Prognostic value of arterial carbon dioxide tension during cardiopulmonary resuscitation in out-of-hospital cardiac arrest patients receiving extracorporeal resuscitation

This retrospective study was conducted in a tertiary hospital in Taipei City, Taiwan, with an emergency department with more than 1,15,000 visits annually and 220 intensive care unit (ICU) beds.

This study included patients with OHCA aged ≥ 18 years who were treated with ECPR between January 2012 and December 2020. Patients were excluded for the following reasons: 1) ECPR was initiated at another hospital and the patient was transferred after ECMO, 2) traumatic OHCA, and 3) OHCA with sustained ROSC (ROSC for more than 20 min), but ECMO was warranted for haemodynamic support.

The prehospital EMS system in the OHCA setting was reported in a previous study [17]. There were basic life support teams with defibrillation ability and advanced life support teams, which are qualified for intubation and intravenous epinephrine injection in the prehospital setting.

Advanced airway was established for 60 percent of patients. Chest compressions were performed with mechanical CPR devices for 85 percent of patients during transport, unless not feasible because of body size or other reasons. The dispatch center would inform the emergency department by telephone of the incoming OHCA patient information, including patient`s age, gender, prehospital DC shock times, prehospital intervention, and estimated arrival time.

If OHCA patients did not achieve ROSC after 10 min of standard Advanced Cardiac Life Support (ACLS), the emergency physician would discuss with the duty cardiovascular surgeon for ECPR eligibility. Patients were considered eligible for ECPR if they met all the following criteria: (1) age < 80 years, (2) witnessed collapse with no-flow time < 10 min, (3) pre-disease cerebral performance category (CPC) of 1–2 and no terminal malignancy, (if CPC category was not available, the pre-disease neurological status, as Glascow Coma Scale, would be used instead. All the eligible patients must have a GCS score of 15) and (4) presumed reversible cause (e.g. acute coronary syndrome or pulmonary embolism). The cardiovascular surgeon made the final decision on ECMO eligibility. The emergency department had a routine team structure while managing patients with OHCA. One nurse focused on blood sampling through puncturing femoral artery and the other nurse obtained venous access and epinephrine injection. The blood gas analysis was performed right after blood sampling and sent for point-of-care analysis using SIEMEMS RAPIDPoint 500 Systems in the resuscitation room. Arterial pH, PaCO2, and lactic acid levels were interpreted to guide further resuscitation.

The ECMO cannulation approach in our hospital is peripheral cannulation with open technique. Cannulation was performed under direct vision of femoral vessels with modified Seldinger method. All the cannulations were performed in the emergency department by the duty cardiovascular surgeon with the assistance of ECMO technicians. The ECMO components included a centrifugal pump and oxygenator (Medtronic, Anaheim, CA; Medos, Stolberg, Germany; Maquet, Rastatt, Germany). After ECMO, the patient underwent computed tomography to survey for possible OHCA causes, and the cardiologist evaluated the feasibility of coronary angiography. The patient was admitted to the ICU for post-resuscitation care.

Baseline characteristics and comorbidities were recorded in the medical records and retrospectively collected. Resuscitation variables were collected from the emergency medical service and hospital records. All time intervals were retrospectively calculated from the hospital records. Arrest-hospital time was defined as the time interval between cardiac arrest (CA) and hospital arrival. The arrest-ECMO time was defined as the time from CA to ECMO implementation. Arterial pH, PaCO₂, and lactic acid levels were recorded from the first blood sample at the emergency department. Data on the intervention after ECPR, survival, and neurological outcomes at discharge were collected from the medical records.

The primary outcome was a favorable neurological outcome at discharge, defined as a Cerebral Performance Category score of 1 (good cerebral performance) or 2 (moderate cerebral disability). The secondary outcome was survival until hospital discharge.

Categorical variables are expressed as percentages and were compared using the chi-squared test. Continuous variables are expressed as means ± standard deviations, and t-tests were used to delineate differences. Statistical significance was set at p-value < 0.05. The predictive abilities of metabolic parameters (pH, PaCO₂, and lactic acid) were tested using the area under the receiver operating characteristic (ROC) curve (AUC). We used a generalised additive model (GAM) to determine the relationship between PaCO₂, FO, and survival. All variables with a p-value < 0.15 were included in multivariable logistic regression to determine the independent variables for predicting FO. All the time variables were treated as continuous variables in the multivariable regression model. A stepwise backward elimination method was used to select the final regression model. The selected model was then compared with current prognostic scores (including the TIPS 65 score [18], OHCA score [19], TTM score [20], and rCAST score [21, 22]). Subgroup analyses were performed to test the discriminative ability of PaCO₂ in different subgroups: initial shockable cardiac rhythm versus non-shockable rhythm, hospital arrival time < 25 min versus > 25 min, and arrest-ECMO time < 60 min versus > 60 min. The p-value for the interaction was tested using an interaction test. All computations were performed using SPSS, version 16.0 (IBM Corp., Armonk, NY, USA).

Between January 2012 and December 2020, 152 OHCA patients who received ECPR were included (Fig. 1). FO at discharge was noted in 21% of the patients (33/152) and survival to discharge in 34% (52/152). The characteristics of the patients who received ECPR are summarised in Table 1 and stratified according to neurological outcomes and survival at discharge. The median age was 55 years, and the patients were predominantly male. Cardiac origin was noted in 68% of the patients (62% with acute coronary syndrome, 5% with fatal arrhythmia or cardiomyopathy, and 1% with acute myocarditis). Shockable cardiac rhythm was noted in 75% of the patients. The mean arrest-ECMO time was 59.6 min. Patients with FO were more likely to have witnessed arrest, shockable cardiac rhythm, shorter hospital arrival time, and shorter arrest-extracorporeal membrane oxygenation (ECMO) time. For the metabolic factors, patients with FO had lower pH value and PaCO₂ (56.7 mmHg versus 71.1 mmHg, p = 0.007), while lactic acid level showed no difference.

The ROC curve and AUC of PaCO₂, pH, and lactic acid for predicting FO are shown in Fig. 2. PaCO₂ had the highest AUC of 0.681 (95% CI, 0.576–0.786, p = 0.002).

We used GAM to test the relationship between PaCO₂, FO, and survival, and the results showed a near-linear reverse relationship (Fig. 3). PaCO₂ 70 mmHg was noted as the cutoff point for differentiating FO from non-FO patients, and PaCO₂ 63 mmHg was the cutoff point for survival. PaCO₂ about 70 mmHg also had the highest Youden index in the ROC curve (Supplementary Table 1: Youden index).

Multivariate logistic regression showed that PaCO₂ < 70 mmHg was independently associated with FO after adjusting for other favorable resuscitation characteristics (Table 2). The final regression model with the highest discriminant ability contained six independent resuscitation variables: no flow duration, PaCO₂ < 70 mmHg, witnessed arrest, rhythm change to non-shockable before ECMO, shockable rhythm at hospital arrival, and arrest at a public location. The AUC of the regression model was higher than that of the other current scores for predicting the neurological outcome prediction (Supplementary Fig. 1).

To study the correlation between PaCO₂ and other resuscitation characteristics, we used a PaCO₂ of 70 mmHg to separate the patients into two groups (Table 3). Patients with a PCO₂ < 70 mmHg had significantly shorter arrest-hospital and arrest-ECMO times. No differences were noted among other favorable characteristics, including no flow time, percentage of witnessed arrest, bystander CPR, public location arrest, and shockable rhythm.

PaCO₂ had prognostic value in different subgroups of patients (Fig. 4), including those with an initial non-shockable rhythm, longer hospital arrival time (OR = 4.21, in patients with hospital arrival time > 25 min), and longer ECMO implementation time (OR = 4.66, in those with ECMO time > 60 min). No subgroup showed a significant p value for the interaction.

The PaCO₂ level before ECMO implementation had prognostic value for neurological outcomes among patients with OHCA. A PaCO₂ level of 70 mmHg could help select patients with a higher possibility of favorable neurological outcomes, even among patients with non-shockable rhythm or longer low-flow duration.

This study had several limitations because of its retrospective nature. First, even though there were pre-specified ECPR initiation criteria in our hospital, the specific reason for initiating ECPR was based on the treating physician’s judgement. Some patients who may benefit from ECPR may have been skipped and not included. Second, the time records in this study were collected from electronic records. The exact no-flow time was difficult to calculate. Third, some patients had missing data on prehospital resuscitation variables, including EtCO₂ and prehospital DC shock times. These data could provide additional information on the resuscitation status of patients. Fourth, some patients had extremely poor haemodynamic status even under ECMO, making the diagnosis or intervention infeasible. This could affect the estimation of the proportion of the cardiac origin.

Our PaCO₂ samples were mostly obtained by direct puncture of the femoral artery during CPR. There might be incidental venous puncture due to difficulty in identifying pulsation, and the percentage of incidental venous puncture. Arterial and venous CO2 levels showed a good correlation. A previous study demonstrated that the mean difference in PCO₂ was 4.8 mmHg with a Pearson correlation of 0.93, in critically ill patients [28]. However, the correlation was less studied in shock status or cardiac arrest [29].