Improved Outcome in an Animal Model of Prolonged Cardiac Arrest Through Pulsatile High Pressure Controlled Automated Reperfusion of the Whole Body
Artificial Organs, 2018 / 42 (10), S. 992
Kreibich M, Trummer G, Beyersdorf F, Scherer C, Förster K, Taunyane I, Benk C.
The reperfusion period after extracorporeal cardiopulmonary resuscitation has been recognized as a key player in improving the outcome after cardiac arrest (CA). Our aim was to evaluate the effects of high mean arterial pressure (MAP) and pulsatile flow during controlled automated reperfusion of the whole body. Following 20 min of normothermic CA, high MAP, and pulsatile blood flow (pulsatile group, n = 10) or low MAP and nonpulsatile flow (nonpulsatile group, n = 6) controlled automated reperfusion of the whole body was commenced through the femoral vessels of German landrace pigs for 60 min. Afterwards, animals were observed for eight days. Blood samples were analyzed throughout the experiment and a species-specific neurologic disability score (NDS) was used for neurologic evaluation. In the pulsatile group, nine animals finished the study protocol, while no animal survived postoperative day four in the nonpulsatile group. NDS were significantly better at any given time in the pulsatile group and reached overall satisfactory outcome values. In addition, blood analyses revealed lower levels of lactate in the pulsatile group compared to the nonpulsatile group. This study demonstrates superior survival and neurologic outcome when using pulsatile high pressure automated reperfusion following 20 min of normothermic CA compared to nonpulsatile flow and low MAP. This study strongly supports regulating the reperfusion period after prolonged periods of CA. Key Words: Controlled reperfusion—Extracorporeal cardiopulmonary resuscitation—Cardiac arrest—Pulsatile.
Survival after cardiac arrest (CA) remains low regardless of evidenced-based updates of cardiopulmonary resuscitation (CPR) protocols (1). Tn a preclinical setting, low survival may be attributed to variable length of time or quality of CPR. Yet, even in an “ideal” setting of high quality CPR within a hospital, there was no significant change in overall survival after CA from 1992 to 2005 (2). Because survival after conventional CPR remains low, extracorporeal cardiopulmonary resuscitation (eCPR) has successfully been established in many centers (3). During eCPR, veno-arterial extracorporeal membrane oxygenation (extracorporeal life support) is established during conventional CPR. However, survival to hospital discharge remains static at 29% for eCPR patients and there has been no change in risk-adjusted survival over this time period (4).
To date, all available eCPR devices are capable of providing nonphysiologic nonpulsatile flow, while pulsatile flow during cardiopulmonary bypass (CPB) has been shown to enhance microcirculatory flow, myocardial and cerebral perfusion, as well as cardiac contractility (5). Patients on pulsatile CPB showed improved cardiac, pulmonary, and renal function compared to a nonpulsatile group (6,7).
The reperfusion period after eCPR has been recognized as a key player in improving the outcome after CA, and our group has recently reported superior neurologic outcome after 15 min of normothermic CA when followed by a novel wholebody reperfusion protocol (Controlled Automated Reperfusion of the whoLe body, CARL) compared to standard nonautomated eCPR (8,9). The principles of CARL were gathered from other organ systems, including myocardial protection during CPB, and focuses on the prevention of the ischemiareperfusion injury (IRI) (10,11) by automatically modifying the initial conditions of the perfusate such as pH-stat, limited arterial oxygen contents, hyperosmolarity, or hypocalcemia. To apply CARL after CA, we used a previously described new eCPR perfusion circuit called controlled integrated resuscitation device (CIRD) (12). So far, the concept of CARL has been used in a total of 13 patients with extremely prolonged CPR (13). The aim of this study was to evaluate the influence of high mean arterial pressure (MAP) and pulsatile flow to low MAP and nonpulsatile blood flow during CARL in an animal model of 20 min of normothermic CA.
Male and female German landrace pigs (weight: 45-60 kg) were used in this experiment. All animals received humane care and were kept under standard conditions with free access to water and standard chew except the night prior to the experiment. All experiments were approved by the local committee for ethics (University Hospital Freiburg, Freiburg, Germany, Institutional protocol number: G10/90) and conform to the Guide fur the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH publication No.
85-23, updated 2011).
Animals were premedicated (20 mg/kg ketamine and 0.3 mg/kg midazolam), intubated (after the administration of 0.2 mg/kg of vecuronium and 2-4 mg/kg of propofol), and ventilated (respiratory rate: 12-14/min, PEEP 5 mm Hg, tidal volume 8-12 mL/kg). Continuous anesthesia was maintained through 1.5-2.0% isoflurane in ambient air, intravenous vecuronium (0.2 mg/kg/h), and fentanyl (2-10 pg/kg/h). Antibiotic prophylaxis was provided with 2 g ceftriaxone intravenously. Animals were preheparinized prior to cardiac arrest.
Following the induction of general anesthesia, ventricular fibrillation (VF) was induced electrically by a probe placed on the apex of the heart through a CA. small intercostal incision in the left hemithorax to induce CA and ventilation was suspended during the VF period. CA was defined as persistent VF with pulselessness. Following 20 min of normothenuic CA, animals were randomly assigned to two groups receiving high MAP (target MAP: 100-120 mm Hg) and pulsatile flow (amplitude: 15-25 mm Hg, pulsatile frequency = 40/min) CARL (pulsatile group, n = 10) or receiving low MAP (target MAP: 40-60 mm Hg) and nonpulsatile blood flow CARL (nonpulsatile group, n = 6). To achieve the MAP goal, CARL was set to 6—7 L/min in the pulsatile high MAP group and to 3.5-4.5 L/min in the nonpulsatile low MAP group. MAP range deviations were treated with bolus application of norepinephrine or urapidil. Isotonic saline was used as a carrier solution and no other volume substitution was performed. In both groups, CARL was the treatment for 60 min using CIRD 1.0 after the normothermic CA period of 20 min. After initiation of the CIRD, the ongoing VF was converted into asystole with the application of a bolus of intravenous potassium. Shortly thereafter, the heart regained a stable sinus rhythm.
The CIRD 1.0 was used to apply the automated reperfusion protocol CARL in both groups. The device consists of two diagonal pumps (Deltastream DP3, MEDOS Medizintechnik AG, Stolberg, Germany), a membrane oxygenator (Hilite 7000 LT, MEDOS Medizintechnik AG, Stolberg, Germany), and a heater cooler unit (Stockert 3T, Sorin Group, Mirandola, Italy) to provide immediate mild hypothermia. CIRD provides continuous venous and arterial blood gas monitoring. Gas-flow and –composition are modified accordingly in a near closed-loop fashion. The CIRD circuit was primed with a hyperosmolar priming solution (including albumin, mannitol, sodium-citrate, and lidocaine) to provide maximum organ protection after CA. Cannulation (Sorin Group, Arvada, CO, USA) was established via the right jugular external vein and the right femoral artery during the VF period. A 22 Fr or 23/25 Fr cannula was inserted for venous drainage and a 14 or 16 Fr cannula was placed for arterial inflow. Cannulas were flushed with heparinized saline solution (500 IU/100 mL) and connected to the CIRD 1.0.
Measurements and recordings
Electrocardiogram, arterial saturation, and temperature were monitored noninvasively. The carotid artery and the jugular vein were prepared and exposed through a right paratracheal surgical dissection. For continuous blood pressure monitoring and arterial blood sampling, the right common carotid artery was cannulated in caudal direction. Arterial blood gas analyses were performed throughout the experiment Blood count analyses and measurement of urea, creatinine, bilirubin, aspartate transaminase (AST), alanine transaminase (ALT), creatinine kinase (CK), and CK-MB were performed before CA, 1, 5, 10, 30, and 60 min after the beginning of CARL as well as at the end of the experiment and on postoperative day (POD) 1. Neuronal-specific enolase (NSE) was measured before CA, at the end of the experiment, and on POD 1.
After 20 min of CA and 60 min of CARL, animals were weaned from the ventilator, extubated, and transferred to animal facility for further observation. Animals were examined daily by a veterinary scientist and a research investigator blinded to the study groups. A modified species-specific neurological deficit scoring (NDS) system ranging from 0 (=normal) to 500 (=brain death) was used to evaluate neurologic outcome. A neurologic score of below 50 is considered as a satisfactory outcome. A NDS of above 200 after 24 h and a NDS of above 120 after 48 h in the absence of sedation or other explanations are considered as predictive of vegetative state and were defined as a moribund condition study endpoint in accordance with the Guide for the Care and Use of Laboratory Animals. Early euthanasia was performed in those animals to prevent inhumane suffering or prolonged death (12).
All values are expressed as mean } standard deviation (SD). Parameters between groups were compared by an unpaired t-test with the calculation of exact P values. Survival was analyzed using the Kaplan-Meier method and log rank calculations. IBM SPSS Statistic and SAS software were used for data analysis. P values were considered significant if P < 0.05. The primary end point was neurologic satisfactory survival.
Mean arterial pressure
MAP in all animals dropped below 20 mm Hg after the induction of VF marking the start of CA (Fig. 1). During the 60 min of CARL treatment, MAP was significantly higher in the pulsatile group (P<0.01) and remained higher after CARL treatment without statistical significance. CARL flows were within the set target range during the experiment. CARL was successfully applied in 10 animals in the pulsatile group and in 6 animals in the nonpulsatile group.
Body temperature dropped during CARL to as low as 32.8°C in both groups due to the cooling ability of the CIRD 1.0, while the temperature increased again after the intended 30 min cooling period. There was no statistical difference between the two groups.
Table 1 lists blood gas parameters before, during, and after CARL. Baseline blood gas parameters before induction of CA did not differ between the two groups. Regarding acid-base homeostasis parameters, there was only one significant difference between the two groups: in the nonpulsatile group, HC03 levels after 10 min of CARL were significantly lower. Furthermore, lactate levels were significantly higher in the nonpulsatile group after 45 and 60 min of CARL. Electrolyte values (not shown) were within physiologic levels and differed significantly at three-time points: in the nonpulsatile group, sodium levels were significantly lower after 30 and 45 min of CARL and calcium levels were significantly lower after 1 min of CARL.
Blood count analyses (Table 2) showed a decrease in white blood cells and platelets during the experiment. There was no significant difference between the two groups at any time point. Red cell count, hematocrit, and levels of hemoglobin were significantly elevated in the pulsatile group compared to the nonpulsatile group throughout the experiment.
Table 3 shows that there were no significant differences in baseline levels of renal (blood urea, creatinine) and hepatic parameters (bilirubin, AST, ALT), creatine kinase (CK) and CK-MB, as well as neuron-specific enolase (NSE). Renal parameters did not differ during CARL. After the experiment, urea and creatinine kinase were elevated in the nonpulsatile group, but the difference did not reach statistical significance. Bilirubin was elevated in the pulsatile group and the difference reached statistical significance after 30 and 60 min of CARL and at the end of the experiment. AST and ALT were elevated in the nonpulsatile group and the difference reached statistical significance after 1, 5, and 10 of CARL and on POD 1. CK and CK-MB did not differ significantly during CARL, but levels were significantly higher on POD 1 in the nonpulsatile group. NSE was not measured during CARL
Survival and neurological deficit scoring
In the pulsatile group, one animal died during the immediate post-CARL period due to ventricular fibrillation. The other nine animals finished the study protocol. In the nonpulsatile group, one animal died during the immediate post-CARL period due to sudden asystole, two animals were euthanatized on POD 1 and on POD 4, respectively, because of vegetative state (moribund condition study endpoint). Also, three animals in the nonpulsatile group were found dead: one on POD 1 and two on POD 2. The cause of death is unknown. No animal finished the study protocol in the nonpulsatile group. Figure 2 shows the cumulative survival of the animals and the survival was significantly better in the pulsatile high MAP group (log rank: P<0.01).
Neurological deficit scoring was performed in all surviving animals (Fig. 3). Values were significantly lower in the pulsatile group compared to the nonpulsatile group on POD 1 (PcO.Ol) and POD 2 (P < 0.05). On POD 3, only one animal was alive in the nonpulsatile group and the NDS was higher compared to any animal in the pulsatile group. NDS remained low in the pulsatile group throughout the observational period.
Our data show that survival in the pulsatile, high pressure group was significantly better compared to the nonpulsatile low-pressure group (Fig. 2). In addition, the neurologic deficit score was also significantly better in the group with high MAP and pulsatile flow (Fig. 3). These results point to a very important and clinically relevant possibility of improving the results after prolonged CA with treatment of the whole body by a new controlled reperfusion strategy with higher and pulsatile MAP goals.
According to the American Heart Association guidelines for cardiopulmonary resuscitation, eCPR may be considered in settings where the technology is readily available and can be rapidly implemented since it may provide additional time to treat reversible underlying causes of cardiac arrest (14). Survival and satisfactory neurologic outcome tend to be superior in eCPR patients, yet overall neurological outcome rates remain variable (3,15). Our group has recently investigated the influence of our CARL strategy after CA by regulating the conditions of reperfusion and the composition of the reperfusate (8,9,12). We were able to show preserved brain morphology and function after CARL compared to conventional CPR and conventional eCPR (12). In this study, we wanted to investigate the influence of pulsatile flow and high MAP during CARL in comparison to nonpulsatile flow and lower pressure during CARL.
The concept of including pulsatile flow and high MAP in our CARL treatment was derived from studies investigating high pressure and high flow in cardiac surgery patients on cardiopulmonary bypass (CPB) and from physiological considerations (16-18). While the concept of pulsatile perfusion is still debated (various studies were unable to demonstrate any significant influence of the perfusion technique (19-21)), several studies favour high MAP to reduce major cardiac and neurological morbidity (18,22). In fact, Siepe et al. reported lower rates of neurocognitive dysfunction and delirium in patients with higher pressure during CPB (23). The authors hypothesized that low pressure and nonpulsatile flow may lead to regional cerebral hypoperfusion of areas in need of higher pressure (23). Moreover, low blood pressure during CPB may impair the efficiency of cerebral autoregulation and oxygen saturation especially in atherosclerotic and chronically hypertensive patients (24,25) that are prone to major cardiovascular events leading to CA.
Organ hypoperfusion or ischemia after CPB has frequently been linked to inflammation. In fact, regional lung ischemia during CPB is a main reason for pulmonary impairment that can be successfully counteracted by pulsatile flow (26). Pulsatile flow may lower pulmonary artery pressures (27) and cause lower endothelial activation and higher anti-inflammatory cytokines secretion (28). Other studies have also suggested that pulsatile extracorporeal
flow provides superior end-organ protection with improved renal function and systemic vascular tone (29) possibly through improved systemic microcirculation (30). Therefore, in this study, we tested a high pulsatile pressure during CARL and the MAP data demonstrated in Figure 1 show that we were able to provide high pressure CARL compared to the low pressure and nonpulsatile flow CARL.
The pulsatile high pressure reperfusion did not influence overall arterial blood gas values and the difference in blood gas values was not as severe as compared to other studies with similar CA times (31) because of the concept of controlled reperfusion. Also, blood gas analyses did not yield significant differences regarding white blood or platelet count. Yet, a significant difference was observed in the red blood count, the hemoglobin, and the hematocrit between the two groups, but the difference lost statistical significance during the postoperative period. It seems unlikely that the slightly higher red blood cell levels observed in the pulsatile group have a profound effect on the overall outcome of the study and are most likely secondary to the limited number of animals.
The analysis of kidney specific parameters did not reveal a difference during CARL most likely due to the short time after CA. However, a significant difference during CARL was observed in the liver specific transaminases AST and ALT in favour of the high flow high pressure group. The significant difference was also visible during the postoperative period. Regarding CK and CK-MB levels, differences between the two groups did not reach statistical significance throughout the experiment. Even though CK levels tended to be higher in the pulsatile high pressure group, cardiac specific CKMB levels tended to be lower in this group compared to the nonpulsatile low pressure flow CARL group.
We did not observe a difference in NSE levels, even though it has been suggested to be a sensitive marker of hypoxic brain damage and short-term outcome in humans (32). This may be because NSE levels increase by any sort of extracorporeal circulation through hemolysis and activation of platelets (33). Of note, bilirubin, a marker for hemolysis, increased in both groups during and after CARL, while the increase was significantly higher in the pulsatile high pressure group compared to the nonpulsatile low pressure group. This may be a sign of increased hemolysis through higher MAP and pulsatile reperfusion, particularly in conjunction with the decrease in red blood cell levels during the postoperative group. The effect of hemolysis during high pressure and pulsatile reperfusion warrants further investigation particularly in a clinical setting.
Limitations and strengths
In the study protocol, we aimed at an equal study cohort number of n = 10 in both groups. However, due to the obvious worse survival and neurological outcome measured by the species-specific neurological deficit scoring we deemed it unethical to continue the study protocol in the nonpulsatility group.
Therefore, the study population in this group is limited to n = 6 animals. This may be considered a major limitation to the study, as it complicates the comparison of data derived after the experiment. However, the analysis of the primary endpoints of the study—neurological outcome and overall survival—still is evident and allows sustainable conclusions. Further research in the area of high MAP and pulsatile reperfusion is warranted, as this study only investigated the combined effect of high MAP and pulsatile reperfusion. In fact, we are not able to report individual effects of high MAP and conventional nonpulsatile flow or low MAP and pulsatile flow in this study .
This study demonstrated superior survival and neurologic outcome when using pulsatile high pressure CARL following 20 min of normothermic CA as compared to CARL treatment with nonpulsatile flow and lower MAP. The data presented are strongly in favor of regulation and controlling the reperfusion period after prolonged periods of CA to increase survival and neurological outcome. In the controlled setting of this experiment, even prolonged normothermic CA for a total of 20 min caused only minor neurological damage when pulsatile high pressure CARL is used compared to nonpulsatile flow low pressure CARL. Further studies investigating the optimal reperfusion strategies after CA and the individual effects of high MAP and pulsatility are needed. Data presented here tend to favor the combination of higher pressure and pulsatile flow following CA.
MK performed data analysis, interpretation of the data, and drafted the manuscript. GT conceived of the study, participated in the design of the study, coordinated the study and performed critical revision of the article. FB participated in the design of the study, co-coordinated the study and helped to draft the manuscript. CS, KF, and IT carried out the data collection and performed critical revision of the article. CB carried out the data collection, conceived of the study, participated in the design of the study, co-coordinated the study and helped to draft the manuscript. All authors read and approved the final manuscript.
Conflict of Interest:
MK, CS, KF, and IT have no conflict of interest to declare. GT, FB, and CB are shareholders of Resuscitec Ltd.
This study was financially supported by Resuscitec Ltd.
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