Carotid Flow Time Compared with Invasive Monitoring as a Predictor of Volume Responsiveness in ICU patients

Abstract Objectives: Identifying patients who will have an increase in their cardiac output from volume administration is difficult to identify. We propose the use of carotid flow time, which is a non-invasive means to determine if a patient is volume responsive. Methods: Patients admitted to a critical care unit with a pulmonary artery catheter in place were enrolled. We perform a carotid flow time and pulmonary artery catheter measurement of cardiac output pre and post-passive leg raise and comparing the two. An increase of 10% change in the pre- vs. post-passive leg raise measurement would be indicative of a patient who is volume responsive. Results: We identified 8 patients who were volume responsive as determined by the gold standard pulmonary artery catheter. The sensitivity 87.5% and specificity 90.9%. Pearson correlation coefficient between PA-CO measurements and CFT was r=0.8316, indicative of strong correlation between the two measurements. Conclusion: In our patient sample of critically ill patients with pulmonary artery catheters, we found a strong correlation between corrected carotid flow times and cardiac output measurements from pulmonary artery catheters.

Patients were excluded if they had any cardiac dysrhythmia, known severe valvular lesions and if they were deemed too hemodynamically unstable to participate by intensive care staff.
Two emergency physicians with significant point of care ultrasound (POCUS) experience enrolled patients in the study.A 10-5 high frequency linear probe (Mindray Medical Ltd, Shenzen, China) was placed over the carotid artery and the carotid bulb was identified.Pulsed wave doppler tracings were obtained with the patient at 30 degrees of head elevation.As previously described, the CFT was measured from the beginning of systole to the dicrotic notch [6].As the CFT measurement was being obtained, a PAC measurement of cardiac output was performed.The ultrasonographer was blinded to the PAC cardiac output measurements.All images were saved for subsequent review.PAC measurements were performed using the thermodilution method.
After initial measurements were obtained, a passive leg raise was performed as per a standardized protocol [7].A repeat carotid flow time and PAC cardiac output measurement was taken.A total of three CFT and PAC cardiac output measurements were taken during the pre and post-leg raise and were averaged.If there was significant variability (>10%) between the readings of the PAC, five measurements were taken, with the two outlying measurements removed and the three remaining measurements were averaged.The patient's hemodynamic parameters were also monitored pre and post-passive leg raise.A difference of 10% between the PAC cardiac output readings was considered positive for volume responsiveness as defined in previous literature [8].
A corrected CFT was calculated as systole time/√ cycle time to correct for changes in heart rate.Changes in PAC and CFT cardiac output measurements after the passive leg raise were compared using a two-sided t-test.The changes in CFT were assessed using ROC analysis.Cohen's kappa coefficient was calculated to assess the agreement between PAC and CFT.Statistical significance was set at p<0.05.

Results
28 patients were approached for enrollment.Six patients were not enrolled due to consent not being provided by next of kin.One patient was not enrolled as the treating physician felt they were too unstable to participate.A total of 21 patients were subsequently enrolled in the study.Of the 21 patients enrolled, 2 patients were excluded due to a malfunctioning pulmonary artery catheter.Baseline demographics and patient information can be found in Table 1.
The pre and post-leg raise hemodynamic measurements are described in Table 2. Overall, 8/19 (38%) patients exhibited a 10% increase in cardiac output as determined by PAC and were therefore considered volume responsive.
Table 3 highlights changes in hemodynamics in those who were deemed volume responsive.It is noted that while a change in cardiac output was demonstrated with the CFT and PAC, the patients heart rate and blood pressure did not change significantly, highlighting that an improvement in blood pressure for example, does not necessarily reflect the cardiac output status of the patient.
The receiver operating curve for carotid flow time measurements had an area under the curve (AUC) of 0.9.The odds ratio is 1.6098, p-value 0.043 (95% CI) (Sensitivity 87.5%, specificity 90.9%, PPV 0.875, NPV The inferior vena cava (IVC) and its respirophasic variability in the spontaneously breathing patient has shown some promise [9], however there are uncertainties about its utility [10,11] and ability to accurately predict volume responsiveness.Other methods such as measurements of cardiac output using transthoracic echocardiography can be technically challenging due to the difficulty in obtaining adequate views in critically ill patients [12].
The rationale for evaluating changes in the CFT is based on common physiologic principles.The CFT measures the time spent in ventricular systole and corrected for changes in heart rate.If a patient is fluid responsive, then their time spent in ventricular systole should increase when faced with a fluid challenge due to increased ventricular filling.This indicates that increased cardiac filling during ventricular diastole results in an increased stroke volume.The time spent is systole is easily measured on a carotid artery pulse waveform from the beginning of the carotid upstroke to the dicrotic notch on the doppler waveform.See Figure 1 for an example of CFT measurement in a volume non-responder and Figure 2 for a volume responder.In the volume responder example, the image on the left is pre-passive leg raise with CFT calculated at 244.05ms.The image on the right is post-passive leg raise with CFT calculated at 314.00ms.This increase of greater than 10% indicated a volume responsive patient that was corroborated by our gold standard.
Recently, the CFT has been evaluated for its potential use in determining fluid responsiveness.In a study by Mackenzie et al in 2015 demonstrated that in blood donors, a demonstrated change in corrected carotid flow time after blood loss with a passive leg raise maneuver [6].A study by Ma et al published in 2017 compared various carotid blood flow measurements to invasive pulmonary artery catheter measurements in non-critically ill patients.Their study found that an average of three waveforms measuring the corrected flow time had a high degree of correlation with cardiac output measurements [13].In 2018, a study by Barjaktarevic et al in a critical care patient population demonstrated that CFT could demonstrate fluid responsiveness compared to a noninvasive gold standard.The study also found that a 7ms change in CFT had a high positive predictive value for identifying patients who will be fluid responder.Barjaktarevic also demonstrated that mechanical ventilation, respiratory rate and variable positive end expiratory pressure had no impact on the performance of CFT [14].Our study has unique aspects compared to other previously published papers on carotid flow time.First, this study uses a critically ill patient population of which 17/19 were mechanically ventilated and 10/19 on vasoactive agents.Secondly, this study used a invasive means to assess cardiac output with a pulmonary artery catheter.Other published studies used non-invasive means to assess cardiac output [14], which has been shown to be a potentially non-reliable method to assess changes in cardiac output [15].

Limitations
This study has several important limitations.The sample size was small, which limits the generalizability of our findings.Larger studies should be performed to confirm these findings.Due to investigator availability, a convenience sample was included.However, all eligible patients were approached for enrollment when the investigators were available.Study participants were primarily composed of recent post-operative cardiac surgery patients.These patients may have had unique causes of shock that may not generalize to a broader patient population.We did not measure inter-rater reliability of the CFT measurements.The time taken to complete the scans was not recorded, however it was noted that the measurements could all be completed in less than 10 minutes.

Conclusion
The corrected carotid flow time has a high accuracy for predicting volume responsiveness in ICU patients when compared with invasive measurements.An increase in CFT of 9.1% was predictive of a significant increase in cardiac output.Future studies with larger and more heterogenous patient populations should be performed to validate these findings.

Figure 2 .
Figure 2. Corrected carotid flow time measurement in volume responder .

Figure 1 .
Figure 1.Corrected carotid flow time measurement in a volume non-responder.

Table 1 .
Patient demographics and baseline data.

Table 2 .
Difference Between Pre-and Post-Passive Leg Raise Measurements for Mean Arterial Blood Pressure, Pulse and Corrected Carotid Flow Times for all patients.

Table 3 .
Mean difference between pre-and post-passive leg raise measurements for mean arterial blood pressure, pulse and correct carotid flow times in volume responders.