a b s t r a c t

Introduction: Current guidelines recommend systematic care for patients who experience out-of-hospital cardiac arrest (OHCA) and the development of cardiac arrest centers (CACs). However, data regarding prolonged trans- port time of these often hemodynamically unstable patients are limited.

Methods: Data from a prospective OHCA registry of a regional CAC collected between 2013 and 2017, when all OHCA patients from the district were required to be transferred directly to the CAC, were analyzed. Patients were divided into two subgroups: CAC, when the CAC was the nearest hospital; and bypass, when OHCA occurred in a region of another local hospital but the subject was transferred directly to the CAC (7 hospitals in the district). Data included transport time, baseline characteristics, hemodynamic and laboratory parameters on admission (systolic blood pressure, lactate, pH, oxygen saturation, body temperature, and initial doses of vasopressors and inotropes), and final outcomes (30-day in-hospital mortality, intensive care unit stay, days on artificial ven- tilation, and cerebral performance capacity at 1 year).

Results: A total of 258 subjects experienced OHCA in the study period; however, 27 were excluded due to insuf- ficient data and 17 for secondary transfer to CAC. As such, 214 patients were analyzed, 111 in the CAC group and 103 in the bypass group. The median transport time was significantly longer for the bypass group than the CAC group (40.5 min [IQR 28.3-55.0 min] versus 20.0 min [IQR 13.0-34.0], respectively; p < 0.0001). There were no differences in 30-day in-hospital mortality, 1-year neurological outcome, or median length of mechanical venti- lation. There were no differences in baseline characteristics, initial hemodynamic parameters on admission, cat- echolamine dosage(s).

Conclusion: Individuals who experienced OHCA and taken to a CAC incurred significantly prolonged transport times; however, hemodynamic parameters and/or outcomes were not affected. These findings shows the safety of bypassing local hospitals for a CAC.

(C) 2021

1. Introduction

The incidence of out-of-hospital cardiac arrest (OHCA) in Europe is approximately 55-113 per 100,000 population per year, and return of spontaneous circulation (ROSC) is achieved in 40-50% of patients. Only approximately 15%, however, are discharged with favorable neu- rological status [1-3]. The Quality of cardiopulmonary resuscitation (CPR) is critical to improve survival rates with favorable neurological function [4]. post-resuscitation care has now been included as the fourth circle in the chain-of-survival, and the primary focus is to support brain,

* Corresponding author at: Department of Cardiology, Regional Hospital Liberec, Liberec 460 01, Czech Republic.

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

heart, lung, and kidney function, as well as to prevent bacteremia and the metabolic and hemodynamic disturbances associated with post- cardiac arrest syndrome [5-7]. Post-resuscitation care has been reported to be an important factor contributing to mortality rates in these pa- tients [8,9].

Currently available evidence supports the creation of a network of cardiac arrest centers (CACs), which yield an increasing Survival benefit in high-volume CACs compared with local hospitals [10,11]. Current guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death, therefore, recommend post-resuscitation care in high-volume, expert centers and the creation of networks for the treatment of individuals who experience cardiac ar- rest [12]. This requires patients to be transferred to tertiary centers rather than to the nearest hospital; however, the impact of such

https://doi.org/10.1016/j.ajem.2021.01.080

0735-6757/(C) 2021

transport has not been fully investigated. There are insufficient data to suggest that prolonged transport times with limited pre-hospital emer- gency care influences the condition and outcomes of these patients are insufficient. Accordingly, the present study aimed to determine whether prolonged primary transport of OHCA patients to a regional CAC–thus bypassing the nearest hospital–negatively impacted initial hemodynamic parameters on admission, mortality, and/or neurological outcomes.

1. Methods

Data were collected from a prospective registry of all consecutive pa- tients who experienced OHCA and underwent ROSC and admitted to a tertiary center (CAC; Liberec Central Hospital, North Bohemia, Czech Republic) between January 2013 and March 2017. All adult patients (> 18 years of age) who underwent ROSC were included, while those who experienced traumatic etiology of arrest, had insufficient data, or with secondary transport to a CAC were excluded.

The Liberec Region in North Bohemia has a population of approxi- mately 450,000. One hospital center in Liberec (with a cardiovascular center, percutaneous coronary intervention [PCI], echocardiography and transvenous pacing available 24 h/day, 7 days/week, targeted tem- perature management, intensive care unit [ICU] and extracorporeal membrane oxygenation capability) and 7 local hospitals serve in the area. Before 2013, individuals who experienced OHCA were transferred to the central hospital or to the nearest local hospital according to the decision of the emergency medical service (EMS) physician. If neces- sary, secondary transport to the central hospital was organized, espe- cially when myocardial infarction was the primary suspected cause of cardiac arrest. In the case of OHCA, witnesses activate the EMS system by emergency call, and the EMS dispatcher is trained to recognize OHCA and lead the witness in initiating CPR. Simultaneously, dis- patchers activate EMS staff in emergency priority in the nearest emer- gency and EM physician vehicles. Advanced life support is subsequently provided by four members of EMS. All stations use the “Rendez-vous” model with a physician on board. Only patients undergo- ing ROSC at the event site were included because termination of CPR at the event site by an EMS physician is a common competence in the Czech Republic. Only patients who underwent ROSC were enrolled in this study and re-arrest en route was managed with repeat CPR in a standing car because mechanical chest devices were not available until the end of the study. In 2013, a CAC was established in the Liberec Central Hospital and, since then, all OHCA patients have been trans- ferred primarily to the CAC according to the joint protocol for CAC hos- pitals and EMS. All of these patients have their own OHCA checklist and data are recorded in the CAC registry. In the present study, patients were divided into two subgroups: CAC (patients with OHCA in the region of the CAC hospital); and bypass (patients with OHCA in the region of any other local hospital). The region is divided into 8 areas, and when local hospital served for area is the nearest hospital with ICU in the me- thodic plan of EMS, with the CAC hospital being one of them.

The aim of the present study was to determine whether prolonged

primary transport of patients after OHCA to a regional CAC influenced initial hemodynamic parameters after admission, mortality, or neuro- logical outcome(s). The collected data included duration of transport, baseline characteristics (age, sex, bystander-CPR, ROSC, shockable rhythm, acute coronary syndromes [ACS], vasopressors at transfer), he- modynamic and laboratory parameters on admission (systolic blood pressure [BP], lactate, pH, oxygen saturation [SpO₂], body temperature, and initial dose of vasopressors and inotropic[s]), and final outcomes (30-day in-hospital mortality, days in the ICU, days on artificial ventila- tion [AV], and 1-year neurological outcome). Duration of the transport was difference between time when EMS car leave place of the event and time when EMS car arrive in the hospital (this times are recorded automatically from statuses of each case protocol). Duration of ROSC was recorded from EMS protocol (time of starting of CPR and time of

ROSC). Hemodynamic parameters were measured in the emergency room, ICU, or catheter laboratory immediately after admission, and pH and lactate levels were measured using the arterial Astrup technique at the same time. Primary outcomes included 30-days in-hospital mor- tality and 1-year neurological outcome (cerebral performance capacity [CPC] 1,2 defined as good neurological status), secondary outcomes in- cluded hemodynamic parameters and laboratory results.

Data recorded in the electronic case report form were analyzed using Prism version 7 (GraphPad Software Inc., La Jolla, CA, USA). Categorical variables are expressed as absolute values and percentages, and were compared using the chi-quadrat test or Fisher’s exact test. Continuous variables are expressed as mean +- standard deviation (SD) or median and interquartile range (IQR [i.e., 25th-75th percentile]) for data that were non-normally distributed. Continuous variables were compared using the Student’s two-choice unpaired t-test. Differences with p < 0.05 were considered to be statistically significant.

Descriptive statistical analysis was performed to assess the relation-

ship between variables. Stepwise logistic regression was used to iden- tify variables that were independently associated with the primary outcomes (i.e., 30-day survival and 1-year good neurological outcome). In the regression model, patient outcome (30-day survival and 1-year good neurological outcome) was the dependent variable. An ? < 0.05 was considered to be statistically significant. As part of the analysis, var- iables that were associated with survival were entered into a stepwise logistic regression model. These included age, bystander CPR, shockable rhythm as initial rhythm, time to ROSC, transport time, systolic BP on admission a lactate level by admission and ACS as cause of cardiac arrest and care center volume per year. In addition, transport interval was added to the model to identify whether it was independently associated with survival. An ? < 0.05 was considered to be statistically significant. Data management and logistic regression analysis was performed using MedCalc (Ostend, Belgium). Given the retrospective nature of the study and the use of anonymized data, requirements for informed consent were waived by the ethics board. However, the study was registered with the local ethics board of the regional hospital. Patients or public were not involved in the design, or conduct, or reporting, or dissemina- tion plans of our research.

1. Results

A total of 258 patients, who experienced OHCA with ROSC in the Liberec region and admitted to the regional cardiac center between Jan- uary 2013 and March 2017, were enrolled. Twenty-seven patients with incomplete data and 17 that were transported from local hospitals were excluded from analysis. Therefore, data from 214 patients were ulti- mately analyzed, with 111 and 103 patients comprising the CAC and by- pass groups, respectively.

• 1. Baseline characteristics

There were no significant differences between the CAC and bypass groups in terms of male sex (73.9% versus [vs.] 79.6%, respectively; p = 0.34) and age (64.13 +- 12.9 vs. 61.52 +- 14.3 years, respectively; p = 0.16). Comparable proportions of shockable initial rhythm in the CAC and bypass groups were observed (65.8% vs. 74.8%, respectively; p = 0.3). Comparing the CAC and bypass groups, there were no signifi- cant differences in the proportion who received CPR before the arrival of EMS staff (67.5% vs. 68.9%, respectively; p = 0.88). There was no signif- icant difference between the groups in the median duration of CPR until ROSC by EMS staff (EMS on event-ROSC): 16 min (IQR 10-27 min) vs. 20 (15-27) min (p = 0.39). ACS–as the principal cause of cardiac ar- rest–was diagnosed in 44.0% in the CAC vs. 48.5% in the bypass group (p = 0.58). No differences were observed between the groups in the ad- ministration of catecholamine by EMS staff, which was required to treat Significant hypotension during transport to hospital (80.2% vs. 69.9%; p = 0.73). Based on EMS documentation, it was possible to calculate

Table 1

Demographic and event characteristics

Table 3

Multivariate analysis: variables independently associated with 30 days survival and one year good neurological outcome (CPC1,2)

Group (n) CAC (111) Bypassing (103) P-value

Demographic and event characteristics

Man, n(%)	82 (73.9)	82 (79.6)	0.34
Age, mean +- SD	64, 13 +- 12.9	61.52 +- 14.3	0.16
Shockable rythm n(%)	73 (65.8)	75 (72.8)	0.3

30-days survival Odds ratio (95%CI)

One year good neurological outcome

Odds ratio (95%CI)

Bystander- CPR n(%)	75 (67.6)	71 (68.9)	0.88
ROSC median(IQR)	16 (10-27)	20 (15-27)	0.39	Time to ROSC (minutes)a	0,96 (0,93 to	0,96 (0,92 to 0,98)
ACS n(%)	49 (44)	50 (48.5)	0.58		0,99)
Vasopressors n(%)	89 (80.2)	72 (69.9)	0.73	Shockable rythmb	0,32 (0,14 to	N/A
Lenght of transport (min)	20 (13-34)	40.5 (28.3-55)	p < 0.0001		0,72)

Median (IQR)

ROSC-Admission (min), mean +- SD

52.6 +- 19.8 76.0 +- 24.9 p < 0.0001

^a Time to ROSC (from EMS car arrival to ROSC), ROSC (Restitution of Spontaneous Circulation).

^b Shockable rythm as initial rythm.

Bystander CPR-CPR provided by witness before EMS team arrive. ROSC- Restitution of spontaneous circulation.

ACS- Acute coronary syndrome.

Vasopressors- use of norepinephrine during transport. ROSC-Admission- time from ROSC to Hospital Admission.

the exact transport time for the patients, which was defined as the time from departing the area of collapse to hospital admission. Median transport time was significantly longer for the bypass group than the CAC group (40.5 min [IQR 28.3-55.0 min] vs. 20.0 min [IQR 13.0-34.0 min], respectively; p < 0.0001). Time from ROSC to hospital admission was also significantly longer in the CAC compared with the bypass group (76.0 +- 24.9 min vs. 52.6 +- 19.8 min, respectively, p < 0.0001). Baseline characteristics of the two groups are summarized in Table 1.

• 1. Outcomes and follow-up

Data regarding ICU stay, days on AV, and 30-day mortality were available for all (i.e., 100%) patients, while data regarding CPC at 1- year follow up were available for 92%. There was no difference in good neurological capacity (i.e., CPC 1 or 2) in the CAC group 50.9%. vs. bypass group 54.9% (p = 0.717). There were no differences in the median length of ICU stay between the CAC and bypass groups (9 days [IQR 4-18 days] vs. 8 days [IQR 4-15 days], respectively; p = 0.3), median days on AV (CAC, 4 days [IQR 1-9] vs. bypass, 4 days [IQR 1-8 days]; p = 0.31], 30-day mortality [60 (57.1%) in the CAC group vs. 53 (56.4%) in the Bypassing group, p = 0.99]. Good neurological outcome (CPC 1 or 2) at one-year follow-up was observed in 52 (50.9%) patients in the CAC group vs. 52 (54.9%) in the bypass group (p = 0.717). PCI was performed in 42 (37.8%) patients in the CAC group vs. 41 (39.8%) in the bypass group (p = 0.78). All results are summarized in Table 2.

The adjusted odds ratio (aOR) for factors associated with 30-day sur- vival and 1-year good neurological outcome was estimated using step- wise logistic regression. Only shockable initial rhythm and time to ROSC were found to be independently associated with 30-day survival, and time to ROSC was independently associated with 1-year good neu- rological outcome (Table 3). Logistic regression analysis revealed no

relationship between transport time and 30-day survival in the study group (aOR 1.0041 [95% confidence interval (CI) 0.99-1.02]), and no re- lationship between transport time and 1-year good neurological out- come (aOR 1.01 [95% CI 0.99-1.04).

• 1. Hemodynamic Physiological parameters

After admission, all patients underwent basic hemodynamic and physiological tests including blood gas analysis. No differences were ob- served in systolic BP after admission (CAC, 104 +- 28 mmHg vs. bypass, 108 +- 31 mmHg; p = 0.33). Additionally, no differences were detected in median lactate level between the two groups (CAC, 4.5 mmol/l [IQR 2.3-8.8 mmol/l] vs. bypass, 4.0 mmol/l [IQR 2.0-6.0 mmol/l]; p = 0.07) or median pH level (CAC, 7.12 [IQR 7.0-7.27] vs. bypass, 7.0 [IQR 7.0-7.27]; p = 0.62). Median body temperature (in-ear) was measured after admission, with no difference between the groups (CAC, 36.0 ?C [IQR 35.0-36.5 ?C] vs. bypass, 36.0 ?C [IQR 35.6-36.7 ?C];

p = 0.15). Oxygen saturation was measured using a finger or ear sensor, with no difference in median values between the groups (CAC, 95.5% [IQR 91-100%] vs. bypass, 98% [IQR 94-100%]; p = 0.14]. Initial doses of catecholamines required to maintain systolic BP >= 100 mmHg were analyzed, median norepinephrine doses after admission were not dif- ferent between groups (CAC, 10 ug/min [IQR 4-20 ug/min] vs. bypass, 8 ug/min [IQR 7-17 ug/min]; p = 0.94). There was no difference in the mean dobutamine dose between the groups (CAC, 464 +- 244 ug/min vs. bypass, 518 +- 279 ug/min; p = 0.69). The results are summarized in Table 4.

• 1. Subgroup analysis

We provided analysis of the subgroups of patients with initial shock- able rhythm and subjects with acute coronary syndrom (ACS), because these subgroups are the most relevant for CAC with catheterization

Table 4

Admission characteristics

roup (n) CAC (111) Bypassing (103) P-value

Table 2

Length of stay and follow up

sBP (mm Hg) mean,SD

104 +- 28 108 +- 31 0.33

	LOCAL (111)	Bypassing (103)	p value	Lactate mmol/l Median (IQR)	4.5 (2.3-8.8)	4 (2-6)	0.07
ICU stay median (IQR)	9 (4-18) days	8 (4-15)days	0.3	pH median (IQR)	7.12 (7-7.27)	7 (7-7.27)	0.62
AV days median (IQR)	4 (1-9) days	4 (1-8) days	0.41	TT median (IQR)	36 (35-36.5)	36 (35.6-36.7)	0.15
30 days mortality	60 (57.1)	53 (56.4)	0.9999	SpO2 median(IQR)	95.5 (91-100)	98 (94-100)	0.14
n (%)				Norepinephrine mcg/min	10 (4-20)	8 (7-17)	0.94
1 year follow up	52 (50.9)	52 (54.9)	0.717	median (IQR)
CPC 1,2 n (%)				Dobutamin mcg/min	464 +- 244	518 +- 279	0.69
Revascularisation, n (%)	42 (37.8)	41(39.8)	0.78	mean, SD

AV days-days on arteficial ventilation.

CPC 1,2-cerebral performance capacity with good outcome (good cerebral performance, moderate cerebral disability).

SPB-systolic blood pressure. TT-body temperature.

SpO2-oxygen saturation.

Table 5

Shockable Rythm subgroup

Group	CAC (N =?)	LOCAL (N =?)	P-value
ICU stay median (IQR)	13 (6-21) days	10 (6-15)days	0.04
AV days median (IQR)	4 (1-9) days	4 (1-8) days	0.82
30 days mortality	21 (31.3)	22 (35.5)	0.7
n (%)
1 year follow up	24 (58.5)	28 (58.3)	0.99
CPC 1,2 n (%) PCI n (%)	35 (48.6)	35(47.3)	0.99

AV days-days on arteficial ventilation.

CPC 1,2-cerebral performance capacity with good outcome (good cerebral performance, moderate cerebral disability).

Table 6

Acute Coronary Syndrom (ACS) subgroup

Group CAC (N =?) LOCAL (N =?) P-value ICU stay median (IQR) 8 (4-17) days 9 (4-15)days 0.57

AV days median (IQR) 5 (1-10) days 4 (1-8) days 0.85

remains incompletely understood. Multiple studies have concluded that prolonged transport time is not harmful to OHCA patients [10,20- 22]; however, delays >30 min may be associated with a poorer survival rate [20]. Cudnik et al. [22] reported that transport distance did not in- fluence the survival-to-discharge rate, and that transport to the nearest hospital was associated with a lower survival-to-discharge rate than transport to a tertiary center (12.1% vs. 16.5%, respectively; p < 0.001) because tertiary centers were more likely to have cardiac catheteriza- tion laboratories, electrophysiology laboratories, higher patient vol- umes, and were teaching institutions. For the location of cardiac arrest were used population-weighted centroid of the census tract, and calcu- lated distance formula to each hospital. However, the median transport distance was only 3.9 km and took 6.3 min, and the mean difference in transport distance for patients taken to further hospitals compared with the closest hospital was only 2.74 km. Our differences in transport time were higher (20.0 min for the CAC group vs. 40.5 min for the by- pass group) than in the study by Cudnik et al. (difference, 6.3 min); however our findings in survival-to-discharge were similar and not associated with transport distance. The study by Cudnik et al. preferred to use distance over transport time. In contrast, we elected to use trans-

30 days mortality n (%)

1 year follow up

CPC 1,2 n (%)

15 (33.3) 15 (35.7) 0.83

14 (60.9) 20 (60.6) 0.99

port time as a major variable because it better reflects real-world situations, in which distance can be influenced by many other factors (e.g., vehicular traffic, agglomeration, terrain); as such, the influence

PCI n (%) 36 (80) 37(78.7) 0.99

AV days-days on arteficial ventilation.

CPC 1,2-cerebral performance capacity with good outcome (good cerebral performance, moderate cerebral disability).

laboratories and their outcomes could be different from common OHCA patients. We have observed no differences between both groups in AV days, 30-days mortality, 1 year good neurological follow up (CPC 1,2) and provided PCI. Only ICU stay was significantly longer in CAC (13 days [IQR 6-21 days] vs. 10 days [IQR 6-15 days], respectively; p = 0.04) in subgroup with shockable rhythm. All results are summa- rized in Tables 5 and 6.

1. Discussion

The major finding of our study was that prolonged transport time of OHCA patients to a CAC, bypassing the nearest hospital, did not influ- ence baseline characteristics on admission nor clinical outcomes, in- cluding mortality and neurological status. Although transport time was significantly longer in the bypass compared with the CAC group, patients in two groups exhibited similar baseline characteristics and he- modynamic and physiological parameters on admission, including doses of catecholamine(s). Moreover, we observed no differences in 30-day and 1-year mortality rates, and length of ICU stays and AV. Transport time was not associated with 30-day survival or 1-year neu- rological outcomes. In subgroup analyses only ICU days were signifi- cantly longer in CAC in the subgroup with shockable rhythm.

Several previous studies have reported that OHCA survivors may benefit from admission to a tertiary CAC, especially cardiovascular cen- ters, compared with hospitalization at the nearest local hospital [10,11]. This effect was explained by the availability of early invasive strategies (e.g., coronarography, mild therapeutic hypothermia) and faster learn- ing curves in high-volume centers. A meta-analysis of previous observa- tional studies, in which the CAC was defined as a site equipped to perform PCI–24 h/day, 7 days/week–and targeted temperature man- agement, reported a significantly improved survival rate and good neu- rological outcome compared with local hospitals [13]. These benefits were linked to the effects of PCI because the majority of OHCA cases are associated with coronary artery disease [14-16] and the availability of Multidisciplinary teams with experienced professionals in CACs [17- 19]. The impact of prolonged transport time to a CAC, nevertheless,

on the patient’s condition is determined predominantly by time, not transport distance. Davis et al. [23] reported that the mean transport time was not significantly different for patients with pre-hospital ROSC, who were declared deceased at the emergency department (8.3 min), died following hospital admission (7.8 min), or survived to hospital discharge (8.5 min). Furthermore, the outcomes of patients who had shorter (<= 7 min) or longer transport times were similar. The mean interval between the EMS dispatch and emergency department arrival was 40 min. These data are also similar in outcomes, but based on a shorter transport time compared with our results. A study involv- ing a cohort in Arizona (United States) [24] had a similar sample size as our study (ROSC, n = 253), but with a worse survival rate (17%). This could be explained by a higher rate of shockable rhythm and by- stander CPR in our study. The mean transport interval was shorter than in our study (6.9 min), and there was no significant association be- tween transport interval and outcome (OR 0.94 [95% CI 0.51-1.8), sim- ilar to our findings. In a meta-analysis including four retrospective studies investigating transport time, Geri et al. [21] reported no signifi- cant difference in transport time between survivors and non-survivors (mean time, 4 to 14.9 min across the studies), with mean differences of -0.05 (95% CI -2.2 to 0.8).

Our study had several limitations, the first of which was its single- center, non-randomized design, and limited sample size investigating changes in transport strategy following the constitution of a CAC for a specific region, and was based on an analysis of a prospective registry covering 4 years including 214 patients with ROSC performed at the place of the event. Furthermore, constitution of the EMS team in differ- ent areas may have influenced the outcomes and, as such, introduced potential bias. We used transport time as the principal variable because we expected that complications may be associated with prolonged transport time; however, we cannot rule out the possibility that the use of distance–rather than transport time–may have led to different results. We also compared time from ROSC to admission, which was also significantly longer in CAC group (by approximately 20 min), which was also the difference in median time for transport to admission between the CAC and the bypass groups. Quality of the care during EMS transport which can also influence outcome of the patients was not re- corded in our study. Monitoring of Vital parameters and their maintain- ing are limited in pre-hospital conditions. We can predict it only from initial parameters after admission which are mentioned in the study.

In conclusion, our results revealed that the strategy of bypassing the nearest hospital and primary transport of patients with ROSC after OHCA directly to the CAC significantly prolonged transport time, but

did not affect hemodynamic parameters on admission or patient out- comes. These findings suggest the transport to more distant CAC is safe for the patients.

Declaration of Competing Interest

None.

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