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. 2020 Oct 12;15(10):e0240420. doi: 10.1371/journal.pone.0240420

Ionized calcium level at emergency department arrival is associated with return of spontaneous circulation in out-of-hospital cardiac arrest

Sun Ju Kim 1, Hye Sim Kim 2, Sung Oh Hwang 1, Woo Jin Jung 1, Young Il Roh 1, Kyoung-Chul Cha 1,*, Sang Do Shin 3, Kyoung Jun Song 4; on behalf of the Korean Cardiac Arrest Research Consortium (KoCARC) Investigators
Editor: Andrea Ballotta5
PMCID: PMC7549779  PMID: 33045006

Abstract

Background

Calcium level is associated with sudden cardiac death based on several cohort studies. However, there is limited evidence on the association between ionized calcium, active form of calcium, and resuscitation outcome. This study aimed to evaluate the potential role of ionized calcium in predicting resuscitation outcome in patients with out-of-hospital cardiac arrest.

Methods

We analyzed the Korean Cardiac Arrest Research Consortium data (KoCARC) registry, a web-based multicenter registry that included 65 participating hospitals throughout the Republic of Korea. The patients with out-of-hospital cardiac arrest over 19 years old and acquired laboratory data including calcium, ionized calcium, potassium, phosphorus, creatinine, albumin at emergency department (ED) arrival were included. The primary outcome was successful rate of return of spontaneous circulation (ROSC) and the secondary outcomes were survival hospital discharge and favorable neurological outcome (cerebral performance category 1 or 2) at hospital discharge.

Results

Eight-hundred and eighty-three patients were enrolled in the final analysis and 448 cases (54%) had ROSC. In multivariable logistic regression analysis, ionized calcium level was associated with ROSC (odds ratio, 1.77; 95% CI1.28–2.45; p = 0.001) even though calcium level was not associated with ROSC (odds ratio, 0.87; 95% CI 0.70–1.08; p = 0.199). However, ionized calcium level was not associated with survival discharge (odds ratio, 0.99; 95% CI 0.72–1.36; p = 0.948) or favorable neurologic outcome (odds ratio, 0.45; 95% CI 0.03–6.55, p = 0.560).

Conclusion

A high ionized calcium level measured during cardiopulmonary resuscitation was associated with an increased likelihood of ROSC.

Introduction

Low serum calcium level is associated with the development of sudden cardiac death [1, 2]. Hypocalcemia can cause prolongation of QT interval, resulting in torsade de pointes and cardiac arrest, so it is should be properly managed through the administration of calcium chloride or calcium gluconate [3]. Calcium administration in the treatment of patients with cardiac arrest was initially recommended by the American Heart Association Guidelines for advanced life support in 1974 [4]. At that time, it was recommended in patients with any type of rhythm based on the physiologic effect of calcium on cardiac contractility, not on clinical evidence. Therefore, the recommendation was withdrawn since the establishment of cardiopulmonary resuscitation (CPR) guidelines in 2000 because there were studies against the use of calcium during resuscitation, and this has not been changed despite the references being small population-based studies with low level of evidence [5, 6]. However, the effect of calcium misinterpreted because the administration of calcium in these studies was not based on the serum calcium level during CPR. Furthermore, ionized calcium level is a better parameter than total calcium level in monitoring or treating a patient needing calcium replacement. Thus, monitoring the ionized calcium level might be helpful in maintaining optimal cardiac contractility in a patient with cardiac arrest.

In the Republic of Korea, research collaborators have conducted a large-population-based multicenter cohort study on out-of-hospital cardiac arrest, including total calcium and ionized calcium levels at emergency department (ED) arrival. These calcium levels could be associated with the cause or prognosis of cardiac arrest because these are collected immediately after the occurrence of cardiac arrest. We conducted a study to evaluate the potential role of ionized calcium level on resuscitation outcomes in a patient with out-of-hospital cardiac arrest using a Korean registry.

Methods

Data source

This was a registry-based, prospective observational study that analyzed the Korean Cardiac Arrest Research Consortium (KoCARC) registry data between 2014 and 2018. The KoCARC registry is a web-based multicenter registry including 64 participating hospitals throughout the Republic of Korea (ClinicalTrials.gov, number NCT03222999).

Variables in the KoCARC registry include patient information (e.g., age, sex, medical history, do-not-resuscitate information, and witness of cardiac arrest), community and prehospital resuscitation (e.g., place, time, etiology of cardiac arrest, existence of bystander, bystander CPR, emergency medical service resuscitation, prehospital defibrillation, and resuscitation duration at scene and during transportation), hospital resuscitation (e.g., advanced airway, total administered dose of epinephrine, frequency of defibrillation, and laboratory tests at ED arrival), post-resuscitation care (e.g., targeted temperature management (TTM), vasopressor administration, and coronary intervention), and patient outcomes (e.g., return of spontaneous circulation (ROSC), survival to hospital discharge, and neurologic outcome at hospital discharge and 6 months after cardiac arrest occurrence) [7].

In all participating hospitals, the laboratory test was conducted upon ED arrival and optional at the time of KoCARC registry establishment (October 2015), but it was changed to obligatory variables since July 2017. The test variables were as follows: white blood cell count; hemoglobin count; platelet count; sodium, potassium, blood urea nitrogen (BUN), creatinine, aspartate aminotransferase, alanine aminotransferase, total bilirubin, albumin, calcium, ionized calcium, magnesium, phosphorous, total protein, glucose, total cholesterol, B-type natriuretic peptide, and d-dimer levels; and prothrombin time. Arterial blood gas analysis, including partial pressure of oxygen, partial pressure of carbon dioxide, base excess, arterial saturation, and lactate level, was also performed.

The Data Safety and Monitoring Board Committee of the KoCARC was organized to provide data quality control.

Study variables

The following demographic, clinical, and laboratory parameters were obtained from the KoCARC registry: age; sex; total CPR duration; estimated time from collapse to ED arrival; witness of cardiac arrest; bystander CPR; initial presenting rhythm; total administered dose of epinephrine; and blood tests acquired at ED arrival, including calcium, ionized calcium, and variables parameters known to affect calcium level, such as creatinine, potassium, BUN, magnesium, phosphorus, and albumin levels and arterial pH [8]. Data on TTM, survival to discharge, and favorable neurologic outcome were also collected. Estimated time from collapse to ED arrival was obtained by evaluating the time gap from collapse to blood sampling, and favorable neurologic outcome was defined as having a cerebral performance category score of 1 or 2.

This study protocol was approved by the Institutional Review Board of Wonju Severance Christian Hospital (IRB No.CR319065).

Study endpoints

The primary outcome was the ROSC rate, and secondary outcomes were survival to hospital discharge and favorable neurologic outcome at hospital discharge.

Statistical analysis

To compare the characteristics between the ROSC and non-ROSC groups, two-sample t-test was used for continuous variables, and the chi-square test or Fisher’s exact test was used to compare categorical variables. To analyze the factors associated with ROSC, survival to discharge, and favorable neurologic outcome, univariable and multivariable logistic regression analyses were performed, and cubic spline was fitted to estimate the odds ratio (OR).

Analyses were performed using the SAS program (version 9.4, SAS Institute Inc., Cary, NC, USA). A P-value < 0.05 was considered statistically significant.

Results

General characteristics

During the study period, 7,525 patients were enrolled in the KoCARC registry. Patients who were transferred from other hospitals (n = 1,251), aged <19 years (n = 177), with a do-not-resuscitate order (n = 477), with insufficient data (n = 119), and with missed laboratory data (n = 4,670) were excluded (S1 Fig). Finally, 831 patients were included in the final analysis.

There were 545 (66%) men, and the mean age was 68 (±15) years. The total CPR duration and estimated time from collapse to ED arrival were longer in the non-ROSC group (p = 0.001 and p<0.001, respectively). Witnessed cardiac arrest and bystander CPR were more frequently observed in the ROSC group (p<0.001). Regarding the initial presenting rhythm, ventricular fibrillation and pulseless ventricular tachycardia were more frequently observed in the ROSC group (p<0.001), but the total administered dose of epinephrine was higher in the non-ROSC group (p<0.001). In the laboratory tests, potassium (p = 0.020), calcium (p = 0.015), and magnesium (p = 0.015) levels were higher in the non-ROSC group, whereas ionized calcium level was higher in the ROSC group (p<0.001). TTM was performed in all patients with ROSC (Table 1).

Table 1. General characteristics.

Variable Total (N = 831) Non-ROSC (n = 383) ROSC (n = 448) P value
Male sex, n (%) 545 (65.6) 253 (66.0) 292 (65.2) 0.790
Age, year, mean ± SD 68.3 ± 14.9 70.0 ± 14.6 66.8 ± 15.0 0.002
Total CPR duration 53.8 ± 90.7 65.4 ± 107.4 43.9 ± 72.8 0.001
Estimated time from collapse to ED arrival (min), mean ± SD 41.6 ± 70.5 53.30 ± 93.8 31.6 ± 38.4 <0.001
Witness of cardiac arrest, n (%) 551 (66.3) 221 (57.7) 330 (73.7) <0.001
Bystander CPR, n (%) 434 (52.4) 104 (28.3) 151 (34.7) <0.001
Initial presenting rhythm, n (%) <0.001
 VF/pVT 134 (16.1) 53 (13.8) 81 (18.9)
 Pulseless electrical activity 228 (27.4) 79 (20.6) 149 (33.3)
 Asystole 469 (56.4) 251 (65.5) 218 (48.7)
Total administered dose of epinephrine (mg), mean ± SD 6.67 ± 5.0 8.5 ± 4.74 5.07 ± 4.71 <0.001
Creatinine level (mg/dL), mean ± SD 2.32 ± 5.8 2.2 ± 3.3 2.42 ± 7.3 0.578
Potassium level (mmol/L), mean ± SD 6.15 ± 5.0 6.6 ± 2.2 5.8 ± 6.5 0.020
BUN level (mg/dL), mean ± SD 30.76 ± 29.0 33.0 ± 35.9 28.9 ± 21.5 0.053
Calcium level (mg/dL), mean ± SD 8.61 ± 1.4 8.75 ± 1.6 8.5 ± 1.2 0.015
Ionized calcium level (mmol/L), mean ± SD 2.00 ± 1.5 1.79 ± 1.4 2.2 ± 1.6 <0.001
Magnesium level (mEq/L), mean ± SD 2.45 ± 0.8 2.53 ± 0.8 2.4 ± 0.8 0.015
Phosphorus level (mg/dL), mean ± SD 8.66 ± 8.0 8.73 ± 2.9 8.6 ± 10.6 0.847
Albumin level (g/dL), mean ± SD 3.43 ± 10.8 3.89 ± 15.9 3.0 ± 0.8 0.306
Arterial pH (pH), mean ± SD 7.01 ± 2.1 7.09 ± 3.1 7.0 ± 0.2 0.396
TTM after ROSC, n (%) 448 (100)
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BUN, blood urea nitrogen; CPR, cardiopulmonary resuscitation; ED, emergency department; pVT, pulseless ventricular tachycardia; ROSC, return of spontaneous circulation; SD, standard deviation; TTM, targeted temperature management; VF, ventricular fibrillation. Significance level set at a P < 0.05.

Factors associated with ROSC

In the univariable logistic regression analysis, factors associated with ROSC were verified, and the result is shown in Table 2. Total CPR duration, estimated time from collapse to ED arrival, witnessed cardiac arrest, and total administered dose of epinephrine were associated with ROSC, but bystander CPR was not associated with it. In the laboratory test upon ED arrival, calcium, ionized calcium, and magnesium levels were associated with ROSC.

Table 2. Factors associated with ROSC in the univariate logistic regression analysis.

Variable Odds ratio 95% CI P value
Age 0.99 0.98–1.00 0.002
Sex (ref. female) 0.96 0.72–1.28 0.791
Total CPR duration (min) 0.98 0.97–0.99 <0.001
Estimated time from collapse to ED arrival (min) 0.99 0.98–0.99 <0.001
Witness of cardiac arrest 2.05 1.53–2.75 <0.001
Bystander CPR 1.35 1.00–1.82 0.054
Initial shockable rhythm 1.37 0.94–2.00 0.098
Total administered dose of epinephrine (mg) 0.84 0.81–0.87 <0.001
Creatinine level (mg/dL) 1.01 0.98–1.04 0.607
Potassium level (mmol/L) 0.95 0.90–1.00 0.069
BUN level (mg/dL) 1.00 0.99–1.00 0.051
Calcium level (mg/dL) 0.88 0.80–0.98 0.015
Ionized calcium level (mmol/L) 1.18 1.08–1.29 <0.001
Magnesium level (mEq/L) 0.78 0.64–0.96 0.016
Phosphorus level (mg/dL) 1.00 0.98–1.02 0.847
Albumin level (g/dL) 0.96 0.80–1.16 0.665
Arterial pH 0.96 0.85–1.08 0.465
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BUN, blood urea nitrogen; CI, confidence interval; CPR, cardiopulmonary resuscitation; ED, emergency department.

Analysis of the effect of calcium or ionized calcium level at ED arrival on ROSC

The multivariable logistic regression analysis was performed to verify the effect of calcium or ionized calcium level at ED arrival on ROSC. Model 1 was created based on variables with a P-value <0.1 in the univariable logistic regression analysis. Model 2 was created based on variables known to affect the serum calcium or ionized calcium levels, such as creatinine, potassium, BUN, magnesium, phosphorus, and albumin levels and arterial pH. Models 1 and 2 were adjusted simultaneously in model 3. In adjusted model 3, the ionized calcium level was associated with ROSC (OR: 1.89, 95% CI: 1.35–2.66; p<0.001) even though the total calcium level was not associated with ROSC (OR: 0.87, 95% CI: 0.70–1.08; p = 0.199) (Tables 3 and 4). Cubic spline was fitted to visualize differences in the OR of ROSC according to ionized calcium level, and the difference in OR by sex was also analyzed. The OR of ROSC increased proportionally to the ionized calcium level, and this tendency was shown in both sexes (Fig 1).

Table 3. Correlation between calcium level and ROSC in the multivariate logistic regression analysis.

Model Odds ratio 95% CI P value
Crude 0.88 0.80–0.98 0.014
Model 1† 0.90 0.79–1.02 0.110
Model 2‡ 0.88 0.73–1.06 0.171
Model 3§ 0.87 0.70–1.08 0.199
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CI, confidence interval; CPR, cardiopulmonary resuscitation; ED, emergency department; ROSC, return of spontaneous circulation.

†Adjusted for age, sex, total CPR duration, estimated time from collapse to ED arrival, witness of cardiac arrest, bystander CPR, and total administered epinephrine dose.

‡Adjusted for magnesium, albumin, phosphorus, blood urea nitrogen, and creatinine levels and arterial pH.

§Adjusted for Model 1 + Model 2.

Table 4. Relationship between ionized calcium level and ROSC in the multivariate logistic regression analysis.

Model Odds ratio 95% CI P value
Crude 1.18 1.08–1.29 <0.001
Model 1† 1.19 1.06–1.34 0.003
Model 2‡ 1.98 1.45–2.69 <0.001
Model 3§ 1.89 1.35–2.66 <0.001
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CI, confidence interval; CPR, cardiopulmonary resuscitation; ED, emergency department; ROSC, return of spontaneous circulation.

†Adjusted for age, sex, total CPR duration, estimated time from collapse to ED arrival, witness of cardiac arrest, bystander CPR, total administered epinephrine dose, and calcium level.

‡Adjusted for magnesium, albumin, phosphorus, blood urea nitrogen, creatinine, and calcium levels and arterial pH.

§Adjusted for Model 1 + Model 2.

Fig 1. The trend of odds ratio of return of spontaneous circulation followed by the ionized calcium.

Fig 1

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Relationship between survival to discharge and favorable neurologic outcome and ionized calcium level

Ionized calcium level was not associated with survival to discharge (OR: 0.99, 95% CI: 0.72–1.36; p = 0.948) or favorable neurologic outcome (OR: 0.45, 95% CI: 0.03–6.55; p = 0.560) (S1 Table).

Discussion

The ionized calcium level at ED arrival was associated with successful ROSC in this study.

Hypocalcemia can induce fatal arrhythmia or cardiac arrest, because calcium is an essential cation in the generation of myocardial action potential resulting in contraction of cardiac muscles and maintenance of vascular tone [9–11]. Therefore, the maintenance of optimal calcium level is important to maintain normal cardiac function and systemic perfusion [12]. There was trial to promote cardiac contractility during CPR based on above biochemical background, but it was withdrawn from CPR guidelines because of lack of evidence for improving resuscitation outcomes [4–6]. However, this recommendation was based on a small population based studies analyzing the relation between resuscitation outcomes and total calcium level, not the ionized calcium [13, 14]. Unfortunately, total calcium level is influenced by various conditions, such as hypoalbuminemia, azotemia, metabolic acidosis, hyperphosphatemia, lactic acidosis, and bicarbonate infusion [15, 16]. On the contrary, the free calcium cation, generally called ionized form, effect the movement between intracellular compartments and specific membrane protein pumps directly, which acts more important than other forms of calcium in the human body metabolism associated with calcium in physiology and biochemistry [8]. Therefore, it is recommended that the level of ionized calcium, a more reliable parameter and metabolized directly in humans, be monitored in clinical practice [17, 18]. We found the ionized calcium level at ED arrival was associated with ROSC and its probability was proportional to the ionized calcium level in this large-population-based observational study. It might imply that a prompt determination of the ionized calcium level at ED arrival and immediate infusion of calcium chloride or gluconate during CPR could promote ROSC [19, 20]. Considering calcium infusion during CPR can be applicable because the ionized calcium level can be obtained in a short time, even during CPR using a point-of-care arterial blood analyzer widely used in ED or intensive care unit. Furthermore the effect of calcium can be observed immediately after infusion because calcium chloride or calcium gluconate can be infused intravenously and acts like ionized calcium without metabolism [21].

The ionized calcium level was not associated with survival to discharge and favorable neurologic outcome in this study. Because post-cardiac arrest care should be performed in patients with ROSC, most patients resuscitated successfully would be monitored and managed in the intensive care unit [22]. Electrolyte imbalance would be properly monitored and managed because it can promote poor prognosis [23, 24]. Therefore, it might be difficult to confirm survival to discharge with a single parameter such as ionized calcium level at ED arrival, which is why ionized calcium level was not associated with survival to discharge in this study. TTM is the most important treatment modality in promoting neurologic outcome and was performed in all patients with ROSC in this study [25]. It would not affect neurologic outcomes in enrolled patients and was also the reason that ionized calcium level was not associated with favorable neurologic outcome in this study.

The administered epinephrine during CPR could change the level of ionized calcium. In a previous study, it was noticed that catecholamine could lower the calcium concentration [26]. However the opposite or neutral results from other animal studies were also reported and all above studies were not performed in patients with cardiac arrest [27, 28]. Therefore we couldn’t figure out the relation between administered dose of epinephrine and the level of ionized calcium during resuscitation yet. We hope further study could verify the dose responsiveness of epinephrine for the level of ionized calcium in patient with cardiac arrest.

This study had several limitations. First, although this study was based on a relatively large population, selection bias might be present because laboratory tests were not performed in all patients registered in the KoCARC registry. Second, we did not account diseases that affect calcium homeostasis, such as parathyroid disease, in the medical history. Lastly, although all participating hospitals performed advanced life support following current CPR guidelines, additional calcium or sodium bicarbonate might be administered during resuscitation and could affect ROSC.

Conclusion

The ionized calcium level at ED arrival is associated with ROSC. Future randomized controlled studies are needed to verify the precise effect of calcium infusion based on the ionized calcium level at ED arrival in promoting ROSC.

Supporting information

S1 Table. Correlation between ionized calcium concentration and survival discharge and favourable neurologic outcome by multivariable logistic regression test.

(DOCX)

Click here for additional data file. (14.8KB, docx)
S2 Table. The correlation analysis between total administered dose of epinephrine and the ionized calcium.

(DOCX)

Click here for additional data file. (12.6KB, docx)
S1 Fig. Patient flow of out-of-hospital cardiac arrest from 2014 to 2018 in KoCARC registry.

*KoCARC: Korean Cardiac Arrest Research Consortium data.

(TIF)

Click here for additional data file. (100.3KB, tif)
S2 Fig. A scatter plot analysis between total administered dose of epinephrine and ionized calcium.

(TIF)

Click here for additional data file. (1.4MB, tif)

Acknowledgments

The Korean Cardiac Arrest Research Consortium was supported administratively by the Korea Centers for Disease Control and Prevention during the organizing stage.

We would like to acknowledge the chairman of the KoCARC: Sung Oh Hwang (Yonsei University Wonju College of Medicine, e-mail: sheang@yonsei.ac.kr) and members of the Secretariat: Jeong Ho Park (Seoul National University Hospital), Sun Young Lee (Seoul National University Hospital), Jung Eun Kim (Seoul National University Hospital), Na Young Kim (Seoul National University Hospital), and Min Ji Kwon (Seoul National University Hospital). We also thank the investigators from all participating hospitals in KoCARC: Myoung Chun Kim (Kyung Hee University Hospital at Gangdong), Sang Kuk Han (Kangbuk Samsung Medical Center), Kwang Je Baek (Konkuk University Medical Center), Han Sung Choi (Kyung Hee University Hospital), Sung Hyuk Choi (Korea University Guro Hospital), Ik Joon Jo (Samsung Medical Center), Jong Whan Shin (SMG-SNU Boramae Medical Center), Sang Hyun Park (Seoul Medical Center), In Cheol Park (Yonsei University Severance Hospital), Chul Han (Ewha Womans University Mokdong Hospital), Chu Hyun Kim (Inje University Seoul Paik Hospital), Gu Hyun Kang (Hallym University Kangnam Sacred Heart Hospital), Tai Ho Im (Hanyang University Seoul Hospital), Seok Ran Yeom (Pusan National University Hospital), Jae Hoon Lee (Dong-a University Hospital), Ha Young Park (Inje University Haeundae Hospital), Jeong Bae Park (Kyungpook National University Hospital), Sung Jin Kim (Keimyung University Dongsan Medical Center), Kyung Woo Lee (Daegu Catholic University Medical Center), Woon Jeong Lee (The Catholic University of Korea Incheon ST. Mary’s Hospital), Sung Hyun Yun (Catholic Kwandong University), Ah Jin Kim (Inha University Hospital), Kyung Woon Jeong (Chonnam National University Hospital), Sun Pyo Kim (Chosun University Hospital), Jin Woong Lee (Chungnam National University Hospital), Sung Soo Park (Konyang University Hospital), Ryeok Ahn (Konyang University Hospital), Kyoung Ho Choi (The Catholic University of Korea Uijeongbu St. Mary’s Hospital), Young Gi Min (Ajou University Hospital), In Byung Kim (Myongji Hospital), Ji Hoon Kim (The Catholic University of Korea Buchen St. Mary’s Hospital), Seung Chul Lee (Dongguk University Ilsan Hospital), Young Sik Kim (Bundang Jesaeng General Hospital), Hun Lim (Soonchunhyang University Bucheon Hospital), Jin Sik Park (Sejong Hospital), Jun Seok Park (Inje University Ilsan Paik Hospital), Dai Han Wi (Wonkwang University Sanbon Hospital), Ok Jun Kim (Cha University Bundang Cha Hospital), Bo Seung Kang (Hanyang University Guri Hospital), Soon Joo Wang (Hallym University Dongtan Sacred Heart Hospital), Se Hyun Oh (GangNeung Asan Hospital), Jun Hwi Cho (Kangwon National University Hospital), Mu Eob An (Hallym University Chuncheon Sacred Heart Hospital), Ji Han Lee (Chungbuk National University Hospital), Han Joo Choi (Dankook University Hospital), Jung Won Lee (Soonchunhyang University Cheonan Hospital), Tae Oh Jung (Chonbuk National University Hospital), Dai Hai Choi (Dongguk University Gyeongju Hospital), Seong Chun Kim (Gyeongsang National University Hospital), Ji Ho Ryu (Pusan National University Yangsan Hospital), Won Kim (Cheju Halla General Hospital), and Sung Wook Song (Jeju National University Hospital).

Data Availability

Data cannot be shared publicly because of consent of personal information. Data are available from the Korean Cardiac Arrest Research Consortium data registry (KoCARC) commitee. (ClinicalTrials.gov, number NCT03222999) The data can be accessed under the permission from Data Access Committee of KoCARC registry. The contact information is as follows; E-mail address: kocarc_cc@naver.com.

Funding Statement

This study was supported by the Korea Centers for Disease Control and Prevention.

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Decision Letter 0

Andrea Ballotta

7 Aug 2020

PONE-D-20-12193

Ionized calcium level at emergency department arrival is associated with return of spontaneous circulation in out-of-hospital cardiac arrest

PLOS ONE

Dear Dr. Cha,

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.

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We look forward to receiving your revised manuscript.

Kind regards,

Andrea Ballotta

Academic Editor

PLOS ONE

Additional Editor Comments:

Tx for having submitted your manuscript entitled "Ionized calcium level at emergency department arrival is associated with return of spontaneous circulation in out-of-hospital cardiac arrest". After careful consideration the two reviewers supported the option of acceptance for publication but just after addressing some minor issues.

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3. Thank you for stating the following in the Acknowledgments Section of your manuscript:

"This consortium was supported by the Korea Centers for Disease Control and Prevention

during the organizing stage. Currently, the KoCARC is partly supported by the Korean

Association of Cardiopulmonary Resuscitation."

We note that you have provided funding information that is not currently declared in your Funding Statement. However, funding information should not appear in the Acknowledgments section or other areas of your manuscript. We will only publish funding information present in the Funding Statement section of the online submission form.

Please remove any funding-related text from the manuscript and let us know how you would like to update your Funding Statement. Currently, your Funding Statement reads as follows:

"The authors received no specific funding for this work."

4. We note that you have indicated that data from this study are available upon request. PLOS only allows data to be available upon request if there are legal or ethical restrictions on sharing data publicly. For information on unacceptable data access restrictions, please see http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions.

In your revised cover letter, please address the following prompts:

a) If there are ethical or legal restrictions on sharing a de-identified data set, please explain them in detail (e.g., data contain potentially identifying or sensitive patient information) and who has imposed them (e.g., an ethics committee). Please also provide contact information for a data access committee, ethics committee, or other institutional body to which data requests may be sent.

b) If there are no restrictions, please upload the minimal anonymized data set necessary to replicate your study findings as either Supporting Information files or to a stable, public repository and provide us with the relevant URLs, DOIs, or accession numbers. Please see http://www.bmj.com/content/340/bmj.c181.long for guidelines on how to de-identify and prepare clinical data for publication. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories.

We will update your Data Availability statement on your behalf to reflect the information you provide.

5. One of the noted authors is a group or consortium [Korean Cardiac Arrest Research Consortium (KoCARC) Investigators]. In addition to naming the author group and listing the individual authors and affiliations within this group in the acknowledgments section of your manuscript, please also indicate clearly a lead author for this group along with a contact email address.

6. Please include a caption for figure 1.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: It's mine opinion that it's an interesting study that deserves further investigation useful to define the causes of non difference in terms of mortality.

Evalute treatment with calcium administration during cardiac arrest.

Reviewer #2: The authors have presented and addressed a potential important point in the field of cardiopulmonary resucitation where many uncertainty are still to be determined.

The paper is well written and message is clear with some practical insights.

Minor comments

Introduction line 63

might be misunderstood

Please change to “misled” or "misinterpreted" or "should be contextualised"

Line 70

Change “would” with “could”

“Relationship between survival to discharge and favorable  neurologic outcome and ionized calcium level”

It is hard to think that the first measurement of ionized calcium level in patients with ROSC may affect the outcome of the post-cardiac arrest syndrome. I would add this concept in the discussion.

Is it known How exogenous adrenaline administration affect ionized calcium? If yes, and the data are reliable, this should be referenced otherwise it could be a point for further analysis/study.

**********

6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

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Reviewer #1: No

Reviewer #2: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

PLoS One. 2020 Oct 12;15(10):e0240420. doi: 10.1371/journal.pone.0240420.r002

Author response to Decision Letter 0

27 Aug 2020

Response to reviewers

We appreciate your kind recommendations for improving the quality of our manuscript. Here we present our responses or revised content corresponding to your suggestions.

Comment 1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming.

Answer 1: We checked it once more and confirmed the style requirement.

Comment 2. In ethics statement in the manuscript and in the online submission form, please provide additional information about the patient records used in your retrospective study. Specifically, please ensure that you have discussed whether all data were fully anonymized before you accessed them and/or whether the IRB or ethics committee waived the requirement for informed consent. If patients provided informed written consent to have data from their medical records used in research, please include this information.

Answer 2: We added the comments about data coding and informed consent as follows;

Patient information was coded as anonymous so that researchers could not recognize the patient’s personal information.

This study protocol was approved by the Institutional Review Board of Wonju Severance Christian Hospital (IRB No.CR319065) and informed consent was waived in case of unsuccessful resuscitation and obtained after intensive care unit admission in case of successful resuscitation.

 

Comment 3. Thank you for stating the following in the Acknowledgments Section of your manuscript:

"This consortium was supported by the Korea Centers for Disease Control and Prevention

during the organizing stage. Currently, the KoCARC is partly supported by the Korean

Association of Cardiopulmonary Resuscitation."

We note that you have provided funding information that is not currently declared in your Funding Statement. However, funding information should not appear in the Acknowledgments section or other areas of your manuscript. We will only publish funding information present in the Funding Statement section of the online submission form.

Please remove any funding-related text from the manuscript and let us know how you would like to update your Funding Statement. Currently, your Funding Statement reads as follows:

"The authors received no specific funding for this work."

Answer 3: We removed the funding statement from Acknowledgement section and added it in online submission form. We revised the comments about Korea Centers for Disease Control and Prevention because the institution supported administrative work, not a fund. The revised comment is as follows;

The Korean Cardiac Arrest Research Consortium was supported administratively by the Korea Centers for Disease Control and Prevention during the organizing stage.

Comment 4. We note that you have indicated that data from this study are available upon request. PLOS only allows data to be available upon request if there are legal or ethical restrictions on sharing data publicly. For information on unacceptable data access restrictions, please see http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions.

In your revised cover letter, please address the following prompts:

a) If there are ethical or legal restrictions on sharing a de-identified data set, please explain them in detail (e.g., data contain potentially identifying or sensitive patient information) and who has imposed them (e.g., an ethics committee). Please also provide contact information for a data access committee, ethics committee, or other institutional body to which data requests may be sent.

b) If there are no restrictions, please upload the minimal anonymized data set necessary to replicate your study findings as either Supporting Information files or to a stable, public repository and provide us with the relevant URLs, DOIs, or accession numbers. Please see http://www.bmj.com/content/340/bmj.c181.long for guidelines on how to de-identify and prepare clinical data for publication. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories.

We will update your Data Availability statement on your behalf to reflect the information you provide.

Answer 4: We added the following policy for data access in the cover letter.

Comment 5. One of the noted authors is a group or consortium [Korean Cardiac Arrest Research Consortium (KoCARC) Investigators]. In addition to naming the author group and listing the individual authors and affiliations within this group in the acknowledgments section of your manuscript, please also indicate clearly a lead author for this group along with a contact email address.

Answer 5: We have indicated a chairman for our KoCARC registry with a contact e-mail address as follows;

We would like to acknowledge the chairman of the KoCARC: Sung Oh Hwang (Yonsei University Wonju College of Medicine, e-mail address: shwang@yonsei.ac.kr)

Comment 6. Please include a caption for figure 1.

Answer 6. We added a caption for fig 1.

Comment 7. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: It's mine opinion that it's an interesting study that deserves further investigation useful to define the causes of no difference in terms of mortality.

Evaluate treatment with calcium administration during cardiac arrest.

Reviewer #2: The authors have presented and addressed a potential important point in the field of cardiopulmonary resuscitation where many uncertainty are still to be determined.

The paper is well written and message is clear with some practical insights.

Minor comments

7-1: Introduction line 63

might be misunderstood

Please change to “misled” or "misinterpreted" or "should be contextualised"

Answer 7-1: Thank you for your comment. We corrected word as you recommended.

Comment 7-2: Line 70

Change “would” with “could”

Answer 7-2: Thank you for your comment. We corrected word as you recommended.

Comment 7-3: “Relationship between survival to discharge and favorable neurologic outcome and ionized calcium level”

It is hard to think that the first measurement of ionized calcium level in patients with ROSC may affect the outcome of the post-cardiac arrest syndrome. I would add this concept in the discussion.

Answer 7-3) Thank you very much for commenting on what we were worried about. As you mentioned, it is difficult to evaluate the predictability of the ionized calcium drawn at ED arrival for survival discharge or favorable neurologic outcome because there was high risk of bias from patient’s physiologic or pathologic status and treatment modalities or responsibility during post-cardiac arrest care. We removed the description about the relationship between ionized calcium and survival discharge or favorable neurologic outcome at first paragraph on discussion section and the related description was left on discussion section, line 233 through 243.

Comment 7-4: Is it known How exogenous adrenaline administration affect ionized calcium? If yes, and the data are reliable, this should be referenced otherwise it could be a point for further analysis/study.

Answer 7-4: Thank you for your important comments. For confirming your suggestion, we drew a scatter plot and performed a correlation analysis between total administered dose of epinephrine and ionized calcium.

In a scatter plot, there is no linear correlation between the two variables (Supplementary _ fig 2).

As a result of the correlation analysis, it was analyzed that there was a negative correlation between the two variables, but the correlation coefficient was close to 0, so there was little correlation between the two variables (R=-0.0135) (Supplementary_table 2).

There were some studies [1-3] on the relationship between administration of epinephrine and ionized calcium in non-cardiac arrest situation, but we cannot find a study in cardiac arrest situation.

Judging from descriptions above, it seems hard to believe that there is any correlation between total administered dose of epinephrine and the ionized calcium.

We added the above results on the supplements.

 

Reference

1. Kenny, A.D., Effect of catecholamines on serum calcium and phosphorus levels in intact and parathyroidectomized rats. Naunyn-Schmiedebergs Archiv für experimentelle Pathologie und Pharmakologie, 1964. 248(2): p. 144-152.

2. Ljunhgall, S., et al., Effects of epinephrine and norepinephrine on serum parathyroid hormone and calcium in normal subjects. Exp Clin Endocrinol, 1984. 84(3): p. 313-8.

3. Musso, E. and M. Vassalle, Effects of norepinephine, calcium, and rate of discharge on 42K movements in canine cardiac Purkinje fibers. Circulation research, 1978. 42(2): p. 276-284.

Attachment

Submitted filename: Response to Reviewers.docx

Click here for additional data file. (27.2KB, docx)

Decision Letter 1

Andrea Ballotta

28 Sep 2020

Ionized calcium level at emergency department arrival is associated with return of spontaneous circulation in out-of-hospital cardiac arrest

PONE-D-20-12193R1

Dear Dr. Cha,

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

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. 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.

Kind regards,

Andrea Ballotta

Academic Editor

PLOS ONE

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #2: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #2: (No Response)

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #2: No

Acceptance letter

Andrea Ballotta

2 Oct 2020

PONE-D-20-12193R1

Ionized calcium level at emergency department arrival is associated with return of spontaneous circulation in out-of-hospital cardiac arrest

Dear Dr. Cha:

I'm 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 let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, 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.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Andrea Ballotta

Academic Editor

PLOS ONE

Associated Data

    This section collects any data citations, data availability statements, or supplementary materials included in this article.

    Supplementary Materials

    S1 Table. Correlation between ionized calcium concentration and survival discharge and favourable neurologic outcome by multivariable logistic regression test.

    (DOCX)

    Click here for additional data file. (14.8KB, docx)
    S2 Table. The correlation analysis between total administered dose of epinephrine and the ionized calcium.

    (DOCX)

    Click here for additional data file. (12.6KB, docx)
    S1 Fig. Patient flow of out-of-hospital cardiac arrest from 2014 to 2018 in KoCARC registry.

    *KoCARC: Korean Cardiac Arrest Research Consortium data.

    (TIF)

    Click here for additional data file. (100.3KB, tif)
    S2 Fig. A scatter plot analysis between total administered dose of epinephrine and ionized calcium.

    (TIF)

    Click here for additional data file. (1.4MB, tif)
    Attachment

    Submitted filename: Response to Reviewers.docx

    Click here for additional data file. (27.2KB, docx)

    Data Availability Statement

    Data cannot be shared publicly because of consent of personal information. Data are available from the Korean Cardiac Arrest Research Consortium data registry (KoCARC) commitee. (ClinicalTrials.gov, number NCT03222999) The data can be accessed under the permission from Data Access Committee of KoCARC registry. The contact information is as follows; E-mail address: kocarc_cc@naver.com.

    Articles from PLoS ONE are provided here courtesy of PLOS

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