Article, Cardiology

Corrected flow time: a noninvasive ultrasound measure to detect preload reduction by nitroglycerin

a b s t r a c t

Objective: Monitoring of patient’s intravascular volume status without invasive measures remains challenging and unreliable. Our objective was to determine if corrected flow time (FTc) measurement could detect preload reduction with administration of nitroglycerin (NTG) as a surrogate for volume loss.

Methods: Post hoc FTc analysis was performed for a prospective cohort study of pulsed wave spectral Doppler measurements before and after administration of NTG. Patients enrolled were eligible for inclusion if they were admitted to a chest pain center for cardiac evaluation. Descriptive statistics, t tests, bivariate regression, and intraclass correlation coefficient were performed as appropriate.

Results: Fifty-four patients had Doppler measurements available for review. Mean FTc decreased from 339 milli- seconds (95% confidence interval, 332-346) to 325 milliseconds (95% confidence interval, 318-331) with admin- istration of 0.3 mg of sublingual NTG (P = .0001). Mean heart rate increased 5 beats/min with administration of NTG (P b .0001); however, there was no significant change in systolic or diastolic blood pressure.

Conclusion: CorrectED flow time was able to detect a significant difference in preload reduction with 0.3 mg of NTG. The FTc may be an early reliable noninvasive measure to detect changes in intravascular volume status.

(C) 2016

  1. Introduction

noninvasive methods to accurately detect changes in vascular status could aid in Treatment decisions regarding fluids and vasopressor med- ication in critically ill patients. Invasive monitoring is often used to pro- vide these data. Preliminary research has suggested that Doppler analysis of arterial flow may provide accurate and easily obtained non- invasive measures of preload and cardiac output [1-3]. One technique proposed to assess these cardiovascular status changes is “corrected flow time” (FTc) [3]. The FTc uses pulsed wave spectral Doppler to measure systole (flow) time (ST) corrected for heart rate. It is relatively easy to perform compared with other Doppler applications, as measure- ments are not dependent on operator-dependent settings such as gate location or Doppler angle [3]. The FTc has been shown to increase after intravenous (IV) fluid administration in patients with clinical Volume depletion [3]. Our objective was to determine if FTc has a

? Funding acknowledgments: the original prospective study was a grant-funded inves- tigation provided by Women’s Health Research at Yale. The post hoc analysis was conduct- ed without any direct funding or support.

?? Presentation of work (oral presentation accepted): American Institute of Ultrasound

in Medicine, Annual Convention, March 19, 2016, New York, NY.

? Data: this research was produced from a prospective study on microvascular dysfunc-

tion. [1] Safdar B, Ali A, D’Onofrio G, Katz SD. Microvascular dysfunction as opposed to con- duit artery disease explains sex-specific chest pain in emergency department patients with low to moderate cardiac risk. Clin Ther 2016. doi:10.1016/j.clinthera.2015.12.010.

* Corresponding author. Tel.: +1 203 737 2518; fax: +1 203 785 4580.

E-mail address: [email protected] (J.R. Pare).

reciprocal correlation with preload reduction in patients receiving ni- troglycerin (NTG).

  1. Materials and methods

Measurements were obtained from a prospective cohort study mea- suring flow-mediated dilatation of the Brachial artery in patients with suspected coronary artery disease [4]. Patients screened for enrollment were admitted to a chest pain observation center from the emergency department (ED) for low-to-moderate probability of acute coronary syndrome. Patients were enrolled during defined periods from 7:30 AM to 1 PM, Monday to Friday to minimize physiological variation in measurements. All patients were fasting for at least 12 hours before study enrollment. Exclusion criteria for enrollment are presented in Table 1. Institutional review board approval and informed consent were obtained for all enrolled patients.

A Philips HD11 machine equipped with a 12-MHz linear array trans- ducer was used to obtain measurements. Patients were enrolled and had measures performed in a chest pain observation unit. Patients had measures taken in semiprivate rooms with curtains for privacy. The pa- tient was placed in a supine position for measures. The ultrasound probe was placed 5 cm proximal to the elbow on longitudinal axis of the bra- chial artery. At this location, baseline images were obtained, including a pulsed wave spectral Doppler measurement of the brachial artery. The patient was then given 0.3 mg of sublingual NTG, and pulsed wave spec- tral Doppler measurements were taken 5 minutes after medication

http://dx.doi.org/10.1016/j.ajem.2016.06.077

0735-6757/(C) 2016

1860 J.R. Pare et al. / American Journal of Emergency Medicine 34 (2016) 18591862

Table 1

Exclusion criteria from study enrollment.

  1. Inability to read or understand English
  2. Suffering from a condition that precludes interview, that is, cognitive or communication impairment
  3. A resting blood pressure N200/120 mm Hg or b100/50 mm Hg
  4. Previous serious adverse reaction to NTG
  5. Patients with known structural heart disease
  6. Patients with systolic murmur on examination
  7. Unable to provide contact number for follow-up study
  8. On IV heparin, GpIIb-IIIa inhibitors, phosphodiesterase inhibitors, or IV NTG
  9. Currently on dialysis
  10. Used heroin, cocaine, or alcohol in the past 72 h
  11. Is in police custody at the time of presentation
  12. Active psychiatric condition such as psychosis or suicidal ideation
  13. Pregnancy

Abbreviation: GpIIb-IIIa, platelet glycoprotein IIb/IIIa complex.

delivery. Two trained physicians with expertise in this technique per- formed all Ultrasound measurements. Training included adherence to a protocol manual, and training was performed over a 3-month period in a vascular laboratory [5]. Patients enrolled had medical histories and demographics recorded. Vital signs were recorded before and after administration of NTG. Images were stored as JPEG files for review. This study had institutional review board approval. Fifty-four patients had a complete set of pre- and post-NTG images and were included in our FTc analysis. The JPEG images were imported into OsiriX (Geneva, Switzerland) and converted to Digital Imaging and Communications in Medicine (DICOM) utilizing a software plugin. The ST, measured from the beginning of systole to the dicrotic notch, was measured at 3 beats and averaged. The cycle time (CT) was also measured and averaged for 3 beats (Fig. 1). The ST and CT were determined by measuring distance in pixels and converting pixels to time using the time reference on the spectral wave form recording. Measurements were performed and re- corded for pulsed wave spectral Doppler recordings pre- and post-NTG (Fig. 2). The FTc was calculated as previously described: ST/?(CT). A trained physician with at least 4 years of ultrasound experience per- formed all FTc measurements. A second independent review was con- ducted by a trained physician to assess for consistency of agreement

among 20% of enrollments.

STATA (College Station, TX) was used for statistical analysis. Descrip- tive statistics, Student t tests of paired samples, and bivariate linear

Image of Fig. 1

Fig. 1. Corrected flow time measurement.

regressions were performed where appropriate. A box plot was gener- ated to display FTc values pre- and post-NTG administration. Interrater reliability was evaluated by a mean intraclass correlation coefficient for the measurements of FTc pre- and post-NTG.

  1. Results

Of 57 patients prospectively enrolled, 54 patients had data for anal- ysis. Patient demographics and medical history are provided in Table 2. Mean FTc decreased from 339 milliseconds (95% confidence interval, 332-346) to 325 milliseconds (95% confidence interval, 318-331) (P = .0001) after administration of 0.3 mg of NTG (Fig. 3). The change in FTc of individual patients is supplied (Fig. 4). Heart rate, ST, and CT also changed after NTG: 70 beats per minute (bpm) vs 75 bpm, P b .0001; 317 milliseconds vs 293 milliseconds, P b .0001; and 883 mil- liseconds vs 817 milliseconds, P b .0001. Mean brachial artery diameter changed from 3.28 mm to 4.06 mm post-NTG. Systolic blood pressure, diastolic blood pressure, resistive index, mean velocity, and maximum systolic velocity had no measurable difference that was significant with administration of NTG (Table 3).

The change in FTc was associated with age (P = .022) and smoking (P = .037). There was no detectable association between FTc and sex, diabetes, hypertension, dyslipidemia, body mass index (BMI), or the use of ?-blocker or calcium channel blocker medications Table 4. Mean interrater reliability assessed by ICC for FTc measurement was 0.69.

  1. Discussion

Our results show that FTc drops significantly after administration of

0.3 mg sublingual NTG. This is the first study to our knowledge reporting change in FTc after NTG administration and that also of FTc being studied at the brachial artery. We chose NTG administration as a preload-reducing agent in our study because of its widespread availabil- ity and established safety in patients. Administration of NTG generally results in a greater physiologic decrease in preload as compared with afterload. The NTG, therefore, can produce a reduction in cardiac pre- load and simulate volume depletion. It is, however, documented that there is a variable endothelial response to NTG, and this can result in variable preload and afterload changes [6]. It is possible that variable re- sponses to NTG or other factors such as anxiety after NTG administra- tion may have resulted in the small proportion of patients that showed a rise rather than fall in FTc values. In addition, by enrolling pa- tients in a chest pain observation unit, there may be differences in auto- nomic influences, and these measures should be further explored in patients with pathology in a true ED setting.

The FTc measurement has been shown to detect changes in volume status before changes in blood pressure or a Clinically significant change in heart rate [3]. Examples of specific scenarios that we anticipate FTc could hold clinical value would be patients with dynamic intravascular volume status or preload reduction. Disease states that may be particu- larly helpful to perform FTc to monitor volume status might be sepsis or occult bleeding such as gastrointestinal, trauma, or postprocedural. Changes in FTc may detect changes in clinical status sooner than serial hematocrits, exam findings, or vital signs. Although our study did not in- volve children or young adults, these patients are known to have rela- tively stable vital signs until decompensation, and if reproducible in children, FTc may offer a measure to alert physicians to changes in clin- ical status earlier.

Corrected flow time has previously been shown to increase with vol- ume repletion, as well as to decrease with blood loss in healthy volun- teers [3,7]. However, its use in detection of preload reduction in clinical scenarios has not been well explored. Based on our findings, we propose that FTc can be used for early assessment of intravascular status changes. Intravascular volume fluctuations affect ventricular fill- ing and ejection times, providing a proposed mechanism for FTc to track changes in physiologic states.

J.R. Pare et al. / American Journal of Emergency Medicine 34 (2016) 18591862 1861

Fig. 2. Paired FTc measure.

In our study, heart rate did have a statistically significant increase after administration of NTG. However, the clinical significance of mean 5-bmp change in heart rate is less clear. It is possible that vital signs may lag behind FTc as a marker for changes in volume status [3]. Never- theless, FTc shows promise as a reliable, noninvasive measure to detect changes in volume status.

We analyzed data of patients with low-to-moderate suspicion of having acute coronary syndrome. It is possible that this subset of pa- tients may have a unique response to NTG measured by FTc that may not be reproducible in a general population. However, all 54 patients were enrolled only after myocardial infarction was ruled out with serial cardiac enzymes, and almost all (92.6%) had a normal stress test. This in- dicates low risk for cardiac disease and a more generalizable population. Of the variables selected, we found that there were only significant associations between age and FTc, and smoking and FTc. Previous liter- ature has suggested that with an increase in age, there is an exaggerated response to NTG due to insufficient baroreceptor response, causing in- creased hypotension [8]. Flow-mediated dilatation measurements are known to be lower in smokers who receive NTG to test endothelial- independent dilation [9,10]. Further research into the interactions of smoking and age on FTc should be investigated to determine direct, in- direct, and independent associations with NTG. It has also been reported that ?-blocker and calcium channel blocker medications are associated with prolonged ST [11]. We did not identify an association between

these medications and FTc in our cohort.

Other reported protocols of FTc measurements have been performed at the right carotid artery [3,7]. We performed our measurements at the brachial artery. There have not been any studies performed that we are aware of that compare a higher resistance vessel such as the brachial ar- tery with other vessels such as the carotid that have previously been studied. Further research into the optimal location to perform pulsed wave spectral Doppler analysis is important to determine if FTc values performed at different locations with different physiologic responses

Table 2

Demographics & history of patients.

Total patients: 54 Data presented as median (IQR) or N (%)

in vascular resistance are reliable, reproducible, and important for clin- ical outcomes. Our findings at the brachial artery should be studied against more established measures at central arteries such as the carotid or aorta. The brachial artery, however, may hold benefits over using the carotid or aorta to avoid causing a vagal response with the pressure of the probe or in specific disease states such as carotid stenosis. In addi- tion, the brachial artery may be an easier location to obtain FTc mea- sures and would likely be preferable for patient’s comfort, all of which would be of clinical utility.

Both physicians performing the post hoc FTc measurements were fa- miliar with the objectives of the study. However, they used anonymized images and were blinded to the results of the pilot study, minimizing in- vestigator bias. The mean ICC for FTc measurements between reviewers was 0.69. It is possible that FTc is difficult to perform by hand and is prone to variability for manual measures. It is also likely that reviewers selected different portions of the spectral Doppler tracing to perform FTc measurements. It is unclear if beat-to-beat variability could impact the agreement between reviewers. An autotrace function, if created, av- eraging FTc over a longer period of time, would greatly improve the agreement and reduce interreader variability for FTc.

Validation of this information should be performed before complete conclusions are made regarding FTc measurements for patients with preload reduction. Our sample size was small; however, we were able to demonstrate a significant difference in FTc measurements. We pro- pose our results to be hypothesis generating and hope to test this asso- ciation in larger samples of undifferentiated ED patients.

Corrected flow time is a promising measure, which could be of sig- nificant clinical value. It is easy to perform, is a noninvasive ultrasound measure, and can be repeated multiple times without exposing the

Variable

Results

Variable

Results

Age

52.5 (45-59 y)

BMI

29.4 (25.1-33.6)

Male

25 (46.3%)

Diabetes

8 (15.4%)

Race

Dyslipidemia

31 (59.6%)

White

37 (68.5%)

Smoker

26 (48.2%)

Non-White

17 (31.5%)

Coronary artery disease

4 (7.4%)

Ethnicity hispanic

9 (16.7%)

?-Blocker

6 (11.1%)

Abnormal stress test

4 (7.4%)

Calcium channel blocker

8 (14.8%)

Image of Fig. 3Abbreviation: IQR, interquartile range.

?-Blocker taken as outpatient.

Calcium channel blocker taken as outpatient. Fig. 3. Change in FTc with NTG administration.

1862 J.R. Pare et al. / American Journal of Emergency Medicine 34 (2016) 18591862

Image of Fig. 4Table 4

Associations for % change in FTc and clinical variables.

P

?

SE

Age

.022

-.002

0.0009

Sex

.057

.036

0.0360

Diabetes

.730

-.009

0.0269

Hypertension

.950

-.001

0.0196

Dyslipidemia

.197

.026

0.0195

Smoking

.037

.040

0.0184

?-Blocker

.176

.041

0.0299

Calcium channel blocker

.628

-.013

0.0269

BMI

.595

.001

0.0017

Abbreviations: * FTc = Corrected Flow Time.

Table 3

Fig. 4. Individual FTc data.

to invasive methods. J Ultrasound 2014. http://dx.doi.org/10.1007/s40477-014- 0139-9.

  1. Marik PE, Levitov A, Young A, Andrews L. The use of bioreactance and carotid Dopp- ler to determine volume responsiveness and blood flow redistribution following passive leg raising in hemodynamically unstable patients. Chest 2013;143:364-70. http://dx.doi.org/10.1378/chest.12-1274.
  2. Blehar DJ, Glazier S, Gaspari RJ. Correlation of corrected flow time in the carotid ar- tery with changes in intravascular volume status. J Crit Care 2014;29:486-8. http:// dx.doi.org/10.1016/j.jcrc.2014.03.025.

Differences in parameters pre- and post-NTG.

Variable Pre-NTG

mean (SD)

Heart rate (bpm)

69.9 (11.2)

74.8 (10.2)

b.0001

Systolic blood pressure (mm Hg)

121.5 (15.0)

122.8 (15.5)

.2263

Diastolic blood pressure (mm Hg)

75.8 (9.0)

75.4 (9.1)

.6271

Resistive index

0.923 (.08)

0.912 (.09)

.0997

Mean velocity (cm/s)

18.7 (10.5)

18.6 (11.5)

.8512

Maximum systolic velocity (cm/s)

78.7 (17.3)

81.0 (17.2)

.1488

CT (ms)

883 (140)

817 (110)

b.0001

ST (ms)

317 (27)

293(28)

b.0001

FTc (ms)

339 (25.2)

325 (23.9)

.0001

Post-NTG P

mean (SD)

  1. Safdar B, Ali A, D’Onofrio G, Katz SD. Microvascular dysfunction as opposed to con- duit artery disease explains sex-specific chest pain in emergency department pa- tients with low to moderate cardiac risk. Clin Ther 2016. http://dx.doi.org/10. 1016/j.clinthera.2015.12.010.
  2. Corretti MC, Anderson TJ, Benjamin EJ, Celermajer D, Charbonneau F, Creager MA, et al. Guidelines for the ultrasound assessment of endothelial-dependent flow- mediated vasodilation of the brachial artery: a report of the International Brachial Artery Reactivity Task Force. J Am Coll Cardiol 2002;39:257-65. http://dx.doi.org/ 10.1016/S0735-1097(01)01746-6.
  3. Haber HL, Simek CL, Bergin JD, Sadun A, Gimple LW, Powers ER, et al. Bolus intrave- nous nitroglycerin predominantly reduces afterload in patients with excessive arte- rial elastance. J Am Coll Cardiol 1993;22:251-7.
  4. Mackenzie DC, Khan NA, Blehar D, Glazier S, Chang Y, Stowell CP, et al. Carotid flow time changes with volume status in acute blood loss. Ann Emerg Med 2015. http:// dx.doi.org/10.1016/j.annemergmed.2015.04.014.
  5. Verheyden B, Gisolf J, Beckers F, Karemaker JM, Wesseling KH, Aubert AE, et al. Impact of age on the vasovagal response provoked by sublingual nitroglycerine in routine tilt

patient to significant risks. We are optimistic that FTc with additional re- search could be incorporated into the care of patients for whom changes in intravascular Volume status monitoring are important.

References

[1] Gassner M, Killu K, Bauman Z, Coba V, Rosso K, Blyden D. Feasibility of Common carotid artery Point of Care Ultrasound in cardiac output measurements compared

testing. Clin Sci (Lond) 2007;113:329-37. http://dx.doi.org/10.1042/CS20070042.

  1. Lanza GA, Spera FR, Villano A, Russo G, Di Franco A, Lamendola P, et al. Effect of smoking on endothelium-independent vasodilatation. Atherosclerosis 2015;240: 330-2. http://dx.doi.org/10.1016/j.atherosclerosis.2015.03.041.
  2. Kawano N, Emoto M, Mori K, Yamazaki Y, Urata H, Tsuchikura S, et al. Association of endothelial and vascular smooth Muscle dysfunction with cardiovascular risk fac- tors, vascular complications, and subclinical carotid atherosclerosis in type 2 diabetic patients. J Atheroscler Thromb 2012;19:276-84.
  3. O’Rourke MF, Pauca A, Jiang X-J. Pulse wave analysis. Br J Clin Pharmacol 2001;51: 507-22. http://dx.doi.org/10.1046/j.0306-5251.2001.01400.x.

Leave a Reply

Your email address will not be published. Required fields are marked *