Association between pH and neurological outcome among cardiac arrest patients treated by extracorporeal CPR: a prospective observational cohort study in Japan

We aimed to identify the association of pH value in blood gas assessment with neurological outcome among out-of-hospital cardiac arrest (OHCA) patients treated by extracorporeal cardiopulmonary resuscitation (ECPR). We retrospectively analysed the database of a multicentre prospective observational study to collect pre-hospital and in-hospital data among OHCA patients in Osaka prefecture, Japan (CRITICAL study), from 1 July 2012 to 31 December 2016. We included the adult OHCA patients treated by ECPR with blood gas assessment before starting ECPR. Patients with OHCA of external causes, such as trauma, were excluded. The patients were divided into three approximately equal groups based on the pH values. We conducted logistic regression analysis to identify the odds ratio (OR) and 95% confidence interval (CI) of the groups for the 1-month neurological favourable outcome adjusted by the potential confounders of sex, age, witnessed by bystander, CPR by bystander, pre-hospital initial cardiac rhythm, and cardiac rhythm on hospital arrival.

among OHCA patients treated with ECPR. It may be helpful to consider the candidate for ECPR.

Background
Extracorporeal cardiopulmonary resuscitation (ECPR) is a mechanical haemodynamic support for out-of-hospital cardiac arrest (OHCA) patients using veno-arterial extracorporeal membrane oxygenation (V-A ECMO). Although this advanced resuscitation is expected to improve outcomes among patients with refractory cardiac arrest, it is invasive and expensive and requires huge human resources. 1− 3 Therefore, it is important to judge whether this is appropriate for a patient immediately after hospital arrival, based on the available information associated with neurological outcome. 4,5 Blood gas assessment (BGA) is performed easily and commonly to identify the treatable causes and predict prognosis in resuscitation for OHCA. 6− 10 Of the factors assessed in BGA, pH value in particular is influenced by metabolic and respiratory acidosis and is representative of haemodynamic and respiratory conditions. 11 Some observational studies show that the pH value after the return of spontaneous circulation (ROSC) is associated with neurological outcome among OHCA patients. 6− 8 These results may be helpful in neurological outcome, among OHCA patients treated with ECPR.

Methods
We have reported the methodology of this study according to the STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) statement. 12 The Ethics Committee of Kyoto University and each participating institution approved this study protocol (R1045), and written informed consent was waived.

Study design and settings
We performed retrospective analysis of the database of the Comprehensive Registry of Intensive Care for OHCA Survival (CRITICAL) study. This is a multicentre prospective observational study to collect pre-hospital and in-hospital data among OHCA patients in Osaka prefecture, Japan. The pre-hospital data was obtained from the All-Japan Utstein Registry of the Fire and Disaster Management Agency (FDMA). 13− 16 In-hospital data were from 13 tertiary critical care medical centres (CCMCs) and 1 non-CCMC community hospital with an emergency department, all in Osaka prefecture in Japan. Osaka prefecture is an urban area of 1,905 km 2 , and it had a residential population of about 8.8 million in 2015. 17 In Osaka Prefecture, a total of 7,500 OHCA cases occur every year, 18 and approximately 1 in 4 OHCA patients (approximately 2,000 cases or more) have been registered every year from 2012 to 2016. This registry is still ongoing, with an undefined study period. In-hospital data were recorded by the physicians in charge of the patients and registered by the physicians or medical administrators using a predefined online form.
Finally, the working group checked and confirmed the quality of data. If the data were incomplete, they were returned to each institution, and then the data were completed. 16 A detailed description of the All-Japan Utstein Registry of FDMA and the CRITICAL study were previously published. 16

Study patients
From the CRITICAL database, we included all adult (aged ≥ 18 years) patients with OHCA due to internal medical causes, who were treated with ECPR, between 1 July 2012 and 31 December 2016. We defined ECPR as initiation of cardiopulmonary bypass using V-A ECMO with the emergency cannulation of a large vein and artery for OHCA patients on hospital arrival during the resuscitation. 19 We excluded patients as follows: those who did not receive any resuscitation or treatment in the hospital, whose pre-hospital record was unavailable, whose age was 17 years or less or unknown, or who collapsed with cardiac arrest due to external causes such as trauma, drowning, or hanging and those who did not undergo ECPR. We also excluded those without available BGA results before implementation of ECPR. In this cohort, the implementation of ECPR was decided by the physicians in charge of the patients or by each institution's protocol.

Outcome
The primary outcome of our study was 1-month survival with favourable neurological outcome, defined as Cerebral Performance Category (CPC) 1 or 2. CPC is most commonly used to evaluate neurological status as follows: category 1, good cerebral performance; category 2, moderate cerebral disability; category 3, severe cerebral disability; category 4, coma or vegetative state; and category 5, death. 15 Data measurement and collection From the CRITICAL database, we obtained clinical information as follows: sex, age (< 65, 65-74, ≥ 75), cause of cardiac arrest (cardiac, others), witnessed by bystander (yes, no), CPR performed by bystander (yes, no), pre-hospital initial cardiac rhythm (shockable, nonshockable), cardiac rhythm on hospital arrival (shockable, non-shockable, ROSC), pH in the BGA before the implementation of ECPR, resuscitation time course, and outcomes. Age categories were defined on the basis of a government reference. 17 The pH value in venous BGA can be used interchangeably with that in arterial BGA because they are well related to each other. 20,21 Thus, we treated them as the same. The resuscitation time courses were defined as the time from emergency call (E-call) for ambulance to hospital arrival, BGA, and start of ECPR in the hospital. The included patients were divided into three groups of approximately equal size, based on the pH value in the BGA (Tertiles 1 to 3).

Potential bias
We excluded patients who lacked BGA data from the main analysis (complete case analysis). If data are missing completely at random, excluding patients with missing data does not lead to biased results; thus, it can be acceptable. 22 However, if the missing happens not at random and depends on the outcome and exposure, then it would introduce selection bias. 22 Therefore, to demonstrate the robustness of our results and compensate for the risk of selection bias, we described the characteristics of patients with missing data and performed a sensitivity analysis using the scenario that missing depended on exposure and outcome, described in additional file1. (The details of the sensitivity analysis are also described in additional file1.)

Statistical analysis
We described the patients' characteristics in each patient group. To identify the associations of the pH with the primary outcome, we calculated crude odds ratios (OR) and adjusted OR with 95% confidence intervals (CI) of each patient group for the outcome, using a logistic regression model. We adjusted for potential confounders as follows: sex (male, female), age (< 65, 65-74, ≥ 75), witnessed by bystander, CPR by bystander, prehospital initial cardiac rhythm (shockable, non-shockable), and cardiac rhythm on hospital arrival (shockable, non-shockable, ROSC). Moreover, for better understanding of the results, we described the characteristics of those who had favourable neurological outcomes in each group.
We did not estimate a sample size because our analysis was secondary usage on already available data. 12 All statistical results were considered significant at a two-sided P-value of < 0.05. All statistical analyses were performed using JMP Pro® 14 software (SAS Institute Inc., Cary, NC, USA).

Study participants
Among the 9,822 patients in the CRITICAL database, 260 patients were finally included in the analysis (Fig. 1). The three groups into which the included patients were divided were   2). According to these results, Tertile 2 (pH 6.875-7.029) and Tertile 3 (pH < 6.875) were associated with unfavourable neurological outcome, compared with Tertile 1 (pH ≥ 7.03).

The characteristics of patients with favourable neurological outcome
The characteristics of patients with favourable neurological outcome are shown in Table 2.
Those in Tertiles 2 and 3 were more likely to be young, have OHCA witnessed by bystanders, and have ECPR implemented early after arrival. Table 2 The characteristics in the patients with neurological favourable outcome pH on Blood gas analysis before ECPR started

Interpretation of the results
We suggest that our results may be explained as follows: severe acidaemia, including metabolic and respiratory acidosis, is representative of the severe conditions of hypoperfusion of vital organs and insufficient discharge of carbon dioxide during resuscitation, and these conditions may lead to cerebral injury or multiple organ failure and unfavourable outcomes. Metabolic acidosis, especially lactic acidosis, is caused by inadequate oxygen delivery, impaired tissue oxygenation, and anaerobic glycolysis. 24 In cardiac arrest patients, it may be affected by low cardiac output by chest compression during resuscitation. 25 Some observational studies have reported that metabolic acidosis after ROSC is correlated with the duration from arrest to ROSC and associated with neurological outcome among OHCA patients. 8,26− 29 Respiratory acidosis, the other cause of severe acidaemia, indicates inadequate discharge of carbon dioxide and is mostly caused by low venous return by chest compression and insufficient alveolar ventilation during resuscitation. 25,30 Previous observational studies also reported that respiratory acidosis is associated with cerebral injury and unfavourable neurological outcome among post-cardiac arrest patients or those with head trauma injury. 31,32 Thus, it is reasonable that lower pH values may represent the severe conditions of longer duration of cardiac arrest, lower cerebral blood flow and venous return, and insufficient ventilation, and these conditions are associated with unfavourable neurological outcome.

Clinical implication
We conclude that pH measurement may be helpful to judge the indication of ECPR. If OHCA patients have a pH value higher than 7.03, they have a higher probability of favourable neurological outcome. The results of BGA are objective, reproductive, and available as soon as a blood sample is collected. Further, when ECPR is attempted, obtaining access to the femoral artery enables continual collection of blood samples.
Therefore, pH measurement can be easily applied to real clinical settings.
It should be noted that in our results, some patients with severe acidaemia did survive with favourable neurological outcome. These patients were relatively young, with shockable rhythm and OHCA witnessed by bystanders. A previous case series also reported that some patients with severe acidaemia could achieve good recovery from OHCA in some situations. 33 According to these findings, physicians considering the indication of ECPR should not jump to conclusions too quickly based only on the pH value.

Strengths and limitations
The strength of our study compared with previous studies was that we could identify the association between pH value and neurological outcome adjusting for potential confounders. Among ECPR patients, a previous systematic review reported that witnessed cardiac arrest, CPR performed by bystander, initial shockable rhythm, arrest to ECPR duration, and higher pH value during resuscitation can be potential predictors for survival. 23 In the meta-analysis including five observational studies in this review, there were statistical differences between survivors and non-survivors based on pH value (7.16 ± 0.04 vs 7.01 ± 0.06, mean difference 0.14 [95% CI: 0.08-0.21]) during resuscitation. 23 However, this analysis did not consider the effect of confounding. Further, it did not identify an association with neurological outcome. On the other hand, our analysis adjusted for several major confounders using a logistic regression model and showed the association with neurological outcome. Therefore, our results showed a more robust association than previous studies.
Our study also has several limitations.  Crude and adjusted odds ratios and 95% CI of Tertiles 2 and 3 for the primary outcome. Adjusted by sex, age, witness of collapse, bystander CPR, prehospital initial rhythm, and initial rhythm on hospital arrival. OR: odds ratio, CI: confidence interval