Associations between early intra-arrest blood acidaemia and outcomes of adult in-hospital cardiac arrest: A retrospective cohort study

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Journal of the Formosan Medical Association xxx (xxxx) xxx

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Original Article

Associations between early intra-arrest blood acidaemia and outcomes of adult in-hospital cardiac arrest: A retrospective cohort study Chih-Hung Wang a,b, Wei-Tien Chang a,b, Chien-Hua Huang a,b, Min-Shan Tsai a,b, Ping-Hsun Yu c, Yen-Wen Wu d,e,f, Wen-Jone Chen a,b,g,* a

Department of Emergency Medicine, National Taiwan University Hospital, Taipei, Taiwan Department of Emergency Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan c Department of Emergency Medicine, Taipei Hospital, Ministry of Health and Welfare, New Taipei City, Taiwan d Departments of Internal Medicine and Nuclear Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan e Department of Nuclear Medicine and Cardiology, Division of Cardiovascular Medical Center, Far Eastern Memorial Hospital, New Taipei City, Taiwan f National Yang-Ming University School of Medicine, Taipei, Taiwan g Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan b

Received 25 June 2019; received in revised form 30 July 2019; accepted 21 August 2019

KEYWORDS Acidaemia; pH; Carbon dioxide; Bicarbonate; In-hospital cardiac arrest

Background: Resuscitation guidelines list acidaemia as a potentially reversible cause of cardiac arrest without specifying the threshold defining acidaemia. We examined the association between early intra-arrest arterial blood gas (ABG) data and outcomes of in-hospital cardiac arrest (IHCA). Methods: This single-centred retrospective study reviewed patients with IHCA between 2006 and 2015. Early intra-arrest ABG data were measured within 10 min of initiating cardiopulmonary resuscitation. The ABG analysis included measurements of blood pH, PaCO2, and HCO3-. Results: Among the 1065 included patients, 60 (5.6%) achieved neurologically intact survival. Mean blood pH was 7.2. Mean PaCO2 and HCO3- levels were 59.7 mmHg and 22.1 mmol/L, respectively. A blood pH of 7.2 was identified by a generalised additive models plot to define severe acidaemia. The PaCO2 level was higher in patients with severe acidaemia (mean: 74.5 vs. 44.1 mmHg) than in those without. Multivariable logistic regression analyses indicated that

* Corresponding author. No. 7, Zhongshan S. Rd., Zhongzheng Dist., Taipei City, 100, Taiwan. Fax: þ886 2 2322 3150. E-mail address: [email protected] (W.-J. Chen). https://doi.org/10.1016/j.jfma.2019.08.020 0929-6646/Copyright ª 2019, Formosan Medical Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Please cite this article as: Wang C-H et al., Associations between early intra-arrest blood acidaemia and outcomes of adult in-hospital cardiac arrest: A retrospective cohort study, Journal of the Formosan Medical Association, https://doi.org/10.1016/j.jfma.2019.08.020

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C.-H. Wang et al. blood pH > 7.2 was associated with a favourable neurological recovery (odds ratio [OR]: 2.79, 95% confidence interval [CI]: 1.43e5.46; p-value Z 0.003) and blood pH was positively associated with survival at hospital discharge (OR: 5.80, 95% CI: 1.62e20.69; p-value Z 0.007). Conclusion: Early intra-arrest blood pH was associated with IHCA outcomes, while levels of PaCO2 and HCO3- were not. A blood pH of 7.2 could be used as the threshold defining severe acidaemia during arrest and help profile patients with IHCA. Innovative interventions should be developed to improve the outcomes of patients with severe acidaemia, such as novel ventilation methods. Copyright ª 2019, Formosan Medical Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/bync-nd/4.0/).

Introduction

Materials and methods

Approximately 209,000 patients experience in-hospital cardiac arrest (IHCA) each year in the United States.1 Despite continuing efforts to improve the “chain of survival”, IHCA outcomes remain poor. Approximately 24% of patients with IHCA survive to hospital discharge; among these patients, about 14% experience significant neurological disability.1 Resuscitation guidelines2,3 suggest that potentially reversible causes of cardiac arrest should be identified and corrected promptly during cardiopulmonary resuscitation (CPR). These reversible causes include the so-called “Hs” and “Ts.” Hypovolemia, hypoxia, hydrogen ions (acidaemia), hyper-/hypokalaemia, and hypothermia are listed as the “Hs.2,3” Besides being a potentially reversible cause, acidaemia has also been suggested to be an indicator of noflow duration and severity of ischemic injury.4 After ventilation and perfusion stop, the partial pressure of carbon dioxide (PaCO2) and other anaerobic metabolites increase, leading to mixed respiratory and metabolic acidaemia.5e7 Point-of-care blood gas analysers have been recommended to detect acidaemia during CPR, along with other metabolic derangements.2,3 Nevertheless, studies investigating the association between arterial blood gas (ABG) data (including levels of blood pH, PaCO2, and bicarbonate [HCO-3]) and CPR outcomes are scarce. Spindelboeck et al.8 performed the first prospective study to investigate the association between intra-arrest ABG data and outcomes of out-of-hospital cardiac arrest (OHCA). Because of the limited number of patients, Spindelboeck et al.8 did not detect any association between blood pH/ PaCO2/HCO-3 levels and OHCA outcomes. Shin et al.9 revealed that intra-arrest blood pH level is positively associated with neurologically intact survival of patients with OHCA after retrospectively analysing prospective registry data. Nevertheless, the ABG samples obtained by Spindelboeck et al.8 and Shin et al.9 may have been taken late during the CPR process and may more likely reflect the results of prolonged CPR. ABG samples are usually obtained earlier for patients with IHCA than for patients with OHCA, which may more likely reveal the potential cause of cardiac arrest. Therefore, the current analysis investigated the association between early intra-arrest ABG data (including blood pH/PaCO2/HCO-3 levels) and IHCA outcomes.

Setting This retrospective cohort study was performed in a tertiary medical centre, the National Taiwan University Hospital (NTUH). NTUH has 2600 beds, including 220 beds in intensive care units (ICUs). This study was conducted in accordance with the Declaration of Helsinki amendments. The Research Ethics Committee of NTUH approved this study (reference number: 201805098RINC) and waived the requirement for informed consent before data collection. According to hospital policy, a resuscitation team is activated when a cardiac arrest event occurs in the general wards. A resuscitation team consists of a senior resident, several junior residents, a respiratory therapist, the head nurse, and several ICU nurses. Each code team member is certified to provide advanced cardiac life support and is capable of offering CPR according to current resuscitation guidelines. A code team is not mobilised for cardiac arrest events in the ICUs as a sufficient number of experienced staff is always present in the ICUs. In this case, resuscitation is performed by the ICU staff where the cardiac arrest event occurred and by staff from neighbouring ICUs.

Participants Patients who experienced IHCA at NTUH from 2006 to 2015 were screened. Patients who met the following criteria were included in the study: (1) aged  18 years, (2) documented absence of pulse with performance of chest compressions for at least 2 min, (3) no documentation of a donot-resuscitate order before arrest and (4) analysis of early intra-arrest ABG sample with available blood pH, PaCO2, and HCO-3 level data. Sustained return of spontaneous circulation (ROSC) was defined as ROSC lasting  20 min without resumption of chest compressions. If multiple cardiac arrest events occurred in a single patient during hospitalisation, only the first event was recorded. Patients who experienced cardiac arrest related to major trauma were excluded from the study.

Data collection and outcome measures The following information was recorded for each patient: age, gender, comorbidities,10 variables derived from the

Please cite this article as: Wang C-H et al., Associations between early intra-arrest blood acidaemia and outcomes of adult in-hospital cardiac arrest: A retrospective cohort study, Journal of the Formosan Medical Association, https://doi.org/10.1016/j.jfma.2019.08.020

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Acidaemia and in-hospital cardiac arrest outcome Utstein template,11 early intra-arrest ABG data and critical interventions implemented at the time of cardiac arrest and after sustained ROSC. Early intra-arrest ABG data were measured within 10 min of initiating CPR. Blood pH, PaCO2 and HCO-3 was measured by point-of-care blood gas analysers. Severe acidaemia was defined as a blood pH & 7.2.12 Duration of CPR was defined as the time interval from the first chest compression initiated by the resuscitation team or ICU member to the termination of resuscitation efforts, either due to sustained ROSC or declaration of death. The primary outcome was favourable neurological status at hospital discharge. Favourable neurological status was defined as a score of 1 or 2 on the Cerebral Performance Category (CPC) scale.13 Patients with a CPC score of 1 or 2 had sufficient cerebral function to live independently. The CPC score was retrospectively determined by reviewing the medical records of each patient. The secondary outcome was survival to hospital discharge.

Statistical analysis R 3.3.1 software (R Foundation for Statistical Computing, Vienna, Austria) was used for the data analysis. Categorical data are expressed as counts and proportions; continuous data are expressed as means and standard deviations. Categorical variables were compared using the Fisher’s exact test, and continuous variables were examined with the Wilcoxon rank-sum test. A two-tailed p-value < 0.05 was considered significant. The odds ratio (OR) was selected as the outcome measure, and multivariable logistic regression analyses were performed to examine the associations between the independent variables and outcomes. All available independent variables were considered in the regression model, regardless of whether they were significant in the univariate analysis. The stepwise variable selection procedure (with iterations between the forward and backward steps) was applied to obtain the final regression model. Significance levels for entry and stay were set at 0.15 to avoid exclusion of potential candidate variables. The final regression model was identified by sequentially excluding individual variables with a p-value > 0.05 until all regression coefficients were statistically significant. We used generalised additive models (GAMs)14 to examine the nonlinear effects of continuous variables and, if necessary, to identify the appropriate cut-off point(s) for dichotomising a continuous variable during the variable selection procedure. We assessed the goodness-of-fit of the fitted regression model using c statistics, adjusted generalised R2 and the HosmereLemeshow goodness-of-fit test.

Results A total of 1698 adult non-trauma patients at NTUH received CPR for 2 min between 2006 and 2015. Of these, 633 patients were excluded because of a lack of early intra-arrest blood pH, PaCO2 or HCO-3 levels. The remaining 1065 patients were included for analysis. Tables 1 and 2 provide the features of cardiac arrest events before, during and after CPR for all patients in the cohort. The mean age of the patients was 66.1 years. A

3 total of 475 cardiac arrest events (44.6%) occurred in the ICUs, and 527 events (49.5%) occurred on the general wards. The majority (918 patients, 86.2%) of initial rhythms were non-shockable, including pulseless electrical activity and asystole. The average CPR duration was 37.4 min. The mean blood pH was 7.2, with a higher proportion of severe acidaemia in patients without favourable neurological recovery. The mean PaCO2 and HCO-3 levels were 59.7 mmHg and 22.1 mmol/L, respectively. Only 126 patients (11.8%) survived to hospital discharge; of these, 60 patients (5.6%) demonstrated favourable neurological status. We placed all independent variables listed in Tables 1 and 2 in the regression analysis to select the variables. The GAM plot demonstrated a non-linear association of logit (p), where p represented the probability for a favourable neurological status, with blood pH (Fig. 1). If logit (p) was greater than zero, the odds for a favourable neurological outcome were greater than one. Therefore, a blood pH of 7.2 was used as the cut-off point to transform blood pH into a binary variable during the model-fitting process. The baseline and resuscitation characteristics of the patients stratified by blood pH are presented in Supplemental Tables 1 and 2. In patients with blood gas pH  7.2, the PaCO2 level was higher (mean: 74.5 vs. 44.1 mmHg) and the HCO-3 level was lower (mean: 20.5 vs. 23.7 mmol/L) than those in patients with blood gas pH > 7.2. As shown in Tables 3 and 4, blood pH > 7.2 was associated with a favourable neurological outcome (OR: 2.79, 95% confidence interval [CI]: 1.43e5.46; p-value Z 0.003), and blood pH was positively associated with survival (OR: 5.80, 95% CI: 1.62e20.69; p-value Z 0.007).

Discussion Main findings In the current analysis, we noted that early intra-arrest blood pH was associated with IHCA outcomes while levels of PaCO2 and HCO-3 were not. A blood pH > 7.2 was associated with a favourable neurological recovery in IHCA patients after the effects of multiple confounding factors were considered. This cut-off point was consistent with the threshold used by previous studies12 to define severe acidaemia in critically ill patients. Most of the patients with severe acidaemia in our cohort seemed to suffer predominantly from hypercapnic respiratory acidaemia with a mean PaCO2 level of 74.5 mmHg.

Comparison with previous studies Blood pH is reportedly associated with CPR outcomes.15e18 Nevertheless, instead of blood pH measured during CPR, most previous studies15e18 used blood pH measured after ROSC. In these studies,15e18 blood pH was identified as a significant prognosticator and integrated into a composite risk score predicting neurological outcomes of patients with OHCA. Blood pH is used as a continuous variable in the CAHP score,15,18 showing that a lower blood pH is associated with a lower probability of neurological recovery. In the C-GRApH score16 and TTM score,17 blood pH is used as a binary16 or categorical17 variable, respectively. These

Please cite this article as: Wang C-H et al., Associations between early intra-arrest blood acidaemia and outcomes of adult in-hospital cardiac arrest: A retrospective cohort study, Journal of the Formosan Medical Association, https://doi.org/10.1016/j.jfma.2019.08.020

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C.-H. Wang et al. Table 1

Baseline characteristics of the study patients stratified by neurological outcome.

Variables

All patients (n Z 1065)

Patients with favourable neurological outcome at hospital discharge (n Z 60)

Patients without favourable neurological outcome at hospital discharge (n Z 1005)

p-value

Age, y (SDa) Male, n (%) Comorbidities, n (%) Heart failure, this admission Heart failure, prior admission Myocardial infarction, this admission Myocardial infarction, prior admission Arrhythmia Hypotension Respiratory insufficiency Renal insufficiency Hepatic insufficiency Metabolic or electrolyte abnormality Diabetes mellitus Baseline evidence of motor, cognitive, or functional deficits Acute stroke Favourable neurological status 24 h before cardiac arrest Pneumonia Cirrhosis Chronic obstructive pulmonary disease Dialysis Bacteraemia Metastatic cancer or any blood borne malignancy Charlson comorbidity index (SD)

66.1 (16.5) 653 (61.3)

61.6 (13.8) 45 (75.0)

66.3 (16.4) 608 (60.5)

0.007 0.028

209 (19.6) 172 (16.2) 121 (11.4) 39 (3.7) 193 (18.1) 261 (24.5) 769 (72.2) 448 (42.1) 183 (17.2) 186 (17.5) 354 (33.2) 329 (30.9)

17 (28.3) 11 (18.3) 13 (21.7) 4 (6.7) 9 (15.0) 12 (20.0) 38 (63.3) 24 (40.0) 8 (13.3) 8 (13.3) 17 (28.3) 13 (21.7)

192 (19.1) 161 (16.0) 108 (10.7) 35 (3.5) 184 (18.3) 249 (24.8) 731 (72.7) 424 (42.2) 175 (17.4) 178 (17.7) 337 (33.5) 316 (31.4)

0.093 0.591 0.018 0.272 0.607 0.444 0.137 0.789 0.485 0.485 0.481 0.116

45 (4.2) 465 (43.7)

1 (1.7) 37 (61.7)

44 (4.4) 428 (42.6)

0.509 0.005

338 (31.7) 71 (6.7) 62 (5.8) 191 (17.9) 87 (8.2) 248 (23.3)

8 (13.3) 1 (1.7) 4 (6.7) 10 (16.7) 0 (0) 4 (6.7)

330 (32.8) 70 (7.0) 58 (5.8) 181 (18.0) 87 (8.7) 244 (24.3)

0.001 0.175 0.774 >0.99 0.012 <0.001

2.9 (2.2)

2.2 (2.0)

3.0 (2.3)

0.003

a

SD, standard deviation.

scores16,17 indicate that when blood pH is < 7.016 or <7.2,17 the probability of recovering favourable neurological status following OHCA decreases. However, recovered ventilation and circulation may start to eliminate carbon dioxide from the lungs and slow down the anaerobic metabolic rate after sustained ROSC is achieved. As indicated by Spindelboeck et al.,8 blood pH and base excess increase and PaCO2 decreases after OHCA patients achieve ROSC. Therefore, the ABG data measured after ROSC may not be generalisable to interpret the ABG data obtained during ongoing CPR. Spindelboeck et al.8 and Shin et al.9 used OHCA patients for analysis, whose median intra-arrest blood pH values were both about 7.0,8,9 whereas the mean intra-arrest blood pH in our IHCA cohort was 7.2. The median time interval between initiating CPR until the ABG analysis was 25 min in the study by Spindelboeck et al.,8 whereas Shin et al.9 conducted the ABG analysis promptly after patients were transported to the hospital, and prehospital CPR lasted about 23 min. Therefore, the intra-arrest ABG data obtained in the studies by Spindelboeck et al.8 and Shin et al.9 may more likely reflect the pathophysiological response to prolonged CPR and may be more suitably viewed as a prognosticator for CPR outcome. As the only research that has investigated IHCA patients, the intraarrest ABG data used in our study may be more closely

related in time to CPR initiation and more likely to reveal the potential cause leading to a cardiac arrest.

Interpretation of intra-arrest blood pH Acidaemia is listed as a potentially reversible cause of cardiac arrest in resuscitation guidelines2,3 with limited evidence. Blood pH has been demonstrated to be inversely associated with call-to-hospital arrival time in witnessed OHCA patients.9 Blood pH may be deemed as a proxy for low-flow time and, therefore, acidaemia may simply be a sign of poor prognosis rather than a reversible cause. As demonstrated by previous studies, blood pH, as a significant prognosticator, has been integrated into various risk scores, such as the CAHP,15,18 C-GRApH16 and TTM scores.17 However, regardless of the aetiology, acidaemia is undesirable during CPR because it increases the potential for ventricular fibrillation, reduces myocardial contractility and promotes a paradoxical response to adrenaline causing reduced cardiac contractility.19e22 Despite that resuscitation guidelines2,3 list acidaemia as a potentially reversible cause of cardiac arrest, they do not specify the definition of acidaemia or the threshold blood pH below which acidaemia-targeted therapeutics should be administered.

Please cite this article as: Wang C-H et al., Associations between early intra-arrest blood acidaemia and outcomes of adult in-hospital cardiac arrest: A retrospective cohort study, Journal of the Formosan Medical Association, https://doi.org/10.1016/j.jfma.2019.08.020

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Acidaemia and in-hospital cardiac arrest outcome Table 2

Features, interventions and outcomes of cardiac arrest events stratified by neurological outcome.

Variables

All patients (n Z 1065)

Arrest at night, n (%) 386 (36.2) Arrest on weekend, n (%) 301 (28.3) Arrest location, n (%) Intensive care unit 475 (44.6) General ward 527 (49.5) Others 63 (5.9) Witnessed arrest, n (%) 739 (69.4) Monitored status, n (%) 649 (60.9) Shockable rhythm, n (%) 147 (13.8) Critical care interventions in place at time of arrest, n (%) Mechanical ventilation 268 (25.2) Antiarrhythmics 120 (11.3) Vasopressors 475 (44.6) Dialysis 79 (7.4) Pulmonary artery catheter 6 (0.6) Intra-aortic balloon pumping 8 (0.8) 37.4 (37.5) CPRa duration, min (SDb) Intra-arrest laboratory data Blood pH (SD) 7.2 (0.2) Severe acidaemia, n (%) 545 (51.2) 59.7 (40.5) PaCO2,c mmHg (SD) 22.1 (14.2) HCO3-, mmol/L (SD) Post-ROSCd interventions, n (%) Extracorporeal membrane oxygenation 85 (8.0) Targeted temperature management 12 (1.1) Percutaneous coronary intervention 35 (3.3) Survival to hospital discharge, n (%) 126 (11.8) a b c d

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Patients with favourable neurological outcome at hospital discharge (n Z 60)

Patients without favourable neurological outcome at hospital discharge (n Z 1005)

p-value

22 (36.7) 11 (18.3)

364 (36.2) 290 (28.9)

>0.99 0.103 0.028

29 (48.3) 23 (38.3) 8 (13.3) 44 (73.3) 43 (71.7) 20 (33.3)

446 (44.4) 504 (50.1) 55 (5.5) 695 (69.2) 606 (60.3) 127 (12.6)

0.565 0.101 <0.001

14 (23.3) 5 (8.3) 21 (35.0) 3 (5.0) 2 (3.3) 1 (1.7) 13.3 (10.4)

254 (25.3) 115 (11.4) 454 (45.2) 76 (7.6) 4 (0.4) 7 (0.7) 38.8 (38.1)

0.878 0.673 0.142 0.616 0.040 0.372 <0.001

7.3 (0.2) 18 (30.0) 46.0 (23.7) 21.4 (7.1)

7.2 (0.2) 527 (52.4) 60.5 (41.1) 22.1 (14.5)

<0.001 <0.001 0.003 0.491

8 (13.3) 3 (5.0) 12 (20.0) 60 (100)

77 (7.7) 9 (0.9) 23 (2.3) 66 (6.6)

0.135 0.026 <0.001 <0.001

CPR, cardiopulmonary resuscitation. SD, standard deviation. PaCO2, partial pressure of arterial carbon dioxide. ROSC, return of spontaneous circulation.

The cut-off point of blood pH as 7.2 identified by the GAM plot (Fig. 1) was consistent with the threshold used to define severe acidaemia in other critically ill patients.12,23 Buffer therapy does not decrease mortality in critically ill patients with severe metabolic acidaemia.23 It may be that a mild or moderate degree of acidaemia should be viewed as reversible and treatable to improve CPR outcomes; however, treatments for severe acidaemia may be futile, and it could be considered a harbinger of a dismal CPR outcome. As patient-centred CPR24 has been shown to improve resuscitation outcomes, intra-arrest ABG analysis may provide a comprehensive profile of patient status and facilitate decision-making regarding tailored treatments. In addition, intra-arrest blood pH may help phenotype cardiac arrest and categorise patients into different subgroups, facilitating comparing the therapeutic effects of interventions across different subgroups.

Applications for future studies Vasopressin had been removed from the resuscitation guidelines2,3 in the adult cardiac arrest algorithm. In

comparison with adrenaline, vasopressin had been suggested to be potentially more effective during acidaemia. In a small retrospective study, Turner et al.25 reported no outcome differences between OHCA patients who received vasopressin in combination with adrenaline compared to adrenaline alone. Nevertheless, Turner et al.25 revealed in a subgroup analysis that an increased ROSC rate was noted in the vasopressin plus adrenaline group versus the adrenaline alone group among patients with blood pH < 7.2. In a randomised controlled trial of IHCA patients, Mentzelopoulos et al.26 demonstrated that patients receiving a combination of vasopressin/adrenaline/methylprednisolone during CPR and post-resuscitation stress-dose hydrocortisone had a higher rate of neurologically intact survival than patients receiving adrenaline alone. Among the enrolled IHCA patients, mean blood pH was about 7.1.26 It should be further examined whether intra-arrest ABG analysis, particularly the pH value, could assist in identifying the patient subgroup for whom vasopressin may offer additional benefit. In our study, the PaCO2 level was higher in patients with blood pH  7.2 compared with patients with blood pH > 7.2

Please cite this article as: Wang C-H et al., Associations between early intra-arrest blood acidaemia and outcomes of adult in-hospital cardiac arrest: A retrospective cohort study, Journal of the Formosan Medical Association, https://doi.org/10.1016/j.jfma.2019.08.020

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C.-H. Wang et al.

Figure 1 Generalised additive model plot for nonparametric modelling of the effect of intra-arrest blood pH on the logit of probability for a favourable neurological outcome at hospital discharge.

(74.5 vs. 44.1 mmHg, Supplemental Table 2), suggesting that most severe acidaemia might be caused by respiratory acidosis. Although resuscitation guidelines2,3 list acidaemia as a reversible cause of cardiac arrest, the guidelines do not suggest how to reverse this pathological process. In the American Heart Association: Get With The GuidelinesResuscitation registry, pre-arrest respiratory insufficiency accounts for about 40e45% of IHCA patients,27 while in our cohort, patients with pre-arrest respiratory insufficiency accounted for about 70% of IHCA patients. Intubation and mechanical ventilation would be suggested for patients with respiratory insufficiency or failure. Instead, once these patients sustain IHCA, the benefits of intubation become controversial.28,29 Whether early intubation improves outcomes of IHCA patients whose intra-arrest ABG analysis reveals signs of respiratory acidosis should be further examined.

Another unresolved issue is whether the ventilation rate should be changed for IHCA patients with signs of respiratory acidosis. Resuscitation guidelines2,3 suggest that rescuers should avoid hyperventilation and focus on implementing high-quality CPR, which is the best treatment for acidaemia. However, expiration of carbon dioxide requires not only adequate perfusion to deliver carbon dioxide to the lungs but alveolar ventilation to eliminate it. Given that CPR-driven hemodynamic effects are optimised, hypoventilation-related hypercapnia might negatively affect resuscitation outcomes.30 In contrast, as PaCO2 is an important regulator of cerebral blood flow, mild hypercapnia may increase cerebral oxygenation and attenuate ischaemia-reperfusion injury by mitigating oxidative stress.31,32 An overzealous correction of acidaemia may inadvertently worsen the cerebral injury; therefore, ventilation should be handled with caution.

Table 3 Multiple logistic regression model with favourable neurological outcome at hospital discharge as the dependent variable. Independent variablea

Odds ratio

95% confidence interval

p value

CPRb duration Post-ROSCc percutaneous coronary intervention Age between 24 and 70 years Blood pH > 7.2 Metastatic cancer or any blood borne malignancy Favourable neurological status 24 h before cardiac arrest Baseline evidence of motor, cognitive, or functional deficits Pneumonia Post-ROSC targeted temperature management Pulmonary artery catheter in place at time of arrest

0.91 10.45 3.10 2.79 0.19 2.53 0.33 0.35 9.47 19.31

0.89e0.94 3.97e27.51 1.60e6.01 1.43e5.46 0.06e0.56 1.34e4.77 0.15e0.73 0.15e0.81 1.50e59.59 1.40e265.65

<0.001 <0.001 <0.001 0.003 0.003 0.004 0.006 0.014 0.017 0.027

Goodness-of-fit assessment: n Z 1065, adjusted generalised R2 Z 0.40, the estimated area under the receiver operating characteristic curve Z 0.91, and the HosmereLemeshow goodness-of-fit chi-square test p Z 0.002. a The display of independent variables is arranged in the order of the p-values. b CPR, cardiopulmonary resuscitation. c ROSC, return of spontaneous circulation.

Please cite this article as: Wang C-H et al., Associations between early intra-arrest blood acidaemia and outcomes of adult in-hospital cardiac arrest: A retrospective cohort study, Journal of the Formosan Medical Association, https://doi.org/10.1016/j.jfma.2019.08.020

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Acidaemia and in-hospital cardiac arrest outcome Table 4

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Multiple logistic regression model with survival to hospital discharge as the dependent variable.

Independent variablea

Odds ratio

95% confidence interval

p value

CPRb duration Post-ROSCc percutaneous coronary intervention Hypotension Pulmonary artery catheter in place at time of arrest Blood pH Hepatic insufficiency Metastatic cancer or any blood borne malignancy Favourable neurological status 24 h before cardiac arrest Shockable rhythm

0.93 4.99 0.34 28.62 5.80 0.37 0.46 1.75 1.82

0.91e0.95 2.08e11.96 0.19e0.62 3.15e260.01 1.62e20.69 0.18e0.77 0.25e0.84 1.13e2.72 1.05e3.13

<0.001 <0.001 <0.001 0.003 0.007 0.008 0.011 0.013 0.032

Goodness-of-fit assessment: n Z 1065, adjusted generalized R2 Z 0.35, the estimated area under the Receiver Operating Characteristic (ROC) curve Z 0.86, and the Hosmer and Lemeshow goodness-of-fit Chi-Squared test p Z 0.11. a The display of independent variables is arranged by the order of p value. b CPR, cardiopulmonary resuscitation. c ROSC, return of spontaneous circulation.

There is a complex heartelung interaction during CPR. Elucidating such physiology is of great importance, but studies dedicated to investigating ventilation during CPR are scarce.33 Because of study limitations, our research may not be able to fully investigate these questions but our results may be hypothesis-generating and serve as a foundation for future study.

Study limitations First, this was an observational study, which can only establish an association, rather than a causal relationship between independent and dependent variables. Second, the effects of unmeasured confounders may have biased the results despite that we used the multivariable analysis to adjust for the effects of the measured confounders. Periarrest events leading to the ABG results could not be verified in a retrospective manner. It was probable that patients had received buffer therapy or intubation just before the ABG analysis. The intra-arrest ABG data may just reflect the changes caused by these interventions. Finally, we could not verify that the blood samples sent for ABG analysis were truly obtained from arterial sources. However, in a porcine experiment, Jousi et al.34 indicated that blood pH levels obtained during CPR do not differ significantly between arterial or venous sources, which may make our results more applicable to clinical practice. In addition, ABG values may not represent the actual tissue acid-base state during cardiac arrest.35 Analysis of central venous blood may offer a better estimate of tissue pH, but this practice would be difficult to generalise to clinical settings.

pH  7.2), innovative interventions, such as a novel ventilation method, should be developed to improve their outcomes.

Funding Author CHW received a grant (108-S4091) from the National Taiwan University Hospital. Author WJC received a grant (108-S4236) from the National Taiwan University Hospital. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Conflicts of interest The authors have no conflicts of interest relevant to this article.

Acknowledgments We thank Centre of Quality Management of National Taiwan University Hospital for providing the list of patients sustaining in-hospital cardiac arrest. We thank the staff of the 3rd Core Lab, Department of Medical Research, National Taiwan University Hospital for technical support.

Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi.org/10.1016/j.jfma.2019.08.020.

Conclusions Early intra-arrest blood pH level was associated with IHCA outcomes, while levels of PaCO2 and HCO-3 were not. After multiple confounders were considered, a blood pH > 7.2 was positively associated with a favourable neurological recovery. Blood pH of 7.2 may be used as a threshold for defining severe acidaemia during arrest and help profile IHCA patients. For patients with severe acidaemia (blood

References 1. Benjamin EJ, Blaha MJ, Chiuve SE, Cushman M, Das SR, Deo R, et al. Heart disease and stroke statistics-2017 update: a report from the American heart association. Circulation 2017;135: e146e603. 2. Soar J, Nolan JP, Bo ¨ttiger BW, Perkins GD, Lott C, Carli P, et al. European resuscitation council guidelines for resuscitation

Please cite this article as: Wang C-H et al., Associations between early intra-arrest blood acidaemia and outcomes of adult in-hospital cardiac arrest: A retrospective cohort study, Journal of the Formosan Medical Association, https://doi.org/10.1016/j.jfma.2019.08.020

+

MODEL

8

3.

4.

5.

6.

7.

8.

9.

10.

11.

12.

13.

14. 15.

16.

17.

18.

C.-H. Wang et al. 2015: section 3. Adult advanced life support. Resuscitation 2015;95:100e47. Link MS, Berkow LC, Kudenchuk PJ, Halperin HR, Hess EP, Moitra VK, et al. Part 7: adult advanced cardiovascular life support: 2015 American heart association guidelines update for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation 2015;132:S444e64. Seeger FH, Toenne M, Lehmann R, Ehrlich JR. Simplistic approach to prognosis after cardiopulmonary resuscitationvalue of pH and lactate. J Crit Care 2013;28. 317.e13-20. Prause G, Ratzenhofer-Comenda B, Smolle-Ju ¨ttner F, HeydarFadai J, Wildner G, Spernbauer P, et al. Comparison of lactate or BE during out-of-hospital cardiac arrest to determine metabolic acidosis. Resuscitation 2001;51:297e300. Takasu A, Sakamoto T, Okada Y. Arterial base excess after CPR: the relationship to CPR duration and the characteristics related to outcome. Resuscitation 2007;73:394e9. Ahn S, Kim WY, Sohn CH, Seo DW, Kim W, Lim KS. Potassium values in cardiac arrest patients measured with a point-of-care blood gas analyzer. Resuscitation 2011;82:e25e6. Spindelboeck W, Gemes G, Strasser C, Toescher K, Kores B, Metnitz P, et al. Arterial blood gases during and their dynamic changes after cardiopulmonary resuscitation: a prospective clinical study. Resuscitation 2016;106:24e9. Shin J, Lim YS, Kim K, Lee HJ, Lee SJ, Jung E, et al. Initial blood pH during cardiopulmonary resuscitation in out-of-hospital cardiac arrest patients: a multicenter observational registrybased study. Crit Care 2017;21:322. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis 1987;40: 373e83. Jacobs I, Nadkarni V, Bahr J, Berg RA, Billi JE, Bossaert L, et al. Cardiac arrest and cardiopulmonary resuscitation outcome reports: update and simplification of the Utstein templates for resuscitation registries: a statement for healthcare professionals from a task force of the international Liaison committee on resuscitation (American heart association, european resuscitation council, Australian resuscitation council, New Zealand resuscitation council, heart and stroke foundation of Canada, InterAmerican heart foundation, resuscitation councils of southern Africa). Circulation 2004;110:3385e97. Jung B, Rimmele T, Le Goff C, Chanques G, Corne P, Jonquet O, et al. Severe metabolic or mixed acidemia on intensive care unit admission: incidence, prognosis and administration of buffer therapy. A prospective, multiple-center study. Crit Care 2011;15:R238. Becker LB, Aufderheide TP, Geocadin RG, Callaway CW, Lazar RM, Donnino MW, et al. Primary outcomes for resuscitation science studies: a consensus statement from the American Heart Association. Circulation 2011;124:2158e77. Hastie TJ, Tibshirani RJ. Generalized additive models. London and New York: Chapman & Hall; 1990. Maupain C, Bougouin W, Lamhaut L, Deye N, Diehl JL, Geri G, et al. The CAHP (Cardiac Arrest Hospital Prognosis) score: a tool for risk stratification after out-of-hospital cardiac arrest. Eur Heart J 2016;37:3222e8. Kiehl EL, Parker AM, Matar RM, Gottbrecht MF, Johansen MC, Adams MP, et al. C-GRApH: a validated scoring system for early stratification of neurologic outcome after out-of-hospital cardiac arrest treated with targeted temperature management. J Am Heart Assoc 2017;6:e003821. Martinell L, Nielsen N, Herlitz J, Karlsson T, Horn J, Wise MP, et al. Early predictors of poor outcome after out-of-hospital cardiac arrest. Crit Care 2017;21:96. Wang CH, Huang CH, Chang WT, Tsai MS, Yu PH, Wu YW, et al. Prognostic performance of simplified out-of-hospital cardiac arrest (OHCA) and cardiac arrest hospital prognosis (CAHP)

19.

20.

21.

22.

23.

24.

25.

26.

27.

28.

29.

30.

31.

32.

33.

34.

35.

scores in an East Asian population: a prospective cohort study. Resuscitation 2019;137:133e9. Azran C, Wolk O, Zur M, Fine-Shamir N, Shaked G, Czeiger D, et al. Oral drug therapy following bariatric surgery: an overview of fundamentals, literature and clinical recommendations. Obes Rev 2016;17:1050e66. Cingolani HE, Mattiazzi AR, Blesa ES, Gonzalez NC. Contractility in isolated mammalian heart muscle after acid-base changes. Circ Res 1970;26:269e78. Darby TD, Aldinger EE, Gadsden RH, Thrower WB. Effects of metabolic acidosis on ventricular isometric systolic tension and the response to epinephrine and levarterenol. Circ Res 1960;8: 1242e53. Houle DB, Weil MH, Brown Jr EB, Campbell GS. Influence of respiratory acidosis on ECG and pressor responses to epinephrine, norepinephrine and metaraminol. Proc Soc Exp Biol Med 1957;94:561e4. Jaber S, Paugam C, Futier E, Lefrant JY, Lasocki S, Lescot T, et al. Sodium bicarbonate therapy for patients with severe metabolic acidaemia in the intensive care unit (BICAR-ICU): a multicentre, open-label, randomised controlled, phase 3 trial. Lancet 2018;392:31e40. Chopra AS, Wong N, Ziegler CP, Morrison LJ. Systematic review and meta-analysis of hemodynamic-directed feedback during cardiopulmonary resuscitation in cardiac arrest. Resuscitation 2016;101:102e7. Turner DW, Attridge RL, Hughes DW. Vasopressin associated with an increase in return of spontaneous circulation in acidotic cardiopulmonary arrest patients. Ann Pharmacother 2014;48:986e91. Mentzelopoulos SD, Malachias S, Chamos C, Konstantopoulos D, Ntaidou T, Papastylianou A, et al. Vasopressin, steroids, and epinephrine and neurologically favorable survival after inhospital cardiac arrest: a randomized clinical trial. JAMA 2013;310:270e9. Girotra S, Nallamothu BK, Spertus JA, Li Y, Krumholz HM, Chan PS, et al. Trends in survival after in-hospital cardiac arrest. N Engl J Med 2012;367:1912e20. Andersen LW, Granfeldt A, Callaway CW, Bradley SM, Soar J, Nolan JP, et al. Association between tracheal intubation during adult in-hospital cardiac arrest and survival. JAMA 2017;317: 494e506. Wang CH, Chen WJ, Chang WT, Tsai MS, Yu PH, Wu YW, et al. The association between timing of tracheal intubation and outcomes of adult in-hospital cardiac arrest: a retrospective cohort study. Resuscitation 2016;105:59e65. Yannopoulos D, Matsuura T, McKnite S, Goodman N, Idris A, Tang W, et al. No assisted ventilation cardiopulmonary resuscitation and 24-hour neurological outcomes in a porcine model of cardiac arrest. Crit Care Med 2010;38:254e60. Eastwood GM, Young PJ, Bellomo R. The impact of oxygen and carbon dioxide management on outcome after cardiac arrest. Curr Opin Crit Care 2014;20:266e72. Shoja MM, Tubbs RS, Shokouhi G, Loukas M, Ghabili K, Ansarin K. The potential role of carbon dioxide in the neuroimmunoendocrine changes following cerebral ischemia. Life Sci 2008;83:381e7. Cordioli RL, Grieco DL, Charbonney E, Richard JC, Savary D. New physiological insights in ventilation during cardiopulmonary resuscitation. Curr Opin Crit Care 2019;25:37e44. Jousi M, Skrifvars MB, Nelskyla ¨ A, Ristagno G, Schramko A, Nurmi J. Point-of-care laboratory analyses of intraosseous, arterial and central venous samples during experimental cardiopulmonary resuscitation. Resuscitation 2019;137:124e32. Weil MH, Rackow EC, Trevino R, Grundler W, Falk JL, Griffel MI. Difference in acid-base state between venous and arterial blood during cardiopulmonary resuscitation. N Engl J Med 1986;315:153e6.

Please cite this article as: Wang C-H et al., Associations between early intra-arrest blood acidaemia and outcomes of adult in-hospital cardiac arrest: A retrospective cohort study, Journal of the Formosan Medical Association, https://doi.org/10.1016/j.jfma.2019.08.020