Continuous chest compressions improve su”>American Journal of Emergency Medicine (2012) 30, 1389-1394

Original Contribution

Continuous chest compressions improve survival and neurologic outcome in a swine model of prolonged ventricular fibrillation^?

Theodoros Xanthos PhD^a, Theodoros Karatzas PhD^b,

Konstantinos Stroumpoulis PhD^a,?, Pavlos Lelovas MSc^c, Panagiotis Simitsis MD^d, Ioannis Vlachos MPhil^d, Grigorios Kouraklis PhD^b,

Evangelia Kouskouni PhD^e, Ismene Dontas PhD^f

^aDepartment of Anatomy, University of Athens, Medical School, 11527 Athens, Greece

^bSecond Department of Propaedeutic Surgery, School of Medicine, University of Athens, LAIKON University Hospital, 11527 Athens, Greece

^cLaboratory for Research of the musculoskeletal system, School of Medicine, University of Athens, 14561 Athens, Greece ^dMsc Program “Cardiopulmonary Resuscitation,” University of Athens, Medical School, 11527 Athens, Greece ^eDepartment of Biochemistry and Microbiology, Aretaieion Hospital, University of Athens, Medical School,

11527 Athens, Greece

^fLaboratory of Experimental Surgery and Surgical Research, School of Medicine, University of Athens, 11527 Athens, Greece

Received 1 May 2011; revised 15 August 2011; accepted 5 October 2011

Abstract

Introduction: Evidence suggests that any interruptions, including those of rescue breaths, during cardiopulmonary resuscitation (CPR) have significant, detrimental effects on survival. The 2010 International Liaison Committee on Resuscitation guidelines strongly emphasized on the importance of minimizing interruptions during chest compressions. However, those guidelines also stress the need for ventilations in the case of prolonged cardiac arrest , and it is not at present clear at which point of CA the necessity of providing ventilations overcomes the Hemodynamic compromise caused by chest compressions’ interruption.

Methods: Ventricular fibrillation was electrically induced in 20 piglets (19 +- 2 kg) and left untreated for 8 minutes. Animals were randomized to receive 2 minutes of either chest compression-only CPR (group CC) or standard 30:2 compressions/ventilations CPR (group S) before defibrillation. Resuscitated animals were monitored under anesthesia for 4 hours and then were awakened and placed in a maintenance facility for 24 hours.

Results: There was no significant difference among groups for both return of spontaneous circulation and 1-hour survival. There was a significant difference in 24-hour survival (group CC, 7/10 vs group S, 2/10; P = .025). blood lactate levels were significantly lower in group CC compared with group S in both 1 (P = .019) and 4 hours (P = .034) after return of spontaneous circulation. Furthermore, group CC animals exhibited significantly higher mean neurologic alertness score (58 +- 42.4 vs 8 +- 16.9) (P b .05).

^? This project was financed by the authors.

* Corresponding author. Department of Anatomy, University of Athens, Medical School, 11527 Athens, Greece.

E-mail address: [email protected] (K. Stroumpoulis).

0735-6757/$ - see front matter (C) 2012 doi:10.1016/j.ajem.2011.10.008

Conclusion: In this swine CA model, where defibrillation was first attempted at 10 minutes of untreated ventricular fibrillation, uninterrupted chest compressions resulted in significantly higher survival rates and higher 24-hour neurologic scores, compared with standard 30:2 CPR.

(C) 2012

Introduction

Cardiac arrest remains one of the leading causes of death in Europe and the United States, accounting for more than 250 000 incidents per year in each continent [1-5]. Cardiac causes are identified in 50% to 78% of cases, whereas 30% to 43% of these are attributed to ventricular fibrillation (VF) or ventricular tachycardia [4-6]. Initiation of cardiopulmonary resuscitation (CPR) and Early defibrillation until return of spontaneous circulation (ROSC) remain the treatment of choice in adults with VF at the time of CA [7]. Several studies have shown that frequent or prolonged interruption of chest compressions is associated with reduced coronary perfusion pressure, reduced ROSC, reduced survival rates, and reduced postresuscitation myocardial function [6,8,9]. Hence, in the 2010 European Resuscitation guidelines, the recommended chest compression/ventilation ratio remained 30:2, but the importance of further minimiz- ing any interruptions in chest compressions was greatly emphasized [7]. Therefore, we aimed at comparing whether ventilation would affect ROSC, survival rates, and neuro- logic outcome in an established model of prolonged VF.

Methods

Ethical approval for the investigation and the experimental procedures in accordance with Greek legislation was given by the General Directorate of Veterinary Services. Twenty healthy Landrace/Large-White male piglets aged 10 to 15 weeks and whose average weight was 19 +- 2 kg were used in the study. The animals were randomized with the use of a sealed envelope into 2 groups: standard group (group S), 10 animals that were resuscitated using 2010 resuscitation guidelines and continuous compressions group (group CC), 10 animals that were resuscitated with chest compression- only CPR.

After initial sedation with ketamine, midazolam, and atropine, the auricular vein was cannulated, and propofol anesthesia was initiated. The animals were then intubated, and anesthesia was maintained with propofol, cis-atracur- ium, and fentanyl. Animals were ventilated by a volume- controlled ventilator (ventiPac Sims pneuPac, Luton, UK) with a total tidal volume of 15 mL/kg, supplying FiO2 of 30%. End-tidal CO₂ was monitored with a side-stream infrared CO₂ analyzer (Nihon Kohden Corp, Bergamo, Italy), when the animals were ventilated. The respiratory frequency was adjusted to maintain end-tidal CO₂ between 35 and 40 mm Hg. The electrocardiogram was recorded continuously, using leads II and V₅. Pulse oximetry (SpO2)

(Vet/Ox Plus 4700; Heska, Loveland, CO, USA) was monitored continuously.

The left internal jugular vein and left carotid artery were dissected. For measurement of the aortic pressure, a normal saline-filled (model 6523, USCI CR; Bart Inc, Salt Lake City, UT, USA) arterial catheter was inserted into the aorta via the left carotid artery. Mean arterial pressure was determined by the electronic integration of the aortic blood pressure waveform. Arterial blood gas samples were collected from the arterial catheter. A Swan-Ganz catheter (Opticath 5.5 F, 75 cm; Abbott, Athens, Greece) was inserted into the right atrium via the left jugular vein for continuous measurement of right atrial pressure. The Right internal jugular vein was also surgically prepared. After allowing the animals to stabilize for 60 minutes, blood was drawn from this vessel for measurements of baseline serum levels of lactate, S-100 protein, and Neuron-specific enolase . S- 100 and NSE are considered to be promising biomarkers for the Early prediction of neurologic outcome after CA. Low values of these biomarkers may indicate a favorable neurologic prognosis, whereas elevated values may indicate neurologic impairment [10-12]. A 5F pacemaker catheter (100 cm, Pacel; St Jude Medical, Ladakis SA, Athens, Greece) was then inserted into the right ventricle, through the exposed right jugular vein, and used to induce VF, which was left untreated for 8 minutes.

In group S, animals were resuscitated with 12 ventilations per minute delivered by a self-inflating bag and 100 chest compressions per minute delivered at a rate of 30:2 with a mechanical chest compressor (LUCAS TM Chest Compres- sion System; Jolife AB, Mantzaris, Greece) with a 50% Duty cycle and a compression depth of 25% of the anterior- posterior chest diameter for 2 minutes. Animals in the group CC were resuscitated for 2 minutes with chest compressions delivered via the same mechanical chest compressor. Afterwards (in the 10th minute of VF), defibrillation with 4 J/kg monophasic waveform shock (Porta Pak/90; Medical Research Laboratories, Inc, Buffalo Grove IL, USA) was attempted, and precordial compressions were resumed for 2 more minutes before delivery of a second shock, if necessary. No resuscitative medications were used during CPR, as this experimental protocol attempted to model bystander CPR followed by bystander defibrillation. The same resuscitation sequence continued, and the end points of the experiment were defined as either ROSC or asystole. Return of spontaneous circulation was defined as the presence of an organized cardiac rhythm with a mean arterial pressure of at least 60 mm Hg for a minimum of 10 minutes.

The animals, which Restored spontaneous circulation, were monitored for 240 minutes, whereas anesthesia was

maintained. Blood samples were collected at baseline, 60, 120, and 240 minutes in the postresuscitation phase. Lactate was measured with a Blood gas analyzer (Nova Biomedical pHOx plus C, Waltham, MA, USA). For measurements of serum levels of S-100 protein and NSE, each blood sample was centrifuged at 3000 rpm for 10 minutes, and the serum was collected and stored in liquid nitrogen at -70?C, until required. The serum levels of S-100 protein and NSE were determined by an immuneluminometric assay (LIAISON Sangtec 100; Sangtec Medical, Bromma, Sweden). All assays were performed in a blinded manner.

After 4 hours of postresuscitation monitoring, the intravenous infusions of the Muscle relaxant and propofol were discontinued. All catheters were removed as previously described [13]. The ventilator was then switched off, and the animals were manually ventilated with 100% FiO2. Atropine

0.2 mg/kg and neostigmine 0.05 mg/kg were administered

after the first swallowing reflex of the animal. Animals were extubated when adequate inspiration depth was ascertained. Afterwards, each successfully resuscitated animal returned to its cage. Neurologic alertness score was determined 24 hours after ROSC by a researcher blinded to the resuscitation algorithm followed, as previously described [14], and the surviving animals were then humanely euthanatized by a fatal overdose of thiopental. Necropsy was performed in each animal to detect any underlying pathology and resuscitation- related injuries.

Data are expressed as mean +- 1 SD for continuous variables and as frequency (percentages) for categorical data. The normality of the distributions was assessed with Kolmogorov-Smirnov test and graphic methods. Continuous variables that were not following a Gaussian distribution are reported as median (interquartile range [range]). Compari- sons of continuous variables were performed using the Student t test and Mann-Whitney U, nonparametric test, as appropriate. Categorical data were compared by the ?2 test. All tests were 2 sided. Differences were considered as statistically significant if the null hypothesis could be rejected with greater than 95% confidence (P b .05). All analyses were conducted using the SPSS, version 17.00 (SPSS, Inc, Chicago, IL).

Results

Baseline measurements for both hemodynamic and hematologic parameters did not differ between the 2 groups, and in addition, no differences were apparent between the 2 groups throughout the 8 minutes of untreated VF (Table 1). In the first minute of CPR, a statistically significant difference was observed in arterial CO₂ values between group CC (19.8 +- 2.4 mm Hg) vs group S (11.2 +- 4.3) (P b

.001). Furthermore, although not statistically significant, a trend of higher median values of diastolic pressures in the thoracic aorta was observed in group CC animals (19.50 mm Hg [19-22 {15-22}] vs 15.00 mm Hg [12-21 {10-25}]);

Group S Group CC P (mean +- SD) (mean +- SD)

Systolic pressure TA 89.3 +- 10.1 93.3 +- 6.9 NS Diastolic pressure TA 70.7 +- 8.5 75 +- 10.4 NS Systolic pressure RA 11.4 +- 2.4 10.5 +- 1.2 NS Diastolic pressure RA 8.1 +- 1.5 8 +- 1.3 NS CPP 62.6 +- 7.8 67 +- 10.7 NS ETCO2 35.4 +- 4.5 33.9 +- 4.3 NS Lactate 1.4 +- 0.6 1.4 +- 0.7 NS NSE 0.38 +- 0.35 0.35 +- 0.31 NS S-100 0.68 +- 0.51 0.66 +- 0.57 NS

TA indicates thoracic aorta; RA, right atrium; ETCO2, end-tidal CO2; NS, nonsignificant.

P = .08. In the second minute of CPR, no statistically significant difference was observed between the 2 groups, whereas in the third minute of CPR, there was a significant difference between the 2 groups for both the diastolic pressure in the thoracic aorta (group CC, 32.17 +- 3.06 mm Hg vs group S, 22.33 +- 7.76 mm Hg; P = .016) and the coronary perfusion pressure (group CC, 19.83 +- 3.31 mm Hg vs group S, 9.50 +- 9.40 mm Hg; P = .029).

Table 1 Baseline characteristics of the 2 study groups

This difference was further maintained and even accen- tuated in the fourth minute of CPR, where in addition to the significant differences regarding the diastolic pressure in the thoracic aorta (group CC, 36.50 +- 2.66 mm Hg vs group S, 22.17 +- 9.00 mm Hg; P = .004) and CPP (group CC, 26.67 +-

2.42 mm Hg vs group S, 10.50 +- 9.09 mm Hg; P = .002), arterial CO₂ was also higher for group CC, 24.33 +- 2.58 mm Hg vs 13.50 +- 5.86 mm Hg (P = .002). Diastolic aortic pressure, CPP, and arterial CO₂ variation throughout the experiment are depicted in Figs. 1 to 3.

After the first 2 minutes of CPR, 4 of 10 animals in group CC and 4 of 10 animals in group S achieved ROSC (P, nonsignificant). In the second cycle of CPR, another 5 animals attained ROSC in group CC compared with only 1 in group S. One hour after ROSC, 9 of 10 animals were alive in group CC and 4 of 10 in group S (P = .051). Four hours after ROSC, the percentages remained the same for both groups. On the contrary, there was a significant

Fig. 1 Diastolic aortic pressure variation throughout the experiment. Asterisk indicates statistically significant difference.

Fig. 2 Coronary perfusion pressure variation throughout the experiment. Asterisk indicates statistically significant difference.

difference in the 24-hour survival, where 7 of 10 animals of group CC were still alive in contrast to only 2 of 10 for group S (P = .025).

Neuron-specific enolase and S-100 measurements did not reveal any significant differences throughout the post-ROSC period. On the contrary, blood lactate levels were signifi- cantly lower in group CC in both 1 hour (3.83 +- 1.13 vs 5.40 +- 0.84 mmol/L; P = .019) and 4 hours (1.24 +- 0.51 vs 1.88 +- 0.41 mmol/L; P = .034) after ROSC when compared with group S.

Group CC exhibited significantly higher mean neurologic score (58 +- 42.4), compared with group S (8 +- 16.9) (P b

.05). Surviving animals in group CC exhibited more than 100% higher mean neurologic score (82.86 vs 40) than animals belonging to group S (P b .05). The animals that exhibited the lowest neurologic score in group CC had 50% higher score than animals belonging to group S. Further- more, 2 group CC animals had perfect score (100), whereas a total of 5 animals had scores more than 90.

Necropsy findings did not reveal any differences between groups neither for the animals that survived nor for those that did not.

Discussion

In 2010 International Liaison Committee on Resuscita- tion Guidelines, the importance of minimal interruption of chest compressions during CPR is further emphasized, and the authors state that “Even short interruptions to chest compressions are disastrous for outcome and every effort must be made to ensure that continuous, effective chest compression is maintained throughout the resuscitation attempt” [7]. Furthermore, it is stressed that chest compressions should only be briefly interrupted for specific interventions [7]. However, it is well known that any interruption in chest compressions immediately annihilates CPP, a major determinant of successful resuscitation outcome [15,16]. Furthermore, there is evidence that, in the clinical setting, interruptions of chest compressions last too long, minimizing thus the chances of survival [17-22].

There is already evidence from previous studies that uninterrupted chest compressions after VF of Short duration may improve ROSC and survival [9,23], fact that probably could be expected because oxygen and energy stores are not yet depleted. On the other hand, data on prolonged VF are scarce especially regarding the years after the implementa- tion of the International Liaison Committee on Resuscita- tion 2005 guidelines and the 30:2 compression:ventilation ratio [24-26].

In this animal model of prolonged VF, continuous chest compressions not only significantly improved arterial pressures but also improved CPP, which is of paramount importance for ROSC. This effect was more pronounced during the second cycle of CPR, fact that stresses the importance of uninterrupted chest compressions as implied by previous studies [23,27]. Hence, although in the first cycle of CPR, there was no difference among the hemodynamic parameters of both groups, during the second cycle of CPR continuous chest compressions resulted in significantly higher arterial pressures and presumably better overall perfusion.

Furthermore, in this experimental protocol, no vasopres- sor therapy was used in contrast to other similar studies reporting improved outcomes with continuous chest com- pressions. Despite the absence of vasopressor therapy, the present study demonstrated increased CPP and arterial CO₂ values, especially as resuscitation efforts progressed. This is indicative of the improved organ perfusion and the significant impact of continuous chest compressions in establishing circulatory conditions that will improve ROSC and, on the other hand, underlines the importance of chest compressions’ interruption detrimental effects. These obser- vations are further supported by previous studies (using vasopressors) reporting improved CPP and ROSC rates in similar Experimental models before the initiation of vaso- pressor therapy [9,23].

Improved perfusion is also evidenced by the significantly lower blood lactate levels in group CC in the immediate post- ROSC period. In CA setting, tissue oxygen delivery ceases, leading thus to an impairment of the oxidative phosphory- lation mechanism with consecutive initiation of anaerobic glycolysis [28] and a Rapid increase of cellular lactate production. Furthermore, blood lactate levels are propor- tionally related to Tissue oxygenation [29], and the decrease of blood lactate levels has been associated with successful resuscitation in several critical settings such as sepsis, burns, and trauma [30-32]. In addition to the above, there is evidence that there is an association between lactate levels and outcome of post-CA patients [33,34]. Hence, in this experimental model, improved vital organ perfusion proba- bly led to significantly higher ROSC rates and most importantly improved 24-hour neurologic score, which is indicative of meaningful survival.

Despite the significant differences in neurologic out- come, no differences were observed between the NSE and S-100 values. Although these biomarkers are estimated to

Fig. 3 Arterial CO₂ variation throughout the experiment. Asterisk indicates statistically significant difference.

become in the future helpful tools for predicting meaningful survival, neither the optimal timing for their measurement nor the appropriate cutoff values have been yet identified [11,12]. Therefore, it is possible that measurements were not performed in the appropriate time to demonstrate significant differences.

In this animal model, continuous chest compression CPR even in prolonged VF seems to provide significantly improved conditions for a successful defibrillation and, what is most important, Neurologically intact survival. It is already known that chest compressions without rescue breaths can provide adequate tissue oxygenation in cases of short-duration VF arrest possibly via gasping or passive inhalation during CPR [35-37]. The present study demon- strates that continuous chest compression CPR can provide significantly improved outcomes not only in short-duration VF but even in prolonged CA.

On the other hand, there is recent clinical evidence that standard 30:2 CPR in cases of extremely prolonged VF (N15 minutes) leads to significantly improved outcomes when compared with continuous chest compressions CPR [26]. The important study by Kitamura et al [26] demonstrated that continuous chest compression CPR was at least as effective as standard 30:2 CPR in CA when the duration of VF was less than 15 minutes. However, the authors stated that the quality of the chest compressions provided by bystanders was not assessed and, what is most important, they recognized that that none of the bystanders that provided chest compression-only CPR was trained in a course to do so. On the contrary, bystanders who provided rescue breaths might have been trained and, therefore, might have provided chest compressions of better quality. Lastly, although this was a very large clinical trial, the authors recognize that the incremental benefit of the provision of Rescue breathing might be small [26].

It is true that, in cases of prolonged CA, oxygen stores will eventually be depleted and even if effective chest compressions that ensure adequate perfusion are adopted, they will not probably suffice for brain oxygenation if there are not combined with rescue breaths. On the other hand, it is also well recognized that interruptions in chest compressions for the provision of rescue breaths are frequent and lengthy

especially in lay rescuers (health care providers also are frequently ineffective) [17-22]. Furthermore, many lay rescuers may have related CPR with rescue breaths and, often for various reasons, may be reluctant to provide them and, consequently, do not even provide chest compressions [38-41]. Therefore, it would be possibly unwise to prematurely abandon the idea of continuous chest compres- sion CPR, especially for the lay rescuers, because there is evidence that this strategy can improve outcomes. The same approach was adopted when the search for a pulse in basic life support was abandoned. A different strategy for lay rescuer CPR and health care provider CPR may be a realistic approach, in order to achieve higher bystander CPR rates and increased chances of survival because bystander CPR is positively correlated to hospital discharge [42].

This study has several limitations. This study was performed in healthy, young swine with probably no preexisting coronary artery disease. In addition, the presence of an endotracheal tube does not simulate the clinical conditions in CA where most probably in some point the unconscious victim’s tongue will obstruct the upper airway. Lastly, as in all animal studies, the results coming from a different species should be cautiously extrapolated in humans as interspecies differences in pathophysiologic functions and drug effects certainly are difficult to assess.

In this swine model of CA, where defibrillation was first attempted at 10 minutes of untreated VF, uninterrupted chest compressions resulted in significantly higher ROSC rates and higher 24-hour neurologic scores when compared with standard 30:2 CPR.

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