A Pilot Study to Examine the Effect of Passive Straight Leg Raise Performed During Cardiopulmonary Resuscitation on Cerebral Perfusion Measured by Noninvasive Cerebral Oximetry

A significant morbidity is experienced by survivors of cardiac arrest following successful resuscitation attempts, even in the in-hospital setting. The bulk of this morbidity is neurologic in nature (¹), and as such, efforts continue to find new resuscitation methods, which may improve the short- and long-term neurologic outcome of the survivors. The nature of neurologic injury following cardiopulmonary resuscitation (CPR) relates to a lack of blood flow to the brain during resuscitation efforts, resulting in significant cerebral ischemia.

Initial CPR guidelines have previously stated that “elevation of the lower extremities may promote venous return and augment artificial circulation during external cardiac compression” (²). However, as a result of lack of clinical evidence for this technique, the statement was removed from CPR guidelines in 1992 (³). Subsequently, studies have demonstrated that passive leg raise (PLR) can result in a shift of fluid from the lower extremities toward the intrathoracic compartment (⁴), and in the preload dependent heart, a 4-minute leg elevation at 45° increases right and left ventricular stroke volume (⁵). Furthermore, the efficacy of PLR has been demonstrated using end-tidal carbon dioxide (ETco₂) measurements as a surrogate of cardiac output and the echocardiographic demonstration of increased cardiac output (^6,7). Use of PLR has been shown to improve coronary perfusion pressure in an animal model (⁸) and improve cardiac output, coronary perfusion pressure, and systemic perfusion pressure in computation models (^9,10). However, there is lack of human data supporting its use in cardiac arrest (^11,12).

The demonstration in animal and computerized models of improved coronary and/or cerebral blood flow would suggest an opportunity to improve upon resuscitation attempts with a simple to institute maneuver that may result in improved outcomes for patients surviving CPR. Currently, a proof of concept study is required to support larger prospective randomized control trials, which would evaluate the effects of this maneuver on clinically relevant outcomes in survivors.

We aimed to examine the effect of PLR on cerebral perfusion in real time, in subjects undergoing CPR, using a randomized cross-over study design. We used near infrared spectroscopy (NIRS) as a surrogate measure of cerebral perfusion (¹³). We hypothesized that PLR during CPR is feasible and when compared with CPR alone will either achieve higher NIRS value when applied earlier or will attenuate the expected decline in NIRS when applied later.

METHODS

Ethics

This trial was designed as a prospective proof of concept study, which aimed to enroll 10 subjects to assess the effects of PLR maneuver during CPR, on surrogate measures of cerebral perfusion. The trial was approved by the Southern Adelaide Health Local Network Human Research and Ethics Committee (HREC) (application number 259.17), and procedures were followed in accordance with the ethical standards of the responsible committee on human experimentation and with the Helsinki Declaration of 1975. Given the incapacitation of trial subjects at the time of enrolment, a waiver of consent was sought and approved by the HREC, citing the low risk nature of the intervention. Consent for inclusion of data in the final analysis was sought retrospectively where possible, from the subject or their appropriate next of kin.

Study Design and Settings

The project was a randomized double cross-over physiologic study and was not designed to examine patient-centered outcomes. The study was conducted at Flinders Medical Centre, which is a tertiary academic hospital supporting Southern Adelaide, SA, Australia, with an ICU admitting more than 2,200 patients every year. Subjects were enrolled by attendance of the ICU medical emergency team (MET) to in-hospital cardiac arrest at Flinders Medical Centre, where CPR was deemed an appropriate intervention according to the clinical history and documented wishes of the subject or surrogate decision-maker. Subjects who had a cardiac arrest while in ICU were also enrolled in the study. Enrolment of participants took place between November 2018 and May 2021.

Study Intervention

NIRS is a noninvasive measure of whole tissue oxygenation. It consists of near infrared light absorption data received from the probes placed on forehead. The reading from the NIRS probes reflects a composite of mixed venous, arterial, and capillary blood oxygen saturation (¹⁴). Hence, it represents a noninvasive surrogate measure of the effectiveness of CPR in improving cerebral perfusion (^15–17). The previous studies have consistently shown that NIRS values act as a marker of return of spontaneous circulation (ROSC) and are lower and decline progressively during CPR in patients who do not achieve ROSC (^16,17).

All deteriorating patients including patients in cardiac arrest are attended by MET team led by ICU clinicians (nursing staff, physicians, and registrar trainees). Extensive education of the intervention (PLR during CPR and placement of NIRS electrodes) was provided to all members of the MET, who would attend in-hospital cardiopulmonary arrests and provide CPR.

Subjects found to be in cardiac arrest on MET arrival and where CPR was deemed an appropriate medical intervention were enrolled by the attending ICU clinician. Subjects who had a cardiac arrest while in ICU were also enrolled in the study. It was considered imperative that the study measures did not affect the provision of best practice CPR. Patients were only enrolled in the study when an extra staff member was available to help with the study. This was done in order to maintain delivery of high-quality CPR. Standard CPR cycles were performed according to the current Australian Resuscitation Council guidelines (¹⁸).

The prescription of a PLR for the trial intervention was between 30° and 45° based on computerized modeling (^9,10). Either the legs were held up manually or this was achieved by placement of a stool of fixed height under the legs at the time of CPR. This stool was kept together with the MET trolley, along with equipment for NIRS measurement.

Due to time critical nature of the study, subjects were prerandomized into receiving either two cycles of CPR with a PLR followed by two standard cycles of CPR (Group I) or two cycles of standard CPR followed by two cycles of CPR with a PLR (Group II). Upon enrolment, subjects had their forehead fitted bilaterally with NIRS probes (Masimo-Adult O3 sensors, Masimo corporation Forty Parker, Irvine, CA). During the four study cycles of CPR, readings were recorded and documented prior to the end of a cycle and rhythm check. The Masimo root monitor and the attached sensors were kept in a “ready-to-use” state with the MET trolley.

Following completion of the four cycles of CPR with NIRS, the MET team continued resuscitation of the patient according to current guidelines, and subsequently, where resuscitation efforts were successful, the subject was then transferred to the ICU for ongoing management. If the patient achieved ROSC before completion of four cycles of CPR, then the patient data were not included in the study. Baseline demographic data such as age, sex, type of rhythm, duration of CPR before enrolment in the study, total duration of CPR, and patient-centered outcomes were also recorded in the study. As this was a proof of concept study and there was no previous work to guide our sample size calculation, we planned to enroll 10 subjects in the study—5 with PLR first (Group I) and 5 with PLR second (Group II). This was based on a similar study with the use of NIRS in early cardiac arrest survivors (¹⁹).

Statistical Analysis

Data were reported as means with sd or median with interquartile range (IQR), as appropriate for the distribution of each variable. Normality of data was assessed using Kolmogrov-Smirnov test, and data transformations such as log transformation were performed accordingly. Analysis was performed using SPSS Version 27.0 (SPSS Inc, IBM Corp. Released 2020, IBM SPSS Statistics for Windows, Version 27.0, Armonk, NY). NIRS data on both left and right side were recorded in a 2-second cycle; this was averaged and reported to every 10-second epoch for the duration of the study for each subject individually. The groups were compared with an independent sample t test. Delta NIRS value was calculated as the difference between average NIRS values between the first two cycles of CPR and the next two cycles in both the group. A conventional alpha level of 0.05 was used for all significance testing.

RESULTS

Prior to and during the study period, we trained 50 ICU MET nurses and 15 ICU doctors for this study. They were provided an in-service (around 15 min of duration) regarding the study objectives, placement of the NIRS sensors, and providing PLR during CPR (based on the prerandomized sequence). PLR was allowed either manually or with the use of foldable stool which was kept with the MET trolley. This study was conducted when there was an additional trained staff member available and was not involved in other aspects of CPR.

Total of 14 subjects were enrolled. Four subjects were excluded as they had ROSC before the study intervention or data collection. In three of these subjects, although the NIRS electrodes were attached, they achieved ROSC before data collection began. In one subject, in whom PLR was performed first, ROSC happened within the first 2 minutes of CPR. As preplanned, 10 subjects who underwent randomization were examined. PLR was achieved by placement of a stool of fixed height under the legs at the time of CPR in seven subjects. All of these randomized subjects completed the entire protocol without interruption, and there were no technical difficulties in performing PLR during CPR.

Demographics and Outcomes

The demographics and study characteristics of the individual subjects are displayed in Table 1. The median (IQR) age of subjects was 74.5 years (60.8–85.0 yr); 50% were male. The most common admission diagnosis was acute coronary syndrome (n = 4), and the most common initial recorded rhythm was asystole (n = 7). Half of the subjects sustained cardiac arrest on the wards, and the rest in ICU. The median (IQR) duration of CPR prior to enrolment was 8 minutes (IQR 4.8–16.2 min) minutes. The median total duration of CPR was 27.5 minutes (IQR 15.0–37.0 min). Three subjects survived to discharge from hospital, and the other seven subjects died in hospital.

Study Main Findings

In Group I, where the subjects had the PLR performed during the first two cycles, there was a higher NIRS value as measured in both right and left electrodes when compared with the next cycles without PLR (Supplemental eTable 1, https://links.lww.com/CCX/B153). In Group II, where the PLR was performed in the second/subsequent two cycles of CPR, either there was no difference in the NIRS values between the first and second set of two cycles (all five subjects as measured on left and two subjects as measured on right), or there was an increase in NIRS values (two subjects as measured on right) when PLR was performed second (Supplemental eTable 1, https://links.lww.com/CCX/B153). The individual time course changes in NIRS in all 10 subjects in both groups are shown in Supplemental eFigures 1–10 (https://links.lww.com/CCX/B153).

We compared the delta NIRS (between the first and the next two cycles of CPR) between the Group I and Group II. The mean (sd) of delta NIRS on the right side in Group I was 1.29 (0.51), whereas it was –0.29 (1.29) in Group II (p = 0.034 [95% CI 0.15–3.01]). The mean (sd) of delta NIRS on the left side in Group I was 1.68 (0.35), whereas it was 0.03 (0.11) in Group II (p < 0.001 [95% CI 1.28–2.03]) (Fig. 1).

DISCUSSION

In this proof of concept study, we found that it is feasible to perform PLR during CPR without interrupting resuscitation. Moreover, when applied in the first two cycles of CPR post enrolment, we demonstrated a statistically significant increase in the absolute value of NIRS. When the PLR was applied during the second two cycles of CPR post enrolment, there was an attenuation in the expected decline in the absolute NIRS value. The cerebral oxygenation (and NIRS value) is expected to decline in patients with continued and longer resuscitations attempts who do not achieve ROSC (^16,17).

PLR is not only feasible during CPR but also leads to significant differences in the NIRS value. The proposed mechanisms for these findings could include a combination of preload optimization by increasing venous return and preventing peripheral venous blood pooling/stasis, as well as a favorable arterial blood flow to dependent regions during CPR, when a PLR is applied. This has been demonstrated previously in critically ill patients (^6,7). In a swine model of prolonged ventricular fibrillation, the use of PLR improved coronary perfusion pressure, where autotransfusion of the aorta was deemed the only explanation (⁸). In computational models and in some extreme situations (only with pure thoracic pump), it has no effect on cardiac output and coronary perfusion but still improves cerebral perfusion (¹⁰). Although not directly measured, our results suggest improvement in cerebral oxygenation during CPR attempts with the use of a noninvasive and easy to implement strategy that can be readily incorporated into a basic life support algorithm.

Previous studies did not show survival benefit of PLR in out-of-hospital cardiac arrest (OHCA) patients (^20,21). The different design, patient population, and study outcomes prohibit direct comparison. The OHCA poses several challenges, which result in greater delays in commencement of advance life support in most circumstances. In these studies, the time intervals between collapse to emergency medical service (EMS) call and EMS arrival indicate significantly longer delays in commencement of PLR as compared to our study Table 1. There was a trend toward increased survival with PLR in shockable rhythms, probably indicating shorter duration of CPR. PLR has been found to be safe and feasible to perform in these patients and coupled with the findings of our study of improved cerebral oxygenation particularly when PLR is applied early warrants further exploration.

We did not compare the effects of rapid IV fluid administration in addition to PLR or as an alternative to it. According to the study by Preau et al (⁴), the effect of PLR is equivalent to a rapid IV volume expander by shifting blood from the lower extremities toward the intrathoracic compartment. Other researchers have also shown that PLR shifts fluid from the lower extremities to the central circulation (^22,23). However, additional factors aside from central compartment volume expansion may contribute to the findings demonstrated in this study, such as preferential effects on afterload as outlined previously. The effect of IV fluid administration in addition or as an alternative to PLR should be explored in future studies.

There are certain limitations in this study. We chose an angle of leg elevation between 30° and 45°. This was done to make the study practical, and furthermore, the beneficial effect of PLR on systemic perfusion pressure begins to saturate after 45° and after ∼70°, and the rate of increase in systemic perfusion pressure significantly decreases (^9,10). Hence, a range between 30° and 45° was chosen to make the study practical. Subjects were enrolled at varying time points during CPR, which has resulted in different levels of NIRS in our examined subjects. This aspect was impractical to control for. On an average, a significant period of CPR had already occurred before the application of the study protocol (median 8 min; IQR 4.8–16.2 min), which could significantly attenuate the effects of this maneuver. Given the simplicity of this maneuver, it can be potentially introduced during the first cycle of CPR when there are enough personnel available. Furthermore, PLR was only performed for two cycles of CPR, and a longer duration of PLR should be examined in future studies. However in healthy volunteers, the beneficial effects on stroke volume and cardiac output disappeared after 7 minutes of PLR. This suggests that the increase in cardiac output induced by PLR maneuver might be a short term benefit (²⁴).

There were 140 patients who were admitted to the ICU with cardiac arrest during the study period. Majority of these patients could not be studied due to practical limitations, and the study was only conducted when additional staffs were available to facilitate the study protocol. We had four patients where we could not collect NIRS data as they had ROSC during the study time period. Although all the members of our MET and ICU team undergo intensive CPR training as a part of hospital accreditation, we cannot objectively rule intra- and interpersonnel variability in the delivering the quality of CPR in these subjects. Furthermore, these subjects had different comorbid conditions and diagnosis which could have led to clinical variability, but as subjects served as their own control, overall this would have little impact on our main findings. There were instances of loss of data capture due to electrode displacement during CPR, which reflects the difficult nature of the study design. However, these instances were minimal, and we had data at least from one electrode in the majority of our subjects. Finally, data regarding ETco₂ were not prospectively recorded in our study which could have been a surrogate for improved blood flow from the heart (²⁵).

It is important to recognize that these results do not correlate directly with clinical outcomes for patients undergoing CPR, and this was not the goal of the current trial. A higher NIRS or rise in NIRS with CPR predicts ROSC and better neurologic outcomes as measured by Glasgow-Pittsburgh cerebral performance categories post ROSC in these patients (^15,16,26,27). However, for inclusion of PLR as a part of current basic life support algorithm, this trial will need to be followed up with larger randomized controlled trials focusing on assessing clinically meaningful patient outcomes. Given the current poor prognosis for patients sustaining in-hospital cardiac arrest, efforts to assess strategies to maximize patient outcomes in this cohort are an area of great interest for ongoing research in the realm of critical care medicine.

Our study had some strengths as we provide mechanistic rationale to the use of PLR during CPR in real-time patients. Although we did not examine any clinical outcomes and this study was limited to in-hospital cardiac arrest with a high number of nonshockable rhythms, it does still provide rationale to further research to examine PLR in OHCA.

In conclusion, these results suggest that performing PLR is feasible during CPR and results in augmentation of NIRS readings. This suggests augmentation of cerebral oxygenation and attenuation of the expected decline during CPR by PLR. The clinical significance of these findings is uncertain and requires further investigations.