INTRODUCTION
Sudden cardiac arrest (SCA) is a life-threatening medical condition highly-relevant to both out-of-hospital and inpatient settings. It involves the sudden cessation of cardiac activity where the victim becomes unresponsive with abnormal breathing and absence of circulation [
1]. If active interventions are not started rapidly, SCA progresses to sudden cardiac death (SCD) [
1]. Each year, SCD accounts for almost 25% of 17 million deaths worldwide, making it one of the most common causes of death [
2]. Early commencement of effective cardiopulmonary resuscitation (CPR) improves survival [
3–
5]. Yet, clinical outcomes have remained poor, with a pooled global 30-day survival rate for out-of-hospital cardiac arrest (OHCA) patients of 10.7% [
6]. Hence there remains an urgent need to discover therapeutics to improve clinical outcomes.
Passive leg raise (PLR) is an experimental CPR technique which involves elevation of the lower limbs from the horizontal plane during CPR [
7]. It is a simple maneuver that works through intravenous volume expansion—where blood is rapidly shifted from the lower extremities towards the intrathoracic compartment to improve venous return [
8]. Prior to 1992, it was recommended as part of the International Standards and Guidelines for CPR [
9], but was subsequently removed due to paucity of supporting clinical evidence. Recent years have seen a resurgence of interest in this topic due to its ease of applicability and plausible physiological basis for improving cardiac output during CPR [
8]. Various animal and human studies have suggested better neurological outcomes [
7], as well as an improved cardiac preload and blood flow during chest compressions [
10].
With renewed interest in the role of PLR in the treatment of SCA [
11], there is a need to consolidate the literature, both preclinical and clinical, to clarify the role of PLR in SCA. In this systematic review and meta-analysis, we primarily hypothesized that PLR improves survival (30-day survival or survival to discharge) in SCA as compared to conventional (supine) CPR (C-CPR). We further hypothesized that PLR improves secondary outcomes, namely, neurologically intact survival and return of spontaneous circulation (ROSC). Clarity on the effectiveness of PLR in SCA will inform CPR techniques, translating to improved clinical outcomes.
DISCUSSION
In recent years, PLR-CPR has garnered significant interest in its role during CPR for the treatment of SCA. While there have been studies focusing on its predictive value for fluid responsiveness and mortality benefit on septic shock patients, there has been no systematic review and meta-analysis on the survival benefits of PLR-CPR in SCA patients to date. In this study, we describe the survival outcomes of SCA subjects with PLR-CPR, and report several important findings that might have potential implications in clarifying the effectiveness of PLR-CPR in SCA patients.
First, meta-analytic estimates showed no statistically significant difference for the outcomes of survival to 30 days or survival to hospital discharge as well as survival at hospital admission when comparing PLR-CPR to C-CPR. Second, there was no significant difference between PLR-CPR and C-CPR groups for the outcome of ROSC in both Axelsson et al. [
8] and Dragoumanos et al. [
7]. Third, CPP was reported to be higher in the PLR arm compared to the C-CPR arm in both Dragoumanos et al. [
7] and Qvigstad et al. [
17]. However, the difference was only statistically significant in Dragoumanos et al. [
7]. Fourth, Zadini et al. [
16] reported a statistically significant increase of carotid blood flow during CPR in the Trendelenburg position.
Our pooled analysis suggests that there was no significant difference for the outcomes of survival to 30 days or survival to hospital discharge as well as survival to hospital admission when comparing PLR-CPR to C-CPR. This is consistent with existing literature, where 3 human studies, Holmen et al. [
14], Azeli et al. [
15] and Axelsson et al. [
8], found that the difference between PLR-CPR and C-CPR groups was statistically insignificant (P=0.69, P=0.81, P=0.12, respectively). Moreover, Azeli et al. [
15] and Axelsson et al. [
8] also reported no significant difference between the PLR-CPR and C-CPR groups for the outcome of survival to hospital admission (P=0.18, P=0.69). A similar trend was noted for neurologically intact survival, where Azeli et al. [
15] reported no difference in one year survival of patients with CPC scores 1 to 2 for both PLR-CPR and C-CPR groups (P=0.81). This may be due to PLR delaying other important interventions, such as defibrillation [
14]. Further, studies have shown that the blood volume mobilized by leg-raising is unpredictable, and is especially unreliable in severely hypovolemic patients [
18,
19]. This is supported by Axelsson et al. [
8] and Dragoumanos et al. [
7], which both reported no significant difference between PLR-CPR and C-CPR groups for ROSC (P=0.85, 0.121, respectively). These findings allude to the unpredictability of the augmentation of artificial circulation by PLR during external cardiac compression. Importantly, it emphasises a need for more trials to be conducted to investigate such survival outcomes [
10,
14].
However, there are studies that indicate a trend favouring PLR-CPR to C-CPR for certain situations. An animal study, Dragoumanos et al. [
7], found that all animals that achieved ROSC survived within 24 hours, though not to the point of statistical significance. In the same study, animals with PLR-CPR were also shown to have a significantly higher neurological alertness score compared to those with C-CPR (P=0.037). These findings might suggest PLR-CPR acts as a rapid intravenous volume expander to shift blood from the lower extremities towards the intrathoracic compartment [
14]. According to Reuter et al. [
20], a 45-degree leg elevation for 4 minutes increases right and left ventricular preload and, by definition, the stroke volume, if the heart is preload dependent. Indeed, 2 animal studies, Dragoumanos et al. [
7] and Qvigstad et al. [
17], demonstrated this particular effect through a rise in ETCO
2 values for their PLR arms. As ETCO
2 values are proven quantitative predictors of stroke volume [
21], a rise in ETCO
2 values for PLR-CPR suggests increased blood flow during the PLR technique for CPR [
19,
22–
24]. Additionally, Dragoumanos et al. [
7] reported a statistically significant increase in CPP for the PLR-CPR group and Zadini et al. [
16] recorded a statistically significant increase (of up to 1.4 times) of carotid blood flow in the Trendelenburg position during CPR. Given the positive outcomes for PLR in animal studies, a case can be made to trial PLR-CPR in the real world.
The contrast in survival and perfusion outcomes between animal and human studies underscores the conflicting evidence behind the effectiveness of PLR-CPR and spotlights the ongoing debate on how PLR may improve outcomes of resuscitation maneuvers in CPR [
8]. While there exist studies that suggest the purported benefits of PLR-CPR [
7,
16,
17], such conclusions need to be made with caution. This is due to 2 reasons. First, the PLR-favored outcome of survival to 24 hours in Dragoumanos et al. [
7] is statistically insignificant. Second, studies which showed relatively favourable survival outcomes for the PLR group were animal studies [
7,
16,
17]. There is an inherent difficulty in extrapolating outcomes from animal studies to humans due to fundamental differences in anatomy and physiology [
25].
While there is conflicting evidence on the effectiveness of PLR as a treatment, there is general consensus that PLR is a reliable predictor of fluid responsiveness among patients with circulatory failure [
26]. An observational study by Preau et al. [
27] notes that certain indices induced by PLR are accurate for predicting fluid responsiveness in nonintubated patients with severe sepsis or acute pancreatitis. Further, PLR has been recommended as part of haemodynamic monitoring in recent international recommendations [
28,
29]. In its capacity as a predictor for fluid responsiveness, PLR is a useful technique to be performed.
PLR appears promising as a fast and accessible technique, with generally good outcomes in animal studies. However, in human studies, we found no statistically significant difference between C-CPR and PLR-CPR. In the current literature, there exists a paucity of data as shown by the fact that our study was only able to pool 2 studies for meta-analysis. Moving forward, PLR-CPR should continue to be used as a predictor for fluid responsiveness in patients with circulatory failure. However, medical professionals should exercise caution if the aim of performing PLR-CPR is to improve survival outcomes in SCA patients. We recommend more studies to be conducted focusing on survival outcomes in order to best elucidate the effect of PLR-CPR.
The findings of this analysis should be interpreted in the context of known limitations. First, our findings are limited by the paucity of studies and data, with only 6 included studies in our systematic review. With regards to survival outcomes, not all studies reported survival outcomes, and the 2 human studies that accounted for survival outcomes had contrasting results. Second, survival outcomes might be influenced by many confounding factors, which might unduly influence results from the studies. Third, PLR-CPR may result in false negative findings in patients with raised intra-abdominal pressure, which our included studies did not take into account. Finally, significant heterogeneity is expected due to the paucity of data and varying methodologies utilized in the included studies. For example, Zadini et al. [
16] implemented PLR-CPR in a Trendelenburg position in contrast to the standardized horizontal plane used in other studies. Additionally, the inclusion criteria of both animal and human studies in the analysis contributed to inherent heterogeneity in our results. These factors limited our ability to generalize the effect of PLR.
In conclusion, PLR is an experimental technique used in CPR that has purported benefits for SCA patients due to its ease of applicability and plausible physiological basis for improving cardiac output during CPR. Despite several animal studies showing benefit from PLR-CPR, there is no human data supporting its use in human cardiac arrest. Future research needs to ascertain the best positioning during CPR to optimize clinical outcomes.