Evaluation of PVR and reactivity in PVR are currently the primary means of determining the severity of pediatric pulmonary hypertension, classifying patients pre-operatively, and determining appropriate therapy for PAH [12
]. Although PVR is a dominant component of RV afterload, it is not the only component. Pulmonary vascular stiffness can play a significant role in maintaining low RV afterload in healthy patients and conversely, exacerbating afterload in patients with pulmonary hypertension. Vascular input impedance, which theoretically includes both resistance and stiffness components, should thus be the best global measure of RV afterload, and consequently should also provide a better means of predicting outcomes than PVR alone [1
]. Although impedance is not a new concept, its application to clinically relevant diagnostics has been hampered by the lack of an easy-to-implement method to obtain it. We have shown [4
] using in vitro and preliminary clinical data the utility of a method combining measurement of main PA pressure with computation of instantaneous PA flow using Doppler velocity measurements to obtain impedance easily during routine cardiac catheterization of patients with PAH. This study extends this prior work significantly by: 1) studying a larger number of patients; 2) providing explicit correlations between Z0
and PVR, and between Z1
and hemodynamically measured pulmonary vascular stiffness; 3) correlating the correction factor, required to “correct” Doppler-measured velocities and obtain instantaneous flow, to facilitate future use of this method; and 4) obtaining regressions of outcomes against impedance and PVR to show the clinical utility of impedance measurement. Results show impedance is a highly promising clinically realizable measurement for comprehensively evaluating pulmonary vascular function in patients with PAH.
Measurement of impedance possesses several advantages over the traditionally derived hemodynamic variables (PVR, PP/SV) obtained through right-heart catheterization. First, it enables quantification of both system resistance and stiffness with a single measurement, which is important given the relatively moderate correlations that have been found between reactivity in PVR and clinical outcomes [12
]. Because impedance is measured at a single position in the vasculature, it also does not require the measurement of wedge pressure, which may be problematic in certain patients. Through use of the presented correlation Acorr
with BSA, or with imaging measurements of MPA area, measurement of instantaneous flow with or without measured cardiac output becomes much simpler. Note that if cardiac output were available it would only add confidence to the instantaneous flow measurement obtained from Doppler since the correction factor can be explicitly calculated for each patient and condition. Finally, the measurement of impedance adds roughly 5 minutes to the catheterization study, primarily for the Doppler measurement.
The importance of vascular stiffness in determining ventricular afterload is becoming increasingly recognized in hypertension management strategies in the pulmonary circulation [5
] and on the systemic side [13
]. Links between arterial stiffening and systemic hypertension are well established [17
]. Here we demonstrate the same on the pulmonary side, and additionally establish that impedance well-quantifies stiffness in the clinical situation, as Z1
is clearly a good correlate of indexed pulse pressure over stroke volume (BSA·PP/SV), or pulmonary vascular stiffness (PVS). Of the three hemodynamics variables with which correlation was attempted, PVS is the best constitutive measure in that it expresses the ratio of a given change in a kinetic or force variable (pulse pressure) over a resulting change in a kinematic or displacement variable (normalized vascular displacement, SV/BSA). We have explored other constitutive measures such as the dynamic compliance [19
]; although promising as well, these require measurement of both pressure and arterial wall displacements. PVRI is purely indicative of viscous flow losses, whereas the mean pulmonary pressure is simply a kinetic measure, without any link to a resultant displacement; hence it is no surprise that both have lesser correlations with Z1
. We note that stiffness as represented by Z1
, unlike resistance and the other clinical measures it is compared to, is already independent of body mass; thus it is not normalized with BSA prior to comparison.
There are several ways this method may be used clinically. For example, this study provides some guidance on how to classify indexed impedance sum values, similar to how PVRI values are used clinically. From the outcomes analysis (, ) we see that, in general, ZsumI < 10 indicates a relatively healthy pulmonary circulation and appear to predict good to moderately good outcomes. ZsumI > 18 appears to indicate high RV afterloads and predict poorer outcomes. Based purely on comparison to PVRI, we calculate that ZsumI predicts a PVRI of > 3 m2 mm Hg/(L/min) with an 87.2% sensitivity and an 91.7% specificity; thus pre-operative evaluation may alternatively use a ZsumI value of 8 as indicative of onset of PAH (= PVRI > 3) and of 18 as a means of generally classifying patients into outcomes categories. Although the outcomes analysis is preliminary in nature (n=25), it reveals that inclusion of stiffness effects enhances outcomes prediction in terms of goodness-of-fit and changes the form of outcomes probabilities for patients in poor health. Future studies will investigate Z0 and Z1+Z2 as independent predictors of outcomes (i.e. multivariate regression); for the current small data set, such models were not statistically significant and thus were not included. Impedance may also provide a means of distinguishing effects of novel therapies, especially those that may affect upstream vascular tone and therefore alter pulmonary vascular stiffness versus those that affect downstream vascular tone and therefore alter pulmonary vascular resistance. We continue to perform impedance studies in our catheterization laboratory and will continue to expand our database of impedance correlations to further cement these findings.
There are several limitations that must be acknowledged. Impedance values at higher harmonics (beyond the 2nd
) were not included due to their higher levels of measurement uncertainty and minuscule power content. In certain patients, this may underestimate true RV afterload since wave reflections, which typically manifest at higher harmonics, are not taken into account. The use of a constant area factor does affect the calculation of flow, although previous in-vitro studies on compliant models [4
] suggest only a moderate impact on the harmonics of impedance. The regression for the area correction factor may need to be further refined for reactivity testing since we found as much as 20% variation in this factor due to reactivity. This could be done through additional secondary and/or tertiary correlates, such as the systolic acceleration time or the ratio of this time to the ejection time, which may influence the velocity profile and correspondingly the area correction factor. Other methods such as MRI could also be used to measure instantaneous flow directly without any need for correction factors. We did not examine reactivity in impedance as another potential predictor of outcomes, nor did we evaluate how impedance changes with the administration of different therapies; this work is ongoing. We note that exclusion of the non-responder data – which may represent dependent observations – was seen to have a minor impact on the regressions performed. Thus, inclusion of such data does not appear to invalidate the statistical analysis. We note that the Doppler data was acquired at 100Hz, which provides useful frequency information up to 50Hz; additionally, the fluid-filled catheters used have been shown to have flat frequency response up to 15Hz. Thus, we may have confidence in the harmonics of impedance up to at least the sixth harmonic (for a heart rate of 120BPM), and to higher harmonics for lower heart rates.
In summary, we have shown in a relatively large pediatric patient population that pulmonary vascular input impedance provides a comprehensive yet easy-to-obtain measure of RV afterload in that it includes both resistance and vascular stiffness effects. Using a sub-set of patients where we also obtained outcomes, we also show impedance as a better and more significant predictor of clinical outcomes than PVR alone.