The Relationship between Carotid Arterial Flow and the Left Ventricular Area is valid to indicate contractility in states of cerebral autoregulation and decreased arterial pressure
J Broscheit, F Weidemann, B Grein, M Lange, R Muellenbach, F Schuster, A Koca, C Lintner, E Kunze, J Brederlau, N Roewer, P Steendijk, C Greim
cerebral, contractility, esmolol, lp-ratio, po, sodium nitroprusside
J Broscheit, F Weidemann, B Grein, M Lange, R Muellenbach, F Schuster, A Koca, C Lintner, E Kunze, J Brederlau, N Roewer, P Steendijk, C Greim. The Relationship between Carotid Arterial Flow and the Left Ventricular Area is valid to indicate contractility in states of cerebral autoregulation and decreased arterial pressure. The Internet Journal of Anesthesiology. 2007 Volume 18 Number 2.
In this study, we estimated the range of the ultrasound based index E'es in estimating left ventricular (LV) contractility by measuring E'es in cases of arterial hypotension. 1,2 The arterial hypotension indicates a decrease in LV afterload which severely alters contractility measurements except the standard index Ees. In organ tissues arterial hypotension may lead to shock, a potentially life-threatening condition leading to hypoxia of the tissues and consecutively to cell damage 3 . A variety of mechanisms are automatically activated to avoid this fatal outcome. The cerebral autoregulation is an important and well described response of the cerebral arterioles to vary the intraluminary diameter by activating smooth muscles to keep flow constant in cases of pressure variations. A gold standard for the assessment of cerebral autoregulation is not available and the literature shows a considerable disparity of methods and criteria. (This is understandable since cerebral autoregulation is rather just a concept than a physically measurable entity.)
The most common approach to assess cerebral autoregulation tests the effects of changes in mean arterial blood pressure (MAP) on cerebral blood flow in the middle cerebral arteries. The arteries are located close to the internal carotid artery, and the tested effect is known as pressure autoregulation (Gao). The pressure autoregulation only occurs between certain pressure limits – if the pressure drop is to low autoregulation fails, and perfusion of the tissue is comprised. Practically the lower limit is defined as the point where, as the perfusion pressure drops, the flow drops by a predefined value, commonly at 15% and reliable occurring at values below 45 mmHg. It was previously thought that this flow in the cerebral arteries will be constant throughout the “autoregulatory range”, and than drop off at a precise lower threshold. More recent and general work suggests that it is simplistic, and that autoregulation follows interindividual varying curves that near the lower limits of autoregulation (Gao). If the lower limit once is exceeded the organ perfusion is comprised consecutively leading to cell damage and organ dysfunction. Thus an adequate monitoring of sufficient tissue perfusion is essential for testing the hypothesis. The testing of pressure autoregulation requires acute blood pressure-lowering which is broadly performed intravenously by the potent peripheral vasodilator sodium nitroprusside (SNP) (Circulation 2004, Immink, van den Born, van Montfrans, Koopmans, Karemaker, van Lieshout).
The hypothesis of the present investigation is that the index E´es, estimating contractility by the relationship of blood flow velocity in the internal carotid artery and area of the left ventricular cavity is not comprised by cerebral autoregulation and furthermore by decreased arterial pressure indicating an increase in afterload. We therefore decreased MAP down to 50mmHg by the use of SNP. Since in the operating room it is common to lower MAP down to hypotensive values, e.g. during microscopic surgery to decrease bleeding by applying beta-blocking agents, we also expanded our protocol by lowering MAP with the cardioselective beta-blocker esmolol.
Materials and Methods
In one case we could not analyse the metabolites because of a defect microcatheter. Nine Merino sheep (mean age 2 ± 0.2 y; mean weight 63 ± 4 kg) were used for this study. The study protocol was approved by the Committee for Laboratory Animal Care at our university; the protocol also conforms to the guiding principles of the American Heart Association on research animal use 4 .
Anesthesia was performed according to our previously published protocol 2 , except that intramuscular premedication was performed with 1.5–2.0 mg/kg xylazine hydrochloride (Rompun; Bayer AG, Leverkusen, Germany). Arterial oxygen saturation was monitored by continuous-pulse oximetry at the shaved ear of the sheep, and arterial blood gases were controlled periodically (995-AVL; Medizintechnik GmbH, Bad Homburg, Germany).
Figure 1 illustrates the placement of the probe, lines, and catheters, and explains which catheters were used to monitor which parameters. Under X-ray guidance a conductance catheter (Zoetermeer, The Netherlands) was placed into the LV cavity, via the left femoral artery, along the long axis to permit continuous measurement of intraventricular pressure and volume. A polyethylene catheter was advanced 15 cm into the descending aorta from the right femoral artery, and another was advanced into the inferior vena cava from the femoral vein. A thermodilution catheter was advanced into the pulmonary artery via the left internal jugular vein to the superior vena cava to measure stroke volume. A Fogarty catheter was advanced into the inferior vena cava from the right femoral vein to achieve temporary rapid preload reduction by inflating the terminal balloon. Via a left-sided thoracotomy, a 5-MHz echoprobe (T6210, Hewlett Packard, Andover, MA) was sutured onto the myocardial wall to acquire the cross-sectional view of the left ventricle. A U-shaped Doppler flow probe was placed around the exposed right carotid artery. A pacemaker was not applied to maintain a constant heart rate during the sequential periods.
After craniotomy, a laser Doppler flowmeter 5 was fixed in the brain cortex to measure relative flux transdurally in the right frontal area. A ti-pO2 catheter (Licox Systems, GMS Kiel-Mielkendorf, Germany) and a microdialysis-catheter (CMA 70 Microdialysis Brain Catheter, Solna, Sweden ) were inserted subcortically in the right frontal area. The ti-pO2 and microdialysis catheters were fixed at 10 mm subdurally in the white matter of the frontal region. Care was taken to ensure that the distance between both catheters was at least 1 cm. After the surgical procedure of approximately 1.5–2 h, the animals were observed for 60 min to document hemodynamic stability.
To determine Ees, we continuously calculated LV volume from the specific conductivity of the blood 6,7 , as well as the offset of the conductivity and fluids surrounding the LV cavity 8 . The contribution of parallel conductance to the total conductance signal was derived from a measurement of the conductance signal during passage of the bolus through the LV. For absolute volume measurements, we determined the slope factor α, which was introduced to account for the finding that the relationship between “true” volume and conductance did not fall on the line of identity, even after correcting for parallel conductance 7 . This may result from the fact that equipotential planes are not exactly parallel in the cavity, indicating a nonhomogeneous current distribution. In addition, it may partly result from a mismatch between the electrode distances and the ventricular long axis 9 . There is no simple way to determine α; its value can be estimated by comparing conductance-derived volume with an independent measure, such as changes in cardiac output (CO) following thermodilution 10 .
Global contractility of the LV was determined by applying the time-varying elastance model 11 . Time-varying elastance was carried out during rapid preload reduction by occlusion of the inferior vena cava every 7 ms of the cardiac cycle, beginning with the end-diastolic point and continuing past the end-systolic point. Maximal elastance was the elastance connecting the zero point on the coordinate cross with the end-systolic point. Linear regression analysis of the end-systolic values during occlusion of the inferior vena cava by rapid preload reduction was used to obtain the slope of LV Ees. The amount of the decrease in LV end-systolic pressure-volume relationship (LVESPV) as a response to the rapid preload reduction depends on the myocardial contractility as expressed by the index Ees. The equation for calculating Ees is:
A gently inclined linear curve implies a substantial decrease in LV volume and a concomitant smooth decrease in LV pressure, which characterizes compromised contractility.
At each time point, a segmental signal was defined as dyssynchronous if its change (i.e., dVseg/dt) was opposite to the simultaneous change in the total LV volume (dVLV/dt). Segmental dyssynchrony is quantified by calculating the percentage of time within the cardiac cycle when a segment is dyssynchronous. Overall LV dyssynchrony (DYS) was calculated as the mean of the segmental dyssynchronies 12 . DYS can be calculated within each specified time interval: we determined DYS during systole (DYSS) and diastole (DYSD), with systole defined as the period between the moments of dP/dtmax and dP/dtmin.
Nonuniform contraction and filling is associated with ineffective shifting of blood volume within the LV. This internal flow (IF) is quantified by calculating the sum of the absolute volume changes of all segments and subtracting the absolute total volume change: IF(t) = [|dVseg,i(t)/dt | – | dVLV(t)/dt|]/2. Note that dVLV(t)/dt represents the effective flow into or out of the LV. Thus, IF measures the segment-to-segment blood volume shifts, which do not result in effective filling or ejection. Division by two takes into account that any noneffective segmental volume change is balanced by an equal and opposite volume change in the remaining segments. Systolic IF fraction (IFFS) is calculated by integrating IF(t) over the full cardiac cycle and dividing by the integrated absolute effective flow (28).
Blood-Flow Velocity/LV Area Relationship
Continuous ultrasound-mediated estimation of LV volume for determining E'es was performed using an automated detection technique as previously described 1,2 . To obtain the time-varying elastance E'es from the blood-flow velocity-area loops, we used two-dimensional echocardiograms of the LV cavity in short-axis view recorded simultaneously with measurements of blood-flow velocity in the carotid artery, as previously performed 1 . We plotted arterial blood-flow velocity against the corresponding area. The end of systole was defined as the time at which the elastance reached a maximal value, termed E'max, for every loading beat synchronized in time 11 . These points on the end-systolic blood-flow velocity area loops were obtained during rapid LV preload reduction induced by inferior caval vein occlusion. The slope of the regression curve calculated from the end-systolic blood-flow velocity area points was defined as elastance E'es 13 . Analogous to Ees, the decrease in LV end-systolic flow-area relationship (LVESFA) as a response to the rapid preload reduction equals the myocardial contractility as expressed by the index E'es. The equation for calculating E'es is:
Compromised contractility is characterized by a gently inclined slope, which implies a substantial decrease in LV area and a concomitant smooth decrease in LV blood flow velocity.
We monitored cerebral microcirculation by laser Doppler flowmetry, an established technique for real-time measurement of microvascular red blood cell perfusion in tissue 5 . Perfusion is also referred to as microvascular blood flow or red blood cell flux and is proportional to the product of the average speed of the blood cells and their number concentration (often referred to as blood volume). This value is expressed in arbitrary “perfusion units” and is calculated using the first moment of the power spectral density. Although such measurements are proportional to perfusion, the factor of proportionality varies for different tissues. A calibration of the Doppler-flow measurement using the conductance catheter is not yet available. Therefore, we calculated the relative flux by dividing the flux obtained during the interventions by their corresponding baseline values. The laser Doppler imager recorded cerebral perfusion in the temporal domain and presented the data throughout the experiment. The relative flux served as a record of the cerebral microcirculation, whereas the blood-flow velocity of the carotid artery established the blood-flow velocity-area relationship to calculate E'es.
Cerebral autoregulation is locally heterogeneous due to the anatomical variation of the brain cortex 14,15 . This heterogeneity necessitated a sequential procedure that excluded alternative methods of perfusion measurement, such as the tracer microsphere technique. This technique delivers absolute measures but only allows documentation of the status quo without disturbing microcirculation. Consequently, we excluded relative flux from the multiple testing procedures because all other parameters were absolute values.
Cerebral microdialysis was used to record whether the lower border of cerebral autoregulation was passed. Changes in p(ti)O2 provide the earliest sign of hypoxia/ischemia 16 ; the microdialysis assays of metabolism provide additional information about the consequences of reduced tissue p(ti)O2 17 . Hypoxia occurs below the p(ti)O2 threshold of 15–10 mmHg 17,18 . Baseline levels of the lactate-to-pyruvate ratio (L/P) can vary between 15–22; an increase above 30 indicates cerebral cell damage, as supported by the decrease in p(ti)O2 19 .
We carefully inserted a microdialysis probe (CMA 70 brain microdialysis catheter; 1-cm membrane tip, 0.62-mm diameter; CMA Microdialysis) into the brain tissue next to a p(ti)O2 probe. Perfusion (CMA107 Microdialysis Pump) of the catheter with sterile modified Ringer's solution was started before implantation. The flow rate was 2 µL/min and fractions were collected every 15 min. Online analysis of samples was performed using the CMA 600 microdialysis analyzer (CMA Microdialysis). Lactate, pyruvate, and p(ti)O2 concentrations were determined using extracellular fluid probes.
To observe the autoregulation pattern, height, and area, we positioned the probe far from large vessels in a relatively avascular region of the cortex; however, the sensitive region measured by the laser Doppler flow probe approaches the 1- to 2-mm spacing in oxygen heterogeneity observed in the normal cat cortex 20 . This distance approached the 300-700 µm spacing between two of Bär's medium vascular nodules 21 , and recent work by Lübbers
We determined all hemodynamic parameters during apnea prior to rapid preload reduction by occlusion on the inferior vena cava.
Esmolol and SNP Administration
Esmolol was used to acutely reduce MAP to 50 mmHg (when compared with the corresponding baseline levels) by impairing myocardial contractility. To exclude influences of cardiac load on E'es, we sequentially induced a similar hypotension in the same animal using the arterial vasodilator SNP. The two hemodynamic stages were induced in random sequence for each sheep; either SNP (4 µg/kg/min) or esmolol (2–5 mg/kg) was infused and held constant for 15 min. Baseline measurements were taken prior to each stage (baselines 1 and 2). SNP decomposes into pharmacologically inactive metabolites within a few minutes of infusion 24 . Esmolol is an ultra short-acting cardioselective beta-antagonist with an extremely short elimination half-life (mean, 9 min; range, 4–16 min) that has a total body clearance [285 ml/min/kg (17.1 L/h/kg)] approaching three times CO and 14 times hepatic blood flow 25 . We waited 60 min after the end of each intervention before initiating the next intervention.
Data are expressed as mean ± standard deviation (SD). Direct comparisons were made using either the Student's
The relative changes (ς) of elastance in both systems (ςEes and ςE'es) that followed each intervention were calculated by the formulae:
Positive and negative values of ςEes indicated an increase or decrease in LV contractility, respectively. The agreement between ςEes and ςE'es was tested according to Bland and Altman 26 : differences and arithmetic means were plotted and the SD of the differences was calculated.
All hemodynamic parameters are shown in Table 1. MAP decreased significantly from the baseline following both SNP (50 ± 11 mmHg) and esmolol (48 ± 6 mmHg) infusions, reaching intended levels. There was no significant difference between the baseline values. Esmolol infusion caused heart rate to decrease significantly (73 ± 14 min -1 ) as compared with baseline (90 ± 21 min -1 ) and SNP (94 ± 23 min -1 ) values. CO decreased significantly as a result of esmolol infusion, as compared with the baseline (2.4 ± 1.0 ml·min -1 ) and following SNP infusion (3.2 ± 2.0 ml·min -1 ).
Abbreviations: CO, cardiac output; DYSsys, LV dyssynchrony during systole; Ees, end-systolic elastance; E´e,s end-systolic elastance of the flow velocity-area relationship; EF, ejection fraction; HR, heart rate; IFFsys, LV internal flow fraction during systole; L/P-ratio, ratio of lactate and pyruvate values; LVEDV, LV end-diastolic volume; LVEDP, end-diastolic pressure; LVESV, end-systolic volume; LVESP, end-systolic pressure; MAP, mean arterial pressure; p(ti)O2, partial oxygen pressure in the tissue; SNP, sodium nitroprusside; SW, stroke work;
The blood-flow velocity-area relationship in a single animal during the sequential pharmacological interventions is displayed in Figure 2. The Ees of each relationship indicated a significant decrease in LV contractility attributable to esmolol (1.0 ± 0.2 mmHg·cm -3 ) as compared with baseline (3.0 ± 0.9 mmHg·cm -3 ) and SNP (3.0 ± 0.7 mmHg·cm -3 ) values. The E'es decreased following esmolol infusion (0.36 ± 0.21 sec -1 ·cm -1 ) as compared with baseline values (0.88 ± 0.26 sec -1 ·cm - ) and the value following SNP infusion (0.76 ± 0.27 sec -1 ·cm -1 ).
Figure 2. Loops of the flow-area and pressure-volume relationship during sequential periods. Pressure-volume and velocity–LV area data from one animal at baseline, during sodium nitroprusside SNP administration, and during esmolol administration. End-systolic points and corresponding slopes are shown, demonstrating increased and decreased end-systolic elastance.
The parameter flux acquired by laser Doppler flowmetry is shown in Table 1. The decrease of Flux following SNP infusion was within the range of 15% deviation from baseline and therefore within the limits of autoregulation. The decrease following esmolol was significantly stronger than the decrease following SNP infusion averaging at 37% deviation from baseline values and therefore ranging below cerebral autoregulation.
p(ti)O2 = 69.3 LP -0.5 (1)
Precision of E' in Indicating Contractility
Analysis of the changes in Ees and E'es are presented in Table 1. Sharing common units, we forwarded
The effects of altered LV contractility on E'es and Ees of the left ventricle are shown in Table 1, and are expressed by the relative contractility changes and . The analysis of the SNP and baseline values to estimate the changes in contractility revealed a systematic bias (mean ± SE) of 0.029 (2.9%) ± 0.064 (6.4%) in estimating Ees by E'es. The 95% confidence interval was ± 1.96 SE, which equals 13%. The response to SNP infusion resulted in good agreement between Ees and E'es, as indicated by regression analysis, and Bland-Altman analysis demonstrated an acceptable agreement between Ees and E'es in indicating contractility changes (Figure 4A).
The bias plot of the esmolol values of the parameters
Figure 4. Plot of the difference against the mean for relative contractility change (
(A) Values for SNP vs. baseline before SNP, SNP vs. baseline before esmolol, and baseline before esmolol vs. baseline before SNP.
(B) Values for esmolol vs. baseline before esmolol and esmolol vs. baseline before SNP.
The present study was performed to test whether a new, ultrasound-based index E'es can validly quantify LV myocardial contractility in cases of significant arterial hypotension. The acquired data suggests that the index E'es will not be influenced by the autoregulated perfusion flow of the brain. (Autoregulation of the cerebral arteries implies that varying pressure perfusing those arteries is followed by only little changes of the flow through the brain.) The proof of the hypothesis was evident because E'es is composed of the blood-flow velocity in the internal carotid artery close to the middle cerebral arteries where autoregulated blood flow is reliably detected by established clinical tests.
Arterial hypotension indicates a significant reduction in LV afterload. Most of the tests indicating myocardial contractility are highly dependent on the ventricular load and show substantial variations under varying load. We could demonstrate that the index E´es generates valid data during arterial hypotension until cardiac function is maintained.
The present study also demonstrated that LV dyssynchronic contraction appears to be the major cause of decreased accuracy in the ability of E'es to quantify contractility. Recently, we showed that a dyssysnchronic LV contraction caused by regional ischemia reduces the efficiency of the LV to transpose contractility into an outward flow–directed contraction resulting in an increase of internal flow and in a limited capacity of E´es to quantify contractility (article in press).
For clinical purpose our data underline the necessity to differentiate between impaired contractility and significant volume shift in cases of arterial hypotension. Both states may have a notably different impact on the clinical course. The arterial hypotension due to a volume shift induced no perfusion disturbances. Whereas the same impact on arterial pressure following a decrease in contractility caused reasonable cell damage and cardiac dysfunction. Either way we would emphasize cardiac imaging if the reason of remarkable arterial hypotension tends to be unclear. It should not be unmentioned that impaired contractility and volumeshift require disparate therapeutic consequences.
At this point we want to stress that the analysis of tissue oxygenation in dependence to the acquired hemodynamic data is beyond the scope of tested hypothesis.
In summary, cerebral autoregulation and significant arterial hypotension will not alter E'es measurements up until the occurrence of myocardial ischemia. Therefore, E'es is a valid indicator of myocardial contractility