Pilot Study for a Novel Delta Carotid Sinus Massage in Increasing

대한응급의학회지 제 30 권 제 2 호 � 원저� Volume 30, Number 2, April, 2019

Procedure Pilot study for a novel delta carotid sinus massage in increasing parasympathetic tone: a randomized, prospective, cross-over, comparative study with conventional method

Dong Ik Lee1, Tae Yong Shin2, Hong Chuen Toh3, Min Jung Lee1, Jung Hwan Ahn1

1Department of Emergency Medicine, Ajou University School of Medicine, Suwon, 2Department of Emergency Medicine, Bundang Jesaeng General Hospital, Seongnam, Korea, 3Acute and Emergency Care Centre, Khoo Teck Puat Hospital, Singapore

Objective: This study examined the efficacy of new delta carotid sinus massage (CSM) versus conventional CSM (CM). Methods: This prospective, cross-over study was conducted on 26 healthy volunteers with a normal sinus rhythm. CM and delta CSM (DM) were performed in all participants. In both cases, the CSM was performed, where the maximal carotid pulse was palpated. DM differed from CM in that the physician moves the palpating finger in the opposite direction of the carotid pulse at least twice. The mean and longest R-R intervals and mean and lowest heart rates (HRs) at the baseline and during the procedure for each technique were compared. The mean differences between the baseline and procedure R-R intervals and the HRs for each technique were also evaluated. Results: The baseline mean and longest R-R intervals and baseline mean and lowest HRs were similar both groups (P>0.05). The procedure DM mean and longest R-R intervals (22.7±3.1, 26.4±4.9) were significantly greater than the CM corresponding values (22.0±3.1, 24.6±3.5; P<0.001, P=0.003). Procedure DM mean and lowest HRs (67.3±9.7, 58.6±10.7) were significantly lower than the CM corresponding values (69.4±10.0, 61.8±8.9; P=0.001, P=0.003). The differences in the R-R interval and HR between the procedure and baseline were significant (mean and longest R-R intervals with CM [1.3±1.5 and 2.1±1.9] vs. DM [2.0±1.4 and 3.8±3.1], P<0.001, P=0.004; mean and lowest HRs with CM [4.2±4.3 and 5.8±4.6] vs. DM [6.3±4.6 and 9.1±6.5], P<0.001, P=0.005). Conclusion: DM is more effective in generating a more potent vagal tone than CM.

Keywords: Carotid sinus; Massage; Electrocardiography; Heart rate

cessful conversion of supraventricular tachycardia (SVT) INTRODUCTION with CSM is generally low and very variable, from 11.8% to 48.5%, often necessitating subsueqent pharma- Pressure over carotid sinuses elicits a reflex parasym- cological intervensions such as intravenous adenosine.2,4,5 pathetic response, and can cause bradycardia due to neg- This variability could arise from factors related to the ative dromotropic and chronotropic effects on atrioven- location of the carotid sinus and adequacy and direction tricular nodes and sinus.1-3 Carotid sinus massage (CSM) of force applied.2,6 as a bedside diagnostic test and therapeutic intervention The vagal stimulating effect of CSM results from has been described two centuries ago, with Hering’s stretching or deformation of the wall of the carotid sinus, observation that the carotid sinus was stimulated by pres- in which the nerve endings are embedded.2 The stretching sure on the carotid artery, resulting in the termination of of the sinus could be initiated by a rise in static pressure paroxysmal tachycardia.2,4 Nevertheless, the rate of suc- or increased pulsatile flow, with the latter being more

책임저자: 안 정 환 경기도 수원시 영통구 월드컵로 164 아주대학교 의과대학 응급의학교실 Tel: 031-219-7750, Fax: 031-219-7760, E-mail: [email protected] 접수일: 2018년 8월 17일, 1차 교정일: 2018년 10월 2일, 게재승인일: 2018년 10월 3일

176 Delta carotid sinus massage / 177

September 2016. It was approved by the institutional Capsule Summary review board (IRB) at our hospital and it conformed to the principles outlined in the Declaration of Helsinki What is already known in the previous study (IRB No. XXIRB-MED-MDB-16-277). The written Carotid sinus massage (CSM) has been used as a bedside informed consent was obtained from the enrolled partici- diagnostic test and therapeutic intervention for more pants. The trial was registered in the Clinical Trial than two centuries. On the other hand, the conversion Registry of Korea with an assigned number of KCT rate of supraventricular tachycardia with conventional 0002139. CSM ranges from 11.8% to 48.5%. This variation in conversion rate could be related to the variability in the loca- 2. Participants tion of the carotid sinus, adequacy of force, and correct direction of the application of force. All participants enrolled in this study were volunteers recruited via posters placed in our hospital. Informed What is new in the current study written consent was obtained after explaining the aim This study showed that the new CSM technique could and design of this study. Inclusion criteria were self- elicit a greater vagal stimulation than the conventional reported general good health, age 18 to 60 years, sinus CSM performed with a static pressure. In the new tech- rhythm on initial electrocardiography (ECG), and nique, the physician moves the palpating finger over the absence of bruit over the carotid artery on direct auscul- carotid sinus in the opposite direction to the carotid tation. Exclusion criteria include being on any regular pulse at least twice, generating increased pulsatility of medication (other than oral contraceptives), a history of blood flow to the carotid sinus. This maneuver is called cardiorespiratory disease, syncope, orthostatic hypoten- “delta CSM.” sion, cerebrovascular accident, or transient ischaemic attack. Participants were informed not to smoke or con- sume alcohol or caffeine 6 hours before the procedure. effective than sustained pressure at stimulating the carotid Their demographic data were obtained upon recruitment. sinus.2,7 Applying Bernoulli’s principle, the speed of blood flow through a section of the blood vessel is 3. Randomization expected to increase as the size of the lumen decreases and vice versa. By pressing down on the carotid artery All participants were subjected to both CM and DM, but during the systole, hence decreasing its lumen, and in the order as determined by their allocation. Using the releasing this pressure in diastole, the normal pulsatility randomization sequence generated by a dedicated software of the arterial blood flow is augmented. When applied to (http://www.graphpad.com/quickcalcs), participants are CSM, this manoeuvre could potentially result in a greater randomized to one of the two groups: (1) right DM was vagal stimulation compared to sustained pressure. We performed first, followed by right CM; and (2) right CM call this new technique ‘delta CSM’ (DM), which is per- was performed first, and then right DM. Before and after formed with palpating finger essentially moving in the performing each test, there was a rest time of 3 minutes to opposite direction of the carotid pulse. The aim of this ensure that the participants have made full recovery to study is to investigate the efficacy of DM at raising vagal baseline, as the sinoatrial rate often return to baseline with- tone compared to conventional CSM (CM). in 10-15 seconds of completing the vagal manoeuvre.2,8

4. Intervention and measurements METHODS Fig. 1 outlines the study design. The procedure was 1. Study design and setting performed with the participant lying supine and only on the right carotid bulb, as the cardio-inhibitory effect has The study design was a prospective, randomized been reported to be greater on this side.4 The two CSM crossover trial, conducted between 11 August and 12 techniques were performed at the same location indicat- 178 / Dong Ik Lee et al.

Fig. 1. Study flow. ed with a marker, with the participant’s head tilted back- Cardiac activity was recorded on continuous ECG strip ward and turned slightly to the left. The physicians who (lead II) running at 25 mm/sec (Heartstart XL, Philips, performed the CSM were board-certified emergency Andover, MA, USA). The linear R-R interval, which physicians and not members of the research team. CM was known as an indirect indicator of the level of vagal was performed by applying direct firm pressure for 10 tone, was calculated directly from ECG tracing using the seconds in a posteromedial direction where the carotid electronic ruler (Digital Vernier Caliper, Lenaenergy, pulse was the most strongly palpated, usually immediate- Daegu, Korea) and converted to time intervals.6,8 R-R ly above the level of the thyroid cartilage and anterior to interval was expressed in seconds. Marks indicating the the sternocleidomastoid muscle.2 DM was performed by start and the finish of a procedure were shown on ECG pressing on the carotid artery in the same manner as the strip as a note for the ensuing subsequent R-R interval CM initially. Once the emergency physician was able to calculation. Baseline R-R intervals were measured establish the rhythm of the carotid pulsation, the pressure before starting each technique. “Baseline mean R-R was released during the diastolic phase and reapplied interval” was calculated using the mean of 10 consecu- during the systolic phase. At least two augmented carotid tive R-R intervals and “baseline longest R-R interval” blood flow are generated, within the same total proce- was defined as the longest among the 10 intervals. Based dure time of 10 seconds. The CSM procedure was termi- on previous data, the maximum prolongation of the R-R nated if palpitation, arrhythmia, neurologic symptoms or interval was observed promptly after constant pressure signs, giddiness or syncopal attack was observed. was applied on the carotid sinus, and returning to base- Syncope was defined as partial or complete temporary line level within 10 to 15 seconds after pressure was loss of consciousness with spontaneous recovery. The released.2,8 Therefore, “procedure mean R-R interval” cardiopulmonary resuscitation medication and equip- and “procedure longest R-R interval” corresponding to ment including cardiac defibrillator were prepared and each technique were calculated from the start of the pro- available during the intervention. cedure up to 15 seconds after termination of the tech- Delta carotid sinus massage / 179 nique. R-R intervals that included premature beats were for difference in pain or discomfort resulting from the excluded when determining the longest R-R interval, as two CSM techniques, a numeric rating scale was used. it is accompanied by a compensatory or non-compensatory pause. Before and after performing each test, 3- 5. Data analysis minute rest time was provided for each participant. The heart rate (HR) was variable derived directly from All data were analyzed by using SPSS ver. 23 statistics the R-R interval (using the conversion factor software (IBM Corp., Armonk, NY, USA). Continuous HR=1500/R-R interval). Nevertheless, it will be calculat- data are expressed as mean±standard deviation. ed and reported in this research. Being a vital sign, the Categorical data are shown as absolute values, together HR can illustrate the direct impact of the CSM manoeu- with frequency distribution. Chi-square tests were per- vres on the volunteers’ hemodynamic status. formed to compare the sex between both groups. The The following variables were defined as follow: “Δ differences in results between the two randomized CM mean R-R interval” was defined as the difference groups were analyzed to determine the effect of the order between procedure CM mean R-R interval and baseline of randomization on performances by using Mann- mean R-R interval and “ΔCM longest R-R interval” was Whitney U test or independent t test. The difference in defined as the difference between procedure CM longest mean and longest R-R intervals, and HRs before and R-R interval and baseline longest R-R interval. The “Δ after CSM between CM and DM was analyzed by using DM mean R-R interval” and “ΔDM longest R-R inter- Wilcoxon rank test or paired t test. Also, Δ mean and val” were also defined in the same way as CM. The cor- longest R-R intervals, and HRs between CM and DM responding HR related variables were calculated and were analyzed by Wilcoxon rank test or paired t test. P- derived as for corresponding R-R intervals. To evaluate values of <0.05 were considered statistically significant.

Table 1. General characteristics, R-R intervals, and heart rate according to the effect of order of randomisation on performances CM was performed first (n=13) DM was performed first (n=13) P-valuea) Sex (male:female) 8:5 7:6 0.691 Age (yr) 31.2±3.7 31.6±5.3 0.831 R-R interval (mm/sec) CM Baseline mean 21.1±2.8 20.4±2.8 0.520 Baseline longest 22.8±3.4 22.4±3.0 0.677 Procedure mean 22.5±3.2 21.5±3.1 0.453 Procedure longest 25.2±3.4 24.4±3.8 0.588 DM Baseline mean 21.1±2.8 20.4±2.7 0.530 Baseline longest 23.0±3.4 22.2±2.8 0.494 Procedure mean 23.1±3.1 22.3±3.0 0.499 Procedure longest 26.8±5.2 26.1±4.8 0.727 Heart rate (times/min) CM Baseline mean 72.3±9.9 074.8±10.0 0.524 Baseline lowest 067.0±11.0 68.7±9.3 0.766 Procedure mean 67.9±9.8 070.9±10.4 0.463 Procedure lowest 60.7±8.7 62.8±9.4 0.549 DM Baseline mean 072.4±10.0 74.8±9.9 0.538 Baseline lowest 066.7±10.7 68.7±8.8 0.594 Procedure mean 66.0±9.5 068.6±10.0 0.506 Procedure lowest 057.9±10.8 059.4±10.9 0.734 CM, conventional carotid sinus massage; DM, delta carotid sinus massage. a) P-values were calculated by independent t test. 180 / Dong Ik Lee et al.

Power analysis involving the primary hypothesis was CSM attempt (n=1). A total of 26 participants were based on a previous study, yielding an effective size of included in the final analysis (Fig. 1). No serious compli- 0.607 by using mean difference (standard deviation) cations such as syncope and arrhythmia were observed before and after CSM, 1.2 (0.9) with CM, and 1.9 (1.3) during the study period. The mean (range) age was 31.4± with DM.6 Sample size was calculated using t tests 4.5 years (range, 26-46 years); male to female number was (means: Wilcoxon signed-rank test [matched pairs]) on 15 (57.7%):11 (42.3%). Before analysis of differences in G*power statistical software ver. 3.1.5 (Franz Faul, variables (the mean and longest R-R intervals and HRs) University Kiel, Germany) with a two-sided, type I error between CM and DM, differences in results between the of 0.05 and a desired power of 0.80, and effective size two randomized groups were analyzed to determine the 0.607. Twenty-five participants were needed in the cur- effect of the order of randomization on performances. rent study. Assuming a dropout rate of approximately Table 1 shows the differences in sex, age, mean R-R 5%, we planned to recruit 28 patients. interval, longest R-R interval, mean HR, lowest HR, and numeric rating scale between randomized groups. The baseline characteristics of the two groups were similar. RESULTS The order in which the CSMs were performed (DM first in group 1, or CM first in group 2) had no effect on the Two of the 28 recruited participants were excluded results (P>0.05) (Table 1). because of recent consumption of caffeine (n=1) prior to Table 2 shows the results of variables between CM the intervention, and transient mild giddiness after the first and DM (the baseline mean and longest R-R intervals,

Table 2. Comparison of R-R intervals and heart rate between conventional carotid sinus massage and delta carotid sinus massage CM (n=26) DM (n=26) P-valuea) R-R interval (mm/sec) Baseline mean 20.7±2.8 20.7±2.7 <0.256 Baseline longest 22.7±3.2 22.6±3.1 <0.425 Procedure mean 22.0±3.1 22.7±3.1 <0.001 Procedure longest 24.6±3.5 26.4±4.9 <0.003 Heart rate (times/min) Baseline mean 73.5±9.8 73.6±9.8 <0.308 Baseline lowest 067.6±10.0 67.7±9.6 <0.593 Procedure mean 069.4±10.0 67.3±9.7 <0.001 Procedure lowest 61.8±8.9 058.6±10.7 <0.003 Numeric rating scale 02.9±1.0 02.7±0.8 <0.304 CM, conventional carotid sinus massage; DM, delta carotid sinus massage. a) P-values were calculated by paired t test, except baseline lowest heart rate and numeric rating scale measured using Wilcoxon rank test.

Table 3. Comparison of differences in R-R interval and heart rate between baseline and procedure according to each group CM DM P-valuea) ΔMean R-R interval (mm/sec) 1.3±1.5 2.0±1.4 <0.001 ΔLongest R-R interval (mm/sec) 2.1±1.9 3.8±3.1 <0.004 ΔMean heart rate (times/min) 4.2±4.3 6.3±4.6 <0.001 ΔLowest heart rate (times/min) 5.8±4.6 9.1±6.5 <0.005 Δ mean and longest R-R intervals, and Δ mean and lowest heart rates indicate the difference between procedure and baseline with DM or CM. CM, conventional carotid sinus massage; DM, delta carotid sinus massage. a) P-values were calculated by Wilcoxon rank test, except Δmean R-R interval and Δmean heart rate measured by using paired t test. Delta carotid sinus massage / 181 procedure CM or DM mean and lowest R-R intervals, technique.6 The advantage of DM, however, is that it baseline mean and lowest HRs, and procedure CM or makes use of the principle of augmenting the pulsatile DM mean and lowest HRs). There were no statistically blood flow to the carotid sinus to elicit vagal stimulation, significances in baseline mean and longest R-R intervals, and hence may be less affected by the need for precise and baseline mean and lowest HRs between both groups location of the carotid sinus than the conventional (P>0.05). However, procedure DM mean and longest R- approach. R intervals were statistically greater than CM corre- Stretch or baroreceptors on the arterial and venous side sponding values (P<0.001 and P=0.003, respectively). of the circulation play an integral role in regulating cer- Procedure DM mean and lowest HRs were statistically tain key cardiovascular functions.2,4,7,9 The only receptors lower than CM corresponding values (P=0.001 and that can readily be affected from the outside are carotid P=0.003, respectively). sinuses, situated at the bifurcation of common carotid Table 3 shows the results of ΔCM or DM mean and arteries.2 These baroreceptors are anatomically and func- longest R-R intervals, and ΔCM or DM mean and low- tionally distinct from chemoreceptors situated in the est HRs. There were statistically significantly differences adjoining carotid bodies.2 While the carotid artery pos- in Δmean and longest R-R intervals, and Δmean and sesses other baroreceptors, those in the carotid sinus play lowest HRs between two groups (P<0.05). ΔCM mean a key role.2 The afferent impulses generated in the sinus and longest R-R intervals (1.3±1.5 and 2.1±1.9) were reach the glossopharyngeal nerve via the nerve of smaller than ΔDM mean and longest R-R intervals (2.0 Hering.2 This nerve carries impulses not only from ±1.4 and 3.8±3.1) (P<0.001 and P=0.004). ΔCM baroreceptors located in the carotid sinus and in the mean and lowest HRs (4.2±4.3 and 6.3±4.6) were region of carotid bifurcation, but also from chemorecep- smaller than ΔDM mean and lowest HRs (5.8±4.6 and tors of the carotid body.2 Bradycardia, hypotension, and 9.1±6.5) (P<0.001, P=0.005). apnoea occur when electrical stimulation is limited to the baroreceptor fibers of the nerve of Hering.2 These baroreceptors are activated by stretching or deformation DISCUSSION of the wall of the carotid sinus in which the nerve endings are embedded. Under physiologic conditions, The findings of this research demonstrate that DM stretching of the sinus is initiated by a rise in carotid results in a more potent vagal stimulation compared to artery blood pressure, whether the rise in pressure is stat- CM in healthy subjects, as evidenced by a significant ic or is generated by pulsatile flow.2 Pulsatile stimuli are increase in mean and longest R-R intervals. more effective than sustained pressure at stimulating The use of vagal stimulation to terminate SVT was baroreceptor activity.7 The carotid sinus reflex is initiat- introduced in the late 18th century.9 As mentioned ed at a pressure of 60 mmHg. With each systole, there is above, the success rates of conversion to sinus rhythm a burst of activity in the vagal nerve. As carotid pressure from paroxysmal SVT are reported to range from 11.8% rises, the frequency and duration of firing are increased, to 48.5% likely due to the inaccurate identification of the with progressive recruitment of discharging units.2 This location of the carotid sinus, and inadequacy of strength recruitment can be increased with the DM technique that or incorrect direction of the force applied. Waxman et we have described. al.10 reported a 48.5% conversion rate of SVT with CSM. One of the volunteers randomized to the DM group Mehta et al.11 reported a 22% conversion rate in induced developed non-specific giddiness shortly about 30 sec- SVT. Ornato et al.12 reported an 11.8% success rate. In onds after the start of DM manoeuvre. Her symptom was addition, Klosek and Rungruang13 reported the location mild and transient, lasting a few seconds. Fifty-seven of the carotid bifurcation is different at both sides of the sinus rhythm was recorded on continuous ECG strip neck, and also varies according to sex. This generated (lead II) when her symptom was occurred. While blood earlier research interest in using ultrasound to locate the pressure and 12 lead ECG were performed immediately carotid sinus, which would be more accurate and possi- after the report of these symptoms, she had recovered by bly more useful than the anatomical landmark the time they were completed (blood pressure 95/63 182 / Dong Ik Lee et al. mmHg, sinus rate of 62 beats per minute, compared to cope in patients with Alzheimer’s disease. Europace her baseline of 102/75 mmHg and sinus rate of 70 beats 2007;9:829-34. per minute). Due to concerns for potential recurrence 02. Lown B, Levine SA. The carotid sinus: clinical value of its with the second CSM manoeuvre, this volunteer was stimulation. Circulation 1961;23:766-89. 03. Tea SH, Mansourati J, L’Heveder G, Mabin D, Blanc JJ. removed from the study at that point. She had no further New insights into the pathophysiology of carotid sinus symptoms during observation. syndrome. Circulation 1996;93:1411-6. The study has the following limitations. (1) The subjects 04. Collins NA, Higgins GL 3rd. Reconsidering the effective- enrolled in this study were healthy volunteers with sinus ness and safety of carotid sinus massage as a therapeutic rhythm, without a history of SVT. Also, the R-R interval intervention in patients with supraventricular tachycardia. on ECG was used as an indicator for measuring vagal Am J Emerg Med 2015;33:807-9. tone. The translation of the observed increased vagal stim- 05. Appelboam A, Reuben A, Mann C, et al. Postural modifi- ulation to therapeutic success in aborting SVT clinically cation to the standard Valsalva manoeuvre for emergency remains to be determined. (2) The small number of partic- treatment of supraventricular tachycardias (REVERT): a ipants restrict generalization of the findings, even though randomised controlled trial. Lancet 2015;386:1747-53. 06. Ha SM, Cho YS, Cho GC, Jo CH, Ryu JY. Modified the sample size was enough to achieve adequate power. carotid sinus massage using an ultrasonography for maxi- As with the standard CSM technique, DM could potential- mizing vagal tone: a crossover simulation study. Am J ly result in dislodgement of a carotid artery embolus. Emerg Med 2015;33:963-5. Standard precautions, such as excluding patients with a 07. Ead HW, Green JH, Neil E. A comparison of the effects of carotid bruit or significant cardiovascular risk factors, pulsatile and non-pulsatile blood flow through the carotid should be taken prior to any attempt at this manoeuvre. sinus on the reflexogenic activity of the sinus baroceptors In conclusion, DM elicits a more potent vagal stimula- in the cat. J Physiol 1952;118:509-19. tion than CM. It is a novel way of performing CSM that 08. Wong LF, Taylor DM, Bailey M. Vagal response varies could potentially lead to greater therapeutic success at with Valsalva maneuver technique: a repeated-measures aborting SVT. A randomized trial to evaluate its clinical clinical trial in healthy subjects. Ann Emerg Med 2004; 43:477-82. safety and efficacy is warranted. 09. Lim SH, Anantharaman V, Teo WS, Goh PP, Tan AT. Comparison of treatment of supraventricular tachycardia by Valsalva maneuver and carotid sinus massage. Ann ORCID Emerg Med 1998;31:30-5. 10. Waxman MB, Wald RW, Sharma AD, Huerta F, Cameron Jung Hwan Ahn (https://orcid.org/0000-0002-4676-1716) DA. Vagal techniques for termination of paroxysmal supraventricular tachycardia. Am J Cardiol 1980;46:655- 64. CONFLICT OF INTEREST 11. Mehta D, Wafa S, Ward DE, Camm AJ. Relative efficacy of various physical manoeuvres in the termination of junc- tional tachycardia. Lancet 1988;1:1181-5. No potential conflict of interest relevant to this article 12. Ornato JP, Hallagan LF, Reese WA, et al. Treatment of was reported. paroxysmal supraventricular tachycardia in the emergency department by clinical decision analysis. Am J Emerg Med 1988;6:555-60. REFERENCES 13. Klosek SK, Rungruang T. Topography of carotid bifurcation: considerations for neck examination. Surg Radiol 01. Bordier P, Colsy M, Robert F, Bourenane G. Prevalence Anat 2008;30:383-7. of positive carotid sinus massage and related risk of syn-