Author’s Accepted Manuscript

Comparing Changes in Carotid Flow Time and

Stroke Volume Induced by Passive Leg Raising

Bilal Jalil, Patton Thompson, Rodrigo Cavallazzi,

Paul Marik, Jason Mann, Karim El Kersh, Juan
Guardiola, Mohamed Saad
www.elsevier.com

PII: S0002-9629(17)30519-0
DOI: http://dx.doi.org/10.1016/j.amjms.2017.09.006
Reference: AMJMS546
To appear in: The American Journal of the Medical Sciences
Received date: 20 June 2017
Revised date: 13 September 2017
Accepted date: 18 September 2017
Cite this article as: Bilal Jalil, Patton Thompson, Rodrigo Cavallazzi, Paul Marik,
Jason Mann, Karim El Kersh, Juan Guardiola and Mohamed Saad, Comparing
Changes in Carotid Flow Time and Stroke Volume Induced by Passive Leg
R a i s i n g , The American Journal of the Medical Sciences,
http://dx.doi.org/10.1016/j.amjms.2017.09.006
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Title:

Comparing Changes in Carotid Flow Time and Stroke Volume Induced by Passive Leg Raising

Authors:

Bilal Jalil, MDa

Patton Thompson, MDa

Rodrigo Cavallazzi, MDa

Paul Marik, MDb

Jason Mann, DOa

Karim El Kersh, MDa

Juan Guardiola, MDa

Mohamed Saad, MDa

Institutions:

a. Division of Pulmonary, Critical Care, and Sleep Disorders Medicine

Department of Medicine, University Of Louisville

550 S Jackson St, ACB A3R43, Louisville, KY 40202, USA

b. Division of Pulmonary and Critical Care Medicine

Eastern Virginia Medical School

825 Fairfax Ave, Suite 410, Norfolk, VA 23507, USA

1
Address correspondence to:

Bilal Jalil, MD

Division of Pulmonary, Critical Care and Sleep Disorders Medicine

550 S. Jackson Street, ACB, A3R43

Louisville, KY 40202

Phone: (502) 553-0186; Fax: (502) 852-1359

E-mail: bilaljalil@gmail.com

Conflicts of Interest:

None

Disclosures:

The preliminary results of this study with data on 14 patients were presented as a poster at

CHEST 2015 in Montreal.

Abbreviations:

CFTC: Corrected carotid flow time

CO: Cardiac output

ICU: Intensive care unit

PLR: Passive leg raise

SV: Stroke volume

TED: Transesophageal Doppler

VTI: Velocity time integral

2
Funding:

This research did not receive any specific grant from funding agencies in the public, commercial,

or not-for-profit sectors.

Key Words:

Fluid Responsiveness, Carotid Artery, Ultrasound, Flow Time

Abstract:

Background: Determining volume responsiveness in critically ill patients is challenging. We

sought to determine if passive leg raise (PLR) induced changes in pulsed wave Doppler of the

carotid artery flow time could predict fluid responsiveness in ICU patients.

Materials and methods: Medical ICU patients ≥ 18 years old with a radial arterial line and

FloTrac/Vigileo monitor in place were enrolled. Pulsed wave Doppler of the carotid artery was

performed to measure the change in carotid flow time (CFTC) in response to a PLR. Patients

were categorized as fluid responders if stroke volume increased by ≥ 15% on a Vigileo monitor.

The main outcome measure was the accuracy of CFTC to detect a change in response to a PLR.

We also calculated the percent increase in CFTC that could predict fluid responsiveness.

Results:

We enrolled 22 patients. Using an increase of ≥ 24.6% in the CFTC in response to PLR to predict

fluid responsiveness there was a sensitivity of 60%, specificity of 92%, positive likelihood ratio

3
of 7.2, negative likelihood ratio of 0.4, positive predictive value of 86%, negative predictive

value of 73%, and ROC of 0.75 (95% CI of 0.54 - 0.96).

Conclusions:

CFTC performs well compared to stroke volume measurements on a Vigileo monitor. The utility

of CFTC is highlighted in resource-limited environments and when time limits the use of other

methods. Carotid flow time should be validated in a larger study with more operators against a

variety of hemodynamic monitors.

Introduction:

Acknowledging the struggle to determine volume responsiveness, we sought to study a recently

proposed point of care ultrasound technique to predict fluid responsiveness: corrected carotid

artery flow time (CFTC). The CFTC uses pulsed wave Doppler of the carotid artery to measure

systolic flow time which is corrected for heart rate using Bazzett’s formula, similar to a corrected

QT interval on an electrocardiogram [1, 2] .

The measurements commonly performed in a large vessel such as the descending aorta or the

common carotid artery to assess flow are the peak velocity, velocity time integral (VTI), and

systolic flow time. Peak velocity was studied in a porcine model and found to be load-

independent and had a strong correlation with ventricular contractility [3]. VTI and corrected

flow time are measures of left ventricular preload. Assuming the absence of unlikely swings in

cardiac contractility, the flow time and VTI may be affected by preload and afterload. A low

preload decreases while a low afterload increases flow time and the VTI. Previously, a non-

imaging transesophageal Doppler (TED) probe has been used to measure aortic flow time and

4
VTIs to guide volume loading [4, 5]. These methods involve placing an esophageal Doppler

probe and is thus limited to sedated patients on invasive ventilation. Since a majority of cardiac

output (CO) is delivered to the carotid arteries, carotid Doppler calculations have been studied to

correlate well with preload and volume responsiveness. As carotid measurements are performed

transcutaneously, they are feasible in a larger population including spontaneously breathing

patients. CFTC is the systolic flow time in the carotid artery corrected to a heart rate of 60 using

Bazzett’s formula, as described by multiple prior studies [1, 6, 7]. This correction is necessary as

the length of each cardiac cycle is inversely proportional to heart rate. This correction

standardizes measurements allowing comparison between measurements in time, before and

after fluid loading maneuvers. Carotid measurements are easier to perform due to the ease of

access to the carotid artery, reproducibility, and lower cost. Since the corrected flow time (FTC)

is a measurement of time and not velocity (as in the case of VTIs or peak velocity), the angle of

insonation has negligible effects on results. We aimed to study the change in CFTC induced by a

passive leg raise (PLR) to predict fluid responsiveness in critically ill patients.

5
Methods:

We performed a prospective, cohort study and included all patients admitted to the medical ICU

at the University of Louisville and Jewish Hospitals between July 2014 and June 2015. The study

was approved by the University Institutional Review Board, and informed consent was obtained

from the patients enrolled, or their proxies. The study was performed in accordance with The

Code of Ethics of the World Medical Association (Declaration of Helsinki) for experiments

involving human subjects (http://www.wma.net/en/30publications/10policies/b3/index.html).

Patient Population:

Inclusion criteria for enrollment in the study were age ≥ 18, the presence of a radial or brachial

arterial line and FloTrac sensor, and the need for an intravenous fluid bolus as determined by the

treating physician. Exclusion criteria were: lack of sinus rhythm, clinically suspected or known

intra-abdominal hypertension, lower extremity amputee, femoral arterial line, poor or unreliable

arterial line waveform, history of carotid endarterectomy in the artery being measured, and

pregnancy. Patients were identified by asking the ICU fellow or attending physician on a daily

basis if there were any patients on their service that met the inclusion and exclusion criteria.

Once eligibility criteria were established, informed consent was obtained from the patient or their

proxy.

Measurements:

Enrolled patients were initially started in the 45 degree semi-recumbent position. After a brief

period of stabilization, stroke volume (SV) was recorded using a FloTrac sensor in conjunction

with the Vigileo platform (software version 3.02/3.06) (Edwards Lifesciences, Irvine, CA). A

baseline carotid flow time was recorded in the following manner: On venous settings, the linear

6
high-frequency probe of the Sonosite M-turbo (FujiFilm Sonosite Inc, Bothell, WA) was placed

on the neck. The common carotid artery (we chose the opposite side of the neck when there were

central venous catheters on one side) was identified in the short-axis. The probe was then rotated

90 degrees with the probe marker oriented towards the patient’s head to obtain a long axis view.

Pulsed wave Doppler was then performed in the center of the vessel with settings of angle

correction +60 degrees, gate size 1 mm, and steering angle +15 degrees. The uncorrected flow

time was measured in a representative beat by measuring the time from the beginning of systole

to the dichroitic notch and recorded in milliseconds. The cycle time was measured from the

beginning of the current beat to the beginning of the adjacent beat and recorded in seconds as

shown in figure 1. Flow time was then corrected for heart rate using the following formula:

CFTC =
√

At this point, an assistant laid the patient flat and raised both legs 45 degrees. Measurement of

the CFTC was performed as previously described at 1, 2, and 3 minutes and the maximal value

was recorded.

Although the FloTrac derived SV updated measurements every 20 seconds, measurements were

only recorded at intervals coinciding with CFTC measurements. The largest change in FloTrac

derived SV in the 3 minute period was compared to its corresponding CFTC measurement. After

completion of the maneuver, the patient was returned to the 45-degree semi-recumbent position.

All CFTC measurements were performed by a single operator, a pulmonary and critical care

medicine fellow, whose prior ultrasound experience included completing the American College

of Chest Physicians critical care ultrasound certificate program. The study was not designed to

blind the operator to FloTrac measurements, however, since the operator was involved in
7
performing 3 CFTC measurements at 1-minute intervals, he was only aware of FloTrac

measurements after he had recorded CFTC measurements.

Statistical Analysis:

We present continuous variables as median and interquartile range, and categorical variables as

proportion with corresponding 95% confidence interval. We provide the accuracy of the percent

change in CFTC to predict fluid responsiveness using as a reference the percent change in SV as

determined by FloTrac. The percentage change was obtained as the difference between the

maximal value and the baseline value, divided by the baseline value. An increase in SV of 15%

or more classified the patient as volume responsive. We used standard formulas for the

calculation of sensitivity, specificity, positive predictive value, and negative predictive value. We

built an area under the receiver operating characteristic curve (ROC) to evaluate the

discriminative property of CFTC. We chose the CFTC cutoff that maximizes the accuracy of the

test while also generating a high specificity. We calculated that with an estimated sensitivity of

90%, a sample size of 34 patients should give us a 90% confidence interval of approximately

30%. Statistical analysis was performed with the statistical software Stata 10 (StataCorp, College

Station, Texas).

8
Results:

The patients were enrolled from a general population of medical ICU patients at the University

of Louisville and Jewish Hospital. We included 22 patients in the analysis as detailed by the

CONSORT flowchart in figure 2. The characteristics of patients are reviewed in table 1. The

median age was 56 years with 10 males (45%), the average APACHE II score was 19, and SAPS

II was 46. The majority of patients, 18 (82%), were mechanically ventilated; 3 (14%) were

passively breathing on the ventilator. Fourteen (64%) were in shock receiving vasopressors; of

these 12 (86%) were in shock from sepsis or distributive shock, while the remainder of those

patients had cardiogenic shock. Ten (45%) patients were fluid responsive by FloTrac.

Diagnostic Accuracy:

Using a cut-off value of a 24.68% increase in CFTC with passive leg raising the maneuver was

able to predict fluid responsiveness with a sensitivity of 60%, specificity of 92%, positive

likelihood ratio of 7.2, negative likelihood ratio of 0.4, positive predictive value of 86%, negative

predictive value of 73%, and ROC of 0.75 (95% CI of 0.54 -0.96). The ROC curve is shown in

figure 3. Using this cutoff value, 77% of patients were classified correctly as fluid responders or

non-responders. Figure 4 shows the percent increase in CFTC in fluid responders and non-

responders. The cutoff values with their corresponding performance characteristics are shown in

table 2.

9
Discussion:

Predicting fluid responsiveness in the ICU is a challenging task. Clearly, early recognition and

aggressive resuscitation in patients with severe sepsis and septic shock improves outcomes [8].

Conversely, over resuscitation is associated with increased mortality in patients with septic shock

and acute lung injury [9, 10]. Furthermore, recent studies have challenged conventional thought

that clinical exam, central venous pressure or pulmonary artery occlusion pressure are able to

predict volume status or fluid responsiveness [11-15].

Only approximately 50% of ICU patients have been shown to respond to volume expansion in

studies examining fluid responsiveness [16]. Ideally, intensivists would have access to a cheap,

reliable, continuously operating, non-invasive, and user friendly device such that fluid could be

administered until their patient is no longer fluid responsive. Stroke volume can be maximized

via the Frank-Starling relationship and over resuscitation with its potential deleterious effects

could be avoided. Although measurement of thermodilution CO by the pulmonary artery catheter

is considered the “gold standard” by which new devices are validated, it has a limited role in

modern ICUs [17]. Existing technologies such as esophageal Doppler, transpulmonary indicator

dilution, and arterial catheter based methods, while not as invasive as a pulmonary artery

catheter, are still invasive procedures.

In this small pilot study, CFTC performed with fair accuracy (AUROC 0.75) compared to

FloTrac/Vigileo. A PLR induced increase in the CFTC of 24.6% was observed to be a reasonable

predictor of fluid responsiveness in critically-ill medical patients with a sensitivity of 60% and

specificity of 92%. Although a cutoff of 14.8% conferred a better sensitivity (80%), a cutoff at

10
25% maximizes specificity and reaches a higher positive predictive value and positive likelihood

ratio.

Although CFTC performs better than static measurements of volume responsiveness such as CVP

and PAOP [17, 18], more accurate methods such as pulse pressure variation, stroke volume

variation, and non-invasive cardiac measurements via bioreactance are available, which require

minimal training [18-20]. That said, there are some key advantages of utilizing CFTC to

determine volume responsiveness. Most other methods used to determine volume responsiveness

utilize specialized equipment or require the placement of monitoring catheters. The most critical

time for patients in shock is the early phase when placement of arterial catheters may not be

feasible or specialized equipment may not be available, causing delays in appropriate treatment.

Other measurements that involve bedside ultrasonography include inferior vena cava (IVC)

collapsibility index and VTI of the left-ventricular outflow tract. Both methods are subject to

erroneous measurements related to the angle of insonation, a problem that is not encountered in

measuring CFTC, though a similar duration of training would be required to perform the other

measurements. Poor acoustic windows that are related to sonographic penetration through air in

the lungs or bowels is not encountered when performing carotid measurements. From a personal

experience, CFTC measurements are performed quicker than the IVC or a VTI of the left

ventricular outflow tract. CFTC would be indispensable in resource limited environments or in

clinical situations where time is of the essence and other options are not available. Because

carotid measurements are easy to perform, measurements can be repeated to allow clinicians to

ensure adequate responses to volume loading maneuvers.

Measurements to determine CFTC in this study were performed using a Sonosite M-Turbo

machine, using a high frequency vascular probe that is commonly used for guided vascular

11
access in most ICUs. This forgoes the need for invasive monitoring catheters or specialized

equipment, and guided volume resuscitation can be commenced in the early period of shock.

Additionally, a single operator who had undergone formal training in ultrasound and brief

training in measuring CFTC performed measurements in this study. The operator was not an

expert sonographer, which highlights the potential for use of this modality by non-experts with

brief training in performing CFTC measurements.

The use of carotid Doppler to determine volume responsiveness has recently gained popularity.

In a study by Marik et al [19], an increase in carotid VTI by 20% predicted fluid responsiveness

with a sensitivity of 94% and specificity of 86%. The VTI, a measure of blood flow, is different

from CFTC which is a measure of time. VTI measures stroke distance, and when the cross-

sectional area of the carotid artery is multiplied by the VTI, it can estimate the volume of blood

flowing through the vessel per cardiac cycle, essentially the SV received by the carotid artery.

Theoretically, this method is prone to a variation in readings as it depends on the angle of

insonation of the ultrasound probe.

Another method of evaluating the carotid artery for fluid responsiveness, the CFTC, has shown to

increase in clinically dehydrated patients after fluid administration, as well as decrease after

blood donation with normal values being restored after a PLR [1, 21]. Both carotid artery VTI

and CFTC may be useful parameters to use in conjunction with other end-points.

The concept of flow time is not new. As mentioned earlier, it has been studied as a marker of

preload and afterload using a non-imaging TED probe [5]. TED monitors display a wave form of

the velocity versus time similar to the image one might obtain doing pulsed wave Doppler of the

carotid artery. A study performed in 20 neurosurgical patients with TED showed that aortic flow

12
time was able to predict fluid responsiveness when used as a static measure with a cutoff of 357

ms prior to loading with 7 ml/kg of colloid infusion with an AUROC of 0.944 [4].

This is the first study to our knowledge to attempt to validate a PLR-induced increase in the

CFTC to predict fluid responsiveness in critically-ill patients with a CO monitor

(Vigileo/FloTrac). Another small study found that in clinically dehydrated patients presenting to

the emergency department the CFTC increased by 14.9% after an average of 1,110 ml of

intravenous fluid [22]. These patients would be assumed to be fluid responsive, however, a CO

monitor was not used to validate this assumption as the goal was to ascertain its feasibility in the

emergency department. The average CFTC prior to IVF was 299 ms and increased to 340 ms

after fluid loading. In another study, healthy blood donors had an average CFTC of 320 ms prior

to blood donation, and 296 ms after donating a mean of 450 cc of whole blood. This corrected

back to pre-donation values with a PLR [21]. In our study, fluid responders had an average CFTC

of 331 ms prior to PLR, and average maximum CFTC of 393 ms after 3 minutes of PLR. The

higher starting value in our study could reflect the fact that the vast majority of the patients in

this study were enrolled after they had already been in the ICU for several hours if not a full 24

hours. In other words, we were likely measuring CFTC in patients who were already partially

fluid resuscitated.

Our study has several limitations. We did not reach our target of 34 patients due to slow

enrollment, which resulted in wide confidence intervals. The measurements of CFTC were

performed by a single operator in a medical ICU population of patients. Our patients were

classified as fluid responders or non-responders based on a 15% increase in SV on the Vigileo

monitor in response to a PLR; therefore, our study is inherently dependent on the accuracy of the

Vigileo monitor to make this distinction. The dose of vasopressors was not taken into account,

13
which at higher doses, would increase the afterload and hence decrease the CTFc, blunting the

associated change induced by a PLR maneuver. The Vigileo monitor cycled reading every 20

seconds however, the carotid measurements were only performed at one minute intervals for 3

minutes. Since the time taken to record the 3 carotid measurements was just under a minute, it

was not feasible to record carotid measurements more frequently. We acknowledge that a higher

reading on the Vigileo may have been recorded at a time other than the one-minute intervals at

which Vigileo and CTFc measurements were recorded. We note that even though CFTC

measurements may be repeated, continuous measurements are not possible using this method

rendering it inferior to other methods such as PPV, bioreactance, and pulse contour analysis via

Vigileo, EV1000, and PiCCO platforms. Another limitation of this study is that PLR was

performed by manually lifting legs to 45 degrees. The preferred method of performing the PLR

maneuver is to use automated motorized beds that have the capability to raise the foot-end of the

bed. The foot-ends of our ICU beds were not motorized and hence a manual maneuver was

performed. Manually raising legs may alter sympathetic tone which may lead to erroneous

readings. While this may not affect the correlation between CFTC and SV by Vigileo, it may

have an effect on the percentage of patients who were volume responsive.

While the absolute values of CO obtained with the Vigileo when compared with the pulmonary

artery catheter are debatable, the ability of the device to track changes in CO/SV in response to

changes in preload and PLR have been shown to be accurate [23-26]. In addition, Hofer et al

[27] evaluated SV variation for fluid responsiveness by comparing FloTrac/Vigileo and the

PICCO Plus system (Pulsion Medical Systems, Munich, Germany) and found clinically

acceptable agreement between the systems [27]. A meta-analysis published by Cavallaro [28]

showed that PLR induced changes in CO were able to predict fluid responsiveness with a

14
sensitivity and specificity of 89.4% and 91.4% with a pooled area under the ROC value of 0.95

regardless of ventilation mode, underlying cardiac rhythm, and technique of measurement [28].

Thus, an increase in SV  15% with PLR detected by a Vigileo monitor (without the need for a

fluid bolus) should have been sufficient to determine whether PLR induced changes in CFTC

were able to detect fluid responsiveness.

Corrected carotid flow time is a useful method of evaluating volume responsiveness and

performs with fair accuracy compared to FloTrac/Vigileo. An increase in CFTC of 24.6% may be

a practical adjunctive end-point to predict fluid responsiveness when used with other indicators

in medical ICU patients. Resource-limited environments and situations where time is of the

essence are instances where CFTC may play a vital role. The results of this study should be

replicated on a larger scale and inter-user reliability needs to be validated.

15
Figure 1: Method used to obtain corrected carotid flow time (CFTC). The calculated CFTC was

310ms in figure 1a. After a 3 minute passive leg raise, the CFTC increased to a maximum of

469ms in figure 1b, a 51.3% increase. In both figures, time A is the uncorrected carotid flow

time and time B is the cycle time.

Figure 2: A flowchart showing the enrollment process via a CONSORT diagram.

Figure 3: Receiver operating characteristic (ROC) curve of corrected carotid artery flow time to

predict fluid responsiveness.

Figure 4: Percent increase in corrected carotid artery flow time in fluid responders and non-

responders.

16
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13. Marik PE, Cavallazzi R. Does the central venous pressure predict fluid responsiveness?
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18. Angappan S, Parida S, Vasudevan A, et al. The comparison of stroke volume variation
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18
Table 1: Patient Characteristics

Age in years, median (IQR) 56 (46-68)

Female, n (%) 12 (55%)

Apache II, median (IQR) 17 (15-24)

SAPS II, median (IQR) 45 (36-54)

Mechanically Ventilated, n (%) 18 (82%)

Receiving IV Pressors, n (%) 14 (63.6%)

Reason for Shock, n (%)

Distributive 12 (86%)

Cardiogenic 2 (14%)

Fluid Responsive, n(%) 10 (45%)

Time to Max CFTC with PLR 40.9% by 1 min, 81.8% by 2 min

IQR: interquartile range; CFTC: corrected carotid artery flow time; PLR: passive leg raise

19
Table 2: Accuracy of different % increase thresholds in corrected carotid artery flow time to

predict fluid responsiveness

Cutoff TP FN FP TN Sens. Spec. PPV NPV +LR -LR

≥ 9.8% 9 1 9 3 90% 25% 50% 75% 1.2 0.4

≥ 14.8% 8 2 5 7 80% 58% 61% 78% 1.9 0.3

≥ 24.6% 6 4 1 11 60% 92% 86% 73% 7.2 0.4

TP: true positive; FN: False negative; FP: false positive; TN: true negative; Sens: sensitivity;

Spec.: specificity; PPV: positive predictive value; NPV: negative predictive value; +LR: positive

likelihood ratio; -LR: negative likelihood ratio

20
Figure 2. A flowchart showing the enrollment process via a CONSORT diagram

72 patients assessed for eligibility

50 patients excluded for one of

the following reasons:
 Declined to participate.
 Proxies were not available
for consent.
 Excluded due to
incarceration per IRB
regulations.

22 patients included in analysis

21
22
23