The ventricular fibrillation waveform in relation to shock success in early vs. late phases of

out-of-hospital cardiac arrest

Jos Thannhauser M.Sc.1, Joris Nas M.D.1, Gjerrit Meinsma Ph.D.2, Hans J. Zwart Ph.D. 2, Pierre van

Grunsven M.D. Ph.D. 3, Menko-Jan de Boer M.D. Ph.D.1, Niels Van Royen M.D. Ph.D. 1, Judith L.

Bonnes M.D. Ph.D. 1, Marc A. Brouwer M.D. Ph.D.1

1 Department of Cardiology, Radboud University Medical Center, Nijmegen, The Netherlands

Address: Geert Grooteplein Zuid 10, 6525 GA Nijmegen, The Netherlands

2 Faculty of Electrical Engineering, Mathematics and Computer Sciences, Department of Applied

Mathematics, University of Twente, Enschede, The Netherlands

Address: P.O. Box 217, 7500 AE Enschede, The Netherlands

3 Regional Ambulance Service Gelderland-Zuid, Nijmegen, The Netherlands

Address: Professor Bellefroidstraat 11, 6525 AG Nijmegen, The Netherlands

Running title: AMSA in early vs. late phase of resuscitation

Word count: abstract: 250; paper: 3003

Number of Tables: 3

Number of Figures: 1

Number of Supplementary Tables/Figures/Text: 1/1/1

Funding: None

Conflicts of interest: Prof. De Boer and Prof. Van Royen have conflicts of interest to declare, see page

14.

Address for correspondence: Jos Thannhauser, Radboud University Medical Center, Department of

Cardiology 616, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands. Tel: +31 243616785,

Fax: +31 243635111. E-mail: Jos.Thannhauser@Radboudumc.nl or j.thannhauser@outlook.com

1

Abstract

Background: The amplitude spectrum area (AMSA) of the ventricular fibrillation (VF) waveform

predicts shock success as well as clinical outcome after out-of-hospital cardiac arrest (OHCA).

Recently, also AMSA-changes demonstrated prognostic value. As of yet, most studies focused on

early shocks, while many patients require prolonged resuscitations. We studied AMSA and its

changes in relation to shock success both in the early and the late phase of resuscitation.

Methods: Per-shock analysis on VF-episodes from a prospective OHCA-cohort (Nijmegen, The

Netherlands). AMSA and AMSA-changes between shocks (ΔAMSA) were calculated from three-

second VF-recordings prior to shock delivery. Shocks were categorised as early (1-3) or late (4-8).

Shock success was defined as return of organised rhythm within one minute after the shock.

Results: Of all shocks, 48% was successful (216/448), without difference between early

(131/286=46%) and late shocks (85/162=52%), p=0.18. Early shock success markedly varied from

20% to 70% with increasing quartiles of AMSA (p-for-trend<0.001). For late shocks, we also observed

an association with AMSA (p-for-trend=0.04), and shock success ranged from 40% to 65%. Higher

values of ΔAMSA were significantly associated with shock success in the early, but not in the late

phase of resuscitation.

Conclusion: AMSA relates to shock success during the entire resuscitation, but associations were

most markedly present for early shocks. AMSA-changes were also associated with shock success, but

only in the early phase of resuscitation. We implicate that absolute AMSA values may be of value

beyond the first shocks, whereas the use of AMSA-changes seems restricted to the early phase.

Keywords: Out-of-hospital cardiac arrest, Ventricular fibrillation, amplitude spectrum area

2

Introduction

Ventricular fibrillation (VF) is the first observed cardiac rhythm in about one third of all out-of-

hospital cardiac arrests (OHCAs). Despite all improvements in the chain of care, survival to hospital

discharge is still only 5-20%.1-4 Based on the principle that defibrillation on so-called “coarse” VF is

more successful than on “fine” VF, analysis of the VF-waveform was introduced. In this context, the

amplitude spectrum area (AMSA) has become a topic of increasing interest. 5

Recently, a series of studies on the VF-waveform demonstrated the impact of AMSA in the prediction

of outcome. It has repeatedly been demonstrated that the absolute AMSA value predicts not only

shock success, but also neurologically favourable outcome.6-8 Moreover, a randomised controlled

trial is currently being conducted, investigating shock timing according to the absolute AMSA value,

with prolonged chest compressions and delay of compressions if the AMSA considered too low. 9

More recently, changes in AMSA have been implicated to play a role of importance as well. Given the

correlation of AMSA with coronary perfusion and myocardial energy levels, an increasing AMSA

might reflect an improvement of the myocardial metabolic state.10-12 Recent analyses on human data

confirmed that increases of the AMSA are associated with favorable outcome. 7, 13

Currently, most information on the impact of AMSA, and particularly its changes, has been derived

from studies investigating the early resuscitation phase.7, 14 The largest studies to date included

patients with a median number of two shocks.5, 6 However, the amount of defibrillations is known to

vary greatly per patient, and recent studies describe that about half of all patients need more than

three shocks in the prehospital setting. 15, 16 At present, little information is available on how AMSA

evolves over a longer period of resuscitation, and how these changes relate to shock success.

In view of the above, it seems prudent to improve our understanding of the VF-waveform and its

relation with shock success over a longer period of resuscitation. In a cohort including prolonged

3

resuscitations, we therefore assessed AMSA and AMSA-changes in relation to shock success for both

the early and late phase of resuscitation.

4

Methods

Study population

Prospective registry of OHCA-patients in the Nijmegen area, The Netherlands (≥18 years, non-

traumatic arrests), of which details have been described earlier.15 For the current study, we included

all patients with VF as first observed cardiac rhythm, who had at least one defibrillation attempt on

VF in the prehospital setting. To ensure comparability of the analysed shocks, we excluded patients

who received AED shocks prior to arrival of the emergency medical services (EMS). Further exclusion

criteria were the absence of either electrocardiogram (ECG) or shock outcome data. Given the

observational design, for the present study written informed consent was not necessary to obtain

according to the Dutch Act on Medical Research involving Human Subjects.

Emergency medical services

The Nijmegen area (Gelderland-Zuid) has a population of about 530,000 residents and covered 1,040

square kilometres, including urban, suburban and rural areas. The EMS system is activated by calling

112. Paramedics give instructions to the caller to initiate basic life support (BLS), and at least one

ambulance is dispatched to the location of the emergency. CPR delivery was performed by EMS

personnel according to the prevailing guidelines at the time of arrest. A mechanical chest

compression device (Autopulse®) was part of the standard EMS-equipment, but not routinely used.

As it was an observational study , ambulance personnel were not instructed to interrupt chest

compressions.

Data acquisition

Demographic and arrest characteristics were collected using EMS and hospital records, according to

the Utstein style definitions.17 ECG and transthoracic impedance (TTI) data (sample frequency of 125

5

Hz and 61 Hz respectively) were recorded with the defibrillator paddles. During the study period, all

patients were treated with defibrillators of the same manufacturer (Lifepak, Physio Control,

Redmond, WA, USA), with identical signal processing characteristics (e.g. built-in bandpass filters).

The ECG and TTI data were visualised with Codestat (Version 7.0, Physio Control, Redmond, WA,

USA) and exported to Matlab-files (.mat) for signal analysis.

VF waveform analysis

VF-waveform analysis was performed with Matlab (Version R2014b, Mathworks, Natick, USA). In this

per-shock analysis, we performed analyses at different time points during the resuscitation, i.e.

analyses of all first shocks, second shocks, third shocks etc. We specified a minimum of 10 analysable

registrations per time point. VF-waveform segments were selected prior to shock delivery, visually

free of (chest compression) artefacts and occurring within 30 seconds prior to the shock. Signals

were pre-processed with a fourth-order Butterworth bandpass filter with cutoff frequencies of 2 and

48 Hz. A three-second segment of VF (N=376 samples) was used for calculation of the VF-

characteristics. All VF-segments were assessed in a uniform manner, blinded for shock outcome.

A discrete fast Fourier transform was performed on all 376 data points for conversion to the

frequency domain. The AMSA was calculated from the obtained frequency spectrum, as the summed

product of individual frequencies and their corresponding amplitudes over an interval from 4 to 48

Hz. A more detailed description of the AMSA can be found in Supplement 1.

Furthermore, we calculated the relative difference of the AMSA compared to the previous shock

delivery (e.g. the relative change of AMSA between shock 1 and shock 2 is calculated as ∆AMSA =

AMSAshock 2/AMSAshock1).

6

Study groups

Shocks were categorised as either shocks in the early phase, or shocks in the late phase of

resuscitation. Dichotomization was based on the median number of shocks in our population.:

Early shocks: Shocks earlier than the median number of shocks in our population

Late shocks: Shocks later than, or equal to, the median number of shocks in our population.

End point and aim of the study

The primary end point of the study was return of organised rhythm (ROOR), defined as at least 2 QRS

complexes within 5 seconds, within 60 seconds after shock delivery. We analysed the AMSA and the

∆AMSA in relation to shock success, separately for the early phase (shocks 1 to 3) and the late phase

of resuscitation (shocks 4 to 8).

Statistics

Categorical data were reported as numbers (percentages). Continuous variables were analysed for

Gaussian distribution and reported as means ± standard deviations or medians (interquartile ranges,

IQR), whichever appropriate. Continuous values of AMSA and ΔAMSA were reported as medians with

IQR and compared between successful and unsuccessful shocks using the Mann Whitney U test.

VF-characteristics were subsequently divided into quartiles and compared in relation to shock

success using Chi-square tests for trend. For all tests, we considered a p-value of <0.05 as statistically

significant. All statistical analyses were performed using IBM SPSS statistics software (Version 22, IBM

Corp., Armonk, NY, USA).

7

Results

Study population

Baseline characteristics of the study population are reported in Table 1. We studied a total of 139

OHCA-patients with VF as first observed rhythm. Main reason for exclusion was the absence of

defibrillator ECG recordings (Supplementary Figure 1). Mean age of the study population was 63 ± 14

years, 71% (98/139) was male. Of all patients, 76% (97/128) had a witnessed arrest, 60% (81/135)

received bystander CPR, 45% (61/137) had sustained ROSC at hospital transportation and 24%

(32/132) survived until hospital discharge.

Shock characteristics

The median number of shocks delivered per patient was 4 (IQR 2-7). An overview of in- and excluded

shocks can be found in Supplementary Figure 1. In total, 448 shocks were available for analysis, of

which 48% was successful (216/448). A total of 286 analysed shocks was delivered in the early phase

of resuscitation, of which 46% was successful (131/286), compared to 162 shocks in the late phase,

of which 52% (85/162) was successful, p=0.18.

Amplitude spectrum area: early vs. late phase of resuscitation

The median AMSA of all shocks in the early phase was 10.5 mVHz [IQR 6.7-14.5]. The median AMSA

was higher prior to successful vs. unsuccessful shocks (11.9 mVHz [7.9-15.9] vs. 8.1 mVHz [5.1-11.1],

p<0.001, Table 2). The proportion shock success was 20% in the lowest AMSA quartile and increased

across quartiles to 70% in the highest AMSA quartile (p for trend <0.001, Figure 1).

The median AMSA of all shocks in the late phase was 7.7 mVHz [IQR 5.7-11.9]. There was a trend

towards a higher AMSA prior to successful vs. unsuccessful shocks (8.6 mVHz [6.0-12.3] vs. 6.8 mVHz

8

[5.5-11.0], p=0.065, Table 2). The proportion of shock success ranged between 40 and 65% among

AMSA quartiles (p for trend = 0.041) (Figure 2).

Figure 3 shows the median values per shock of the AMSA over the course of resuscitation, separately

for successful and unsuccessful shocks.

Changes of the AMSA: early vs. late phase of resuscitation

The median ΔAMSA of all shocks in the early phase was 1.06 [IQR 0.89-1.37]. The median ΔAMSA was

higher for successful vs. unsuccessful shocks (1.17 [0.94-1.42] vs. 1.02 [0.84-1.25], p=0.018, Table 2).

The proportion of shock success ranged between 40 and 65% among ΔAMSA quartiles (p for trend =

0.034, Figure 1).

The median ΔAMSA in the late phase was 0.93 [IQR 0.79-1.10], without significant differences

between successful and unsuccessful shocks (p=0.478, Table 2). The proportion of shock success did

not differ significantly among ΔAMSA quartiles (p for trend = 0.480, Figure 2).

9

Discussion

We investigated the VF-waveform in relation to shock success in a real-world cohort of OHCA-

patients, thereby separately focusing on the early and late phase of resuscitation. Interestingly, the

chance of shock success was comparable in both phases of resuscitation. We demonstrated an

association between pre-shock AMSA and shock success in both phases of resuscitation. Notably, this

association appeared more strongly in the early phase, when compared to the late phase, where the

association between AMSA and shock success was less markedly pronounced. Changes of the AMSA

were also positively associated with shock success, but only in the early phase of resuscitation. The

current findings implicate that pre-shock AMSA can be used as an indicator of shock success

throughout resuscitation, but the use of waveform changes seems restricted to the early phase.

Given that a substantial amount of OHCA-patients require more than three shocks in the prehospital

setting, there is need for other factors determining shock success in these patients.

Previous studies

Animal studies: In animal studies investigating the VF waveform, a higher AMSA has been related to

(defibrillation) outcome, based on its relation with arrest duration.18, 19 The time evolution of VF-

waveform characteristics has also been described in experimental studies. In general, after inducing

VF in animal hearts, the VF-waveform tends to develop from “coarse” to “fine”; a mechanism that is

slowed when CPR is applied to the fibrillating heart.20 Interestingly, in two porcine studies comparing

a CPR-first resuscitation strategy with a conventional shock-first strategy, the subsets with CPR

showed increasing frequencies of VF and had a higher shock success rate.21, 22 Although we did not

analyse the effects of CPR on AMSA in our cohort, our findings were similar in that we found an

association between successful shocks and an increasing AMSA in the early phase of cardiac arrest.

10

Most experimental studies focus on VF in the early phase of cardiac arrest, hampering comparisons

with our analyses in the late phase.

Human studies: A recent study investigating the AMSA prior to all shocks in the prehospital setting,

demonstrated that the averaged AMSA over the total resuscitation is a strong prognosticator of

survival.6 The results of that study already implicated that the AMSA is an important predictor for

outcome throughout all phases of resuscitation. Two previous observational studies described

individual shock success later than the first defibrillation attempt in VF cardiac arrests. The largest

study to date distinguished first and subsequent shocks, and demonstrated that AMSA is predictive

for shock success in both shock types.23 It has to be noticed that the abovementioned studies studied

a population with a median of two shocks per patient, which is markedly lower compared to our

population. Presumably, their results were mainly driven by shocks which we would have categorised

as “early”. Therefore, the predictive ability of AMSA for shock success in this cohort remains

unknown for what we call the “late phase” of cardiac arrest. A smaller OHCA-study investigating a

mean number of 4.4 subsequent shocks per patient, demonstrated a good predictive ability of the

AMSA, also in subsequent shocks. 8 As opposed to the latter study, which studied VF-termination, we

used ROOR as our definition of shock success, which is a more robust end point. Our findings suggest

that there is an association between AMSA and shock success, even in the late phase of resuscitation.

Whether the AMSA can consequently be used as a predictor of shock success in late phases of

cardiac arrest, should be investigated in future larger studies.

Interestingly, the abovementioned studies distinguished subsequent shocks according to the success

of the previous shock. If the patient has shock success, this may influence the probability of shock

success of the next shock, and may therefore be a confounding variable. As it was our primary aim to

assess the association between AMSA and shock success in early vs. late phase of resuscitation, we

did not investigate account for this so-called “recurrent” and “shock-resistant” VF.

11

Waveform changes

Although studies on the evolving waveform are scarce, VF changes have been increasingly

investigated over the past years. A study on OHCA patients in 1993 first described the potential

benefits of increasing VF amplitudes for the chances of survival.24 A more recent study on the course

of the AMSA showed that increases between the first three defibrillation attempts are independently

associated with shock success after OHCA.7 Although the latter study did not investigate the course of

VF later than the third shock in a population with very high survival rates, the results are in line with

our observations.

Other recent studies on the course of the AMSA demonstrated that taking into account ΔAMSA-

measures improves predictive models for return of spontaneous circulation.13, 25 Notably, these

studies incorporated resuscitations with a median of 1 to 2 defibrillation attempts per patient. The

described AMSA changes of these articles therefore mainly involved the first two shocks, which is

especially the phase of resuscitation where we also demonstrated benefits of an increasing AMSA.

In summary, our observations that increases of the AMSA occur between early shock deliveries and

indicate a higher likelihood of defibrillation success, are in line with previous studies on this topic,

and support the hypothesis that VF-changes are a sign of improving myocardial metabolic state in the

early phase of resuscitation. Shocks later than the third shock have scarcely been investigated for

waveform changes. Our results indicate that VF-waveform characteristics develop from “coarse” to

“fine” VF over the course of resuscitation, but that AMSA-changes are not associated with shock

success in the late phase of cardiac arrest. As opposed to the early phase, later phases of

resuscitation are typically characterised by a more varying course in terms of refibrillation, the

number of shocks delivered and intermittent (perfusing) organised rhythms. Potentially, in this late

phase of resuscitation, these factors become more important than changes in the VF-waveform.

Moreover, there remains uncertainty about the impact of underlying heart disease on the VF-

waveform and its clinical implications with regard to shock outcome. 14, 26-29 Potentially, the presence

12

or persistence of a myocardial infarction influences the VF-waveform and its relation to shock

success in later phases of resuscitation.

Implications

In follow-up on previous studies, we demonstrated that the chance of shock success is comparable in

the early and late phase of VF cardiac arrest. Throughout resuscitation, shocks result in organised

rhythm in about 50% of the cases. Remarkably, the association of AMSA with shock success is very

strong in the early phase of cardiac arrest. In later phases, the AMSA is also associated with shock

success, although differences between successful and unsuccessful shocks seemed less pronounced.

Appreciating that a substantial amount of VF-patients receive “late” shocks in the prehospital setting,

and given that each additional shock worsens prognosis, factors associated with shock success are

important in these patients.30 To improve current prediction models, future research should focus on

factors other than the VF-waveform that are associated with shock success in this patient group.

Secondly, our findings confirm that increases of the AMSA in the early phase of resuscitation

are a good prognostic sign. Therefore, one could implicate that the AMSA is a good marker of

myocardial metabolic state and increasing waveform measures represent more “readiness” for

defibrillation in the early phase of resuscitation. In the late phase of resuscitation, the VF-waveform

tends to develop from “coarse” to “fine”, reflecting a decrease of myocardial metabolic state. In this

phase, AMSA-changes were not associated with shock success, implicating that benefits of AMSA-

changes are restricted to the early phase of VF. With regard to trials investigating VF-waveform

guided defibrillation strategies, it can be hypothesised that the potential benefits of VF-changes

should be made in the early phase of VF. In the late phase, other factors potentially gain more

importance.

13

Limitations

Although we analysed patients from a prospective registry, only patients with analysable VF data and

known shock success were included. However, no important differences in baseline characteristics

between in- and excluded patients were observed.

Second, in analogy to previous reports, we chose our shock success definition as return of organised

rhythm. It has to be noticed that ROOR does not always imply return of spontaneous circulation.

Therefore, shocks considered as “successful” might in some cases represent a patient with a

pulseless electrical activity.

Conclusion

In the early phase of VF cardiac arrest, both a high AMSA and an increase in AMSA indicated a high

likelihood of a successful defibrillation. Although less pronounced, the association between AMSA

and shock success pertained in the late phase of resuscitation. Contrastingly, no association between

AMSA changes and shock success was found in the late phase of resuscitation. The current findings

implicate that AMSA can be used as predictor of shock success throughout the resuscitation, but the

use of VF-waveform changes seems restricted to the early phase of resuscitation. Future studies are

warranted investigating determinants of shock success in patients with prolonged VF cardiac arrests.

14

Conflicts of Interest

Prof. de Boer is a member of the European advisory board on interventional cardiology of Medtronic.

Prof. van Royen received research grants from Abbott, Biotronik, AstraZeneca and Philips, and

professional fees from Abbott and Medtronic. The other authors have no conflicts of interest to

declare.

15

Tables and Figures

Table 1: Baseline characteristics of the study population. Values are reported as means ± standard deviations, medians (interquartile ranges), or n (%). CPR = cardiopulmonary resuscitation; EMS = emergency medical services; OHCA = out-of-hospital cardiac arrest; ROSC = return of spontaneous circulation. Baseline characteristics were missing for the following variables: Public location (n=136), witnessed arrest (n=128), bystander CPR (n=135) response time (n=111), number of EMS-shocks (n=138), amiodarone (n=115), adrenaline (n=116), any ROSC (n=136), sustained ROSC (n=137) and survival to discharge (n=132).

OHCA-patients (N=139)

Patient characteristics

Age (years) 63 ± 14

Male gender 98 (71)

Arrest characteristics

Public location arrest 58 (43)

Witnessed arrest 97 (76)

Bystander 93 (73)

EMS 4 (3)

Bystander CPR 81 (60)

Response time (minutes) 8 (5-10)

Number of EMS shocks 4 (2-7)

Amiodarone 63 (55)

Adrenaline 95 (82)

Outcome characteristics

Any ROSC during resuscitation

Sustained ROSC

81 (60)

61 (45)

Survival to discharge 32 (24)

16

Table 2: The amplitude spectrum area (AMSA) in relation to shock success (return of organised rhythm). Shocks were divided in early shocks (shocks 1-3, N=282) and late shocks (shocks 4-8, N=162). Both pre-shock AMSA and the ΔAMSA (change of AMSA compared to previous shock) were reported. Values were reported as medians (interquartile ranges). VF=ventricular fibrillation.

VF-waveform in relation to shock success : Early vs. late phase of resuscitation

Shock success No shock success p-value

All shocks

AMSA 9.7 (7.0-14.0) 7.5 (5.3-11.1) <0.001Δ AMSA 0.98 (0.86-1.23) 1.00 (0.79-1.17) 0.246

Shocks 1-3

AMSA 11.9 (7.9-15.9) 8.1 (5.1-11.1) <0.001Δ AMSA 1.17 (0.94-1.42) 1.02 (0.84-1.25) 0.018

Shocks 4-8

AMSA 8.6 (6.0-12.3) 6.8 (5.5-11.0) 0.065Δ AMSA 0.92 (0.80-1.07) 0.95 (0.76-1.13) 0.478

17

Figure 1 – Quartiles of the amplitude spectrum area (AMSA, left) and the change in AMSA (dAMSA, right) in

relation to shock success (return of organised rhythm), for the first three shock deliveries

AMSA - Early phase of resuscitation

18

Figure 2 – Quartiles of the amplitude spectrum area (AMSA, left) and the change in AMSA (dAMSA, right) in

relation to shock success (return of organised rhythm), for shocks later than the third.

AMSA - Late phase of resuscitation

19

Figure 3– Course of the amplitude spectrum area in relation to shock success.

*p < 0.05

20

Appendix

Supplement 1 – Pre-processing steps, definitions and mathematical formulation of the amplitude

spectrum area (AMSA).

The ventricular fibrillation (VF) signal was sampled at a sampling frequency of f s=125 Hz.

Electrocardiographic (ECG) recordings were pre-processed using a fourth-order Butterworth

bandpass filter with cut-off frequencies of 2 and 48 Hz. To cancel phase shift the filter was applied

once forward and once backward in time, which is what the MATLAB command filtfilt does.

The characteristics were determined from a three-second chest compression free segment of

initially-recorded VF (xn ,n=0,1 ,…,N−1¿, with the number of samples of the filtered time

segment N=376. A standard Fast Fourier Transform (FFT) of the VF segment (xn) returns N Fourier

coefficients x̂0 , x̂1 ,…, x̂N−1. Only the first N /2 coefficients are relevant and they correspond to the

N /2 frequencies f k=k ∙ f s/N with k=0,1 ,…,N /2. The amplitude spectrum area (AMSA) is defined

as 2N ∑

k=0

N−1

|x̂k ∙ f k|, but in this sum only those indices k are taken into account for which 4 ≤ f k ≤ 48.

21

Supplementary Tables and Figures

Supplementary Figure 1 – Flowchart of the patient population. AED = automated external defibrillator; EMS =

emergency medical services; VF=ventricular fibrillation

22

VF as first observed rhythm

N = 273 patients

AED use 54

No analyzable ECG tracing 80

Eligible patients

N = 219 patients

Inclusion

N = 139 patients

Shocks

N = 591 EMS shocks

Early phase

N=286shocks

Late phase

N=162shocks

ECG without VF segment < 30s prior to shock 107

No shock outcome determinable 17

< 10 registrations 19Included shocks

N = 448 shocks

Supplementary Table 1: Per-shock analysis of the amplitude spectrum area (AMSA) in relation to shock success (return of organised rhythm).

Amplitude spectrum area

Shock success No shock success p-value

Shock1 10.3 (4.9-14.1) 7.5 (5.0-10.5) 0.001

2 12.6 (9.1-17.0) 8.6 (4.8-11.3) <0.001

3 12.0 (7.8-15.9) 9.1 (5.3-12.8) 0.03

4 10.6 (7.5-13.1) 7.6 (5.5-13.6) 0.17

5 9.6 (8.2-12.4) 6.7 (5.3-8.9) 0.006

6 7.6 (5.9-10.0) 6.1 (4.9-12.4) 0.417

7 6.0 (4.9-9.3) 7.0 (5.6-12.3) 0.308

8 6.9 (5.3-12.0) 6.6 (5.6-8.7) 0.591

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