Mechanical circulatory support for refractory out-of-hospital cardiac arrest: a Danish nationwide multicenter study

Out-of-hospital cardiac arrest (OHCA) is a time-critical condition associated with a high mortality worldwide. Despite various initiatives to improve public engagement and ensure access to a sufficient number of external defibrillators, survival rates remain poor [1]. Short-term mechanical circulatory support (MCS) with extracorporeal membrane oxygenation (ECMO) or Impella devices has emerged as a rescue therapy in adult patients with OHCA that is refractory to conventional cardiopulmonary resuscitation (CPR). MCS may ensure life-saving organ perfusion, lending clinicians crucial time to identify and treat the underlying cause of cardiac arrest. Extracorporeal cardiopulmonary resuscitation (ECPR) refers to the rapid application of ECMO in the setting of refractory cardiac arrest. Several observational studies and recently one randomized clinical trial have demonstrated encouraging results after ECPR [2‐6]. In recent years, the use of Impella devices as MCS for refractory OHCA have also shown potential in this high-risk population [7, 8]. Although the field of MCS for refractory cardiac arrest has evolved rapidly over the past decades, identifying optimal candidates is still an inevitable challenge.

MCS for refractory OHCA has been introduced gradually over the past ten years in Denmark, and a national consensus was adopted in February 2018 [9]. However, detailed knowledge of the full cohort treated remains scarce. Regional differences in triage of patients with OHCA may influence the availability of MCS, which may in turn affect patient selection and outcome. The aims of this study were to describe temporal trends and regional variation in the use of MCS in Denmark, to evaluate adherence to the national consensus on ECPR use and to identify factors associated with outcome.

This nationwide retrospective, observational cohort study was conducted at four tertiary cardiac arrest centers in Denmark (Aalborg University Hospital, Aarhus University Hospital, Odense University Hospital and Copenhagen University Hospital). In Denmark, MCS for refractory OHCA is performed at these four centers exclusively.

Additional file 2: Figure S1 demonstrates the gradual implementation of MCS in Denmark. Between July 2011 and December 2020, a total of 259 patients treated with MCS for OHCA were enrolled in the study: (Aalborg University Hospital, n = 34, Aarhus University Hospital, n = 138, Odense University Hospital, n = 55, and Copenhagen University Hospital, n = 32). Survival to day 30 was seen in 67 (26%). A total of 65 (25%) patients survived to hospital discharge, and 61 (94%) of these patients were discharged with a CPC of 1–2.

The present study is the first nationwide multicenter study of outcomes in patients receiving MCS for refractory OHCA in Denmark. The main findings showed that one in four MCS patients survive to hospital discharge with a good neurological outcome. Outcome was significantly associated with initial presenting rhythm, signs of life during CPR, transient ROSC, pre-hospital low-flow time, initial pH and lactate levels. By offering MCS only to patients meeting the strictest criteria, survival exceeded 48%, but this occurred at the cost of withholding life-saving treatment in the majority of patients saved by MCS in the cohort. Thus, our data rightly questions the validity of stringent patient selection for MCS.

ECPR has emerged as a salvage therapy for patients suffering from refractory OHCA. Although resource demanding, ECPR has been shown to be both feasible and cost effective [13]. Moreover, recent small reports have described the potential of the Impella device as an alternative rescue therapy in cardiac arrest patients [7, 8]. Several previous observational studies have demonstrated encouraging survival rates and a favorable neurological outcome from applying strict inclusion and exclusion criteria in distinctive patient populations [14‐18]. The first randomized clinical trial recently published by Yannopoulos et al. (the ARREST trial) revealed superiority of ECMO-facilitated resuscitation with a survival rate of 43% compared with 7% with standard advanced life support [6]. Survival at six months was also greater in the ECMO group (hazard ratio (HR) 0.16, 95% CI 0.06–0.41, p = 0.0001). Whereas the trial was well-designed and supports use of ECPR in refractory OHCA, apparent limitations are present as this was an open-labelled single-center study with a relatively small and highly selected patient population.

In Denmark, a number of initiatives to improve pre-hospital quality of care for OHCA patients have produced a remarkable increase in 30-day survival rates from 3.9% in 2001 to 16% in 2018 [19]. Concurrently, MCS with ECMO and in limited cases the Impella device, has been evolving steadily and is now an established treatment for selected patients with refractory OHCA in all Danish regions. However, given the formal inclusion and exclusion criteria defined in the Danish national ECPR consensus, one might assume that the results of our study would reflect a more homogeneous population. Despite our intention to select qualified candidates, violation of the national consensus was still seen in 52%. In this population, the fatal consequence of treatment not being provided, opted some ECPR teams to perform MCS despite adverse conditions. Selection of appropriate candidates for MCS is evidently a challenge in real clinical practise. Despite growing interest in and a growing body of literature on MCS for refractory OHCA, robust evidence on patient eligibility is still lacking.

In the present study, the majority of patients treated with MCS were younger (< 65 years) in compliance with the national consensus. This may explain why no statistically significant difference was detected in age between survivors and non-survivors. One may have predicted a worse prognosis in patients above 65 years of age, but survival to hospital discharge with good neurological outcome was similar in this group compared with the younger population < 65 years (26% versus 23%). Previous studies have proposed advanced age as a predictor of a poor outcome in patients with ECPR [20], and some studies have even suggested an age of > 75 years as a contraindication for ECPR [21], which is in line with our results. In our cohort, no one above 72 years of age survived to discharge. However, there is limited and conflicting evidence that older age is associated with poor outcome [22, 23]. The dilemma of initiating ECPR in the elderly remains controversial and more evidence is needed to confirm, whether to proceed or stop advanced life support based on age limits.

Pre-hospital parameters are crucial in the selection of suitable candidates for ECPR. Initial shockable rhythm, transient ROSC and signs of life during CPR are considered favorable prognostic factors in ECPR [24‐26]. In a prospective registry study, Bougouin et al. compared conventional CPR with ECPR in 13,191 consecutive patients with OHCA [27]. Prognostic factors in the ECPR group comprised an initial shockable rhythm (OR 3.9, 95% CI 1.5–10.3) and transient ROSC (OR 2.3, 95% CI 1.1–4.7) prior to ECPR implementation. One of the main findings in our study was that patients with signs of life during CPR had a threefold higher survival rate than patients without signs of life during CPR. This is in correlation with a study recently published by Debaty et al. [28] The authors found that any signs of life before or during CPR substantially improved 30-day survival with favorable neurological outcome in a multivariable prognostic model (OR 7.35, 95% CI 2.71–19.97). These results are supported by our data. Signs of life was a highly significant prognostic factor in relation to initial presenting rhythm and low-flow times. In the present cohort, a pre-hospital low-flow time < 60 min was associated with an increased survival rate; however, patients exceeding pre-hospital low-flow times > 80 min also had an advantageous outcome. Patients with pre-hospital low-flow times > 80 min had a higher rate of signs of life during CPR than patients with a pre-hospital low-flow time of 60–80 min. The presence of signs of life increased survival rates substantially in both groups. Collectively, these observations support the evidence of incorporating signs of life as an important factor in the selection of patients for ECPR. Our results suggest that prolonged resuscitation efforts in the field may not be futile, especially in patients presenting favorable circumstances such as signs of life and where ECPR can be established within a reasonable timeframe. The present findings do not allow us to determine whether any of the patients would have survived without MCS. However, the long total low-flow times observed makes this unlikely.

Historically, the arrest-to-perfusion time has been linked to survival [16, 18, 29, 30]. Wengenmayer et al. reported that among 133 patients with cardiac arrest treated with ECPR, low-flow time was an independent predictor of mortality [30]. Bartos et al. demonstrated a significant association between time from arrest to sufficient ECPR flow and neurological outcome in a cohort of 160 patients [18]. These results are similar to ours. In the present study, hospitals serving patients in remote and rural areas had longer arrest-to-perfusion time due to longer distances to the invasive center. Implementation of systematic pre-hospital ECPR calls, more rapid allocation of helicopter-mediated transport and direct triage to the catheterization laboratory may improve the performance and facilitate a reduction in system delay for these patients. In this setting, pre-hospital ECPR may also shorten the interval from collapse to onset of ECPR [17].

The predictive value of pH and lactate levels in patients with cardiac arrest is well established. Controversy still exists regarding the ECPR population. In our study, initial arterial pH and lactate levels were found to be associated with mortality. This finding is consistent with previous findings [14, 31]. Jung et al. retrospectively reviewed 93 patients with cardiac arrest undergoing ECPR and found results similar to our results [32]. On the contrary, Leick et al. found no association between elevated lactate levels and mortality [33]. Our results support the inclusion of pH and lactate into our decision-making when considering patients for MCS, whereas specific cutoffs still need conformation in other cohorts. Importantly, a stringent use of pH > 6.8 and lactate < 15 mmol/L as selection criteria, may result in denying life-saving therapy to a considerable number of the survivors present in this cohort.

In the present study, we assessed pre-hospital and in-hospital factors in relation to outcome, which may come in benefit for clinicians in the selection of appropriate candidates for MCS. High mortality rates were seen among patients with initial non-shockable rhythm, no-flow times > 10 min and end-tidal CO₂ < 1.3 kPa. On the contrary, our results suggest that a more refined assessment of the inclusion criteria, comprising additional criteria such as signs of life during CPR and lactate levels, may improve survival rates in patients receiving MCS. Nevertheless, one must recognize that limiting patient selection to strict pre-defined criteria will inevitably exclude some patients in whom MCS would have bought valuable time until the reversible cause could be treated. The fact that the national consensus was violated in 52% of patients, of whom 20% survived to hospital discharge with a good neurological outcome in 94% of the cases, indicates that there must be room for individual decision-making, especially in the young patients. Patient selection for MCS continues to be a challenging part of real-world clinical practice and further randomized clinical trials are warranted.

The present study has several limitations. Its retrospective nature makes it subject to patient selection bias. The national consensus was available and adopted to some extent in all centers. This produces risk of bias in the evaluation of the associations with outcome. Although we conducted a multicenter study using nationwide registry data, the heterogeneity of the study population with a mixed cohort of patients with OHCA hampers generalization of the results. Neurological outcome at hospital discharge is a fairly crude measure; it is, however, broadly used in cardiac arrest studies. Studies assessing long-term survival and neurological outcome are necessary.

Patients receiving MCS for refractory OHCA presented promising survival rates with a favorable neurological outcome at hospital discharge. Even though a more stringent patient selection with additional criteria may produce higher survival rates, this would also limit the number of candidates and possibly exclude half of the survivors from treatment, why optimization of the selection criteria is still of essence in the future.