Therapeutic hypothermia after out of hospital cardiac arrest improve 1-year survival rate for selective patients.

BACKGROUND: Therapeutic Hypothermia (TH) is a standard of care after out-of-hospital cardiac arrest (OHCA). Previous reports failed to prove a significant benefit for survival or neurological outcomes. We examined whether the proper selection of patients would enhance treatment efficacy.
METHOD: We conducted a retrospective cohort study. Data was collected from January 2000 and August 2018. Patients were enrolled after OHCA and classified into two groups, patients treated with TH and patients who were not treated with TH.
RESULTS: A total of 92 patients were included in the study. 57 (63%) patients were in the TH Group and 34 (37%) in the Non-TH group. There was no statistical difference in favorable neurological outcomes between the groups. Patients presenting with ventricular fibrillation had a higher 1-year survival rate from TH, while patients with asystole were found to benefit only if they were younger than 65 years (p < .007, p < .02, respectively).
CONCLUSION: Therapeutic Hypothermia patients failed to demonstrate a significant benefit in terms of improved neurological outcomes. Patients treated with TH following ventricular fibrillation experienced the most benefit in terms of 1-year survival, while patients who had suffered from asystole experienced a modest benefit only if they were younger than 65 years of age. Guidelines should address age and primary arrhythmia for proper treatment selection.

1. Introduction

Cardiac Arrest is a sudden cessation of cardiac activity as a result of ventricular fibrillation, asystole, or pulseless electrical activity [1]. The most common cause of cardiac arrest is ischemic heart disease [2-3]. The survival rate of cardiac arrest is very low, with a mortality rate of more than 90%. The only intervention therapy that has been studied so far in randomized trials is therapeutic hypothermia [4-5].

Therapeutic hypothermia was presented to the world in the early 1950s following initial reports of clinical benefits, both in terms of survival and neurological outcomes, in several patients who experienced cardiac arrest. The theoretical basis for starting the treatment was physiological and pathophysiological mechanisms that until now have not been fully understood [6-9].

During cardiac arrest, the blood supply to the body's organs decreases significantly and even stops. Global ischemia transforms the energy processes in the body into anaerobic processes, leading to the secretion of harmful oxidative products such as free radicals, amino acids, and inflammatory products. When blood flow is restored, both by Cardiopulmonary Resuscitation (CPR) and by Return of Spontaneous Circulation (ROSC), the byproduct of long-term ischemia adversely affects cardiac tissues, which are the main oxygen consumers. This leads to irreversible damage. Hypothermia, in this approach, is designed to reduce oxygen consumption of the core organs, reduce free radicals, and protect cell membranes to prevent intracellular oxidation [7-10].

In 2015, the American Cardiology Association, the European Cardiology Association, and the International Liaison Committee on Resuscitation (ILCOR) recommended the use of TH for comatose patients who gained spontaneous circulation after cardiac arrest due to shockable rhythm (class II, LOE A). In non-shockable rhythm cases, such as asystole or PEA, the benefit of therapeutic hypothermia was less evidenced (class II, LOE B) [11-14].

In the following years, several studies supported TH use, while others failed to prove a direct link between treatment and outcomes. Some of the studies regarded the cost-benefit of this complex treatment [15-22].

In 2016, a large meta-analysis of six prospective studies involving approximately 1399 patients found no significant benefit in either neurological outcomes or survival rate from TH use. The limitations of the study concerned mainly patient selection. Several trials included a high proportion of asystole or pulseless electrical activity patients. Patients with cardiac arrest following non-shockable rhythm were represented in small groups in previous studies, and the treatment efficiency was less pronounced in those groups. The broad diversity of target core temperatures among study trials also affected study validity [23].

1.1 Rational of the study

Our institute has been performing mild therapeutic hypothermia since 2008. The goal of the study was to examine its effectiveness in both neurological and survival aspects in subgroup patients.

2. Methods

We designed a retrospective cohort study conducted at our intensive cardiac care center. The study population included patients hospitalized after out-of-hospital cardiac arrest (OHCA) from January 2000 to August 2018. The patient's medical information was collected from the hospital's computer systems and Clalit health data service (Orion, Ofek, and Chameleon). Information regarding the events prior to hospital admission was collected from on-site family members and emergency medical staff (EMS). Medical records from an external defibrillator were collected and analyzed.

Patients eligible for the study (S1 Table. Inclusion and exclusion criteria) were divided into two groups according to the therapeutic approach: patients who were treated with TH (TH-Group) and patients who were not treated (Non-TH Group). Since 2008, TH has been the standard of care in OHCA patients. Therefore, we used a randomized, demographic-matched group of patients from 2000 to 2008 as a control group and assessed treatment efficacy.

TH was initiated in the intensive cardiac care unit with the use of the thermoregulation system Criticool, manufactured by MTRE Advanced Technology Ltd, Israel. The cooling system was connected to a garment to facilitate cooling water over all body surfaces. We also use iced water gastric lavage cooling via a nasogastric tube and the continuous IV infusion of cooled isotonic saline solutions. The target cooling temperature was set to 33°C, and the target re-warming temperature was set to 36°C.

The primary endpoint was defined as the rate of survival of patients during hospitalization and up to one year after discharge. The secondary endpoint was divided, focusing on several points, the first being the rate of major adverse cardiovascular events (MACE), including acute myocardial infarction, congestive heart failure, arrhythmia, cardiac arrest, and sepsis within 30 days and up to one year after discharge. An additional secondary endpoint was the neurological status according to the CPC score during hospitalization, after 30 days, and up to one year following discharge [24].

2.1 Ethics

The study was approved by the Ethics Committee of the hospital in accordance with the Helsinki Convention No. EM-0062-17. Informed consent was not required due to the confidentiality of patent data.

2.2 Research planning

During the study period, 238 patients were hospitalized in our ICCU due to OHCA after regaining spontaneous circulation. 48 patients did not meet the inclusion criteria and two patients were excluded due to the discontinuation of treatment. 190 patients were eligible for study and were divided into two groups based on therapeutic approach. 57 were treated with hypothermia, and 133 were not. We randomly selected a group of 35 patients who were not treated with hypothermia, matched by a demographic propensity score, to serve as a control group (Fig 1. Research Planning).

Fig 1

Research planning.

2.3 Statistics

Considerations in calculating the sample size were based on several key points: incidence of OHCA, primary outcome, and efficacy of therapeutic hypothermia. We estimated an inpatient mortality rate of 30% after OHCA and treatment efficacy among the patient groups of about 10% with a at least 15% group difference. Sample size calculation estimated a total of 88 participants in a 2:1 ratio for 95% CI and 80% power. Differences in the two groups’ demographic data were tested by a χ2 test or Fisher exact test where appropriate for the categorical data and by a student’s t-test or the Mann-Whitney U test in the case of non-parametric data for continuous data. The treatment group was divided into subgroups by age (<65 / ≥65) and primary arrhythmia (VF/asystole). Kaplan Meier survival analysis was performed in order to test differences in one-year survival time between the control group and the four treatment subgroups (age group by primary arrhythmias). Propensity score matching was performed using logistic regression analysis and the greedy matching technique. Calculation was done using both R (MatchIt) and SAS for optimal bipartite matching. Cox regression analysis was performed in order to assess the predictors for 1-year mortality. Statistical analysis was done using SAS software version 9.4 and R (MatchIt). Statistical significance was obtained if p < .05.

3. Results

The study included 92 patients in total: 57 patients in the TH-group and 35 patients in the Non-TH group. The groups, as designed, did not differ in demographic characteristics such as age, gender, cardiovascular risk factors, and prevalence of coronary artery disease (S2 Table. Patients demographic characteristics).

Cardiac arrest events, in both groups, occurred mostly near the residential environment or at home. In more than half of the patients, OHCA was the first cardiac event documented, without prior ACS events having taken place. About 40% of patients complained of chest pain prior to the event. The median time for ROSC was 30 minutes. Ventricular fibrillation was the most common first-documented rhythm seen in patients treated with hypothermia, whereas asystole and PEA were seen mostly in the non-treated group (68.4% and 58.8%, p < .001, respectively) (Table 1. Preliminary admission data).

Table 1

Preliminary admission data (PAD).

	Therapeutic Hypothermia(n = 57)	Non-Therapeutic Hypothermia(n = 35)	p-Value
Place of the event			.98
Home	32 (56.1)	19 (54.3)
Public place	19 (33.3)	12 (34.3)
Medical Clinic X	6 (10.5)	4 (11.4)
Preceding chest pain Y	22 (38.6)	16 (45.7)	.50
Time to CPR (min) Z median ± range)	4.94±8.19(0; 0–40)	9.32±11.31(2.5; 0–35)	.12
Time for ROSCS (min)W (median ± range)	30.48±18.77(28; 5–75)	26.77±14.01(28; 7–50)	.76
First documented arrhythmia			.01
Ventricular Fibrillation	39 (68.4)	14 (41.2)
Asystole/PEA	17 (29.8)	20 (58.8)

X Medical clinic = local clinic with the capability of first care and basic life support assistant

Y Missing/Unclear data appears in three patients

Z Time to CPR = Duration from cardiac arrest to initiation of cardiopulmonary resuscitation (CPR)

W Missing/Unclear data appears in seven patients

S ROSC time = Duration from CPR initiation (by bystander or Emergency medical service) to return of spontaneous circulation (ROSC)

In almost 70% of the patients, ischemic changes were observed in the initial ECG. ST elevation was seen in half of the cases. New LBBB was rarely seen in the TH group. Primary percutaneous coronary intervention (PPCI) was done in more than 70% of patients in both groups, and in more than 90% of patients, a coronary abnormality was seen, and infarct-related artery (IRA) was identified. Three vessels disease (TVD) was seen in 40–50% of cases and only 70–80% of PCIs were considered successful (Table 2. ECG, echocardiographic and coronary angiography data).

Table 2

ECG, echocardiographic and coronary angiography data.

	Therapeutic Hypothermia(n = 57)	Non-Therapeutic Hypothermia(n = 35)	p-Value
ECG	38 (68.7)	26 (74.3)	.44
ST segment elevation	28 (49.1)	11 (31.4)	.10
ST segment depression	8 (14.0)	3 (8.6)	.52
New Left bundle branch block	3 (5.3)	8 (22.9)	.02
New Q pathological Wave	1 (1.8)	4 (11.4)	.07
Primary PCI A	41 (71.9)	25 (71.5)	.96
Identified IRAB	34 (97.1)	22 (91.7)	,56
TVD C	23 (56.1)	9 (39.1)	.19
Opened IRAB	35/41 (85.4)	16/23 (69.6)	.20
LVEF D (%) (median ± range)	29.16 ±23.6(35; 0–60)	20.6 ±22.2(20; 0–60)	.09
LVEF ≤ 40%	28 (52.8)	23 (65.7)	.23
New Mitral regurgitation	15 (28.3)	10 (28.6)	.98

A PCI = Percutaneous coronary intervention

B IRA = Infarct related artery

C TVD = Three vessels disease

D LVEF = Left ventricular ejection fraction

The occurrence of major cardiovascular events (MACE), including myocardial infarction, heart failure, arrhythmias, cardiac arrest, and sepsis, up to one year after discharge did not differ between the study groups (Table 3. Primary and Secondary end points).

Table 3

Primary and Secondary end points.

	Therapeutic Hypothermia(n = 57)	Non-Therapeutic Hypothermia(n = 35)	p-Value
CPC1 on discharge			.39
1	13 (22.8)	7 (43.8)
2	3 (5.3)	1 (6.3)
3	6 (10.5)	3 (18.8)
4	8 (14.0)	1 (6.3)
5	27 (47.4)	4 (25.0)
CPC (average ± SD)–at discharge	3.58±1.65	2.63±1.71	.05
CPC (average ± SD)–at 30 days	3.26±1.78	2.38±1.59	.07
CPC (average ± SD)–at 1 year	3.28±1.84	2.08±1.55	.03
In-hospital mortality	26 (45.6)	19 (54.3)	.42
30 days mortality	0 (0.0)	0 (0.0)	—
1-year mortality	2 (6.4)	3 (18.8)	.32
MACE 2 –at 30 days	1/31 (3.2)	0 (0.0)	>.99
Myocardial Infarction	0 (0.0)	0 (0.0)	—
Congestive heart failure	0 (0.0)	0 (0.0)	—
Ventricular arrhythmia	1 (3.2)	0 (0.0)	>.99
Cardiac arrest	0 (0.0)	0 (0.0)	—
Sepsis	1 (3.2)	0 (0.0)	>.99
MACE2 –at 1-year	7 /31 (22.6)	1/16 (6.2)	.23
Myocardial Infarction	1 (3.2)	0 (0.0)	>.99
Congestive heart failure	0 (0.0)	0 (0.0)	—
Ventricular arrhythmia	3 (9.7)	1 (6.2)	>.99
Cardiac arrest	1 (3.2)	0 (0.0)	>.99
Sepsis	4 (12.9)	0 (0.0)	.28

1 CPC = Cerebral performance category scale

2 MACE = Major adverse cardiovascular events

There was no significant difference in mortality rates during hospitalization and up to one year after discharge between the two study groups. Patients who survived OHCA had a high mortality rate of about 50% during hospitalization. During the first year after discharge, there was an additional mortality risk of approximately 12% (Table 4. 1-year mortality subgroup analysis).

Table 4

1-year mortality subgroup analysis (arranged by survival rate).

Group	N	Mean DaysSurvived	StandardError of the mean	95% CI(days)
Age≥65 and VF1	8	228.5	47.6	135.2–321.8
Age<65 and VF1	12	208.4	33.7	142.3–274.6
Age<65 and asystole	27	191.3	55.0	83. 6–299.0
Control group	10	153.0	28.8	96.5–209.5
Age≥65 and asystole	35	72.0	46.0	0.0–162.3
Overall	92	177.4	18.2	141.8–213.0

1 VF = Ventricular Fibrillation

Sepsis was observed in 51% of patients treated with hypothermia compared to 40% of untreated patients (p < .04). The most common cause for sepsis among both groups was pneumonia. In 65.5% of patients in the TH group, pathogens were identified compared to 35.7% of patients in the Non-TH group. The most common Gram-positive bacteria were Streptococcus pneumonia, followed by Staphylococcus aureus. Escherichia coli and Hemophilus influenza were the predominant Gram-negative pathogens (S3 Table. Cause of sepsis among study groups).

Cox regression analysis indicated that the age, primary arrhythmia, and Time to CPR were the highest-impact variables for 1-year mortality. When adjusting Time to CPR to age, it appears that age and initial arrhythmia were the only significant variables for mortality and had no influence on neurological outcomes.

Patients in the TH group had a larger average CPC scale upon discharge compared to the Non-TH group (3.58±1.65 vs. 2.63±1.71, p < .05). There was no significant improvement in average neurological outcomes after 1 year in both groups (S1 Fig. Neurological outcome—30 days & 1-year average CPC score among study groups).

4. Discussion

Therapeutic hypothermia requires a considerable amount of resources and highly qualified medical staff. It limits medical care during the first 24–48 hours and is accompanied by a significantly high risk of sepsis.

Initial observational studies, in the early 1990s, showed a neurological benefit in reducing intracranial pressure in patients following head trauma. However, years later, some of these researchers contradicted their own findings by failing to prove a direct connection [25-32].

In the beginning, the desired depth of cooling or cooling length was not clear. Initial experiments were performed when cooling was set to a core temperature of 28–32°C. Initial results failed to demonstrate a significant survival benefit, and many studies abandoned this approach. Fifteen years later, this technique was resumed focusing on a modest cooling of 32–34°C. The results of the first animal trials were promising, with significant survival rates and better neurologic outcomes. Therapeutic hypothermia was then classified into three categories depending on the depth or cooling intensity: 35–32°C, 31.9–30°C, and 29.9–28°C, or Mild, Modest, and Deep hypothermia, respectively [32].

In 2002, two randomized trials, from Melbourne, Australia and Europe (multicenter), showed a better neurological outcome and higher survival rate in patients treated with mild therapeutic hypothermia. The larger of the two trials involved 136 patients in several European countries and was administered by a research group comparing unconscious patients with a self-pulse capability who survived cardiac arrest outside the hospital when the first arrhythmia observed was ventricular fibrillation. Survival after 6 months of hospitalization was higher in patients treated with mild hypothermia compared with those who were not treated (41% and 55%, respectively, p = .02). The neurological damage upon discharge was more severe among patients who were not treated with hypothermia (39% and 55% for good neurologic outcomes, respectively, p = .002). Similar results were described in the Australian study [33-35].

Our study retrospectively analyses the treatment efficacy during two different time periods, prior to the TH era and afterward, with a time interval of almost two decades between the first and last patient. Despite the tremendous change in primary PCI catheterization, treatment with therapeutic hypothermia has not demonstrate a significant benefit in terms of both survival rate and neurological outcomes in patients.

Post-hoc analysis indicates that selective patients had higher survival rate benefited more following therapeutic hypothermia. Patients admitted due to ventricular fibrillation had a higher survival rate following therapeutic treatment regardless of their age, while patients admitted due to non-shockable rhythm, such as asystole, experienced a modest benefit only if they were younger than 65 years. Hypothermic treatment in patients older than 65 years who are admitted due to asystole may be at risk of harm from this treatment (Fig 2. Preliminary admission data).

Fig 2

1-year survival rate among subgroup (K-M graph).

Our study did not reveal a significant benefit in neurological outcomes from therapeutic treatment. In our estimation, this could be explained by various factors such as small sample size and lack of an accurate and more specified assessment model to asses neurological status.

We recommend designing a model of targeted patient selection for TH based on data from multiple experienced centers and validating it prospectively. Additionally, we recommend adopting or designing a more accurate and detailed neurological assessment model for cardiac arrest patients.

4.1 Limitations of the study

This is a retrospective study using data spanning a long period of time. Data was taken from computer systems without having the ability to assess their reliability. There is a natural bias in the choice of patients admitted to the cardiac unit in our center, with a high likelihood of suffering from cardiac etiology.

In addition, we used two different time periods that are expressed by different baseline characteristics. This bias was reduced by propensity score matching, yet differing preliminary admission data may still affect the research outcome, e.g., prolonged ischemia time, incidence rates of left bundle branch block, revascularization success rates, etc.

5. Conclusions of the study

Therapeutic hypothermia carries a considerable risk of mortality and morbidity. The use of Therapeutic Hypothermia may not be suitable for all patients and in all cases of out-of-hospital cardiac arrest. Our observation and post-hoc analysis suggest that proper patient selection, based on initial presented arrhythmia and age of the patient, had a significant impact on 1 year mortality. Our research may explain the different results of previous studies.

Inclusion and exclusion criteria.

(DOCX)

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Patients demographic characteristics.

(DOCX)

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Cause of sepsis among study groups.

(DOCX)

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Neurological outcome– 30 days and 1-year average CPC score among study groups.

(DOCX)

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(XLSX)

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9 Oct 2019

PONE-D-19-24905

Proper patient selection for Therapeutic Hypothermia after Out of Hospital Cardiac Arrest improve 1-year Survival rate

PLOS ONE

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Reviewer #1: Thank you very much for giving me the opportunity to review this manuscript. In the present study Koren et al. retrospectively examined whether proper selection of cardiac arrest patients would increase the effectiveness of therapeutic hypothermia (TH) in terms of survival and neurological outcome. They concluded that patients treated with TH following VF benefited the most (in term of 1-year survival), compared to the modest benefit showed in patients under 65 with asystole, which is an interesting finding. No effect was demonstrated regarding neurological outcome. However, the following issues have arisen:

1. The authors report that they included only OHCA patients in the study. Nonetheless, in table 1 it is clear that some patients suffered from cardiac arrest inside a medical facility. Please clarify this in the manuscript.

2. It is not clear at what temperature TH was performed. Please clarify this in the manuscript.

3. Please use the abbreviations that you have already defined, all over the manuscript and define the ones that have not been explained. Also, define all abbreviations used in tables and figures.

4. Sustained VT is not a cardiac arrest rhythm. Pulseless VT is a shockable rhythm. Please change this in the “introduction” section.

5. Due to the grammar and language mistakes in the entire article, I strongly recommend manuscript editing by a native speaker.

6. A huge part of the “introduction section” is a review of the current literature. Please move this part to the “discussion section”.

7. Clarify what “ischemic time” means and how it was measured.

8. All patients were unresponsive after ROSC or did they have a good level of consciousness when they arrived at your hospital?

9. The patients were treated for OHCA with AEDs? How did the authors know the presenting rhythm (PEA, asystole, VF, PVT)? Please include this information in the manuscript.

10. Change sudden cardiac arrest to “cardiac arrest”.

11. Many statements are not followed by a reference. Please insert all necessary references.

12. In the Introduction section you refer to 3 categories of TH depending on the depth of cooling intensity but then you state only 2 categories. Please report all 3.

13. From all patients included in TH and non-TH groups you had information about the preceding symptoms, ischemic time, time for ROSC etc? If not, include the exact number of patients from whom you had information in table 1. Also state what the number in parenthesis represents.

14. Please define what “median time for ROSC” represents. Is it the time from the beginning of CPR by bystanders, the EMS or from the cardiac arrest?

Reviewer #2: Dear authors,

I read with interest your study which examined whether proper selection of patients increase the efficacy of TH and reported that it failed to demonstrate a significant benefit in neurological outcome. Of course, this is a retrospective study with the well-known limitations associated with this type of studies.

Due to ethical issues, I would be very reluctant to withhold TH in any patient admitted in my Department and I would need very strong evidence before I do it. Your study can help the resuscitation community by being used as the first step for conducting large RCTs on proper patient selection. I have some major comments:

1. The issue of proper patient selection is paramount. Of note, there are published studies assessing the effect of BMI in patients who are not treated with TH and adding this information (BMI of your patients) would be important.

2.. The non-significant benefit of TH is a result that cannot be neglected and merits further research. Notably, there was a small difference between the two groups, which could be significant if the study sample was larger. Also, your study confirms the adverse events associated with TH that have been reported by other authors and RCTs, e.g. infection, but you do not describe the method for inducing TH in your institution (initiated in ED/ICU, blankets/IV fluids, etc). Please comment.

3. Some minor comments: Your introduction section must be organized to 3-4 smaller paragraphs. It is too large. Also, please add the matching process (in-detail) to the supplementary material and have the manuscript reviewed by a native English speaker.

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Reviewer #1: No

Reviewer #2: No

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17 Oct 2019

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25 Nov 2019

PONE-D-19-24905R1

Proper patient selection for Therapeutic Hypothermia after Out of Hospital Cardiac Arrest improve 1-year Survival rate

PLOS ONE

Dear Dr. Koren,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Specifically, please address the following editorial requests:

- In your manuscript you state that "Informed consent was not required due to the confidentiality of patent data" and also "researchers contacted the patient or close relatives for further details". If the data was kept confidential please explain how patients or their relatives were contacted.

- In your Methods section, please provide additional details regarding your statistical analyses. A sample size calculation is referred to but not described, nor an appropriate sample size stated. Also, no post-hoc corrections for multiple comparisons are mentioned in your manuscript. If these were performed please include them in the text, or justify their absence.

- Please revise parts of your manuscript (and title) that use the phrase "proper patient selection". This is unclear and open to misinterpretation in the context of whether adequate clinical practice was followed for the patients included in the study, can you therefore revise the title and references to this in the text to ensure it aligns to the analysis undertaken as part of the study. Additionally, avoid referring to any "causal" links in the text. The retrospective nature of this study does not allow for these to be made, please revise references to ‘effectiveness’ or ‘efficacy’ and tone down your 'Conclusions' section accordingly.

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Kind regards,

Natasha Rickett

Associate Editor

PLOS ONE

On behalf of,

Theodoros Xanthos

Academic Editor

PLOS ONE

27 Nov 2019

response to reviewers file was uploaded

Submitted filename: Review 25.11.19.docx

Click here for additional data file.

11 Dec 2019

Therapeutic Hypothermia after Out of Hospital Cardiac Arrest improve 1-year Survival rate for selected patients

PONE-D-19-24905R2

Dear Dr. Koren,

We are pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it complies with all outstanding technical requirements.

Within one week, you will receive an e-mail containing information on the amendments required prior to publication. When all required modifications have been addressed, you will receive a formal acceptance letter and your manuscript will proceed to our production department and be scheduled for publication.

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With kind regards,

Theodoros Xanthos

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

23 Dec 2019

PONE-D-19-24905R2

Therapeutic Hypothermia after Out of Hospital Cardiac Arrest improve 1-year Survival rate for selected patients

Dear Dr. Koren:

I am pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please notify them about your upcoming paper at this point, to enable them to help maximize its impact. If they will be preparing press materials for this manuscript, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

For any other questions or concerns, please email plosone@plos.org.

Thank you for submitting your work to PLOS ONE.

With kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Professor Theodoros Xanthos

Academic Editor

PLOS ONE