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Cardiac arrest (CA) triggers neuroinflammation that could play a role in a delayed neuronal death. In our previously established rat model of ventricular fibrillation (VF) CA characterized by extensive neuronal death, we tested the hypothesis that individual brain regions have specific neuroinflammatory responses, as reflected by regional brain tissue levels of tumor necrosis factor (TNF)α and other cytokines. In a prospective study, rats were randomized to 6min (CA6), 8min (CA8) or 10min (CA10) of VF CA, or sham group. Cortex, striatum, hippocampus and cerebellum were evaluated for TNFα and interleukin (IL)-1α, IL-1β, IL-2, IL-4, IL-6, IL-10, IL-12 and interferon gamma at 3h, 6h or 14 d after CA by ELISA and Luminex. Immunohistochemistry was used to determine the cell source of TNFα. CA resulted in a selective TNFα response with significant regional and temporal differences. At 3h after CA, TNFα-levels increased in all regions depending on the duration of the insult. The most pronounced increase was observed in striatum that showed 20-fold increase in CA10 vs. sham, and 3-fold increase vs. CA6 or CA8 group, respectively (p<0.01). TNFα levels in striatum decreased between 3h and 6h, but increased in other regions between 3h and 14 d. TNFα levels remained twofold higher in CA6 vs. shams across brain regions at 14 d (p<0.01). In contrast to pronounced TNFα response, other cytokines showed only a minimal increase in CA6 and CA8 groups vs. sham in all brain regions with the exception that IL-1β increased twofold in cerebellum and striatum (p<0.01). TNFα colocalized with neurons. In conclusion, CA produced a duration-dependent acute TNFα response, with dramatic increase in the striatum where TNFα colocalized with neurons. Increased TNFα levels persist for at least two weeks. This TNFα surge contrasts the lack of an acute increase in other cytokines in brain after CA. Given that striatum is a selectively vulnerable brain region, our data suggest possible role of neuronal TNFα in striatum after CA and identify therapeutic targets for future experiments. This study was approved by the University of Pittsburgh IACUC 1002340A-3. [ABSTRACT FROM AUTHOR]

Abstract: Cardiac arrest (CA) triggers neuroinflammation that could play a role in a delayed neuronal death. In our previously established rat model of ventricular fibrillation (VF) CA characterized by extensive neuronal death, we tested the hypothesis that individual brain regions have specific neuroinflammatory responses, as reflected by regional brain tissue levels of tumor necrosis factor (TNF)α and other cytokines. In a prospective study, rats were randomized to 6min (CA6), 8min (CA8) or 10min (CA10) of VF CA, or sham group. Cortex, striatum, hippocampus and cerebellum were evaluated for TNFα and interleukin (IL)-1α, IL-1β, IL-2, IL-4, IL-6, IL-10, IL-12 and interferon gamma at 3h, 6h or 14 d after CA by ELISA and Luminex. Immunohistochemistry was used to determine the cell source of TNFα. CA resulted in a selective TNFα response with significant regional and temporal differences. At 3h after CA, TNFα-levels increased in all regions depending on the duration of the insult. The most pronounced increase was observed in striatum that showed 20-fold increase in CA10 vs. sham, and 3-fold increase vs. CA6 or CA8 group, respectively (p <0.01). TNFα levels in striatum decreased between 3h and 6h, but increased in other regions between 3h and 14 d. TNFα levels remained twofold higher in CA6 vs. shams across brain regions at 14 d (p <0.01). In contrast to pronounced TNFα response, other cytokines showed only a minimal increase in CA6 and CA8 groups vs. sham in all brain regions with the exception that IL-1β increased twofold in cerebellum and striatum (p <0.01). TNFα colocalized with neurons. In conclusion, CA produced a duration-dependent acute TNFα response, with dramatic increase in the striatum where TNFα colocalized with neurons. Increased TNFα levels persist for at least two weeks. This TNFα surge contrasts the lack of an acute increase in other cytokines in brain after CA. Given that striatum is a selectively vulnerable brain region, our data suggest possible role of neuronal TNFα in striatum after CA and identify therapeutic targets for future experiments. This study was approved by the University of Pittsburgh IACUC 1002340A-3. [Copyright &y& Elsevier]

Neuro-cognitive disabilities are a well-recognized complication of hypothermic circulatory arrest. We and others have reported that prolonged cardiac arrest (CA) produces neuronal death and microglial proliferation and activation that are only partially mitigated by hypothermia. Microglia, and possibly other cells, are suggested to elaborate tumor necrosis factor alpha (TNF-α), which can trigger neuronal death cascades and exacerbate edema after CNS insults. Minocycline is neuroprotective in some brain ischemia models in part by blunting the microglial response. We tested the hypothesis that minocycline would attenuate neuroinflammation as reflected by brain tissue levels of TNF-α after hypothermic CA in rats. Rats were subjected to rapid exsanguination, followed by a 6 min normothermic CA. Hypothermia (30 °C) was then induced by an aortic saline flush. After a total of 20 min CA, resuscitation was achieved via cardiopulmonary bypass (CPB). After 5 min reperfusion, minocycline (90 mg kg−1; n = 6) or vehicle (PBS; n = 6) was given. Hypothermia (34 °C) was maintained for 6 h. Rats were sacrificed at 6 or 24 h. TNF-α was quantified (ELISA) in four brain regions (cerebellum, CEREB; cortex, CTX; hippocampus, HIP; striatum, STRI). Naïve rats (n = 6) and rats subjected to the same anesthesia and CPB but no CA served as controls (n = 6). Immunocytochemistry was used to localize TNF-α. Naïve rats and CPB controls had no detectable TNF-α in any brain region. CA markedly increased brain TNF-α. Regional differences were seen, with the highest TNF-α levels in striatum in CA groups (10-fold higher, P < 0.05 vs. all other brain regions). TNF-α was undetectable at 24 h. Minocycline attenuated TNF-α levels in CTX, HIP and STRI (P < 0.05). TNF-α showed unique co-localization with neurons. In conclusion, we report region-dependent early increases in brain TNF-α levels after prolonged hypothermic CA, with maximal increases in striatum. Surprisingly, TNF-α co-localized in neurons and not microglia. Minocycline attenuated TNF-α by approximately 50% but did not totally ablate its production. That minocycline decreased brain TNF-α levels suggests that it may represent a therapeutic adjunct to hypothermia in CA neuroprotection. University of Pittsburgh IACUC 0809278B-3. [ABSTRACT FROM AUTHOR]

Neuro-cognitive disabilities are a well-recognized complication of hypothermic circulatory arrest. We and others have reported that prolonged cardiac arrest (CA) produces neuronal death and microglial proliferation and activation that are only partially mitigated by hypothermia. Microglia, and possibly other cells, are suggested to elaborate tumor necrosis factor alpha (TNF-α), which can trigger neuronal death cascades and exacerbate edema after CNS insults. Minocycline is neuroprotective in some brain ischemia models in part by blunting the microglial response. We tested the hypothesis that minocycline would attenuate neuroinflammation as reflected by brain tissue levels of TNF-α after hypothermic CA in rats. Rats were subjected to rapid exsanguination, followed by a 6min normothermic CA. Hypothermia (30°C) was then induced by an aortic saline flush. After a total of 20min CA, resuscitation was achieved via cardiopulmonary bypass (CPB). After 5min reperfusion, minocycline (90mgkg−1; n =6) or vehicle (PBS; n =6) was given. Hypothermia (34°C) was maintained for 6h. Rats were sacrificed at 6 or 24h. TNF-α was quantified (ELISA) in four brain regions (cerebellum, CEREB; cortex, CTX; hippocampus, HIP; striatum, STRI). Naïve rats (n =6) and rats subjected to the same anesthesia and CPB but no CA served as controls (n =6). Immunocytochemistry was used to localize TNF-α. Naïve rats and CPB controls had no detectable TNF-α in any brain region. CA markedly increased brain TNF-α. Regional differences were seen, with the highest TNF-α levels in striatum in CA groups (10-fold higher, P <0.05 vs. all other brain regions). TNF-α was undetectable at 24h. Minocycline attenuated TNF-α levels in CTX, HIP and STRI (P <0.05). TNF-α showed unique co-localization with neurons. In conclusion, we report region-dependent early increases in brain TNF-α levels after prolonged hypothermic CA, with maximal increases in striatum. Surprisingly, TNF-α co-localized in neurons and not microglia. Minocycline attenuated TNF-α by approximately 50% but did not totally ablate its production. That minocycline decreased brain TNF-α levels suggests that it may represent a therapeutic adjunct to hypothermia in CA neuroprotection. University of Pittsburgh IACUC 0809278B-3. [ABSTRACT FROM AUTHOR]

Abstract: Trauma patients who suffer cardiac arrest (CA) from exsanguination rarely survive. Emergency preservation and resuscitation using hypothermia was developed to buy time for resuscitative surgery and delayed resuscitation with cardiopulmonary bypass (CPB), but intact survival is limited by neuronal death associated with microglial proliferation and activation. Pharmacological modulation of microglia may improve outcome following CA. Systemic injection of liposome-encapsulated clodronate (LEC) depletes macrophages. To test the hypothesis that intrahippocampal injection of LEC would attenuate local microglial proliferation after CA in rats, we administered LEC or PBS into the right or left hippocampus, respectively. After rapid exsanguination and 6min no-flow, hypothermia was induced by ice-cold (IC) or room-temperature (RT) flush. Total duration of CA was 20min. Pre-treatment (IC, RTpre) and post-treatment (RTpost) groups were studied, along with shams (cannulation only) and CPB controls. On day 7, shams and CPB groups showed neither neuronal death nor microglial activation. In contrast, the number of microglia in hippocampus in each individual group (IC, RTpre, RTpost) was decreased with LEC vs. PBS by ∼34–46% (P <0.05). Microglial proliferation was attenuated in the IC vs. RT groups (P <0.05). Neuronal death did not differ between hemispheres or IC vs. RT groups. Thus, intrahippocampal injection of LEC attenuated microglial proliferation by ∼40%, but did not alter neuronal death. This suggests that microglia may not play a pivotal role in mediating neuronal death in prolonged hypothermic CA. This novel strategy provides us with a tool to study the specific effects of microglia in hypothermic CA. [Copyright &y& Elsevier]

The article presents a study that tests whether cold aortic flush and chest compressions will improve neurologic outcomes after cardiac arrest in pigs, as compared to conventional resuscitation. Twenty- four female pigs were part of the study wherein experimental protocol was approved by the institutional animal investigation committee. It concludes the feasibility of the preservation and resuscitation by deep cerebral hypothermia with chest compressions and improvement of neurologic outcomes.

Summary: Aim: Patients’ outcomes after prolonged cardiac arrest are often grim. The aim of this study was to find the longest period of normovolemic, normothermic, cardiac arrest no-flow after which good neurologic outcome can be achieved with conventional therapies. Methods: Swine (28–37kg) were subjected to ventricular fibrillation cardiac arrest, after which they were randomized into groups with 13min (n =6), 15min (n =6), or 17min (n =6) of untreated cardiac arrest followed by advanced life support (ALS) for 20min (epinephrine 0.04mg/kg every 3min and vasopressin 0.4IE/kg every 6min, no defibrillation attempts), followed by cardiopulmonary bypass (CPB). To mimic an unresuscitable situation after prolonged cardiac arrest, CPB was initiated 20min after the start of resuscitation, followed by defibrillation attempts. Therapeutic mild hypothermia was applied for 20h and a final neurologic evaluation (neurologic deficit score, NDS; overall performance category, OPC) was done after 9 days. Results: In the 13-min group, restoration of spontaneous circulation (ROSC) was achieved in five of six swine, four of which survived to day 9, and all had favorable neurologic outcomes [one swine OPC 1, three swine OPC 2, NDS 15% (IQR 6–21)]. In the 15- and 17-min groups, ROSC was achieved in three of six and two of six swine, respectively, one survived to day 9 with OPC 3 in each group, and NDS values were 45 and 58%, respectively (Kruskal–Wallis test for OPC, p =0.048). Conclusions: In our model, the limit of normovolemic, normothermic, cardiac arrest no-flow time, followed by ACLS, CPB, and prolonged mild hypothermia, seems to be 13min. [Copyright &y& Elsevier]

Background: Long-term monitoring of patients at risk of arrhythmias would benefit from a miniaturized device. This study evaluated the quality of electrocardiogram (ECG) signals recorded by a miniaturized ECG recorder. Methods: ECG data were concurrently recorded with an investigational device (Philips Medical Systems, Seattle, WA, USA) and a Holter recorder from patients with cardiac-related symptoms at the emergency department of a tertiary care university hospital. The device was attached in one of four locations (L1: below left clavicle, L2: midsternal, L3: below left breast, L4: left anterior axillary line in 5th intercostal space). Selected ECG strips were analyzed for atrial activity, QRS width, and basic rhythm by two physicians. Patients were divided into groups based on their number of strips (A 2–5, B 6–9, C 10–21) for descriptive presentation of the data. For statistical analyses, nonlinear mixed-effects models were used. Results: In 90 patients, 574 pairs of strips were analyzed. In L1 (n = 37), agreement between the device and the Holter recorder on presence of P wave was 58–80% in groups A–C and in L2 (n = 28):94–98%, L3 (n = 12):30–72%, and L4 (n = 13):0–70%; on PR interval in L1:58–80%, L2:94–98%, L3:30–62%, and L4:0–70%; on rhythm in L1:56–79%, L2:94–98%, L3:30–62%, and L4:0–70%; on QRS width in L1:86–100%, L2:88–98%, L3:100%, and L4:96–100%. The agreement of L2 in the parameters P wave, PR interval, and rhythm diagnosis was better than in the other locations (P < 0.01). Conclusions: A miniature ECG monitor provided accurate assessment of atrial beats and rhythm diagnosis at a midsternal location and of QRS width at all locations. [ABSTRACT FROM AUTHOR]

The article examines the hypothesis that the Life Recovery Systems' ThermoSuit System offers effective core cooling by pumping ice water over the skin surface and enhances neurologic outcome after prolonged cardiac arrest. Results reveal that the ThermoSuit System quickly and safely induced mild therapeutic hypothermia. Hypothermia enhanced neurologic outcome in swine after cardiac arrest as compared with normothermia.

Summary: Aim of the study: Mild therapeutic hypothermia is a promising new therapy for patients resuscitated from cardiac arrest. Early and fast induction of hypothermia seems to be crucial for best results. The aim of the study was to investigate the feasibility and safety of a new surface cooling method using cold metal plates. Subjects and methods: Twelve adult human-sized swine (79±9kg) were cooled from 38 to 33°C brain temperature. The skin surface was covered with −20°C metal plates (M), as compared to ice packs, alcohol rubs, and fans used in a control group (C). Each method was tested during spontaneous circulation and, after re-warming, during cardiac arrest. Temperatures were recorded continuously. Data are given as mean±standard deviation or as median (interquartile range), if not normally distributed. Comparisons between the treatment groups were performed with the independent samples t-test, or the Mann–Whitney rank-sum test. Results: During spontaneous circulation, cooling rates were 9.3±1.4°C/h (M), and 6.1±1.4°C/h (C) (p =0.003); no skin lesions were observed. During cardiac arrest, cooling rates were 4.1°C/h (1.8–4.8) (M), and 3.7°C/h (3.1–5.3) (C) (p =0.9); no skin lesions were observed. Conclusion: Cooling with cold metal plates was an effective method for rapid induction of mild therapeutic hypothermia in adult human-sized swine during spontaneous circulation, without any signs of skin damage. This new surface-cooling device, independent of energy supply during use, should be further investigated. [Copyright &y& Elsevier]

The article discusses the feasibility of emergency preservation and resuscitation (EPR) in an experimental pig model and the improvement of survival after prolonged cardiac arrest in pig models. Results showed a decrease in brain temperature of the EPR group. Five pigs were observed to achieve restoration of spontaneous circulation and survived 9 days. The induction of deep hypothermia for EPR during prolonged cardiac arrest is assessed to mitigate the deleterious cascades that improve outcomes.

Summary: Aim of the study: Cold infusions have proved to be effective for induction of therapeutic hypothermia after cardiac arrest but so far have not been used for hypothermia maintenance. This study investigates if hypothermia can be induced and maintained by repetitive infusions of cold fluids and muscle relaxants. Material and methods: Patients were eligible, if they had a cardiac arrest of presumed cardiac origin and no clinical signs of pulmonary oedema or severely reduced left ventricular function. Rocuronium (0.5mg/kg bolus, 0.5mg/kg/h for maintenance) and crystalloids (30ml/kg/30min for induction, 10ml/kg every 6h for 24h maintenance) were administered via large bore peripheral venous cannulae. If patients failed to reach 33±1°C bladder temperature within 60min, endovascular cooling was applied. Results: Twenty patients with a mean age of 57 (±15) years and mean body mass index of 27 (±4)kg/m2 were included (14 males). Mean temperature at initiation of cooling (median 27 (IQR 16; 87)min after admission) was 35.4 (±0.9)°C. In 13 patients (65%) the target temperature was reached within 60min, 7 patients (35%) failed to reach the target temperature. Maintaining the target temperature was possible in three (15%) patients and no adverse events were observed. Conclusion: Cold infusions are effective for induction of hypothermia after cardiac arrest, but for maintenance additional cooling techniques are necessary in most cases. [Copyright &y& Elsevier]

OBJECTIVES: Extracorporeal cardiopulmonary resuscitation with cardiopulmonary bypass potentially provides cerebral reperfusion, cardiovascular support, and temperature control for resuscitation from cardiac arrest. We hypothesized that extracorporeal cardiopulmonary resuscitation is feasible after ventricular fibrillation cardiac arrest in rats and improves outcome versus conventional cardiopulmonary resuscitation. DESIGN: Prospective randomized study. SETTING: University laboratory. SUBJECTS: Adult male Sprague-Dawley rats. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Rats (intubated, instrumented with arterial and venous catheters and cardiopulmonary bypass cannulae) were randomized to conventional cardiopulmonary resuscitation, extracorporeal cardiopulmonary resuscitation with/without therapeutic hypothermia, or sham groups. After 6 minutes of ventricular fibrillation cardiac arrest, resuscitation was performed with drugs (epinephrine, sodium bicarbonate, and heparin), ventilation, either cardiopulmonary resuscitation or extracorporeal cardiopulmonary resuscitation, and defibrillation. Temperature was maintained at 37.0°C or 33.0°C for 12 hours after restoration of spontaneous circulation. Neurologic deficit scores, overall performance category, histological damage scores (viable neuron counts in CA1 hippocampus at 14 days; % of sham), and microglia proliferation and activation (Iba-1 immunohistochemistry) were assessed. RESULTS: Extracorporeal cardiopulmonary resuscitation induced hypothermia more rapidly than surface cooling (p<0.05), although heart rate was lowest in the extracorporeal cardiopulmonary resuscitation hypothermia group (p<0.05). Survival, neurologic deficit scores, overall performance category, and surviving neurons in CA1 did not differ between groups. Hypothermia significantly reduced neuronal damage in subiculum and thalamus and increased the microglial response in CA1 at 14 days (all p<0.05). There was no benefit from extracorporeal cardiopulmonary resuscitation versus cardiopulmonary resuscitation on damage in any brain region and no synergistic benefit from extracorporeal cardiopulmonary resuscitation with hypothermia. CONCLUSIONS: In a rat model of 6-minute ventricular fibrillation cardiac arrest, cardiopulmonary resuscitation or extracorporeal cardiopulmonary resuscitation leads to survival with intact neurologic outcomes. Twelve hours of mild hypothermia attenuated neuronal death in subiculum and thalamus but not CA1 and, surprisingly, increased the microglial response. Resuscitation from ventricular fibrillation cardiac arrest and rigorous temperature control with extracorporeal cardiopulmonary resuscitation in a rat model is feasible, regionally neuroprotective, and alters neuroinflammation versus standard resuscitation. The use of experimental extracorporeal cardiopulmonary resuscitation should be explored using longer insult durations. [ABSTRACT FROM AUTHOR]

Abstract: Both ventricular fibrillation cardiac arrest (VFCA) and asphyxial cardiac arrest (ACA) are frequent causes of CA. However, only isolated reports compared cerebral blood flow (CBF) reperfusion patterns after different types of CA, and even fewer reports used methods that allow serial and regional assessment of CBF. We hypothesized that the reperfusion patterns of CBF will differ between individual types of experimental CA. In a prospective block-randomized study, fentanyl-anesthetized adult rats were subjected to 8min VFCA or ACA. Rats were then resuscitated with epinephrine, bicarbonate, manual chest compressions and mechanical ventilation. After the return of spontaneous circulation, CBF was then serially assessed via arterial spin-labeling magnetic resonance imaging (ASL-MRI) in cortex, thalamus, hippocampus and amygdala/piriform complex over 1h resuscitation time (RT). Both ACA and VFCA produced significant temporal and regional differences in CBF. All regions in both models showed significant changes over time (p <0.01), with early hyperperfusion and delayed hypoperfusion. ACA resulted in early hyperperfusion in cortex and thalamus (both p <0.05 vs. amygdala/piriform complex). In contrast, VFCA induced early hyperperfusion only in cortex (p <0.05 vs. other regions). Hyperperfusion was prolonged after ACA, peaking at 7min RT (RT7; 199% vs. BL, Baseline, in cortex and 201% in thalamus, p <0.05), then returning close to BL at ∼RT15. In contrast, VFCA model induced mild hyperemia, peaking at RT7 (141% vs. BL in cortex). Both ACA and VFCA showed delayed hypoperfusion (ACA, ∼30% below BL in hippocampus and amygdala/piriform complex, p <0.05; VFCA, 34–41% below BL in hippocampus and amygdala/piriform complex, p <0.05). In conclusion, both ACA and VFCA in adult rats produced significant regional and temporal differences in CBF. In ACA, hyperperfusion was most pronounced in cortex and thalamus. In VFCA, the changes were more modest, with hyperperfusion seen only in cortex. Both insults resulted in delayed hypoperfusion in all regions. Both early hyperperfusion and delayed hypoperfusion may be important therapeutic targets. This study was approved by the University of Pittsburgh IACUC 1008816-1. [Copyright &y& Elsevier]

Abstract: Aim of the study: Application of mild hypothermia (32–33°C) has been shown to improve neurological outcome in patients with cardiac arrest. However, hypothermia affects hemostasis, and even mild hypothermia is associated with bleeding and increased transfusion requirements in surgery patients. On the other hand, crystalloid hemodilution has been shown to induce a hypercoagulable state. The study aim was to elucidate in which way the induction of mild therapeutic hypothermia by a bolus infusion of cold crystalloids affects the coagulation system of patients with cardiac arrest. Methods: This was a prospective pilot study in 18 patients with cardiac arrest and return of spontaneous circulation (ROSC). Mild hypothermia was initiated by a bolus infusion of cold 0.9% saline fluid (4°C; 30ml/kg/30min) and maintained for 24h. At 0h (before hypothermia), 1, 6 and 24h we assessed coagulation parameters (PT, APPT), platelet count and performed thrombelastography (ROTEM) after in vitro addition of heparinase. Results: A total amount of 2528 (±528)ml of 0.9% saline fluid was given. Hematocrit (p <0.01) and platelet count (−27%; p <0.05) declined, whereas APTT increased (2.7-fold; p <0.01) during the observation period. All ROTEM parameters besides clotting time (CT) after 1h (−20%; p <0.05) did not significantly change. Conclusion: Mild hypothermia only slightly prolonged clotting time as measured by rotation thrombelastography. Therefore, therapeutic hypothermia initiated by cold crystalloid fluids has only minor overall effects on coagulation in patients with cardiac arrest. [Copyright &y& Elsevier]

Objective: Several cooling methods have been investigated for inducing mild hypothermia (33-36 degrees C) after cardiac arrest, brain trauma, or stroke. To achieve its best effect, therapeutic hypothermia has to be applied very early after the ischemic insult; otherwise, the beneficial effect would be diminished or even abrogated. The aim of this study was to investigate the effectiveness and safety of extracorporeal venovenous cooling as compared with endovascular cooling.Design: Swine were cooled in a randomized crossover design from 38 degrees C to 33 degrees C brain temperature, either with extracorporeal venovenous cooling or with endovascular cooling.Setting: Laboratory investigation.Subjects: Six swine of human size (85 to 101 kg).Interventions: Swine were randomly cooled with the first device, and after achieving the target brain temperature, re-warmed via the same technique and with heating lamps to baseline temperature. Then the other catheter was inserted and cooling was performed with the second device.Measurements: Brain, pulmonary artery and tympanic temperature, blood pressure, and heart rate were recorded continuously. Laboratory samples, including free hemoglobin, were taken at predefined temperature points during cooling. Comparisons between and within (baseline vs. 33 degrees C) the treatment groups were performed with the paired Student's t-test.Main Results: The time needed to reduce brain temperature from 38.0 degrees C to 33.0 degrees C was 41 +/- 17 mins with venovenous cooling and 126 +/- 37 mins with endovascular cooling (p = .001). Heart rate and mean arterial pressure decreased moderately during cooling and were significantly lower at 33 degrees C than at baseline in both groups, without differences between groups. None of the swine developed significant hemolysis, arrhythmias, or bleeding.Conclusions: Extracorporeal venovenous cooling was an effective and safe method to rapidly induce therapeutic mild hypothermia in human-sized swine. It seems to be promising for further application and investigation in patients. [ABSTRACT FROM AUTHOR]

Background: Evaluating beneficial effects of potential protective therapies following cardiac arrest in rodent models could be enhanced by exploring behavior and cognitive functions. The Morris Water Maze is a well-known cognitive paradigm to test spatial learning and memory. Results: Behavioral testing with the Morris Water Maze in Sprague-Dawley rats (300 ± 25 g) resuscitated after 8 min of ventricular fibrillation cardiac arrest was carried out 5 and 12 weeks after cardiac arrest (CA) and compared to results of naïve rats (Control). At 5 weeks, within each group latency time to reach the hidden platform (reflecting spatial learning) decreased equally from day 1 to 4 (CA: 105.6 ± 8.2 vs. 8.9 ± 1.2 s, p < 0.001; Control: 75.5 ± 13.2 vs. 17.1 ± 4.5, p < 0.001) with no differences between groups (p = 0.138). In the probe trial 24 h after the last trial, time spent in the target sector (reflecting memory recall) within each group was significantly longer (CA: 25 ± 1.3; Control: 24.7 ± 2.5 s) than in each of the three other sectors (CA: 7.7 ± 0.7, 14.3 ± 2.5, 8.4 ± 0.8 and Control: 7.8 ± 1.2, 11.7 ± 1.5, 10.3 ± 1.6 s) but with no significantly differences between groups. Seven days later (reflecting memory retention), control group animals remained significantly longer in the target sector compared to every other sector, whereas the cardiac arrest group animals did not. Even 12 weeks after cardiac arrest, the single p values showed that the control animals displayed a trend to perform better than the resuscitated animals. Conclusions: Memory recall was impaired early after 8 min of ventricular fibrillation cardiac arrest and might be a more valuable tool for cognitive testing than learning recall after global ischemia due to cardiac arrest. [ABSTRACT FROM AUTHOR]

Cerebral metabolic alterations during cardiac arrest, cardiopulmonary resuscitation (CPR) and extracorporeal cardiopulmonary life support (ECLS) are poorly explored. Markers are needed for a more personalized resuscitation and post—resuscitation care. Aim of this study was to investigate early metabolic changes in the hippocampal CA1 region during ventricular fibrillation cardiac arrest (VF-CA) and ECLS versus conventional CPR. Male Sprague-Dawley rats (350g) underwent 8min untreated VF-CA followed by ECLS (n = 8; bloodflow 100ml/kg), mechanical CPR (n = 18; 200/min) until return of spontaneous circulation (ROSC). Shams (n = 2) were included. Glucose, glutamate and lactate/pyruvate ratio were compared between treatment groups and animals with and without ROSC. Ten animals (39%) achieved ROSC (ECLS 5/8 vs. CPR 5/18; OR 4,3;CI:0.7–25;p = 0.189). During VF-CA central nervous glucose decreased (0.32±0.1mmol/l to 0.04±0.01mmol/l; p<0.001) and showed a significant rise (0.53±0.1;p<0.001) after resuscitation. Lactate/pyruvate (L/P) ratio showed a 5fold increase (31 to 164; p<0.001; maximum 8min post ROSC). Glutamate showed a 3.5-fold increase to (2.06±1.5 to 7.12±5.1μmol/L; p<0.001) after CA. All parameters normalized after ROSC with no significant differences between ECLS and CPR. Metabolic changes during ischemia and resuscitation can be displayed by cerebral microdialysis in our VF-CA CPR and ECLS rat model. We found similar microdialysate concentrations and patterns of normalization in both resuscitation methods used. Institutional Protocol Number: GZ0064.11/3b/2011 [ABSTRACT FROM AUTHOR]

Abstract: Aim: Mild therapeutic hypothermia (32–34°C) improves neurological recovery and reduces the risk of death in comatose survivors of cardiac arrest when the initial rhythm is ventricular fibrillation or pulseless ventricular tachycardia. The aim of the presented study was to investigate the effect of mild therapeutic hypothermia (32–34°C for 24h) on neurological outcome and mortality in patients who had been successfully resuscitated from non-ventricular fibrillation cardiac arrest. Methods: In this retrospective cohort study we included cardiac arrest survivors of 18 years of age or older suffering a witnessed out-of-hospital cardiac arrest with asystole or pulseless electric activity as the first documented rhythm. Data were collected from 1992 to 2009. Main outcome measures were neurological outcome within six month and mortality after six months. Results: Three hundred and seventy-four patients were analysed. Hypothermia was induced in 135 patients. Patients who were treated with mild therapeutic hypothermia were more likely to have good neurological outcomes in comparison to patients who were not treated with hypothermia with an odds ratio of 1.84 (95% confidence interval: 1.08–3.13). In addition, the rate of mortality was significantly lower in the hypothermia group (odds ratio: 0.56; 95% confidence interval: 0.34–0.93). Conclusion: Treatment with mild therapeutic hypothermia at a temperature of 32–34°C for 24h is associated with improved neurological outcome and a reduced risk of death following out-of-hospital cardiac arrest with non-shockable rhythms. [Copyright &y& Elsevier]

Abstract: Aim of the study: A reproducible long-term intensive care and outcome cardiac arrest model for exploring new cerebral preservation strategies is needed. We tried to determine effects and limitations of current therapies after different ‘no-flow’ times. Methods: Thirty-five female Large White Breed pigs (26–37kg) were included in the study. Three pigs served as sham animals without cardiac arrest (CA). Ventricular fibrillation (VF) CA was induced in 32 animals for 0, 7, 10 and 13min (each group consisting of 8 animals), followed by 8min of chest compressions, mechanical ventilation and vasopressors. Thereafter, up to 3 defibrillations were delivered. After restoration of spontaneous circulation (ROSC), the animals underwent intensive care for 20h. Neurologic examination was performed at designated time points using a neurologic deficit (ND) and an overall performance category (OPC) score. Results: Restoration of spontaneous circulation was achieved in 8 of 8 animals in the 0min-group, 6 of 8 in the 7min-group, 7 of 8 in the 10min-group and 0 of 8 in the 13min-group. All animals of the sham-group and 0min-group were neurologically intact survivors; the 7 and 10min-groups showed a median ND of 55%(26;94) and 73%(58;78), respectively. There were no significant differences between the 7 and 10min-groups regarding OPC and NDS. Coronary perfusion pressure during CPR decreased concordantly with ‘no-flow’ times with a tendency towards significance. Conclusion: This study established a reproducible cardiac arrest and resuscitation model in pigs which will be used to test novel resuscitation strategies to improve neurologic outcome after cardiac arrest. [ABSTRACT FROM AUTHOR]

Abstract: Aim of the study: Mild hypothermia after cardiac arrest should be induced as soon as possible. There is a need for improved feasibility and efficacy of surface cooling in ambulances. We investigated which and how much area of the body surface should be covered to guarantee a sufficient cooling rate. Methods: Each of five adult, human-sized pigs (88–105kg) was randomly cooled in three phases with pads that covered different areas of the body surface corresponding to humans (100% or 30% [thorax and abdomen] or 7% [neck]). The goal was to quickly lower brain temperature (Tbr) from 38 to 33°C within a maximum of 120min. Linear regression analysis was used to test the association between cooling efficacy and surface area. Data are presented as mean±standard deviation. Results: The 100% and 30% cooling pads decreased the pigs’ Tbr from 38 to 33°C within 33±7min (8.2±1.6°C/h) and 92±24min (3.6±1.1°C/h). The 7% achieved a final Tbr of 35.8±0.7°C after 120min (1.1±0.4°C/h). The 30% and 7% cooling surface areas achieved 37±11% and 15±7% of the cooling rate compared to the 100% cooling pads. For every additional percent of surface area cooled, the cooling rate increased linearly by 0.07°C/h (95% CI 0.05–0.09, p =0.001). No skin lesions were observed. Conclusions: The cooling pads were effective and safe for rapid induction of mild hypothermia in adult, human-sized pigs, depending on the percentage of body surface area covered. Covering only the neck, chest, and abdomen might achieve satisfactory cooling rates. [ABSTRACT FROM AUTHOR]

Abstract: Aim of the study: To evaluate all brain regions reported to be selectively vulnerable to global ischaemia in a pig cardiac arrest model with different durations of no-flow by establishing a semi-quantitative brain histopathologic scoring system and to compare histological damage with neurological deficits. Methods: In a prospective randomised laboratory investigation, 35 female Large White pigs weighing 35–45kg underwent ventricular fibrillation cardiac arrest for 0, 7, 10 or 13min. In the brains of all animals that survived until the final endpoint (72h post-arrest), 22 distinct regions were evaluated on paraffin-embedded sections in terms of type and extent of lesions. The results of the histological examination were compared to the results of a neurological outcome evaluation after 72h. Results: Significant differences were found in all cortex regions, the caudate nucleus and putamen, the hippocampal formation, the cerebellar cortex, and the thalamus between the ischaemic groups (7- and 10-min groups) and the control group (0-min group). No 13-min group animal survived. The main findings were neuronal necrosis and oedema. In animals from the 10-min group, many neurons were reabsorbed in the cerebral cortex, caudate nucleus and cerebellar granule cell layer. There was a highly significant correlation between histological damage and neurological deficits. Conclusions: The pattern of neuronal lesions in this pig model bear good resemblance to the pattern known in humans and other animal models. The amount of histological lesions in selectively vulnerable brain regions correlates to neurological outcome. [Copyright &y& Elsevier]

Abstract: Aim of the study: This study aimed at evaluating (I) the impact of different intra-arrest hypothermia levels on the expression of selected cytokines and (II) their prognostic value for 9-day survival. Methods: Female Large White pigs (n =21, 31–38kg) were subjected to 15min of ventricular fibrillation, followed by intra-arrest cardiopulmonary bypass cooling for 1, 3, or 5min achieving brain temperatures (Tbr) of 30.4±1.6, 24.2±4.6 and 18.8±4.0°C. After 40min of controlled rewarming, pigs were defibrillated and kept at Tbr of 34.5°C for 20h, survival was for 9 days. Plasma samples were analysed for interleukin (IL)-6, tumor necrosis factor-α (TNF-α), and IL-10 levels by ELISA. Total RNA out of peripheral blood mononuclear cells was analysed by real-time PCR for IL-1, IL-2, IL-4, IL-10, TNF-α, interferon-γ, inducible NO synthase, and heme oxygenase-1 gene expressions. Results: Plasma IL-6 and TNF-α levels significantly (p =0.0001 and 0.0003) increased in all animals within 1h after resuscitation with no significant differences between groups. Pigs surviving exhibited a decrease in IL-10 expression between baseline and intra-arrest values as compared to non-surviving animals, which showed a slight increase (p =0.0078). ROC curve analysis revealed that changes in IL-10 expression had a good prognostic power for survival to day 9 (area under the curve=0.882). Conclusion: The systemic inflammatory response syndrome after cardiac arrest was reflected by a remarkable increase of plasma IL-6 and TNF-α levels. Intra-arrest hypothermia levels did not influence the expression of selected cytokines. As prognostic marker for survival IL-10 was identified with decreasing mRNA levels during cardiac arrest in survivors. [Copyright &y& Elsevier]

Abstract: Aim of the study: To identify the optimal level of hypothermia during cardiac arrest, just prior to resuscitation with an extracorporeal cooling system and without fluid overload, for neurological outcome at day 9 in pigs. Methods: In a prospective randomised laboratory investigation, 24 female Large White pigs (31–38kg) underwent ventricular-fibrillation cardiac arrest for 15min, followed by 1min, 3min or 5min (n =8 per group) of 4°C cooling with an extracorporeal cooling system via an aortic balloon catheter and resuscitation with cardiopulmonary bypass. Sixty minutes following induction of cardiac arrest, defibrillation attempts were started. Mild hypothermia (34.5°C) and intensive care were continued for 20h and final outcome was evaluated after 9 days. Results: Brain temperature decreased from 38.5°C to 30.4±1.6°C within 221±81s in the 1-min group; to 24.2±4.6°C within 375±127s in the 3-min group; and to 18.8±4.0°C within 450±121s in the 5-min group. Restoration of spontaneous circulation was achieved in seven (1-min group), six (3-min group) and six (5-min group) animals (p =0.78), whereas survival to 9 days was only achieved in six, three and three animals in each group (p =0.22), respectively. Conclusions: An extracorporeal cooling system rapidly induced brain hypothermia following prolonged normovolaemic cardiac arrest in pigs. Difference in outcome was not statistically significant amongst the three groups with various levels of hypothermia (30°C, 24°C and 18°C) during cardiac arrest prior to resuscitation; however, the animals with the least temperature reduction showed a trend to better survival at 9 days. Further studies are necessary to investigate optimised methods for induction, as well as level, of cerebral hypothermia. [Copyright &y& Elsevier]

Abstract: Aim of the study: Out-of-hospital induction of mild therapeutic hypothermia after cardiac arrest needs easy to use and accurate body temperature monitoring. The aim of the study was to evaluate the best temperature probe position on a specially designed tracheal tube, as compared to pulmonary artery temperature (Tpa) during cooling to mild hypothermia in pigs. Methods: Eight swine (29–38kg) were anesthetized and intubated with an endotracheal tube with three temperature probes: T1 was attached to the wall of the tube, 1cm proximal to the cuff-balloon, without contact to the mucosa; T2 and T3 were placed on the cuff-balloon with tight contact to the mucosa, T3 was covered by a small plastic tube to protect the mucosa against mechanical alterations. Body temperature was measured with a pulmonary artery catheter. Pigs were cooled from Tpa 38.5 to 33.0°C with fast surface and slow endovascular cooling in a crossover design. To assess hysteresis, areas under the curve (AUC) were compared. Data are presented as mean and 95% confidence intervals. Results: Temperatures were not different either during fast surface (T1-Tpa: 0.1[−0.3 to 0.5]°C, T2-Tpa: 0.2[0.0 to 0.4]°C, T3-Tpa: 0.4[0.1 to 0.7]°C) or slow endovascular (T1-Tpa: −0.3[−0.5 to 0.2]°C, T2-Tpa: −0.1[−0.3 to 0.0]°C, T3-Tpa: −0.1[−0.5 to 0.3]°C) cooling. There was no difference in hysteresis related to the location of the temperature probes. Faster surface cooling correlated with a larger but not significantly different hysteresis between the probes. Conclusions: Tracheal temperature is an accurate surrogate for body temperature during fast and slow cooling to mild hypothermia in pigs and regardless of the location of the temperature probe on the tube. [Copyright &y& Elsevier]

Abstract: Aim of the study: The appropriate time point of evaluation of functional outcome in cardiac arrest survivors remains a matter of debate. In this cohort study we posed the hypothesis that there are no significant changes in Cerebral Performance Categories (CPC) between one month and six months after out-of hospital cardiac arrest. If changes were present we aimed to identify reasons for these changes. Methods: Based on a cardiac arrest registry, a potential change in CPC and mortality between one month and six months after cardiac arrest was analysed. Variables that were associated with these changes were identified. Results: Thirty percent of 681 patients showed a significant change in functional outcome and mortality between one month and six months after out-of hospital cardiac arrest, 12% improved in CPC, 1% deteriorated, 17% died. The only factor that was associated with an improvement in CPC in the multivariate analysis was time to restoration of spontaneous circulation (ROSC) (RRR 1.04, 95% CI 1.01–1.06, per minute). We could not find any significant factors associated with a deterioration of CPC. Factors that were associated with mortality were age (RRR 1.03, 95% CI 1.01–1.06) and ventricular fibrillation as initial cardiac rhythm (RRR 0.34, 95% CI 0.16–0.71). Conclusions: There is a relevant change of functional outcome even one month after out-of hospital cardiac arrest. Especially when studies compare patient groups with unequal arrest times, and an unequal distribution of initial cardiac rhythms a follow-up period longer than one month should be considered for the final outcome evaluation after cardiac arrest. [Copyright &y& Elsevier]

The article presents a prospective observational study on pronounced platelet hyperfunction in patients with cardiac arrest achieving restoration of spontaneous circulation. It concludes that patients with myocardial ischemia-triggered cardiac arrest had the most eminent degree of platelet hyperfunction below high shear rate. It observes that succeeding trials are essential to elucidate whether rapid, more aggressive antiplatelet therapy improves outcome after cardiac arrest.

Summary: Aim of the study: There is sufficient evidence that therapeutic hypothermia after non-traumatic cardiac arrest improves neurological outcome and reduces mortality. Many different invasive and non-invasive cooling devices are currently available. Our purpose was to show the efficacy, safety and feasibility using a non-invasive cooling device to control patient temperature within a range of 33–37°C. Materials and methods: A convenience sample of patients who have been resuscitated successfully from cardiac arrest and were intended for mild hypothermia therapy according to the guidelines and inclusion criteria were studied in a prospective observational case series at an emergency department of a tertiary care university hospital. The Medivance Arctic Sun System provides a new, non-invasive approach to reach a target temperature of 33°C quickly, to maintain the target temperature for 24h, and then to actively re-warm at 0.4°C/h to normothermia. Cooling was applied using the Arctic Sun in 27 patients. Data are presented as median and the interquartile range (25, 75%). Results: Median age was 58 (49.5, 70) years. Time from cooling start to target temperature was 137 (96, 168)min, cooling rate was 1.2°C/h (0.8, 1.5), stability of target temperature during hypothermia maintenance phase was satisfactory at 33.0°C (32.9, 33.1), and duration of re-warming was 428 (394, 452)min. Conclusion: Using the Arctic Sun System in post-resuscitation care medicine for cooling cardiac arrest survivors is feasible and has proven to be highly effective in lowering patients’ temperature rapidly without inducing skin irritations. [Copyright &y& Elsevier]