Exsanguination Cardiac Arrest Research Articles

Whole Blood Selective Aortic Arch Perfusion for Exsanguination Cardiac Arrest: Assessing Myocardial Tolerance to the Duration of Cardiac Arrest.

Selective aortic arch perfusion (SAAP) is an endovascular technique that consists of aortic occlusion with perfusion of the coronary and cerebral circulation. It been shown to facilitate return of spontaneous circulation (ROSC) after exanguination cardiac arrest (ECA), but it is not known how long arrest may last before the myocardium can no longer be durably recovered. The aim of this study is to assess the myocardial tolerance to exsanguination cardiac arrest before successful ROSC with SAAP. Male adult swine (n = 24) were anesthetized, instrumented, and hemorrhaged to arrest. Animals were randomized into three groups: 5, 10, and 15 min of cardiac arrest before resuscitation with SAAP. Following ROSC, animals were observed for 60 min in a critical care environment. Primary outcomes were ROSC, and survival at 1-h post-ROSC. Shorter cardiac arrest time was associated with higher ROSC rate and better 1-h survival. ROSC was obtained for 100% (8/8) of the 5-min ECA group, 75% (6/8) of the 10-min group, 43% (3/7) of the 15-min group (P = 0.04). One-hour post-ROSC survival was 75%, 50%, and 14% in 5-, 10-, and 15-min groups, respectively (P = 0.02). One-hour survivors in the 5-min group required less norepinephrine (1.31 mg ± 0.83 mg) compared with 10-SAAP (0.76 mg ± 0.24 mg), P = 0.008. Whole blood SAAP can accomplish ROSC at high rates even after 10 min of unsupported cardiac arrest secondary to hemorrhage, with some viability beyond to 15 min. This is promising as a tool for ECA, but requires additional optimization and clinical trials.Animal Use Protocol, IACUC: 0919015.

Open chest selective aortic arch perfusion vs open cardiac massage as a means of perfusion during in exsanguination cardiac arrest: a comparison of coronary hemodynamics in swine.

To describe and compare the aortic-right atrial pressure (AoP-RAP) gradients and mean coronary perfusion pressures (CPPs) generated during open chest selective aortic arch perfusion (OCSAAP) with those generated during open cardiac massage (OCM) in hypovolemic swine. Ten male Hanford swine utilized in a prior poly-trauma study were included in the study. Animals were rendered hypovolemic via a 30% volume bleed. Upon confirmation of death, animals underwent immediate clamshell thoracotomy and aortic cross-clamping followed by 5min of OCM. A catheter suitable for OCSAAP was then inserted into the aorta and animals underwent 1min of OCSAAP at a rate of 10mL/kg/min. Aortic and right atrial pressures were recorded continuously using solid-state blood pressure catheters. Representative 10-s intervals from each resuscitation method were extracted. Hemodynamic parameters including AoP-RAP gradients and CPPs were calculated and compared. At baseline, time from death to intervention was significantly shorter for OCM. However, mean CPPs and AoP-RAP gradients were significantly higher in animals undergoing OCSAAP. 98% of OCSAAP segments had a mean CPP > 15, compared to 35% of OCM intervals. While OCM had a significant negative correlation between time to intervention and maximum CPP, this correlation was not significant for OCSAAP. OCSAAP generates favorable and potentially time-resistant pressure gradients when compared to those generated by OCM. Further investigation of the technique of OCSAAP is warranted, as it may have potential utility as a therapy during resuscitative thoracotomy (RT).

Emergency preservation and resuscitation for cardiac arrest from trauma

Patients who suffer a cardiac arrest from trauma rarely survive. Surgical control of hemorrhage cannot be obtained in time to prevent irreversible organ damage. Emergency preservation and resuscitation (EPR) was developed to utilize hypothermia to buy time to achieve hemostasis and allow delayed resuscitation. Large animal studies have demonstrated that cooling to tympanic membrane temperature 10 °C during exsanguination cardiac arrest can allow up to 2 h of circulatory arrest and repair of simulated injuries with normal neurologic recovery. The Emergency Preservation and Resuscitation for Cardiac Arrest from Trauma (EPR-CAT) trial is testing the feasibility and safety of initiating EPR. Study subjects include patients with penetrating trauma who lose a pulse within 5minutes of hospital arrival and remain pulseless despite standard care. EPR is initiated via an intra-aortic flush of ice-cold saline solution. Following hemostasis, delayed resuscitation and rewarming are accomplished with cardiopulmonary bypass. The primary outcome is survival to hospital discharge without significant neurologic deficits. If trained team members are available, subjects can undergo EPR. If not, subjects can be enrolled as concurrent controls. Ten EPR and 10 control subjects will be enrolled. If successful, EPR could save the lives of trauma patients who are currently dying from exsanguinating hemorrhage.

O10 Myocardial tolerance to exsanguination and retrieval using whole blood-selective aortic arch perfusion

Abstract Introduction Exsanguination cardiac arrest is the leading preventable cause of death in trauma. Treatment modalities are limited, and prognosis remains dismal. Selective aortic arch perfusion (SAAP) is an emerging endovascular resuscitation technique consisting of aortic occlusion and perfusion of coronary and cerebral circulation with oxygenated resuscitation fluid. Translational research has demonstrated promising outcomes; however, little is known about the duration of cardiac arrest beyond which the myocardium cannot be resuscitated. The aims of this study are to assess the myocardial tolerance to exsanguination cardiac arrest before successful return of spontaneous circulation (ROSC) following resuscitation with SAAP, and 1-hour survival. Method 23 male adult swine were anaesthetised and instrumented. Controlled hemorrhage was performed until cardiac arrest defined by MAP <20 mmHg. Animals were randomized into 3 groups: 5, 10 and 15 minutes of cardiac arrest before resuscitation with SAAP. Following ROSC animals were observed for 60 minutes. Result Baseline characteristics were similar between groups (P > 0.05). ROSC was 100% (8/8) in the 5 min group, 75% (6/8) and 43% (3/7) in 10- and 15-min groups respectively (P = 0.042). 60 min survival was 75%, 50% and 14% in 5-, 10- and 15-min groups respectively (P = 0.015). 1-hour survivors in the 5 min group required less noradrenaline 23.6 (±7.4) compared to other animals 40.9 (±25.8), (P = 0.008). Conclusion Selective aortic arch perfusion is an effective resuscitative tool in eliciting ROSC in a swine model of exsanguination cardiac arrest lasting >5 min. Sustainable resuscitability using SAAP declines after 10 min of exsanguination cardiac arrest. Take-home Message SAAP is an emerging resuscitation technique with promising outcomes in exsanguination cardiac arrest and may be a segway to Extracorporeal life support. The time limit for resuscitability of the myocardium lies somewhere between 10 and 15 min after the start of exsanguination cardiac arrest.

Selective aortic arch perfusion versus open cardiac massage in exsanguination cardiac arrest: A comparison of coronary pressure dynamics in swine

AimTo evaluate the mean aortic-right atrial pressure (AoP-RAP) gradients and mean coronary perfusion pressures (CPPs) observed during open cardiac massage (OCM) versus those obtained with selective aortic arch perfusion (SAAP) in post-mortem hypovolemic swine. MethodsPost-mortum, male swine, utilized in prior studies of hemorrhage, were included in the study. Animals were bled ∼25–50% of circulating volume prior to death. Animals either underwent clamshell thoracotomy and OCM immediately after death was confirmed (n = 6) or underwent SAAP within 5−15 min of death (n = 6). Aortic root and right atrial pressures were recorded continuously during each method of resuscitation using solid state blood pressure catheters. Representative five beat samples were extracted; short, similarly timed segments of SAAP were also extracted. Mean AoP-RAP gradient and CPPs were calculated and compared. ResultsMean AoP-RAP gradient and CPP were significantly higher in SAAP animals compared to OCM animals (mean ± SD; 29.1 ± 8.4 vs. 24.5 ± 5.0, p < 0.001; 28.9 ± 8.5 vs. 9.9 ± 6.0, p < 0.001). Mean CPP was not significantly different from mean AoP-RAP gradient in SAAP animals (p = 0.92); mean CPP was significantly lower than mean AoP-RAP gradient in OCM animals (p < 0.001). While 97% of SAAP segments had a CPP > 15 mmHg, only 17% of OCM segments had a CPP > 15 mmHg (p < 0.001). ConclusionSAAP appears to create a more favorable and efficient hemodynamic profile for obtaining ROSC when compared to OCM in this preclinical porcine study.

Development of a Selective Aortic Arch Perfusion System in a Porcine Model of Exsanguination Cardiac Arrest.

Hemorrhage constitutes the majority of potentially preventable deaths from trauma. There is growing interest in endovascular resuscitation techniques such as selective aortic arch perfusion (SAAP) for patients in cardiac arrest. This involves active perfusion of the coronary circulation via a thoracic aortic balloon catheter and is approaching clinical application. However, the technique is complex and requires refinement in animal models before human use can be considered. This paper describes a large animal model of exsanguination cardiac arrest treated with a bespoke SAAP system. Swine were anesthetized, instrumented and a splenectomy was performed before a controlled, logarithmic exsanguination was initiated. Animals were heparinized and the shed blood collected in a reservoir. Once cardiac arrest was observed, the blood was pumped through an extra-corporeal circuit into an oxygenator and then delivered through a 10 Fr balloon catheter placed in the thoracic aorta. This resulted in the return of a spontaneous circulation (ROSC) as demonstrated by ECG and aortic root pressure waveform. This model and accompanying SAAP system allow for standardized and reproducible recovery from exsanguination cardiac arrest.

Comparison of donor hearts from hypoxic cardiac arrest followed by warm ischemia and from exsanguination as non-beating donor models in rat heart transplantation

Non-heart-beating donation, in the situation where a patient cannot be diagnosed as dead using brainstem criteria, may be an alternative to overcome shortage of donors. Preclinical studies showed that functional recovery of hearts after circulatory determination of death (DCDD) were similar to that of hearts from brain-dead donor. However, there are several experimental methods of simulating DCDD conditions such as exsanguination and hypoxic cardiac arrest both followed by warm ischemia.

Sex differences in cardiac injury after severe haemorrhage and ventricular fibrillation in pigs

Aim of the study Experimental studies have shown sex differences in haemodynamic response and outcome after trauma and haemorrhagic shock. We recently reported that female sex protects against cerebral injury after exsanguination cardiac arrest (CA), independent of sexual effects of hormones. The current study examines if female sex is also cardioprotective. Methods In this study 21 sexually immature piglets (12 males and 9 females) were subjected to 5 min of haemorrhagic shock followed by 2 min of ventricular fibrillation and 8 min of cardiopulmonary resuscitation (CPR). Volume resuscitation was started during CPR with intravenous administration of 3 ml kg −1 hypertonic saline-dextran (HSD) solution for 20 min. Sexually immature animals were used to differentiate innate sex differences from the effects of sexual hormones. Sex differences in haemodynamics, myocardial injury (troponin I), and short-term survival (3-h) were evaluated. Results After resuscitation female animals had a higher blood pressure, lower heart rate, lower troponin I concentrations, and higher survival rate (100% and 63% in 3 h) despite comparable sex hormone levels. Conclusions After resuscitation from haemorrhage and circulatory arrest, haemodynamic parameters are better preserved and myocardial injury is smaller in female piglets. This difference in outcome is independent of sexual hormones.

Sex differences in cerebral injury after severe haemorrhage and ventricular fibrillation in pigs

Experimental studies of haemorrhagic shock have documented a superior haemodynamic response and a better outcome in female animals as compared with male controls. Such sexual dimorphism has, nevertheless, not been reported after circulatory arrest that follows exsanguination and shock. We aimed to study differences in cerebral injury markers after exsanguination cardiac arrest in pre-pubertal piglets. The hypothesis was that cerebral injury is less extensive in female animals, and that this difference is independent of sexual hormones or choice of resuscitative fluid. Thirty-two sexually immature piglets (14 males and 18 females) were subjected to 5 min of haemorrhagic shock followed by 2 min of ventricular fibrillation and 8 min of cardiopulmonary resuscitation, using three resuscitation fluid regimens (whole blood, hypertonic saline and dextran, or acetated Ringers' solution plus whole blood and methylene blue). Haemodynamic values, cellular markers of brain injury and brain histology were studied. After successful resuscitation, female piglets had significantly greater cerebral cortical blood flow, tended to have lower S-100beta values and a lower cerebral oxygen extraction ratio. Besides, in female animals, systemic and cerebral venous acidosis were mitigated. Female piglets exhibited a significantly smaller increase in neuronal nitric oxide synthase (nNOS) and inducible nitric oxide synthase (iNOS) expression in their cerebral cortex, smaller blood-brain-barrier (BBB) disruption and significantly smaller neuronal injury. After resuscitation from haemorrhagic circulatory arrest, cerebral reperfusion is greater, and BBB permeability and neuronal injury is smaller in female piglets. An increased cerebral cortical iNOS and nNOS expression in males implies a mechanistic relationship with post-resuscitation neuronal injury and warrants further investigation.

Deep Hypothermia Attenuates Microglial Proliferation Independent of Neuronal Death After Prolonged Cardiac Arrest in Rats

Conventional resuscitation of exsanguination cardiac arrest (CA) victims is generally unsuccessful. Emergency preservation and resuscitation is a novel approach that uses an aortic flush to induce deep hypothermia during CA, followed by delayed resuscitation with cardiopulmonary bypass. Minocycline has been shown to be neuroprotective across a number of brain injury models via attenuating microglial activation. We hypothesized that deep hypothermia and minocycline would attenuate neuronal death and microglial activation and improve outcome after exsanguination CA in rats. Using isoflurane anesthesia, rats were subjected to a lethal hemorrhagic shock. After 5 min of no flow, hypothermia was induced with an aortic flush. Three groups were studied: ice-cold (IC) flush, room-temperature (RT) flush, and RT flush followed by minocycline treatment (RT-M). After 20 min of CA, resuscitation was achieved via cardiopulmonary bypass. Survival, Overall Performance Category (1 = normal, 5 = death), Neurologic Deficit Score (0%-10% = normal, 100% = max deficit), neuronal death (Fluoro-Jade C), and microglial proliferation (Iba1 immunostaining) in hippocampus were assessed at 72 h. Rats in the IC group had lower tympanic temperature during CA versus other groups (IC, 20.9 degrees C +/- 1.3 degrees C; RT, 28.4 degrees C +/- 0.6 degrees C; RT-M, 28.3 degrees C +/- 0.7 degrees C; P < 0.001). Although survival was similar in all groups (RT, 6/9; IC, 6/7; RT-M, 6/11), neurological outcome was better in the IC group versus other groups (Overall Performance Category: IC, 1 +/- 1; RT, 3 +/- 1; RT-M, 2 +/- 1; P < 0.05; Neurologic Deficit Score: IC, 8% +/- 9%; RT, 55% +/- 19%; RT-M, 27% +/- 16%; P < 0.05). Histological damage assessed in survivors showed selective neuronal death in CA1 and dentate gyrus, similar in all groups (P = 0.15). In contrast, microglial proliferation was attenuated in the IC group versus all other groups (P < 0.01). Deeper levels of hypothermia induced by the IC versus RT flush resulted in better neurological outcome in survivors. Surprisingly, deep hypothermia attenuated microglial activation but not hippocampal neuronal death. Minocycline had modest benefit on neurologic outcome in survivors but did not attenuate microglial activation in brain. Our findings suggest a novel effect of deep hypothermia on microglial proliferation during exsanguination CA.

Blood–brain barrier integrity in a rat model of emergency preservation and resuscitation

Emergency Preservation and Resuscitation (EPR) represents a novel approach to treat exsanguination cardiac arrest (CA) victims, using an aortic flush to induce hypothermia during circulatory arrest, followed by delayed resuscitation with cardiopulmonary bypass (CPB). The status of the blood–brain barrier (BBB) integrity after prolonged hypothermic CA is unclear. The objective of this study was to assess BBB permeability in two EPR models in rats, associated with poor outcome. Rats subjected to traumatic brain injury (TBI) and naïve rats served as positive and negative controls, respectively. Hypothesis The BBB will be disrupted after TBI, but intact after prolonged hypothermic CA. Methods Four groups were studied: (1) EPR-IC (ice cold)-75 min CA at 15 °C; (2) EPR-RT (room temperature)-20 min CA at 28 °C; (3) TBI; (4) sham. Rats in EPR groups were subjected to rapid hemorrhage, followed by CA. Rats in the TBI group had a controlled cortical impact to the left hemisphere. Naïves were subjected to the same anesthesia and surgery. 1 h after insult, rats were injected with Evans Blue (EB), a marker of BBB permeability for albumin. Rats were sacrificed after 5 h and EB absorbance was quantified in brain samples. Results TBI produced an approximately 10-fold increase in EB absorbance in the left (injured) hemisphere vs. left hemisphere for all other groups ( p = 0.001). In contrast, EB absorbance in either EPR group did not differ from sham. Conclusion BBB integrity to albumin is not disrupted early after resuscitation from prolonged CA treated with EPR. Neuroprotective adjuncts to hypothermia in this setting should focus on agents that penetrate the BBB. These findings also have implications for deep hypothermic circulatory arrest.

Bakken Lecture: The brain, the heart, and therapeutic hypothermia

Therapeutic hypothermia in acute resuscitation medicine has a long history, but its currently recommended use dates back to work in the mid-1960s by the late Dr. Peter Safar and colleagues. Compared with normothermia, mild therapeutic hypothermia, induced right after restoration of spontaneous circulation in comatose survivors of cardiac arrest, leads to 1 additional patient with intact neurological outcome for every 6 patients treated. Demonstrating benefit from therapeutic hypothermia in other acute neurological insults, such as traumatic brain injury, has been more difficult. Current research to optimize the benefits of mild therapeutic hypothermia in cardiac arrest is focused on hypothermia's profound effects on drug metabolism, determining the best anesthetics and sedatives to use with cooling, and identifying compounds that may promote induction of hypothermia or create a poikilothermic state. Future applications of therapeutic hypothermia may include induction of emergency preservation and resuscitation to buy time for damage-control surgery in patients with exsanguination cardiac arrest.

Protein nitration and poly-ADP-ribosylation in brain after rapid exsanguination cardiac arrest in a rat model of emergency preservation and resuscitation

Emergency preservation and resuscitation (EPR) of 60 min in rats is achievable with favorable outcome, while 75 min is associated with substantial mortality and impaired neurological outcome in survivors. We hypothesized that 75 min but not 60 min of EPR would be associated with activation of two potential secondary injury cascades in brain as reflected by protein nitration and poly (ADP-ribose) polymerase (PARP) activation. Rats were rapidly exsanguinated over 5 min. After 1 min of cardiac arrest (CA), rats were cooled to a target tympanic temperature of 15 degrees C. After either 60 min or 75 min of CA, resuscitation was achieved via cardiopulmonary bypass (CPB). Rats subjected to CPB only served as controls. Overall performance category (OPC) and neurologic deficit score (NDS) were assessed at 24 h. Protein nitration and poly-ADP-ribosylation were assessed by Western blotting and immunohistochemistry for 3-nitrotyrosine and poly-ADP ribose polymers, respectively, in multiple brain regions. Neurologic outcome was better in the 60 min vs. the 75 min EPR group (OPC, P<0.001; NDS, P=0.001). Densitometric analysis of the major 64 kD band showed that nitration and PARP activation were significantly increased in hippocampus, cortex and striatum in the 75 min EPR group vs. other groups. However, there were no differences in cerebellum. Analysis of the full protein spectrum showed significantly increased PARP activation only in hippocampus in the 75 min EPR group vs. other groups. Extending the duration of EPR beyond the limit that can yield favorable recovery in rats was associated with increased nitration and ribosylation of selected proteins in selectively vulnerable brain regions. The impact of these mechanisms on the outcome remains to be determined.

Assessment of the delta opioid agonist DADLE in a rat model of lethal hemorrhage treated by emergency preservation and resuscitation

Emergency preservation and resuscitation (EPR) is a new approach for resuscitation of exsanguination cardiac arrest (CA) victims. EPR uses a cold aortic flush to induce deep hypothermic preservation during no-flow to buy time for transport and damage control surgery, followed by resuscitation with cardiopulmonary bypass (CPB). We reported previously that 20-60 min EPR in rats was associated with intact outcome, while 75 min EPR resulted in high mortality and neurological impairment in survivors. The delta opioid agonist DADLE ([D-Ala(2),D-Leu(5)]-enkephalin) was shown previously to be protective against ischemia-reperfusion injury in multiple organs, including brain. We hypothesized that DADLE could augment neurological outcome after EPR in rats. After rapid lethal hemorrhage, EPR was initiated by perfusion with ice-cold crystalloid to induce hypothermia (15 degrees C). After 75 min EPR, resuscitation was attempted with CPB. After randomization, three groups were studied (n=10 per group): DADLE 0mg/kg (D0), 4 mg/kg (D4) or 10mg/kg (D10) added to the flush and during reperfusion. Survival, overall performance category (OPC; 1=normal, 5=death), neurological deficit score (NDS; 0-10% normal, 100%=max deficit), and histological damage score (HDS) were assessed in survivors on day 3. In D0 group, 2/10 rats survived, while in D4 and D10 groups, 4/10 and 5/10 rats survived, respectively (p=NS). Survival time (h) was 26.7+/-28.2 in D0, 36.3+/-31.9 in D4 and 47.1+/-30.3 in D10 groups, respectively (p=0.3). OPC, NDS and HDS were not significantly different between groups. In conclusion, DADLE failed to confer benefit on functional or histological outcome in our model of prolonged rat EPR.

Emergency Preservation and Resuscitation with Profound Hypothermia, Oxygen, and Glucose Allows Reliable Neurological Recovery after 3 h of Cardiac Arrest from Rapid Exsanguination in Dogs

We have used a rapid induction of profound hypothermia (<10 degrees C) with delayed resuscitation using cardiopulmonary bypass (CPB) as a novel approach for resuscitation from exsanguination cardiac arrest (ExCA). We have defined this approach as emergency preservation and resuscitation (EPR). We observed that 2 h but not 3 h of preservation could be achieved with favorable outcome using ice-cold normal saline flush to induce profound hypothermia. We tested the hypothesis that adding energy substrates to saline during induction of EPR would allow intact recovery after 3 h CA. Dogs underwent rapid ExCA. Two minutes after CA, EPR was induced with arterial ice-cold flush. Four treatments (n=6/group) were defined by a flush solution with or without 2.5% glucose (G+ or G-) and with either oxygen or nitrogen (O+ or O-) rapidly targeting tympanic temperature of 8 degrees C. At 3 h after CA onset, delayed resuscitation was initiated with CPB, followed by intensive care to 72 h. At 72 h, all dogs in the O+G+ group regained consciousness, and the group had better neurological deficit scores and overall performance categories than the O-groups (both P<0.05). In the O+G- group, four of the six dogs regained consciousness. All but one dog in the O-groups remained comatose. Brain histopathology in the O-G+ was worse than the other three groups (P<0.05). We conclude that EPR induced with a flush solution containing oxygen and glucose allowed satisfactory recovery of neurological function after a 3 h of CA, suggesting benefit from substrate delivery during induction or maintenance of a profound hypothermic CA.

Exsanguination cardiac arrest in rats treated by 60 min, but not 75 min, emergency preservation and delayed resuscitation is associated with intact outcome

Emergency preservation and resuscitation (EPR) is a new approach for resuscitation of exsanguination cardiac arrest (CA) victims to buy time for surgical hemostasis. EPR uses a cold aortic flush to induce deep hypothermic preservation, followed by resuscitation with cardiopulmonary bypass (CPB). We previously reported that 20 min of EPR was feasible with intact outcome. In this report, we tested the limits for EPR in rats. Adult male isoflurane-anesthetized rats were subjected to rapid hemorrhage (12.5 ml over 5 min), followed by esmolol/KCl-induced CA and 1 min of no-flow. EPR was then induced by perfusion with 270 ml of ice-cold Plasma-Lyte to decrease body temperature to 15 degrees C. After 60 min (n=7) or 75 min (n=7) of EPR, resuscitation was attempted with CPB over 60 min, blood transfusion, correction of acid-base balance and electrolyte disturbances, and mechanical ventilation for 2h. Survival, overall performance category (OPC: 1=normal, 5=death), neurological deficit score (NDS), and histological damage score (HDS) were assessed in survivors on day 3. While all rats after 60 min EPR survived, only two out of seven rats after 75 min EPR survived (p<0.05). All rats after 60 min EPR achieved OPC 1 and normal NDS by day 3. Survivors after 75 min EPR achieved best OPC 3 (p<0.05 vs. 60 min EPR). HDS of either brain or individual viscera was not statistically different after 60 versus 75 min EPR, except for kidneys (0+/-0 vs. 1.9+/-1.3, respectively; p<0.05), with a strong trend toward greater injury in all extracerebral organs in the 75-min EPR group (p<0.06). Histological findings were dominated by cardiac lesions observed in both groups and acute renal tubular and liver necrosis in the 75-min EPR group. In conclusion, we have shown that 60 min of EPR after exsanguination CA is associated with survival and favorable neurological outcome, while 75 min of EPR results in significant mortality and neurological damage in survivors. Surprisingly, extracerebral lesions predominated at 75-min EPR group. This model should serve as a screening model both for testing new pharmacological adjuncts to improve survival after exsanguination CA, and for elucidating the underlying mechanisms of ischemia/reperfusion injury.

Emergency preservation and delayed resuscitation allows normal recovery after exsanguination cardiac arrest in rats: A feasibility trial*

Emergency preservation and resuscitation (EPR) comprise a novel approach for resuscitation of exsanguination cardiac arrest victims. EPR uses a cold aortic flush to induce deep hypothermic preservation, followed by resuscitation with cardiopulmonary bypass. Development of a rat EPR model would enable study of the molecular mechanisms of neuronal injury and the screening of novel agents for emergency preservation. A prospective, randomized study. University research facility. Adult male Sprague-Dawley rats. Isoflurane-anesthetized rats were subjected to lethal hemorrhage (12.5 mL for 5 mins), followed by KCl-induced cardiac arrest and 1 min of no flow. Three groups (n=6) were studied: hypothermic EPR (H-EPR; 0 degrees C flush; target temperature, 15 degrees C); normothermic EPR (N-EPR; 38 degrees C flush); and controls. After 20 mins of H-EPR or N-EPR, resuscitation was initiated with cardiopulmonary bypass for 60 mins and mechanical ventilation. Controls were subjected to complete experimental preparation and anesthesia without cardiac arrest, followed by 60 mins of cardiopulmonary bypass and mechanical ventilation. Surviving rats were extubated 2 hrs later. Survival, Overall Performance Category (1, normal; 5, death), Neurologic Deficit Score, Histologic Damage Score, and biochemistry were assessed in survivors on day 7. All rats in H-EPR and control groups survived, whereas none of the rats in the N-EPR group had restoration of spontaneous circulation. All rats in the H-EPR and control groups achieved Overall Performance Category 1, normal Neurologic Damage Score, and normal or near normal Histologic Damage Score and biochemical markers of organ injury. We have established an EPR model in rats showing no neurologic injury, despite an exsanguination cardiac arrest, followed by 20 mins of EPR using miniaturized cardiopulmonary bypass. Establishment of this model should facilitate application of molecular tools to study the effects of hypothermic preservation and reperfusion and to screen novel pharmacologic adjuncts.

The Safar Center for Resuscitation Research: Searching for Breakthroughs in the New Millennium

This review, written on the occasion of the 70th anniversary of the Institute for General Reanimatology of the Russian Academy of Medical Sciences, provides an update of recent research in the field of resuscitation medicine carried out at the Safar Center for Resuscitation Research at the University of Pittsburgh School of Medicine. Current and recent studies describing bench to bedside investigation in the areas of traumatic brain injury (TBI), cardiopulmonary arrest, hemorrhagic shock, and ultra-novel approaches to resuscitation are discussed. Investigation in TBI across a variety of topics by many investigators including mechanism of neuronal death, oxidative and nitrative stress, proteomics, adenosine, serotonin, novel magnetic resonance imaging application, inflicted childhood neurotrauma, and TBI rehabilitation is addressed. Research discussed in the program of cardiopulmonary arrest includes optimization of the use of mild hypothermia and novel investigation in experimental asphyxial cardiac arrest. In the program on hemorrhagic shock, our recent work on the application of mild hypothermia to prolong the «golden hour» is presented. Finally, a brief overview of our studies of a novel approach to the resuscitation of exsan-guination cardiac arrest using emergency preservation for resuscitation (EPR) is provided.

Induction of Profound Hypothermia for Emergency Preservation and Resuscitation Allows Intact Survival After Cardiac Arrest Resulting From Prolonged Lethal Hemorrhage and Trauma in Dogs

Induction of profound hypothermia for emergency preservation and resuscitation (EPR) of trauma victims who experience exsanguination cardiac arrest may allow survival from otherwise-lethal injuries. Previously, we achieved intact survival of dogs from 2 hours of EPR after rapid hemorrhage. We tested the hypothesis that EPR would achieve good outcome if prolonged hemorrhage preceded cardiac arrest. Two minutes after cardiac arrest from prolonged hemorrhage and splenic transection, dogs were randomized into 3 groups (n=7 each): (1) the cardiopulmonary resuscitation (CPR) group, resuscitated with conventional CPR, and the (2) EPR-I and (3) EPR-II groups, both of which received 20 L of a 2 degrees C saline aortic flush to achieve a brain temperature of 10 degrees C to 15 degrees C. CPR or EPR lasted 60 minutes and was followed in all groups by a 2-hour resuscitation by cardiopulmonary bypass. Splenectomy was then performed. The CPR dogs were maintained at 38.0 degrees C. In the EPR groups, mild hypothermia (34 degrees C) was maintained for either 12 (EPR-I) or 36 (EPR-II) hours. Function and brain histology were evaluated 60 hours after rewarming in all dogs. Cardiac arrest occurred after 124+/-16 minutes of hemorrhage. In the CPR group, spontaneous circulation could not be restored without cardiopulmonary bypass; none survived. Twelve of 14 EPR dogs survived. Compared with the EPR-I group, the EPR-II group had better overall performance, final neurological deficit scores, and histological damage scores. EPR is superior to conventional CPR in facilitating normal recovery after cardiac arrest from trauma and prolonged hemorrhage. Prolonged mild hypothermia after EPR was critical for achieving intact neurological outcomes.

Therapeutic hypothermia after cardiac arrest

Most patients who suffer a cardiac arrest die after the event. Full neurological recovery occurs in only 6-23%. Until recently no specific post-arrest therapy was available to improve outcome. Application of therapeutic hypothermia (32-34 degrees C for 12-24 h) applied after cardiac arrest could help to improve this dreadful situation. This review covers the background of and recent clinical studies into hypothermia after cardiac arrest, and gives some insights into the future of resuscitation, namely suspended animation. Two randomized clinical trials of mild therapeutic hypothermia applied after successful resuscitation from cardiac arrest showed that hypothermia after cardiac arrest improves neurological outcome as well as overall mortality. The introduction of therapeutic hypothermia after cardiac arrest into routine intensive care practice could save thousands of lives worldwide, because only six patients must be treated to yield one additional patient with favourable neurological recovery. New developments in cooling techniques will make early induction of therapeutic hypothermia simple and convenient. The optimal duration and depth of hypothermia will be determined by future trials. Suspended animation is cooling during cardiac arrest to preserve the organism under conditions of prolonged controlled clinical death, followed by delayed resuscitation, resulting in survival without brain damage. This concept was initially introduced for trauma victims who rapidly bleed to death, and proved to be feasible in studies evaluating outcomes following exsanguination cardiac arrest in large animals. Whether the concept of suspended animation is applicable to normovolemic cardiac arrest is under investigation.