Recipients awaiting liver transplantation frequently present hyperdynamic circulation characterized by increased cardiac output (CO) and decreased systemic vascular resistance (SVR) 1–3. These pathologic conditions can cause further worsening of hypotension and relative hypovolemia related to anesthesia, and thus make it difficult to maintain intraoperative hemodynamic stability. It has been reported that hyperdynamic circulation during liver transplantation is associated with the need for intraoperative transfusion and vasopressor, also correlated with postoperative renal failure and mortality 3.
To assess whether a patient has hyperdynamic circulation, we must obtain the hemodynamic parameters, including CO and SVR, using pulmonary artery catheterization, which is considered the gold standard. Although many medical institutions use pulmonary artery catheterization for liver transplantation, this method has significant complications associated with its invasiveness and it is not always possible to insert the sheath and the catheter. To substitute pulmonary artery catheterization, CO measurement based on arterial pressure waveform analysis has been introduced and widely applied. Although its software has been refined, it remains uncertain whether CO measurement derived from uncalibrated arterial waveform analysis can be considered reliable during liver transplantation, particularly in patients with hyperdynamic circulation 4,5.
It has been suggested previously that pressure-derived parameters, such as the central augmentation index, can be useful indices reflecting the arterial properties and cardiac function 6. Of the pulsatile component of arterial waves, the diastolic reflected wave is generated by overlapping between forward ejected flow from the ventricle and backward traveling flow from peripheral arterioles 7,8. The diastolic reflected wave has been known to be influenced by arterial resistance and stiffness 8. In other words, the diastolic reflected site and its amplitude on the arterial waveform are altered because of alteration of the pulse-wave velocity dependent on arterial properties 7,8. In clinical situations of increased ventricular ejection and decreased vascular resistance in liver recipients with hyperdynamic circulation, the diastolic reflected wave would be also altered and delayed in its appearance, similar to that found during exercise and vasodilation 9,10. Therefore, we aimed to assess whether the variables derived from the diastolic waveform of the radial artery can predict hyperdynamic circulation in liver transplant recipients as a substitute for pulmonary artery catheterization.
Materials and methods
The participants of this study included 93 consecutive recipients undergoing elective liver transplantation between April 2012 and September 2012. After receiving approval from our Institutional Review Board (no. 2014-0269), we retrospectively reviewed the patients’ medical records in accordance with the Helsinki II declaration. All recipients had undergone a preoperative evaluation, including ECG, transthoracic echocardiography, and coronary computed tomography. Patients were excluded if they had frequent premature atrial or ventricular contraction and atrial fibrillation (n=16), coronary artery disease (n=6), significant valvular disease (n=9), or decompensated heart failure. We also excluded patients if their medical records were incomplete or their hemodynamic signal quality was poor (n=32).
General anesthesia and monitoring
We performed routine monitoring using ECG, noninvasive blood pressure monitoring, pulse oximetry, and end-tidal capnography. After tracheal intubation, anesthesia was maintained with inhalation of sevoflurane 1–1.5 vol% and continuous infusions of fentanyl and vecuronium. Direct arterial blood pressure was measured continuously by radial artery catheterization. We also performed pulmonary catheterization (7.5 French, Swan-Ganz Ccombo V; Edwards Lifesciences, Irvine, California, USA) through a central venous access set (9 French, MAC; Arrow International Inc., Reading, Pennsylvania, USA) and connected to a Vigilance device (Vigilance II; Edwards Lifesciences).
Data acquisition and measurement of arterial-derived variables
We routinely recorded the hemodynamic variables, that is, beat-to-beat ECG, systolic and diastolic arterial pressure (DAP), and central venous pressure waveforms, using an analog-to-digital converter (DI-720U; Dataq Instruments, Akron, Ohio, USA). Parameters derived from the continuous thermodilution technique, including the cardiac index (CI), right ventricular ejection fraction, end-diastolic volume index, SVR, and mixed venous oxygen saturation, were also collected automatically from serial digital ports of the Vigilance device using a Multi-Data Logger (Edwards Lifesciences). CI was calculated using the formula CI=CO/body surface area and end-diastolic volume index was obtained using the same formula 11.
From 500 Hz digitized arterial waveforms, data were analyzed offline using a signal processing software program (DADisP/Adv DSP, DSP Development; Dataq Instruments Inc., Cambridge, Massachusetts, USA). Diastolic reflected waveform characteristics were determined by calculating the diastolic augmentation index (DAIx, %), defined as 100×[peak pressure of diastolic reflected wave (DAP0)−DAP]/pulse pressure (PP). The time to the peak of the diastolic reflected wave, corrected by RR intervals (tDA), was also obtained (Fig. 1) 10.
All arterial-derived variables were averaged over 20 consecutive beats during a stable condition before surgical incision following anesthetic induction, and other hemodynamic variables were obtained simultaneously.
Data were presented as mean±SD or the median with range, as appropriate. Pearson or Spearman correlations were performed to assess the associations between CI and SVR and the variables derived from arterial waveforms. We divided the patients on the basis of CI more than 4.0 l/min/m2 (high CI) or SVR less than 800 dynes·s/cm5 (low SVR). The patients were also divided into two groups according to high CI and low SVR (hyperdynamic circulation). To examine the ability of diastolic reflected waveform characteristics to predict hyperdynamic circulation, receiver operating characteristics (ROC) analysis was used. We also determined the best cutoff value and the area under the ROC curve (AUC). For comparison between the two groups divided by CI and/or SVR, the t-test or the Mann–Whitney test was used, as appropriate. A P value less than 0.05 was considered statistically significant. Analyses were carried out using SPSS software (version 21.0; IBM SPSS Inc., Chicago, Illinois, USA) and SigmaPlot (version 12.0; Systat Inc., San Jose, California, USA).
We analyzed the data of 30 patients after excluding 63 patients. The preoperative demographic data and the clinical characteristics of 30 patients are summarized in Table 1.
Patients with high CI (n=15, 50%), low SVR (n=18, 60%), and hyperdynamic circulation (n=13, 43%) had a significantly higher model for end-stage liver disease score, left ventricular end-diastolic volume on preoperative echocardiography, and baseline total bilirubin level than those with normal hemodynamics. However, the preoperative left ventricular ejection fraction, left ventricular mass index, and the B-type natriuretic peptide level did not differ between the two groups (Table 2). Patients with a high CI showed a significantly higher PP compared with those with a normal CI. The DAP was significantly lower in patients with a low SVR than in those with a normal SVR. Both DAIx and tDA showed significant differences in all comparisons (Table 3).
DAIx was correlated inversely with CI (r=−0.553, P=0.002) and correlated positively with SVR (r=0.617, P<0.001). In contrast, tDA showed a positive correlation with CI (r=0.504, P=0.004) and a negative correlation with (r=−0.692, P<0.001) (Fig. 2). The DAP was correlated significantly with the SVR (r=0.522, P=0.003); however, systolic arterial pressure and PP were not associated with CI or SVR.
On ROC curve analysis, the AUCs were 0.884 [95% confidence interval (CI): 0.715–0.971] for DAIx and 0.911 (95% CI: 0.749–0.982) for tDA to predict high CI (>4.0 l/min/m2, n=15), and 0.894 (0.726–0.975) for DAIx and 0.843 (0.664–0.948) for tDA to predict low SVR (<800 dynes·s/cm5, n=12). The AUCs of DAIx and tDA predicting hyperdynamic circulation showed the same value of 0.900 (0.735–0.978) (Fig. 3). DAIx 35% was the best cutoff to discriminate high CI (sensitivity, 86.7%; specificity, 80%) and low SVR (sensitivity, 91.7%; specificity, 83.3%), and to predict hyperdynamic circulation (sensitivity, 92.3%; specificity, 76.5%). The best cutoff values for tDA were 484 ms to predict high CI (sensitivity, 100%; specificity, 80%), low SVR (sensitivity, 83.3%; specificity, 75%), and hyperdynamic circulation (sensitivity 100%; specificity 70.6%), respectively.
To represent the morphologic characteristic of the diastolic reflected waveform, we obtained DAIx, which indicates the amplitude of the peak of the diastolic wave expressed as a percentage of PP and tDA, which is the timing of the peak of the diastolic reflected wave. This study showed that DAIx decreases and tDA was prolonged with increasing CI and decreasing SVR. Moreover, DAIx and tDA can accurately predict hyperdynamic circulation in liver transplant recipients. These results suggest the usefulness of diastolic arterial waveform analysis for predicting hyperdynamic circulation as a simple and minimally invasive monitoring index.
Reflection on the peripheral arterial wave is generated by structural discontinuity between forward ejected blood flow and backward flow from the periphery to the aorta. On the basis of this concept, the morphology of the diastolic reflected wave is influenced by ventricular ejection, arterial compliance, and the peripheral arteriolar tone 7,8,12. In the hyperdynamic condition with high arterial compliance and low vascular resistance, the pulse-wave velocity of blood flow along the arterial tree may be prolonged, and thus the wave reflection point appears delayed 7. Therefore, the reflected wave returns during late diastolic phase, resulting in a further decrease in the peak pressure of the reflected wave. As a result, hyperdynamic circulation induces marked changes in the diastolic reflected wave morphology represented by reduced DAIx and prolonged tDA.
Patients with advanced liver cirrhosis have low overall SVR caused by the abnormal balance of vasoactive substances, which induces splanchnic vasodilation 13,14. Moreover, arterial compliance of the cirrhotic patient is increased, which may be caused by not only changes in peripheral arterioles but also the altered function of large arteries 15–17. With progression of the decrease in SVR, the sympathetic nervous system becomes activated, resulting in an increase in the heart rate and CO. These changes may also influence the morphologic characteristics of diastolic reflected waveforms, similar to vigorous exercise, administration of a vasodilator, or a septic condition 9,10,18. Although there have only been a few studies on the analysis of arterial waveform characteristics in liver cirrhosis, Henriksen et al.19 reported that the arterial pulse is altered with a decrease in pulse reflection according to hyperdynamic circulation in advanced cirrhosis using fast Fourier analysis.
A considerable proportion of the patients with liver cirrhosis have hyperdynamic circulation as shown in this study. In these patients, serious complications, including hepatorenal syndrome, hepatopulmonary syndrome, and cirrhotic cardiomyopathy, become exacerbated with progression of hyperdynamic circulation 2,13,20. Our results also showed that recipients with hyperdynamic circulation had higher model for end-stage liver disease scores compared with those without hyperdynamic circulation. An observational study has reported that hyperdynamic circulation is correlated with hemodynamic instability, the requirement for transfusion, and vasopressor during liver transplantation, thus consequently resulting in worsening postoperative outcomes and increasing mortality 3. However, it is difficult to diagnose whether the recipient would have hyperdynamic circulation at the time of liver transplantation until we directly measure CO and SVR using pulmonary artery catheterization. Because of its invasiveness, pulmonary artery catheterization has not been used for most surgeries other than liver transplantation and cardiac surgery. As an alternative method, uncalibrated arterial waveform analysis has been introduced over the past few years to estimate CO under various conditions. Despite the improvement in software, there has been skepticism regarding the performance of this system for patients with hyperdynamic circulation such as liver cirrhosis and sepsis 4,5.
If DAIx decreases further and tDA is prolonged during surgery, it is considered that excessive vasodilation may be newly developed or pre-existing hyperdynamic circulation may be aggravated under conditions of hemorrhagic hypovolemia, postreperfusion syndrome, or acid–base imbalance. Early detection of hyperdynamic circulation facilitates adequate management in advance with a systemic vasopressor for maintenance of vascular tone, and excessive increase in CO may be improved 21. Because adequate formation of pressure in the diastolic reflected wave in the early diastolic phase has a positive effect on end-organ perfusion including the coronary artery 7, DAIx and tDA are noteworthy for providing information to determine the therapeutic option to avoid end-organ damage during liver transplantation.
In this study, PP was significantly higher in the group of patients with high CI than that in patients with normal CI, and DAP was significantly correlated with SVR. However, these variables in themselves may be insufficient to predict hyperdynamic circulation. It is speculated that PP would increase if only systolic blood pressure increases, resulting from excessive local vasoconstriction at the measuring site of the peripheral artery. PP is also influenced by DAP, which may decrease rather than increase in a patient with stiff arteries 8.
This study had several limitations as follows: first, the results may be confounded because only data from a single institution were analyzed retrospectively. However, we believe that computerized calculation of digitized arterial waveforms may be an objective method. Second, the timing and amplitude of the diastolic reflected wave may be different according to the measuring site. It has been shown that there is a discrepancy in arterial PP between femoral and radial arterial pressure under hyperdynamic conditions during liver transplantation 22,23. Therefore, the cutoff values suggested in this study may be applied to arterial waveform analysis of the radial artery. Third, we have often found that the diastolic reflected wave could hardly be observed or disappeared if SVR decreased markedly during surgery. In this instance, it is impossible to obtain and apply DAIx and tDA indices. In this case, it monitoring of the trend of gradual alterations in diastolic reflected waveforms may be required, comparing arterial waveforms during the baseline status before the main surgery. Finally, we did not consider other factors that could potentially influence CI during liver transplantation, such as portosystemic collaterals, β-blocker use, preload, and heart rate. In addition, factors affecting SVR including age, diabetes, hypertension, and immunosuppressive agents were not examined. These effects should be considered to interpret our findings.
Our study showed that we can predict hyperdynamic circulation in patients with liver cirrhosis using DAIx and tDA. These simple and minimally invasive indices may suggest that prediction of hyperdynamic circulation will aid the management of intraoperative hemodynamic derangement during liver transplantation. It should still be investigated whether analysis of the characteristics of the diastolic reflected wave can be used when direct monitoring of CO and SVR is unavailable in other patients with hyperdynamic circulation.
Conflicts of interest
There are no conflicts of interest.
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