Heart Rate and Mortality After Resuscitation in Patients With Out-of-Hospital Cardiac Arrest　― Insights From the SOS-KANTO Registry ―

Shingo Matsumoto; Rine Nakanishi; Ryo Ichibayashi; Mitsuru Honda; Kei Hayashida; Atsushi Sakurai; Nobuya Kitamura; Takashi Tagami; Taka-aki Nakada; Munekazu Takeda; Takanori Ikeda; SOS-KANTO Study Group

doi:10.1253/circj.CJ-22-0047

Abstract

Background: Heart rate (HR) predicts outcomes in patients with acute coronary syndrome (ACS), whereas the impact of HR on outcomes after out-of-hospital cardiac arrest (OHCA) remains unclear. This study aimed to investigate the impact of HR after resuscitation on outcomes after OHCA and whether the impact differs with OHCA etiology.

Methods and Results: Of 16,452 patients suffering from OHCA, this study analyzed 741 adults for whom HR after resuscitation was recorded by 12-lead electrocardiogram upon hospital arrival. Etiology of OHCA was categorized into 3 groups: ACS, non-ACS, and non-cardiac. Patients in each etiology group were further divided into tachycardia (>100 beats/min) and non-tachycardia (≤100 beats/min). The impact of HR on outcomes was evaluated in each group. Among the 741 patients, the mean age was 67.6 years and 497 (67.1%) patients were male. The primary outcome – 3-month all-cause mortality – was observed in 55.8% of patients. Tachycardia after resuscitation in patients with ACS was significantly associated with higher all-cause mortality at 3 months (P=0.002), but there was no significant association between tachycardia and mortality in non-ACS and non-cardiac etiology patients. In a multivariate analysis model, the incidence of tachycardia after resuscitation independently predicted higher 3-month all-cause mortality in OHCA patients with ACS (hazard ratio: 2.17 [95% confidence interval: 1.05–4.48], P=0.04).

Conclusions: Increased HR after resuscitation was associated with higher mortality only in patients with ACS.

It is widely recognized that heart rate (HR) is a useful prognostic tool for clinical outcomes and a great therapeutic target in patients with cardiovascular disease,¹^–³ especially in those with acute coronary syndrome (ACS).⁴^–⁷ In patients suffering from out-of-hospital cardiac arrest (OHCA) due to ACS, which is the predominant cause and associated with a higher survival rate than in patients with non-cardiac etiology suffering from OHCA (non-CE),⁸^–¹² HR could be a useful predictor of all-cause mortality and poor neurological outcomes, even in the setting of post-cardiac arrest syndrome (PCAS).¹³ Given that HR is also a notable predictor of cardiovascular events and mortality in the general population,¹⁴^–¹⁶ there may be an association between HR after resuscitation and outcomes in patients suffering from OHCA with non-CE. However, it is not known whether the impact of HR after resuscitation on clinical outcomes differs according to the etiology of cardiac arrest among patients suffering from OHCA.

In this study, we aimed to investigate the impact of HR after resuscitation on clinical outcomes in patients suffering from OHCA and whether it differs with the etiology of OHCA, especially the presence of ACS.

Methods

Study Design, Data Collection, and Population

We analyzed the data of the SOS-KANTO registry, a large multicenter prospective study, to evaluate the outcomes of patients suffering from OHCA. Briefly, based on the Utstein style, a total of 16,452 OHCA patients were enrolled from January 2012 to March 2013 in 67 emergency medicine departments in Japan.¹⁷^,¹⁸ This registry waived the individual informed consent to ensure participant anonymity and was approved by the ethical committees of all 67 institutions. Prehospital characteristics were collected by emergency medical service (EMS) providers. Information during the hospital course and follow-up data after discharge were collected by institutional researchers. The follow-up information regarding patients who were transferred to other hospitals was collected by telephone.

The study flowchart is shown in Figure 1. Of the 16,452 OHCA patients in the SOS-KANTO registry, the following patients were sequentially excluded from this study: those aged <18 years (n=288); those with ventricular fibrillation (n=477), pulseless ventricular tachycardia (n=29), pulseless electrical activity (n=2,710), or asystole (n=11,348) on the 12-lead electrocardiogram (ECG) upon hospital arrival; those without 12-lead ECG records at the emergency room (n=211); those without the information of HR on 12-lead ECG (n=410); those without a certain diagnosis of OHCA etiology (n=222); and those without data regarding their clinical course (n=16). Ultimately, we enrolled and analyzed 741 OHCA patients for whom HR after the return of spontaneous circulation (ROSC) was recorded by 12-lead ECG at the time of hospital arrival.

Figure 1.

Study flowchart. ACS, acute coronary syndrome; ECG, echocardiogram; HR, heart rate; OHCA, out-of-hospital cardiac arrest; PEA, pulmonary electrical activity; VF, ventricular fibrillation; VT, ventricular tachycardia.

The 741 patients were categorized into 3 etiologies of OHCA: ACS (n=192), cardiac etiology (CE) without ACS (non-ACS) (n=100), and non-CE (n=449). These etiologies were clinically determined by the critical care physicians during the hospital stay of these patients. A diagnosis of ACS was not required to perform immediate coronary angiography at admission. In the SOS-KANTO registry dataset, non-ACS patients were established to have CE without ACS; however, detailed diagnostic information for non-ACS cases was not available. The conditions and situations for patients in the non-CE group is descried in Figure 1.

To evaluate the impact of HR after resuscitation, we divided the patients within each etiology group into tachycardia and non-tachycardia groups. Tachycardia was defined as >100 beats/min, which is based on the cut-off value of the Global Registry of Acute Coronary Events (GRACE) risk score.⁴ The mean HR during the recording of the 12-lead ECG for each individual was taken as the HR value.

Statistical Analysis

The clinical characteristics of the tachycardia and non-tachycardia groups are described by frequencies, percentages (%) for categorical variables, the mean±standard deviation (SD), and the median value with interquartile range (quartile 1–3) for continuous variables. Variables were appropriately analyzed using Fisher’s exact test, t-test, and one-way ANOVA. The association between HR after resuscitation and 3-month all-cause mortality was analyzed and described by Cox proportional hazards model, Kaplan-Meier plots, and log-rank tests. The correlation between dosage of epinephrine during cardiopulmonary resuscitation (CPR) and HR after resuscitation was evaluated using Spearman’s rank correlation test. A univariate Cox proportional hazards model was used to determine whether HR >100 beats/min was associated with 3-month mortality in the ACS, non-ACS, and non-CE groups. A multivariate Cox proportional hazards model was used after adjusting for age and gender to determine whether HR >100 beats/min was associated with increased 3-month all-cause mortality (Model 1). Furthermore, to estimate the independence of the effect of HR on 3-month all-cause mortality after adjusting for other factors that were previously demonstrated as strong predictors in patients suffering from OHCA, we also used multivariate Cox proportional hazards model as follows: Model 1 + witnessed OHCA (Model 2), Model 2 + an initial rhythm of ventricular tachycardia/ventricular fibrillation (Model 3), and Model 3 + epinephrine dosage (Model 4).⁸^,¹⁹^,²⁰ In patients with non-ACS, the independence of the effect of HR could not be evaluated by the multivariate analysis models given that the number of events was statistically insufficient in this group. All statistical tests were 2-tailed, and the significance level was set at 5%. All analyses were performed by using STATA (Version 15; StataCorp LP, College Station, TX, USA) for Windows.

Results

Patient Baseline Characteristics Before Hospital Arrival

Of the 741 patients, the mean age was 67.6 years and 497 (67.1%) were male. The clinical characteristics associated with each etiology group, and with tachycardia and non-tachycardia within each etiology group are shown in Table 1. Patients with non-CE had a significantly lower prevalence of witnessed OHCA and shockable rhythm as compared to patients with ACS or non-ACS (ACS vs. non-ACS vs. non-CE; witnessed: 81.8% vs. 82.0% vs. 73.1%, P=0.02 for all; shockable rhythm: 42.2% vs. 49.0% vs. 2.3%, P<0.001 for all). Overall, the baseline characteristics corresponding to witnessed OHCA, bystander CPR initiated before EMS arrival, bystander defibrillation, shockable rhythm detected by EMS, and prehospital ROSC did not significantly differ between the tachycardia and non-tachycardia groups in each etiology group. In the non-CE group, patients in the tachycardia group were younger than those in the non-tachycardia group. Concerning the initial status confirmed by EMS, the prevalence of ROSC was significantly higher in patients with tachycardia and ACS.

Table 1. Patient Baseline Characteristics

Characteristic	Overall (N=741)		Cardiac etiology (n=292)								Non-CE (n=449)
	Overall (N=741)		ACS (n=192)				Non-ACS (n=100)				Non-CE (n=449)
	n	Overall	n	Tachycardia (n=108)	Non-tachycardia (n=84)	P value	n	Tachycardia (n=37)	Non-tachycardia (n=63)	P value	n	Tachycardia (n=219)	Non-tachycardia (n=230)	P value
Age (years)	741	67.6±16.6	192	67.0±13.0	64.8±11.9	0.23	100	61.7±17.2	64.6±15.7	0.39	449	66.5±19.3	71.8±16.2	0.002
Male	741	497 (67.1)	192	86 (79.6)	73 (86.9)	0.25	100	24 (64.9)	48 (76.2)	0.25	449	130 (59.4)	136 (59.1)	0.52
BMI (kg/m²)	497	21.5±3.7	140	23.3±3.6	23.0±3.2	0.63	63	21.4±2.2	22.9±3.0	0.03	293	20.7±3.7	20.4±3.7	0.45
β-blocker^a	435	28 (6.4)	114	2 (3.3)	5 (9.3)	0.25	74	6 (22.2)	6 (12.8)	0.34	247	3 (2.5)	6 (4.7)	0.50
Witnessed OHCA	738	565 (76.6)	192	88 (81.5)	69 (82.1)	0.99	100	30 (81.1)	52 (82.5)	0.99	446	156 (71.6)	170 (74.6)	0.52
Bystander CPR	738	391 (52.9)	191	64 (59.3)	47 (56.6)	0.77	100	29 (78.4)	44 (69.8)	0.49	447	99 (45.4)	108 (47.2)	0.78
Bystander defibrillation	738	119 (16.1)	188	25 (23.2)	29 (36.3)	0.053	100	9 (24.3)	18 (28.6)	0.82	440	18 (8.4)	20 (8.9)	0.87
Initial status^b	733		192			0.18	100			0.96	441			0.68
Shockable rhythm^c		140 (19.1)		51 (47.2)	30 (35.7)	0.14		17 (46.0)	32 (50.8)	0.68		5 (2.4)	5 (2.2)	0.99
PEA		214 (29.2)		16 (14.8)	12 (14.3)	0.99		3 (8.1)	5 (7.9)	0.99		92 (43.2)	86 (37.7)	0.34
Asystole		162 (22.1)		11 (10.2)	7 (8.3)	0.80		4 (10.8)	5 (7.9)	0.72		63 (29.6)	72 (31.6)	0.61
ROSC		217 (29.6)		30 (27.8)	35 (41.7)	0.047		13 (35.1)	21 (33.3)	0.99		53 (24.9)	65 (28.5)	0.34
EMS defibrillation	731	202 (27.6)	190	70 (64.8)	49 (59.8)	0.55	97	23 (62.2)	35 (58.3)	0.83	444	12 (5.6)	13 (5.7)	0.99
EMS response time (min)^d	740	9.4±3.9	192	8.8±3.8	9.5±4.3	0.26	100	9.2±3.0	9.5±4.9	0.71	448	9.1±3.5	9.8±4.1	0.06

Data are presented as n (%) or mean±standard deviation. ^aInternal use of β-blocker prior to cardiac arrest. ^bFirst confirmed by EMS. ^cVentricular fibrillation and pulseless ventricular tachycardia. ^dTime from initial call to contact with patient. ACS, acute coronary syndrome; BMI, body mass index; CE, cardiac etiology; CPR, cardiopulmonary resuscitation; EMS, emergency medical services; OHCA, out-of-hospital cardiac arrest; PEA, pulseless electrical activity; ROSC, return of spontaneous circulation.

Clinical Characteristics at the Time of Hospital Arrival

The clinical features of all study groups at the time of hospital arrival and following treatment are shown in Table 2. Overall, the mean HR after resuscitation in the tachycardia and non-tachycardia groups was 122.1±18.2 beats/min and 76.9±17.1 beats/min, respectively.

Table 2. Clinical Features and Treatments After Patient Hospital Arrival

	Overall (N=741)		Cardiac etiology (n=292)								Non-CE (n=449)
	Overall (N=741)		ACS (n=192)				Non-ACS (n=100)				Non-CE (n=449)
	n	Overall	n	Tachycardia (n=108)	Non-tachycardia (n=84)	P value	n	Tachycardia (n=37)	Non-tachycardia (n=63)	P value	n	Tachycardia (n= 29)	Non-tachycardia (n=230)	P value
Clinical features
Heart rate (beats/min)	741	99.1±1.1	192	122.7±18.8	78.1±14.7	<0.001	100	124.4±26.7	78.3±17.5	<0.001	449	121.4±16.2	76.1±17.8	<0.001
Epinephrine use	731	319 (43.6)	192	40 (37.0)	25 (29.8)	0.36	100	11 (30.6)	15 (25.0)	0.64	444	109 (50.9)	119 (51.7)	0.92
Epinephrine dose (mg)	726	1.3±0.1	190	1.38±2.31	1.35±3.83	0.94	96	0.75±1.38	0.62±1.46	0.66	440	1.43±2.46	1.38±2.11	0.83
Prehospital ROSC	741	692 (93.4)	192	102 (94.4)	82 (97.6)	0.47	100	35 (94.6)	62 (98.4)	0.55	449	203 (92.7)	208 (90.4)	0.40
Hospital arrival time (min)^a	741	37.6±0.5	192	36.3±14.1	37.0±18.8	0.76	100	36.6±9.8	37.8±13.9	0.65	449	37.2±12.7	39.0±11.8	0.12
GCS	736		191			0.07	100			0.23	445			0.37
GCS 13–15		71 (9.6)		13 (12.1)	19 (22.6)	0.08		7 (18.9)	17 (27.0)	0.47		6 (2.8)	9 (4.0)	0.60
GCS 9–12		28 (3.8)		5 (4.7)	7 (8.3)	0.37		3 (8.1)	1 (1.6)	0.14		8 (3.7)	4 (1.8)	0.25
GCS 3–8		637 (86.6)		89 (83.2)	58 (69.1)	0.02		27 (73.0)	45 (71.4)	0.99		203 (93.6)	215 (94.3)	0.84
Spontaneous breathing	736	396 (53.8)	191	74 (69.2)	62 (73.8)	0.52	99	27 (75.0)	58 (92.1)	0.03	446	86 (39.3)	89 (39.2)	0.99
Normal light reflex	694	184 (26.5)	179	42 (41.6)	37 (47.4)	0.45	90	15 (42.9)	29 (52.7)	0.39	425	32 (15.8)	29 (13.1)	0.49
Time to ROSC (min)^b	537	24.9±0.5	142	24.3±11.4	21.9±9.4	0.18	67	22.4±10.4	20.6±10.9	0.49	324	25.8±10.5	27.1±11.0	0.27
Body temperature (℃)	647	35.5±0.1	160	35.7±1.1	35.6±0.9	0.43	89	35.8±1.5	35.5±1.6	0.41	394	35.6±1.3	35.2±1.8	0.01
Systolic BP	591	123.8±1.9	154	142.6±47.9	129.7±36.4	0.07	88	137.5±35.4	126.3±31.2	0.12	345	122.6±48.8	109.2±44.7	0.008
Diastolic BP	556	72.5±1.3	149	82.6±32.3	75.8±27.7	0.18	82	84.3±28.0	74.2±21.3	0.07	321	71.5±32.4	63.2±27.1	0.01
STEMI	–	–	145	50 (61.7)	46 (71.9)	0.22	–	–	–	–	–	–	–	–
Laboratory findings
WBC (/μL)	715	10,666±4,271	178	11,954±3,943	10,351±3,435	0.005	97	10,628±4,898	10,708±3,680	0.93	436	11,008±4,558	9,858±4,302	0.007
Hb (mg/dL)	725	12.5±0.93	186	13.7±2.3	13.3±2.3	0.28	97	13.8±2.2	13.3±2.0	0.33	438	12.0±2.4	11.6±2.5	0.12
eGFR (mL/min/1.73 m²)	663	55.7±1.1	170	50.9±20.7	51.2±23.0	0.92	93	61.4±18.7	55.6±32.9	0.34	396	58.8±29.5	55.8±32.8	0.34
K (mEq/L)	722	4.26±0.04	185	4.0±1.1	4.0±0.9	0.79	96	4.0±0.7	4.2±0.8	0.12	437	4.2±1.2	4.5±1.3	0.01
Glucose value (mg/dL)	698	247.0±3.9	177	269.4±95.6	255.7±86.3	0.32	96	246.8±78.9	228.0±85.4	0.29	421	256.1±107.9	230.5±110.9	0.02
Blood gas analysis
pH	702	7.10±0.1	176	7.15±0.21	7.22±0.21	0.046	92	7.19±0.20	7.25±0.18	0.13	430	7.04±0.21	7.03±0.25	0.61
BE (mEq/L)	685	−11.2±0.33	172	−11.8±7.3	−9.8±6.3	0.07	90	−9.8±6.7	−7.5±7.4	0.13	419	−11.7±9.4	−12.1±10.1	0.69
Lactate (mg/dl)	552	31.9±1.8	118	25.5±34.9	29.2±33.7	0.56	76	33.5±42.0	17.3±23.0	0.03	354	33.3±43.6	37.2±45.3	0.41
PaO₂ (mmHg)	701	203.7±5.8	174	221.2±146.5	191.9±143.7	0.19	92	208.3±176.2	203.2±147.1	0.88	431	204.0±160.1	198.8±151.9	0.73
PaCO₂ (mmHg)	701	65.3±1.3	174	51.6±28.9	46.7±23.1	0.22	93	53.6±28.8	48.6±26.8	0.40	430	73.1±33.7	77.0±38.5	0.27
HCO³⁻ (mmHg)	687	18.0±0.22	173	16.3±4.8	17.2±4.3	0.20	89	18.0±5.3	18.6±5.2	0.61	421	18.3±5.9	18.5±6.8	0.73
Echocardiography
LVEF <40%	325	120 (36.9)	122	32 (52.4)	24 (39.3)	0.20	72	10 (34.5)	21 (48.8)	0.33	131	12 (18.5)	21 (31.8)	0.11
Procedure or treatment
Immediate ICA	658	217 (33.0)	176	86 (87.8)	68 (87.2)	0.99	98	23 (62.2)	32 (52.5)	0.40	384	6 (3.2)	2 (1.0)	0.17
Emergent PCI	–	–	140	63 (80.8)	49 (79.0)	0.83	–	–	–	–	–	–	–	–
Mechanical ventilation	695	573 (82.4)	181	87 (84.5)	53 (68.0)	0.01	93	28 (80.0)	39 (67.2)	0.24	421	182 (90.1)	184 (84.0)	0.08
Hypothermia	659	209 (31.7)	177	56 (56.6)	32 (41.0)	0.049	99	20 (54.1)	29 (46.8)	0.54	383	40 (21.7)	32 (16.1)	0.19

Data are presented as n (%) or mean±standard deviation. ^aTime from initial call to hospital arrival. ^bTime from initial call to ROSC. GCS, Glasgow coma scale; BP, blood pressure; STEMI, ST-elevation myocardial infarction; WBC, white blood cell; Hb, hemoglobin; eGFR, estimated glomerular filtration rate; BE, base excess; PaO₂, partial pressure of arterial oxygen; PaCO₂, partial pressure of arterial carbon dioxide; LVEF, left ventricular ejection fraction; ICA, invasive coronary angiography; PCI, percutaneous coronary intervention. Other abbreviations as in Table 1.

Compared with patients in the ACS and non-ACS groups, there were fewer non-CE patients that: had a mild Glasgow coma scale (GCS) score of 13 to 15, showed spontaneous breathing, and had a normal light reflex (GCS of 13 to 15: 16.8% vs. 24.0% vs. 3.4%, P<0.001 for all; spontaneous breathing: 71.2% vs. 85.9% vs. 39.2%, P<0.001 for all; normal light reflex: 44.1% vs. 44.0% vs. 14.4%, P<0.001 for all).

In the comparison between tachycardia and non-tachycardia groups among each etiology, the prevalence of pre-hospital ROSC and a normal light reflex upon admission were comparable regardless of their etiologies. The presence of spontaneous breathing upon admission was significantly lower in the tachycardia group than in the non-tachycardia group among patients with non-ACS.

Epinephrine Status During CPR

In the comparison between ACS, non-ACS, and non-CE groups, patients with ACS or with non-CE had higher doses of epinephrine during CPR compared with patients in the non-ACS group (ACS vs. non-ACS vs. non-CE: 1.37±0.22 mg vs. 0.67±0.15 mg vs. 1.40±0.11 mg, P<0.001 for all). In the subsequent analysis regarding the correlation between HR after resuscitation and epinephrine dosage during CPR, there was no significant correlation between HR and epinephrine dosage across the whole study population (|r|=0.05, P=0.16). Within each etiology group, only patients with ACS had a very weak correlation between HR and epinephrine dosage (ACS: |r|=0.19, P=0.01; Non-ACS: |r|= 0.02, P=0.83; Non-CE: |r|=0.001, P=0.98). Between the tachycardia and non-tachycardia groups among each etiology, the proportion of epinephrine use and the dosage of epinephrine used during CPR did not differ.

Laboratory and Echocardiographic Findings

Table 2 shows laboratory and echographic findings in each group. Baseline hemoglobin levels and renal function were comparable between the tachycardia and non-tachycardia groups regardless of OHCA etiology. Baseline pH levels were significantly lower in ACS patients with tachycardia than in those with no tachycardia. Patients with tachycardia in the non-ACS group had significantly higher baseline lactate levels as compared with those with no tachycardia.

Left ventricular ejection fraction (LVEF) after ROSC was evaluated by echocardiogram in 325 of the 741 patients (43.9%), and LVEF <40% was found in 120 of them (36.9%). The incidence of cardiac dysfunction, as assessed by LVEF <40% upon admission, was significantly higher in patients with ACS and non-ACS than in those with non-CE (ACS vs. non-ACS vs. non-CE: 45.9% vs. 43.1% vs. 25.2%, P=0.001 for all). In each OHCA etiology, there were no significant differences regarding the prevalence of LVEF <40% after ROSC between the tachycardia and non-tachycardia groups.

Procedure and Treatments

Among the whole study population, 585 of 658 patients (88.9%) underwent emergency coronary angiography at the time of admission, and mechanical ventilation was used in 573 of 695 patients (82.4%). Hypothermia therapy was performed in more patients with ACS and non-ACS etiology than in those with non-CE (ACS vs. non-ACS vs. non-CE: 49.7% vs. 49.5% vs. 18.8%, P<0.001).

Of those with ACS etiology, 154 of 176 patients (87.5%) underwent immediate invasive coronary angiography, and emergency percutaneous coronary intervention was performed in 112 of 140 patients (80.0%) (Table 2).

Clinical Outcomes

All-cause mortality at 3-months as evaluated by the Cox proportional hazards model was 55.8% (259 of 464) in the overall population. Compared with the ACS (42 of 166) and non-ACS (16 of 97) groups, the non-CE group (201 of 327) had significantly higher 3-month mortality (26.4% vs. 17.6% vs. 65.1%, P<0.001).

In univariate analyses with the Cox proportional hazards model, tachycardia in patients with ACS was significantly associated with higher mortality at 3 months (Table 3), although there were no significant associations between tachycardia and mortality in the non-ACS and non-CE groups. In the Kaplan-Meier curve and log-rank analyses, tachycardia was significantly associated with higher mortality only in patients suffering from OHCA due to ACS (Figure 2). Multivariate analysis models (Table 3) estimating the independence of HR in the prediction of 3-month mortality suggested that tachycardia was an independent predictor of mortality in patients with ACS (hazard ratio: 2.17 [95% confidence interval: 1.05–4.48], P=0.04; Model 4), although tachycardia did not have a significant impact on mortality in patients with non-CE etiology.

Table 3. Impact of HR >100 beats/min in Univariate and Multivariate Analysis Models for the Prediction of 3-Month All-Cause Mortality in Patients With OHCA

Model	ACS			Non-ACS			Non-CE
Model	n (No. of events)	Hazard ratio (95% CI)	P value	n (No. of events)	Hazard ratio (95% CI)	P value	n (No. of events)	Hazard ratio (95% CI)	P value
Univariate analysis model: HR >100 beats/min	166 (42)	2.82 (1.38–5.74)	0.002	97 (16)	0.98 (0.35–2.69)	0.96	327 (201)	1.01 (0.77–1.34)	0.92
Model 1: HR >100 beats/min + age and gender	166 (42)	2.65 (1.30–5.41)	0.007	–	–	–	327 (201)	1.04 (0.78–1.38)	0.80
Model 2: Model 1 + witnessed OHCA	166 (42)	2.66 (1.30–5.42)	0.007	–	–	–	326 (200)	1.05 (0.79–1.39)	0.74
Model 3: Model 2 + initial rhythm VT/VF	166 (42)	2.76 (1.34–5.65)	0.006	–	–	–	323 (199)	1.06 (0.80–1.41)	0.70
Model 4: Model 3 + epinephrine dosage	164 (42)	2.17 (1.05–4.48)	0.04	–	–	–	317 (196)	1.08 (0.81–1.43)	0.61

CI, confidence interval; HR, heart rate; VT, ventricular tachycardia; VF, ventricular fibrillation. Other abbreviations as in Table 1.

Figure 2.

Kaplan-Meier curves indicating survival rates of tachycardia and non-tachycardia patients suffering from out-of-hospital cardiac arrest (OHCA) in different etiology groups. (A) Patients suffering from OHCA due to acute coronary syndrome (ACS). (B) Patients suffering from OHCA due to cardiac etiology without ACS. (C) Patients suffering from OHCA due to non-cardiac etiology.

Discussion

Using data from a large, multicenter prospective study of patients suffering from OHCA, the current study demonstrated that tachycardia was significantly associated with higher all-cause mortality at 3 months in patients suffering from OHCA due to ACS. Furthermore, the most striking findings of our study were that the association between tachycardia and increased mortality at 3 months was not observed among patients suffering from OHCA when they suffered from cardiac arrest due to non-ACS (but cardiac) etiology or non-cardiac etiology.

We previously reported the impact of HR on clinical and neurological outcomes among patients suffering from OHCA due to ACS after ROSC in a single-center study.¹³ However, it remains unclear whether the findings are consistent for OHCA in the general population or for other etiologies. We herein undertook the current study using this large, multicenter dataset. Notably, the present study data similarly demonstrated that a HR >100 beats/min was significantly associated with higher all-cause mortality at 3 months in patients suffering from OHCA due to ACS. These previous and current studies indicate that patients suffering from OHCA due to ACS constitute a specific population affected by HR after resuscitation, and the presence of ACS potentially causes vulnerability with respect to an increased HR in the setting of post-resuscitation. To the best of our knowledge, this is the first study showing that the different effects of HR on all-cause mortality among patients suffering from OHCA vary by etiology.

Etiology of OHCA

Given that the condition of patients with PCAS is extremely unstable and there are many confounders that affect clinical outcomes, it should be investigated whether the clinical implication of HR after resuscitation is maintained among patients with PCAS. In the present study, we found that HR was an independent predictor of outcomes even in patients suffering from OHCA, if etiology was ACS. In patients with ACS, those in the tachycardia group had a significantly lower prevalence of ROSC at EMS arrival, although almost all the patients with ACS achieved ROSC on admission regardless of their HR.

Patients with impaired cardiac function may need a sufficient oxygen supply to maintain adequate cardiac output and to prevent further cardiac injury based on cardiac oxygen deficiency, although increased HR after resuscitation leads to insufficient coronary blood flow due to a reduction in diastolic time and higher oxygen consumption because of excessive cardiac work.²¹^,²² Our results may be relevant to these cardiac metabolic imbalances associated with insufficient coronary blood flow caused by tachycardia.

It is not clear why tachycardia was not associated with mortality after resuscitation in patients with non-CE; however, there are several possible explanations for the differences in the impact of HR with different etiologies of OHCA. In general, an increased HR contributes more to outcomes in patients with impaired cardiac function such as ACS and heart failure.⁴^–⁶^,²³ Given that survivors of OHCA due to non-CE are likely to have relatively mild cardiac injury and dysfunction as compared with those surviving OHCA due to CE,²⁴ the clinical course of OHCA associated with non-CE may not be affected by HR to a similar extent. Furthermore, we found that the non-CE group had a lower incidence of a witnessed OHCA and of shockable rhythm at the first contact with EMS. In addition, a lower proportion of these patients had spontaneous breathing, a normal light reflex, and a GCS of 13 to 15 at hospital arrival, all of which indicated a more critical condition; these were associated with lower survival rates at 3 months relative to the ACS and non-ACS groups. These findings are similar to general situations in which individuals resuscitated from OHCA with non-CE have lower survival rates than those resuscitated from OHCA caused by CE.⁸ Collectively, the non-CE group may have accumulated more irreversible systemic and neurological damage during resuscitation than the ACS and non-ACS groups

Epinephrine During CPR

Our results indicated that the tachycardia group was not associated with a higher prevalence of epinephrine use or a higher epinephrine dosage during CPR compared with the non-tachycardia group, and this finding was similar within each etiology. Although patients with ACS had a correlation between HR after resuscitation and epinephrine dosage during CPR, this correlation was very low and would not be a clinically meaningful finding. These findings are supported by previous reports suggesting that increased HR after ROSC is mainly caused by hemodynamic instability and a suppressed vagal nerve system subsequent to cerebral brain injury, and not by usage or dosage of epinephrine during CPR.²⁵^–²⁷ In addition, a multivariate analysis of patients suffering from OHCA with ACS suggested that tachycardia is an independent predictor of 3-month mortality after adjusting for epinephrine dosage. Taken together, these results indicate that HR is a useful predictor of outcomes in patients suffering from OHCA due to ACS regardless of epinephrine status during CPR.

Arrhythmia and Outcomes

In the current study, there was no information regarding the presence of arrhythmia including atrial fibrillation (AF). As AF influences HR and outcomes in patients with ACS,²⁸^,²⁹ AF may play a critical role in patients suffering from OHCA, especially with ACS. However, the clinical implications of AF for PCAS are still limited.³⁰ Given our previous data showed that there was no significant difference in the prevalence of AF between the tachycardia and non-tachycardia groups for patients suffering from OHCA due to ACS,¹³ the impact of AF on HR after resuscitation may be definite. Otherwise, patients suffering from OHCA and AF are generally older, have a higher rate of cardiovascular disease, and have a lower LVEF compared to individuals without AF.³¹ Thus, the clinical course of patients suffering from OHCA due to ACS may be influenced more by the presence of AF.³¹ We could not address the significance of arrhythmias, involving AF, in patients suffering from OHCA due to a lack of data. Further research, therefore, is warranted to clarify these issues.

HR as a Therapeutic Target

HR is not only a useful prognostic tool of clinical outcomes in patients with cardiovascular disease, but increased HR is also a notable therapeutic target in patients with cardiovascular disease.³²^–³⁴ Little is known, however, about the benefit of modulating HR in patients with tachycardia after ROSC. Decreasing an excessively higher HR in the setting of PCAS may carry potential benefits on cardiac work through modulating the balance of cardiac oxygen demand and supply.²¹^,²² Thus, the appropriate use of several modulators of HR in the setting of PCAS, such as pharmacotherapies and hypothermia therapy, may be promising therapeutic options in patients suffering from OHCA due to ACS when an excessively increased HR is observed. Further research to evaluate whether increased HR is a modifiable risk factor and a beneficial therapeutic target after ROSC is warranted.

Study Limitations

Patients with CE were clearly categorized as having ‘ACS’ or as ‘CE but not ACS’ in the SOS-KANTO registry dataset, but there was no information about the diagnosis of patients with non-ACS etiology; thus, we did not clarify whether there were additional specific subtypes among the patients with non-ACS etiology in which tachycardia caused worse outcomes. As we focused on the HR recorded by 12-lead ECG on patient admission, all enrolled patients were resuscitated. Thus, there is a concern that our results would include a bias leading to over- and under-estimation of the clinical implication of prehospital ROSC. Additionally, because echocardiographic findings were lacking in approximately half of our study population, we did not fully determine the degree of cardiac injury after ROSC and did not analyze the relationship between cardiac function and HR after resuscitation. Finally, an individual’s HR after resuscitation would be altered by time-dependent effects of several factors such as reflexes, neurohormonal systems, and cardiac conducting systems;³⁵ however, we only analyzed the HR data upon patient admission. Further research is needed to focus on the associations between changes in HR, outcomes after resuscitation, and etiologies in patients suffering from OHCA.

Conclusions

Tachycardia after ROSC was an independent predictor of 3-month all-cause mortality in patients suffering from OHCA due to ACS, although this relationship was not observed in patients with non-ACS etiology and non-CE. HR after ROSC is a useful predictor of clinical outcomes and may be a modifiable therapeutic target after resuscitation in patients suffering from OHCA due to ACS.

Acknowledgments

The authors thank for all the investigators of the SOS-KANTO registry.

Disclosures

T.I. has received a research grant and remuneration from Daiichi-Sankyo. The other authors have no conflicts of interest to declare.

T.I. is a member of Circulation Journal’s Editorial Team.

IRB Information

The investigation conforms with the principles outlined in the Declaration of Helsinki. The protocol of this study was approved by the ethics committee of Toho University Omori Medical Center (no. M21123).

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