The use of extracorporeal cardiopulmonary resuscitation (ECPR), defined as extracorporeal membrane oxygenation (ECMO) implantation during cardiopulmonary resuscitation (CPR) is increasing. Recent data from the Extracorporeal Life Support Organization Registry have demonstrated a more than 20-fold increase in annual ECPR cases from less than 100 in 2009 to more than 2000 in 2021 [1] and the American Heart Association guideline now gives the recommendation to consider ECPR as an alternative method of CPR for patients with reversible causes of cardiac arrest after more than 10 minutes of conventional CPR [2]. With the increasing use of ECPR, it has become crucial to understand proper management to achieve hemodynamic optimization after ECPR to improve outcomes.

One of the most important goals of CPR including ECPR is to preserve higher cortical function of the brain and many studies have been conducted to investigate if markers of tissue hypoxia are correlated with neurologic outcomes in this patient population [3-5]. An oxygen-derived tissue hypoxia marker: lactate has been associated with neurologic outcomes in these patients. [6]. However, lactate levels can increase with stress response, β-2 adrenergic stimulation, or hepatic dysfunction which suggest that elevated lactate level may not always represent deficiency in tissue oxygen delivery [7]. Thus, CO₂-derived markers such as the venous-arterial difference in CO₂ tension (ΔpCO₂) and respiratory quotient (RQ) may be more useful. In hypoxic states, accumulation of proton in tissues may lead to higher CO₂ production due to buffering action of carbonic anhydrase to increase ΔpCO₂. But, there are studies that indicate ΔpCO₂ better represents status of perfusion rather than tissue hypoxia per se [8,9]. In macro- and micro-circulatory failure, RQ can increase through variety of mechanisms including cells converting to anaerobic metabolism to produce the needed energy. The prognostic role of RQ as a CO₂-derived tissue hypoxia marker is relatively well-studied in the sepsis [10,11] and conventional CPR literature [12,13], but the role of RQ in patients with ECPR has not been extensively studied. Thus, this study was performed to investigate whether RQ measured immediately following initiation of ECPR can predict adverse neurologic outcomes in these patients.

During the study period, 433 patients underwent ECPR and survived over 24 hours. Patients transferred from other hospitals (n=12), unsuccessful ECMO implantation (n=32), and insufficient data for initial RQ calculation (n=234) were excluded. Finally, data from 155 patients who received ECPR were retrieved for analysis (Figure 1).

The current study investigated the ability of RQ measured within the first 24 hours after ECPR to predict neurologic outcomes in a relatively large number of ECPR cases. The main clinical findings of this study were as follows: (1) The median RQ was 2.0 (IQR, 1.4–3.0) after ECPR, which was almost twice the normal value. (2) Although RQ was significantly higher in patients with poor neurolgoic outcome, it was not independently associated with poor neurologic outcomes in multivariable logistic regression analysis. (3) Among tissue hypoxia markers studied, only serum lactate >7.1 mmol/L was independently associated with poor neurologic outcomes (odds ratio, 2.26; 95% CI, 1.01–5.04; P=0.047).

The clinical significance of RQ has been studied mainly in the context of septic shock. In previous studies involving patients with acute circulatory failure, usually due to septic shock, investigators found that high RQ was associated with absence of improvement in hyperlactemia [10], increase in oxygen consumption after fluid challenge [11,19], and presence of hyperlactemia [16]. In some studies, patients who had both high RQ and hyperlactemia had the worst outcome [20,21]. Finally, higher RQ was also associated indices of microcirculatory failure using near-infrared spectroscopy [22]. These studies suggest that RQ has potential as marker of tissue hypoxia.

In this study, most of the patients had abnormal RQ of >1 which is marked different compared with few small studies performed in post-CPR patients undergoing targetted temperature after ROSC. In this patient population, median RQ values were less than 1.0 [13,23,24]. There are possible explanations for the discrepancy between RQ in patients who received conventional CPR and our ECPR cohort. First, all patients included in studies of RQ after conventional CPR underwent TTM. Hypothermia may diminish the metabolic rate and thus oxygen consumption and carbon dioxide production, which may have influenced RQ values. However, the use of TTM did not affect RQ in this study. RQ was 2.1 (IQR, 1.6–3.4) in patients who received TTM (n=33) and 2.0 (IQR, 1.3–2.9) in patients who did not (n=122) (P=0.493). Second, the timing of blood sampling to calculate RQ was different among studies, which may have influenced the results. Holzinger et al. [13] measured O₂ consumption and CO₂ production 12 to 24 hours after the patient reached the target temperature of 33 ℃. In the study by Uber et al. [23], blood samples were drawn 5.0 to 18.7 hours (median, 9.9 hours) after the ROSC. Third, there may have been selection bias that could have influenced the results. For example, in this study, patients who died within the first 24 hours because of refractory shock were excluded because we wanted to evaluate the clinical significance of tissue hypoxia parameters in patients with the potential to benefit from hemodynamic optimization. Had these patients not been excluded, the level of RQ might have been different. In addition, each study of RQ in conventional CPR patients had different inclusion and exclusion criteria, so the study populations differed slightly.

The prognostic value of serum lactate level in patients after conventional CPR has been reported in previous studies [6,25-27]. Furthermore, lactate is known to be associated with poor clinical outcomes in patients who receive ECMO [28]. Usually, the in vivo production and consumption of lactate balance each other, so that serum lactate levels are constant. However, in local or general tissue hypoxia, impaired mitochondrial oxidation leads to overproduction and underutilization of lactate. Furthermore, combined metabolic acidosis contributes to decreased hepatic removal of lactate [29]. Thus, lactate has been used as a valuable clinical marker to guide resuscitation. It is unclear as to why RQ was inferior to lactate in predicting poor neurologic outcomes in patients who received ECPR in this study. One possibility is that blood gas measurements may be influenced by sweep gas and ECMO flow rate, which clinicians could calculate. In their recent study on the theoretical effect of extracorporeal CO₂ removal on native lung RQ, Cipriani et al. suggested that native lung RQ increases when more oxygen is delivered extracorporeally [30]. Although veno-arterial ECMO and extracorporeal CO₂ removal differ in many ways, this may be a clue to explaining the poor utility of RQ as a marker of tissue hypoxia in patients who receive ECPR. In other words, not only tissue hypoxia but also the amount of oxygen delivered by ECMO might have affected RQ in patients who received ECPR. The effect of sweep gas and ECMO flow on RQ needs further investigation. Second, we used the difference in CO₂ partial pressure as a surrogate for the difference in CO₂ content to calculate RQ. Although there is good correlation between these two values, these two values are not identical, especially when the CO₂ partial pressure is not in the physiological range [11,20,31]. Clinically, calculating serum CO₂ content requires complex equations, making them impractical to be used at the bedside. Therefore, in many stuides, the CO₂ partial pressure is used as a substitute for the CO₂ content in the calculation of the RQ [17,21,22,32]. Third, the exact proportion of ECMO flow compared with native flow in the radial artery could not be measured, which may have influenced blood gas measurements. The proportion of ECMO flow might have increased when native cardiac function decreased. Fourth, the diet might have affected patients' metabolism and thus the RQ level. Li et al. [33] showed an significant increase in RQ from 0.6 to 1.0 with increasing caloric intake in five pediatric patients receiving ECMO.

There were some limitations to our study. First, this study was conducted with data collected over a long period. During this time, post-arrest management has changed, which could have affected the results. Second, selection bias might have affected the results because this was a retrospective observational study conducted in a single center. In our study, although patients that were excluded due to insufficient data to calculate RQ had similar neurologic outcomes to patients included in this study, some of the outcomes were different between the two groups (data not shown). These differences in different patient groups could have affected the result of this study. Third, to calculate RQ, arterial and venous blood samples drawn within 30 minutes were used in this study. It is not known how this small difference in sampling times could have influenced the overall result. Fourth, more accurate method of measuring RQ such as indirect calorimetry was not used in this study. Future studies using this method may prove to be useful. Finally, although we used a data from a relatively large cohort of ECPR patients, the statistical power might not have been enough. Larger prospective studies are needed to evaluate the utility of RQ as a predictor of poor neurologic outcomes. In patients who received ECPR, RQ was not independently associated with poor neurologic outcome. Further studies on this subject is needed.