monitor a circulatory metric that is an accurate indicator of impending cardiovascular collapse. Accordingly, we assessed which metrics gave the best indication that subjects would prove unable to tolerate the highest levels of LBNP. We found that protection of SV-LTI at −60 mm Hg was a strong predictor (ROC AUC 0.86) of high tolerance to the deepest levels of LBNP (see the Methods section, and Table , for details). The ROC AUC for SV-LTI was significantly higher than SV-EBI (AUC 0.61) and SV-MF (AUC 0.54). In general, SV metrics were more predictive of tolerance than CO metrics. Paradoxically, CO-MF yielded an AUC of <0.50, meaning that the biggest reductions in CO-MF at −60 mm Hg were associated with the most tolerant subjects, which is counter-intuitive (and also inconsistent with prior findings).24,25
Overall, the superior ability of SV-LTI to identify which subjects would prove intolerant of higher levels of LBNP suggests that it may be a more valid assessment of circulatory status compared with the alternatives.
It is interesting to consider why LTI vs
MF, both based on the analysis of the ABP waveform, had different diagnostic performances. CO-MF, with its underlying three-element model, is an example of a ‘lumped parameter’ model, in which a sprawling, complex system—in this case, the arterial tree—is represented by a set of simple elements intended to capture the essential behaviour of the actual system. (The analytic model implicitly assumed when PP is taken as a surrogate for SV is another example of a lumped parameter model.)26
Yet pressure pulses are shaped by many other factors. For instance, different frequency components of a pressure pulse travel down an artery at different velocities, and pulses are reflected backwards from arterial bifurcations and terminal locations.27
As a result of these so-called transmission effects, ABP amplitude (i.e. PP) and shape are quite varied in different arterial locations, which is not considered by simple lumped parameter models. We found that both PP and CO-MF remained reduced during recovery, so that these measures did not reliably indicate when blood volume was restored. We speculate that, perhaps, the simple model upon which the CO-MF method is based was not flexible enough to account for the effects that altered the shape and reduced the amplitude of ABP in recovery.
LTI was developed to address the transmission effects that shape individual pressure pulses.11
When ABP is analysed over longer time scales that span multiple beats, there are fewer factors that affect the elevations and reductions of ABP: fluctuations in ABP over longer timescales are purely a function of cardiac ejection plus the arterial tree's net compliance and its total peripheral vascular resistance (PVR). The reason for this is that over longer time scales, the transmission effects become negligible (just as when a pebble falls in a pond, the resultant splash waves settle out within a minute, so does the to-and-fro of pulses and their reflections within the arterial tree). LTI uses a mathematical technique that analyses a sequence of heartbeats from the measured ABP and estimates the contribution of each individual heartbeat. Specifically, the algorithm generates a theoretical estimate of the ABP waveform that would be generated by one single isolated heartbeat. The LTI method is based on a very well-known engineering technique called system identification.11
In the later portions of that theoretical ABP waveform, the reflected waves and transmission effects have faded away, which is consistent with real-world physics where indeed reflected waves and transmission effects diminish over time. Those later portions, where the waveform is a function of PVR and arterial compliance, are used to estimate PVR, and the ratio of MAP to PVR yields CO. In theory, LTI-CO could therefore be confounded by changes in arterial compliance (the method makes the assumption that changes in arterial compliance are negligible), but reports to date suggest that this is not a major source of error.11,28
In this report, LTI performed quite comparably with a very different measurement modality, EBI. One potential limitation is that LTI metrics will be slower to indicate changes in CO and SV that occur quickly, that is, within the span of several seconds. Also, beat-to-beat changes cannot be resolved. The LTI method is not commercially available presently.
PP has value in the diagnosis of progressive hypovolaemia (Table ), although it was consistently less diagnostic than SV-LTI and SV-EBI, sometimes significantly less so. We found that PP and SV were correlated, which is an expected finding that has been previously noted in other reports (e.g. high correlation of variability of PP and SV during major abdominal surgery).29
At the same time, it is important to appreciate that the magnitude of reduction in PP underestimated
the reduction in SV, that is, they were correlated, but not strictly proportional. This is highlighted by the fact that PP*HR yields an estimate of CO that paradoxically increases
throughout progressive LBNP. Additionally, after recovery, PP again appears to underestimate the recovered SV. Our findings are consistent with a prior investigation on haemodynamic changes from postural change, which reported ‘a greater postural fall in stroke index than the corresponding change in pulse pressure.’30
Our results suggest that any algorithm that assumes PP is a quantitative surrogate for SV, for example, the FloTrac method9
and the PulseCO,10
will need to offer substantial compensation, as we find that those two parameters are not proportional and we speculate that our findings explain why certain PP-based algorithms have shown inconsistent reliability in some clinical reports.31
Sun and colleagues reported on a variation of CO-PP*HR proposed by Liljestrand and Zander32
(in which PP*HR was scaled by MAP to adjust for arterial compliance). In Sun's33
report, this method performed well in an ICU population consisting of older patients with relatively less dynamic changes in PVR. However, in our data set, PP*HR/MAP failed to decline with progressive LBNP (data not shown). Another key implication is that CO-from-ABP algorithms do not necessarily perform equally well in different populations under different conditions, which re-emphasizes the need for direct comparative evaluations in varied subject populations.17,18
There are several limitations to this study. First, the study of healthy subjects in laboratory conditions may not be strictly equivalent to clinical use. For instance, there may be more measurement error in actual clinical use, or other confounding factors, such as vasopressor infusion. However, this study design provided unambiguous outcomes impossible to accomplish through clinical trials, so such controlled laboratory studies may be quite complementary to clinical ‘real world’ investigations.
Secondly, our ABP was measured using the Finometer. It is possible that waveform analysis of ABP measured by an indwelling arterial catheter might behave differently. Therefore, our results may not necessarily generalize to patients with an indwelling ABP. On the other hand, the Finometer has been shown to provide a valid measurement of ABP.34
Moreover, a truly non-invasive method of monitoring CO could be quite useful in the management of the majority of hospitalized patients without invasive lines, and this report illustrates certain capabilities and limitations of several different non-invasive alternatives.
In conclusion, we found that CO and SV measured by LTI, EBI, and MF, all tracked progressive hypovolaemia. SV-PP also declined, but this reduction in PP underestimated the reduction in SV. Hence, CO-PP*HR yielded a paradoxical increase during progressive LBNP. After restoration of circulating volume, CO and SV by LTI and EBI were able to distinguish between ongoing hypovolaemia and resuscitation, whereas the MF and PP metrics were significantly less discriminatory. These results may have serious implications for the utility of non-invasive CO and SV measurements to track progressive bleeding and effective fluid resuscitation, especially those that assume proportionality between PP and SV.