Introduction
Cardiac arrest is the most critical challenge faced by every clinical physician because it has varying etiologies and a high mortality rate [
1]. High-quality cardiopulmonary resuscitation (CPR) and improvement in the emergency medical service (EMS) system have been proven to result in a higher return of spontaneous circulation (ROSC) rate in out-of-hospital cardiac arrest (OHCA) patients, and the survival rate has improved over time since 2006. However, less than 10% of patients survive to hospital discharge, and survival with good neurological outcomes is even lower [
2‐
4].
Insufficient brain perfusion is a key factor in poor neurological outcomes. Cerebral perfusion pressure (CerPP), which is calculated as the mean arterial pressure (MAP) minus the intracranial pressure (ICP), decreases dramatically during cardiac arrest for the following reasons. First, once cardiac arrest occurs, inflammatory systems are activated to respond to whole-body ischemia, which results in increased membrane permeability [
5]. In addition, the blood–brain barrier (BBB) breaks down because of intracellular acidosis, stopping oxidative phosphorylation and leading to accumulation of lactate [
6]. Due to these two effects, serum proteins and water pass from the blood to brain tissue, which leads to neuronal, glial or axonal injuries [
7] and increases ICP. Second, chest compressions are performed to try to expel blood out of the heart and create forward flow, but also cause increased thoracic pressure and impede venous return [
8]. Finally, optimal CPR can provide approximately 20–30% of pre-arrest cardiac output [
9], and only 30% of it flows to the brain [
6]. As a result, the rate of survival with good neurological outcomes is dismal.
Compared to conventional CPR (CCPR), active compression–decompression (ACD) CPR with an impedance threshold device (ITD) has been shown to improve the ROSC rate and survival to discharge with favorable neurological outcomes [
10‐
12]. Theoretically, ACD, by an upwards lifting force during the decompression phase, could decrease intrathoracic pressure, leading to augmented venous return. ITD could cause the same effect by selectively restricting airflow into the lungs during the decompression phase. However, a recent meta-analysis that focused on ACD with/without ITD CPR and CCPR revealed similar ROSC rates [
13].
In recent years, animal studies have revealed the head-up positions (HUP) with ACD + ITD CPR or automated (LUCAS 2.0) + ITD CPR could decrease ICP and improve CerPP [
14] and that it may even improve coronary perfusion pressure (CoPP) [
15] in animal experiments. As to HUP, some studies tilted whole body up, also called “the reverse-Trendelenburg position,” to lower ICP. However, this position could also decrease MAP due to pooling more blood in lower extremities [
15,
16]. To avoid this condition, other studies elevated the “head and chest up only” [
14,
17,
18]. No matter what HUP posed, compared to CCPR, in which the patient lies down at 0 degrees, elevating the head during CPR could accelerate brain venous return and the hydrostatic displacement of cerebrospinal fluid (CSF) from the cerebral ventricles to the spinal cavity [
19]. Thus, ICP decreases and CerPP increases. In addition, facilitating venous return may increase CoPP, and a higher CoPP is associated with a higher ROSC rate [
20]. Furthermore, with the combination of HUP ACD + ITD CPR, a recent animal study found that controlled sequential elevation (CSE) rather than a specific head-up angle could maximize CerPP and improve the ROSC rate and neurological outcome [
21]. However, Park et al. [
22] demonstrated that head-up CPR could worsen the survival rate. HUP might be considered a “next-step” intervention in the ICP-lowering/CPP-enhancing paradigm. Therefore, some of the preclinical data regarding HUP CPR appear to be mixed, thus prompting us to better explore and clarify the effect of HUP CPR. In this article, a comprehensive systematic review and meta-analysis was performed to evaluate the effect of HUP CPR in animal models and to draw conclusions to establish a new strategy for CPR in the future.
Discussion
The most important result of our study is that HUP at 30° during CPR can significantly increase CerPP, mainly by reducing ICP, compared to SUP. CerPP, which is calculated by MAP minus ICP, could be increased by higher MAP and/or lower ICP. The reason for the lower ICP is that when elevating the head and body up to 30° during CPR, ICP will decrease by facilitating brain venous return and CSF movement into the spinal subarachnoid space, which is consistent with previous studies, even at different elevation angles ranging from 10° to 50° [
15]. In addition, the reduction in ICP also decreases the resistance to forward brain blood flow, which is generated by each chest compression. This effect could explain the findings of 2 of our included studies [
15,
17] that demonstrated that brain blood flow increased significantly in HUP compared with SUP. Furthermore, due to the heterogeneous study protocols in our included studies, we analyzed CerPP regarding whether the position during CPR was changed or fixed, and in the fixed position CPR studies, we further evaluated the duration of CPR, which showed significantly increased CerPP in all HUP groups. Thus, HUP CPR can reduce ICP when the head is elevated during CPR, and the effect could last the entire CPR duration.
The other important result is that we did not find a significant difference in MAP between the HUP and SUP groups, regardless of whether the position was changed during CPR or the duration of CPR. Maintaining sufficient blood pressure by pumping upwards to the brain is important in CPR. From a physiological perspective, elevating the head and chest in CPR may reduce MAP because of the gravity effect. Each chest compression will pump more “uphill” than in the supine position. However, ACD-CPR with ITD could generate sustained aortic pressure, and HUP may reduce the resistance of blood flow to the brain. Therefore, the net effect of MAP revealed no significant difference between the 2 groups in our study. The absolute MAP value was much lower in Putzer et al. [
28], who did not use ITD in automated CPR, and MAP along with CerPP decreased gradually over time. Debaty et al. [
15] revealed that MAP and CerPP showed a significant decrease immediately once ITD was removed in HUP CPR. These results could support our inferences. In addition, of our included studies, two [
16,
16,
22] showed decreased MAP in HUP, while the others revealed no significant difference between the 2 groups. Both of them were in the reverse-Trendelenburg position rather than in the “head and chest up only” position. Because more blood deposits in the lower extremities, we speculate that just ACD-CPR with ITD may not overcome the physiological effect of the reverse-Trendelenburg position, which results in a decrease in MAP. Interestingly, pulmonary edema is a common complication of cardiac arrest [
29]. Elevating the chest may have better blood-gas exchange caused by reduced lung congestion and pulmonary vascular resistance because of the gravity effect [
18]. This potential benefit should be confirmed by more studies.
We also found higher CoPP in the HUP group than in the SUP group. CoPP is calculated by diastolic aortic pressure minus right atrial pressure [
30]. Theoretically, while the head and chest are elevated, right atrial pressure is also decreased by the gravity effect. As a result, CoPP could be increased under ACD-CPR with ITD to maintain sufficient diastolic aortic pressure. Kim et al. [
16] revealed that CoPP increased gradually from the head-down position and supine position to the head-up position and reached the highest CoPP at 30°. In contrast, the CoPP and MAP in Park et al. [
22] were much lower than those in the other included studies. The methodology in this study, which is different from the others, did not overcome the effects of gravity for the following reasons: 1. “Not priming the cardio-cerebral circuit” at SUP before head elevation; 2. elevating the head too fast before CPR; 3. maintaining the reverse-Trendelenburg position at a steep angle for a prolonged period; and 4. using a mechanical device that may not provide an optimal ACD effect. However, two of the included studies [
15,
17] directly measured heart flow and revealed no significant difference between the 2 groups. The calculated pressure does not translate directly to actual flow. Thus, further studies need to be conducted to clarify this point.
Only 3 included studies [
17,
18,
22], including 50 Yorkshire farm pigs, reported the ROSC rate, and the results showed no difference between the two groups. In these 3 studies, Park et al. [
22] revealed that the ROSC rate and survival rate were reduced significantly in the HUP group (ROSC rate: 1/8 in HUP vs. 6/8 in SUP,
p = 0.04; survival rate: 0/8 in HUP vs. 6/8 in SUP), while the others [
17,
18] showed no difference. Effective chest compressions with sufficient CoPP are crucial for successful CPR. In addition to the previously mentioned reasons that cause decreased MAP and CoPP, the 15-min untreated ventricular fibrillation (VF) time was also far longer than the others. These reasons could explain the dismal ROSC rate in HUP. Furthermore, due to the heterogeneous study design, we removed this study for analysis, and the result remained unchanged (RR 1.27; 95% CI 0.61–2.65;
p = 0.53;
I2 = 39%).
The overall impact of HUP is that it is now a complementary and pivotal component of the combined ICP lowering approach. HUP alone is not associated with a better outcome. Thus, there are some important findings in addition to HUP CPR. First, by using ACD + ITD in HUP CPR, both ACD and ITD could decrease intrathoracic pressure in the decompression phase, which leads to augmented venous return. HUP could also accelerate brain venous return by the gravity effect. More importantly, combining HUP CPR with both ACD and ITD might not appear to have additive effects but rather to produce a markedly synergistic effect in terms of near-normalizing (sustaining CerPP). These three important components are “interdependent” and have a high synergistic effect that could significantly improve CerPP [
17,
18]. These "interdependent" components should not be lost in all of this. In contrast, two of the included [
15,
28] studies revealed an absolutely lower MAP while not using ITD in HUP CPR. Another study revealed that the CerPP in SUP ACD + ITD CPR is higher than that in HUP CPR, which suggests that ACD + ITD is more effective in increasing CerPP than HUP alone [
18]. In addition, our subgroup analysis revealed that ACD + ITD CPR had better CerPP than automated + ITD CPR. Second, the “priming step” (CPR in the supine position for minutes before HUP) is very important, and raising the head immediately without a priming step would relate to poor outcomes [
31]. From a pathophysiological view, humans lose vessel autoregulation during cardiac arrest. Once we elevate the head/chest up before CPR in the supine position, blood will deposit in the lower body. Chest compressions to pump blood “uphill” will not overcome this effect in the short term, which results in disappointing outcomes. All of our included studies elevated the head/chest in the short term, but with the “priming step,” the CerPP was still higher in the HUP group than in the SUP group. In contrast, two of our inclusion studies [
22,
28] rose subjects immediately after VF had a markedly lower MAP, CerPP (in Putzer et al. [
28]) and CoPP (in Park et al. [
22]). After removing these two studies (one study at a time), the overall results remained unchanged, which suggests that there were other factors that affected MAP. The current study [
32] revealed that the “priming step,” 2 min of relative SUP CPR, had significantly higher CerPP than elevating head/chest immediately after 8 min of untreated VF in an animal model. Our subgroup analysis also supports this inference. With the “priming” step, CerPP, MAP and CoPP increased significantly when compared to “no priming.” In addition, “no priming” deceased the “absolute” MAP value, which means that it caused a lower MAP than SUP. Moreover, performing a dispatch-assisted or bystander SUP CPR until an EMS crew takes over is closer to reality (patients might not receive HUP CPR immediately after going into arrest). Third, the “head/chest up only” position could be superior to the reverse-Trendelenburg position. Due to the gravity effect, the reverse-Trendelenburg position will deposit more blood in the lower extremities. Although CerPP is similar in both positions, the reverse-Trendelenburg position also decreased the “absolute” MAP value found by our subgroup study. Fourth, within 2–4 min of CSE, instead of the absolute HUP angle or rapid elevation, CerPP achieves 50% of baseline in 2.5 min and over 80% in 7 min under CSE HUP ACD + ITD CPR, as noted by a recent study [
31,
32]. Although the mechanism of CSE needs further research, Moore et al. [
21] revealed that HUP CPR had good neurologic survival outcomes in an animal model after combining 4 factors (using ACD + ITD CPR, the “priming” step, elevated head/chest up only and CSE). Overall, we considered that the “priming timing,” “sequencing of HUP” and “using ACD and ITD” during resuscitation are better able to achieve favorable neurological outcomes than just elevating the head and chest. Every factor is very important, and it would be dangerous if any one factor is ignored.
In recent years, Pepe et al. [
33] revealed a great ROSC rate improvement from 17.8 to 34.2% (
p < 0.0001) after applying the CPR bundle on the EMS system in OHCA patients. This bundle combined HUP automated + ITD CPR, “priming” the cardio-cerebral circuit at SUP, the reverse Trendelenburg position and gradually elevating the patient up to 20° (somewhat like CSE), which resulted in a hopeful outcome. Furthermore, a recent study also points out that the priming step and CSE are both important for better outcomes [
31].
The performance of HUP CPR continues to evolve and has been further refined compared to what was initially reported and analyzed by the previous studies mentioned above. In addition, many proven key factors are more important to improve ROCS rates and neurological outcomes, such as early activated EMS, defibrillation and high-quality CPR. Thus, HUP ACD + ITD CPR may be considered in specific situations (i.e., non-VF cases with OHCA) once this concept is applied to human CPR in the future.
To the best of our knowledge, this is the first meta-analysis that compares HUP CPR to SUP CPR in animal models. The strength of this analysis includes further confirming the effect of HUP CPR. In addition, we performed multiple subgroup analysis due to heterogeneous study protocols. Moreover, two authors used the ARRIVE guidelines 2.0 to evaluate the quality of the included studies.
Limitations
There were also some limitations. First and most importantly, the results of our study may not be totally transferrable to humans. All of the included studies used “healthy” animals, and a ventricular fibrillation model was used to simulate cardiac arrest. However, unlike animal experiments, cardiac arrest is caused by more complex factors and has more etiologies in humans. Most initial rhythms of cardiac arrest are non-shockable, both in in-hospital cardiac arrest and in out-of-hospital cardiac arrest, which accounts for 80% [
34,
35], and human CPR physiology is more dynamic. In addition, until now, only one study [
14] revealed that human cadavers had similar changes in the ratio of blood flow in HUP with ACD-CPR despite many different anatomical structures between humans and swine models. Further investigations that focus on HUP CPR physiology in human cadavers are warranted. Therefore, the outcome in this manuscript should not translate completely to humans before larger sample size and well-designed studies are published. Second, most of the included studies (5 over 7) were performed in the same laboratory with the same team. This could lead to single-source bias. Third, all of the included studies used calculated CerPP and CoPP. Only 2 studies further measured brain blood flow and heart blood flow directly by using microspheres. Although high perfusion pressure is associated with high blood flow, the evidence is indirect rather than direct. Finally, even though our study demonstrates strong evidence of increasing CerPP by lower ICP in HUP CPR, it is still unclear whether this benefit could equal an increased survival rate with good neurological outcome. Thus, further large-sample and standardized research is essential to confirm the optimal resuscitation protocols for humans and animals.
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