Anne Brücken

Argon reduces neurohistopathological damage and preserves functional recovery after cardiac arrest in rats

BACKGROUND Xenon has profound neuroprotective effects after neurological injury and is currently undergoing phase 2 clinical trials in cardiac arrest patients. However, xenon is very costly, which might preclude its widespread use. We hypothesized argon, which is more available, might also protect central nervous tissues and allow better functional recovery in a rodent model of global cerebral ischaemia. METHODS Fourteen male Sprague-Dawley rats were subjected to 7 min of cardiac arrest and 3 min of cardiopulmonary resuscitation (CPR). One hour after successful CPR, animals were randomized to either ventilation with 70% argon in oxygen (n = 7) for 1 h or 70% nitrogen (controls, n=7). A neurological deficit score (NDS) was calculated daily for the following 7 days, then the animals were killed and the brains harvested for histopathological analyses. RESULTS All animals survived. Control rats had severe neurological dysfunction, while argon-treated animals showed significant improvements in the NDS at all time points. This was paralleled by a significant reduction in the neuronal damage index in the neocortex and the hippocampal CA 3/4 region. CONCLUSIONS Our study demonstrates that a single 1 h application of 70% argon significantly reduced histopathological damage of the neocortex and hippocampus, associated with a marked improvement in functional neurological recovery.

Combining xenon and mild therapeutic hypothermia preserves neurological function after prolonged cardiac arrest in pigs

Objective:Despite the introduction of mild therapeutic hypothermia into postcardiac arrest care, cerebral and myocardial injuries represent the limiting factors for survival after cardiac arrest. Administering xenon may confer an additional neuroprotective effect after successful cardiopulmonary resuscitation due to its ability to stabilize cellular calcium homeostasis via N-methyl-D-aspartate-receptor antagonism. Design:In a porcine model, we evaluated effects of xenon treatment in addition to therapeutic hypothermia on neuropathologic and functional outcomes after cardiopulmonary resuscitation. Setting:Prospective, randomized, laboratory animal study. Subjects:Fifteen male pigs. Interventions:Following 10 mins of cardiac arrest and 6 mins of cardiopulmonary resuscitation, ten pigs were randomized to receive either mild therapeutic hypothermia (33°C for 16 hrs) or mild therapeutic hypothermia 1 xenon (70% for 1 hr). Five animals served as normothermic controls. Measurements and Main Results:Gross hemodynamic variables were measured using right-heart catheterization. Neurocognitive performance was evaluated for 5 days after cardiopulmonary resuscitation using a neurologic deficit score before the brains were harvested for histopathological analysis. All animals survived the observation period in the mild therapeutic hypothermia 1 xenon group while one animal in each of the other two groups died. Mild therapeutic hypothermia 1 xenon preserved cardiac output during the induction of mild therapeutic hypothermia significantly better than did mild therapeutic hypothermia alone (4.6 6 0.6 L/min vs. 3.2 6 1.6 L/min, p # .05). Both treatment groups showed significantly fewer necrotic lesions in the cerebral cortex, caudate nucleus, putamen, and in hippocampal sectors CA1 and CA3/4. However, only the combination of mild therapeutic hypothermia and xenon resulted in reduced astrogliosis in the CA1 sector and diminished microgliosis and perivascular inflammation in the putamen. Clinically, only the mild therapeutic hypothermia 1 xenon-treated animals showed significantly improved neurologic deficit scores over time (day 1 = 59.0 6 27.0 vs. day 5 = 4.0 6 5.5, p ø .05) as well as in comparison to the untreated controls on days 3 through 5 after cardiopulmonary resuscitation. Conclusions:These results demonstrate that even a short exposure to xenon during induction of mild therapeutic hypothermia results in significant improvements in functional recovery and ameliorated myocardial dysfunction. (Crit Care Med 2012; 40:–1303)

Reducing the duration of 100% oxygen ventilation in the early reperfusion period after cardiopulmonary resuscitation decreases striatal brain damage

PURPOSE Previous data indicate that 100% O(2) ventilation during early reperfusion after cardiac arrest (CA) and cardiopulmonary resuscitation (CPR) increases neuronal death. However, current guidelines encourage the use of 100% O(2) during resuscitation and for an undefined period thereafter. We retrospectively analyzed data from a porcine CA model and hypothesized that prolonged hyperoxic reperfusion would be associated with increased neurohistopathological damage and impaired neurological recovery. METHODS Fifteen male pigs underwent 8 min of CA and 5 min of CPR. After resuscitation animals were ventilated with either 100% oxygen for 60 min (hyperoxia; n=8) or 10 min (normoxia; n=7). Physiological variables were obtained at baseline and 10, 60 and 240 min after resuscitation. Daily functional performance was assessed using an established neurocognitive test in parallel to a neurological deficit score (NDS). On day 5, brains of the re-anaesthetized pigs were harvested for neurohistopathological analyses. RESULTS At baseline there were no differences in hemodynamics and neurological status between groups. Post-arrest only PaO(2), as a result of the different inspired oxygen fractions, was significantly higher in the hyperoxia group. There was a numerical trend towards improved clinical recovery in both the NDS and the neurocognitive testing for animals exposed to 10 min of 100% oxygen. However, hyperoxic animals showed a significantly greater degree of necrotic neurons and perivascular inflammation in the striatum in comparison to normoxic animals. CONCLUSION In this retrospective analysis prolonged hyperoxia after CA aggravated necrotic brain damage and perivascular inflammation in the striatum of pigs.

Dose dependent neuroprotection of the noble gas argon after cardiac arrest in rats is not mediated by KATP—Channel opening

PURPOSE Argon at a dosage of 70% is neuroprotective when given 1 h after cardiac arrest (CA) in rats. In a rodent model, we investigated if the neuroprotective effects of argon are dose dependent and mediated by adenosine triphosphate dependent potassium (K(ATP)) channels. METHODS Forty-seven male Sprague-Dawley rats were subjected to 7 min of CA and 3 min of cardiopulmonary resuscitation (CPR). In protocol I animals were randomized to receive either 70% or 40% argon ventilation 1 h after successful CPR or no argon-treatment. Animals of the second protocol also received 1 h of 70% argon ventilation or no argon treatment but were randomized to a group receiving the K(ATP) channel blocker 5-hydroxydecanoate (5-HD). For all animals a neurological deficit score (NDS) was calculated daily for seven days following the experiment before the animals were killed and the brains harvested for histopathological analyses. RESULTS All animals survived. Control animals exhibited severe neurologic dysfunction at all points in time as measured with the NDS. Argon treated animals showed significant improvements in the NDS through all postoperative days in a dose dependent fashion. This was paralleled by a significant reduction in the neuronal damage index in the neocortex and the hippocampal CA 3/4 region. Administration of 5-HD neither abolished the positive effects on functional recovery nor on histopathologic changes observed in the argon group. CONCLUSION Our study demonstrates a dose dependent neuroprotective effect of argon administration in this rodent model, which is not mediated via ATP dependent potassium channels.

Early kynurenine pathway activation following cardiac arrest in rats, pigs, and humans

AIM OF THE STUDY Kynurenine pathway (KP) is a major route of the tryptophan (TRP) catabolism. In the present study, TRP and KP metabolites concentrations were measured in plasma from rats, pigs and humans after cardiac arrest (CA) in order to assess KP activation and its potential role in post-resuscitation outcome. METHODS Plasma was obtained from: (A) 24 rats, subjected to 6 min CA and 6 min of cardiopulmonary resuscitation (CPR); (B) 10 pigs, subjected to 10 min CA and 5 min CPR; and (C) 3 healthy human volunteers and 5 patients resuscitated from CA. KP metabolites were quantified by liquid chromatography multiple reaction monitoring mass spectrometry. Assessments were available at baseline, and 1-4h, and 3-5 days post-CA. RESULTS KP was activated after CA in rats, pigs, and humans. Decreases in TRP occurred during the post-resuscitation period and were accompanied by significant increases in its major metabolites, 3-hydroxyanthranilic acid (3-HAA) and kynurenic acid in each species, that persisted up to 3-5 days post-CA (p<0.01). In rats, changes in KP metabolites reflected changes in post-resuscitation myocardial function. In pigs, changes in TRP and increases in 3-HAA were significanlty related to the severity of cerebral histopathogical injuries. In humans, KP activation was observed, together with systemic inflammation. Post-CA increases in 3-HAA were greater in patients that did not survive. CONCLUSION In this fully translational investigation, the KP was activated early following resuscitation from CA in rats, pigs, and humans, and might have contributed to post-resuscitation outcome.

Brief inhalation of nitric oxide increases resuscitation success and improves 7-day-survival after cardiac arrest in rats: a randomized controlled animal study

IntroductionInhaled nitric oxide (iNO) improves outcomes when given post systemic ischemia/reperfusion injury. iNO given during cardiopulmonary resuscitation (CPR) may therefore improve return of spontaneous circulation (ROSC) rates and functional outcome after cardiac arrest (CA).MethodsThirty male Sprague-Dawley rats were subjected to 10 minutes of CA and at least 3 minutes of CPR. Animals were randomized to receive either 0 (n = 10, Control), 20 (n = 10, 20 ppm), or 40 (n = 10, 40 ppm) ppm iNO during CPR until 30 minutes after ROSC. A neurological deficit score was assessed daily for seven days following the experiment. On day 7, brains, hearts, and blood were sampled for histological and biochemical evaluation.ResultsDuring CPR, 20 ppm iNO significantly increased diastolic arterial pressure (Control: 57 ± 5.04 mmHg; 20 ppm: 71.57 ± 57.3 mmHg, p < 0.046) and decreased time to ROSC (Control: 842 ± 21 s; 20 ppm: 792 ± 5 s, (p = 0.02)).Thirty minutes following ROSC, 20 ppm iNO resulted in an increase in mean arterial pressure (Control: 83 ± 4 mmHg; 20 ppm: 98 ± 4 mmHg, p = 0.035), a less pronounced rise in lactate and inflammatory cytokine levels, and attenuated cardiac damage. Inhalation of NO at 20 ppm improved neurological outcomes in rats 2 to 7 days after CA and CPR. This translated into increases in 7 day survival (Control: 4; 20 ppm: 10; 40 ppm 6, (p ≤ 0.05 20 ppm vs Control and 40 ppm).ConclusionsOur study revealed that breathing NO during CPR markedly improved resuscitation success, 7-day neurological outcomes and survival in a rat model of VF-induced cardiac arrest and CPR. These results support the beneficial effects of NO inhalation after cardiac arrest and CPR.

Current developments in xenon research. Importance for anesthesia and intensive care medicine

The noble gas xenon exerts favorable anesthetic properties along with remarkable hemodynamic stability in healthy patients undergoing elective surgery. It represents the nearly ideal anesthetic and provides safe and well controllable anesthesia although the exact mechanism by which xenon produces anesthesia remains to be elucidated. In addition xenon offers organ protective properties for vital organs including the brain, heart and kidneys which seem to be synergistic when used in combination with therapeutic hypothermia. As the high cost of xenon will probably preclude its wider use as a routine anesthetic, data from extensive tests in large numbers of high risk patients is needed to confirm its possible superiority in this setting.ZusammenfassungDas Edelgas Xenon kommt in der Summe seiner Eigenschaften den Vorstellungen von einem idealen Anästhetikum sehr nahe. Es vereint optimale anästhetische Eigenschaften mit einem hohen Maß an hämodynamischer Stabilität. Daneben ermöglicht Xenon eine exzellent steuerbare und sichere Anästhesie. Lediglich der molekulare Wirkmechanismus im Gehirn ist nach wie vor nicht endgültig geklärt. Experimentell konnte gezeigt werden, dass Xenon, anscheinend ohne relevante Nebenwirkungen, organprotektive Eigenschaften an Herz, Gehirn und Nieren aufweist. Da der Einsatz von Xenon in der täglichen Routine aufgrund hoher Kosten und begrenzter Ressourcen weiterhin limitiert sein wird, ist es die Aufgabe zukünftiger Studien, seinen Stellenwert bei spezifischen Indikationen in Anästhesie und Intensivmedizin aufzuzeigen.AbstractThe noble gas xenon exerts favorable anesthetic properties along with remarkable hemodynamic stability in healthy patients undergoing elective surgery. It represents the nearly ideal anesthetic and provides safe and well controllable anesthesia although the exact mechanism by which xenon produces anesthesia remains to be elucidated. In addition xenon offers organ protective properties for vital organs including the brain, heart and kidneys which seem to be synergistic when used in combination with therapeutic hypothermia. As the high cost of xenon will probably preclude its wider use as a routine anesthetic, data from extensive tests in large numbers of high risk patients is needed to confirm its possible superiority in this setting.

Inhaled nitric oxide improves transpulmonary blood flow and clinical outcomes after prolonged cardiac arrest: a large animal study

IntroductionThe probability to achieve a return of spontaneous circulation (ROSC) after cardiac arrest can be improved by optimizing circulation during cardiopulomonary resuscitation using a percutaneous left ventricular assist device (iCPR). Inhaled nitric oxide may facilitate transpulmonary blood flow during iCPR and may therefore improve organ perfusion and outcome.MethodsVentricular fibrillation was electrically induced in 20 anesthetized male pigs. Animals were left untreated for 10 minutes before iCPR was attempted. Subjects received either 20 ppm of inhaled nitric oxide (iNO, n = 10) or 0 ppm iNO (Control, n = 10), simultaneously started with iCPR until 5 hours following ROSC. Animals were weaned from the respirator and followed up for five days using overall performance categories (OPC) and a spatial memory task. On day six, all animals were anesthetized again, and brains were harvested for neurohistopathologic evaluation.ResultsAll animals in both groups achieved ROSC. Administration of iNO markedly increased iCPR flow during CPR (iNO: 1.81 ± 0.30 vs Control: 1.64 ± 0.51 L/min, p < 0.001), leading to significantly higher coronary perfusion pressure (CPP) during the 6 minutes of CPR (25 ± 13 vs 16 ± 6 mmHg, p = 0.002). iNO-treated animals showed significantly lower S-100 serum levels thirty minutes post ROSC (0.26 ± 0.09 vs 0.38 ± 0.15 ng/mL, p = 0.048), as well as lower blood glucose levels 120–360 minutes following ROSC. Lower S-100 serum levels were reflected by superior clinical outcome of iNO-treated animals as estimated with OPC (3 ± 2 vs. 5 ± 1, p = 0.036 on days 3 to 5). Three out of ten iNO-treated, but none of the Control animals were able to successfully participate in the spatial memory task. Neurohistopathological examination of vulnerable cerebral structures revealed a trend towards less cerebral lesions in neocortex, archicortex, and striatum in iNO-treated animals compared to Controls.ConclusionsIn pigs resuscitated with mechanically-assisted CPR from prolonged cardiac arrest, the administration of 20 ppm iNO during and following iCPR improved transpulmonary blood flow, leading to improved clinical neurological outcomes.

Aktuelle Entwicklungen in der Xenonforschung

The noble gas xenon exerts favorable anesthetic properties along with remarkable hemodynamic stability in healthy patients undergoing elective surgery. It represents the nearly ideal anesthetic and provides safe and well controllable anesthesia although the exact mechanism by which xenon produces anesthesia remains to be elucidated. In addition xenon offers organ protective properties for vital organs including the brain, heart and kidneys which seem to be synergistic when used in combination with therapeutic hypothermia. As the high cost of xenon will probably preclude its wider use as a routine anesthetic, data from extensive tests in large numbers of high risk patients is needed to confirm its possible superiority in this setting.ZusammenfassungDas Edelgas Xenon kommt in der Summe seiner Eigenschaften den Vorstellungen von einem idealen Anästhetikum sehr nahe. Es vereint optimale anästhetische Eigenschaften mit einem hohen Maß an hämodynamischer Stabilität. Daneben ermöglicht Xenon eine exzellent steuerbare und sichere Anästhesie. Lediglich der molekulare Wirkmechanismus im Gehirn ist nach wie vor nicht endgültig geklärt. Experimentell konnte gezeigt werden, dass Xenon, anscheinend ohne relevante Nebenwirkungen, organprotektive Eigenschaften an Herz, Gehirn und Nieren aufweist. Da der Einsatz von Xenon in der täglichen Routine aufgrund hoher Kosten und begrenzter Ressourcen weiterhin limitiert sein wird, ist es die Aufgabe zukünftiger Studien, seinen Stellenwert bei spezifischen Indikationen in Anästhesie und Intensivmedizin aufzuzeigen.AbstractThe noble gas xenon exerts favorable anesthetic properties along with remarkable hemodynamic stability in healthy patients undergoing elective surgery. It represents the nearly ideal anesthetic and provides safe and well controllable anesthesia although the exact mechanism by which xenon produces anesthesia remains to be elucidated. In addition xenon offers organ protective properties for vital organs including the brain, heart and kidneys which seem to be synergistic when used in combination with therapeutic hypothermia. As the high cost of xenon will probably preclude its wider use as a routine anesthetic, data from extensive tests in large numbers of high risk patients is needed to confirm its possible superiority in this setting.

Die mechanische Kreislaufunterstützung in der Herzinsuffizienz

ZusammenfassungHintergrundNach Ausschöpfung aller konservativen Maßnahmen bei der Behandlung der akuten und chronischen Herzinsuffizienz besteht die Möglichkeit, durch mechanische Systeme die Pumpleistung des Herzens passager oder permanent zu unterstützen oder zu ersetzen.Ziel der ArbeitDarstellung der für die Intensivmedizin wichtigsten Herzunterstützungssysteme, ihrer Indikationen und wichtiger Risiken.Material und MethodenZusammenfassung von Herstellervorgaben, Grundlagenarbeiten und Expertenempfehlungen.ErgebnisseDas Spektrum der zur Verfügung stehenden Kreislaufunterstützungsverfahren reicht von mechanischen Hilfsmitteln zur kardiopulmonalen Reanimation über katheterbasierte Mikropumpen bis hin zum vollständigen Kunstherz. Die Auswahl des verwendeten Systems hängt davon ab, ob es sich um ein mono- oder biventrikuläres Pumpversagen handelt, wie lange der Einsatz beabsichtigt ist und wie eingeschränkt sich die Lungenfunktion darstellt. Die Entscheidung zwischen minimalinvasivem und offen-chirurgischem Verfahren hängt davon ab, ob das entsprechende Verfahren vor Ort etabliert ist, und ob die Herzleistung permanent oder passager unterstützt oder ersetzt werden soll. Der Beachtung der herstellerspezifisch festgelegten Antikoagulationsregime für die verschiedenen mechanischen Unterstützungssysteme kommt im Hinblick auf Blutungs- und thrombembolische Komplikationen besondere Bedeutung zu.SchlussfolgerungenAufgrund der zunehmenden Anzahl an Patienten mit langfristiger Kunstherzversorgung kommen auch Kollegen, die nicht in ihrer täglichen Routine diese Therapien anwenden, im Notarztdienst oder als erstaufnehmende Klinik im Notfall mit diesen Geräten in Berührung. Deshalb kommt auch der Kenntnis dieser Verfahren und deren Komplikationen zunehmende Bedeutung zu.AbstractBackgroundAfter exhaustion of all conservative measures in the treatment of acute and chronic heart insufficiency, there is the possibility to temporarily or permanently support or replace the pump performance of the heart by mechanical circulatory support (MCS) systems.ObjectivePresentation of the most important cardiac support systems for intensive care medicine, their indications and important risk factors.Material and methodsCritical review of device manufacturer’s specifications, current research and expert opinions.ResultsThe spectrum of available MCS procedures include mechanical chest compression devices, catheter-based micropumps and complete artificial hearts. Device selection depends on the severity of heart failure (monoventricular or biventricular pump failure), the expected duration of treatment and the degree of lung function impairment. The decision between minimally invasive and open surgical procedures depends on the options established at the specific healthcare institution and whether the heart function is to be temporarily or permanently replaced. Compliance with the anticoagulation regimens defined by the manufacturer is especially important as they differ vastly between devices and are critical to avoid bleeding or thromboembolic complications.ConclusionDue to the increasing number of patients on long-term mechanical circulatory support, the chances are that physicians in the initial emergency admission are unfamiliar with these devices but need to operate them in emergency cases. Therefore, knowledge of these procedures and their complications becomes increasingly important.BACKGROUND After exhaustion of all conservative measures in the treatment of acute and chronic heart insufficiency, there is the possibility to temporarily or permanently support or replace the pump performance of the heart by mechanical circulatory support (MCS) systems. OBJECTIVE Presentation of the most important cardiac support systems for intensive care medicine, their indications and important risk factors. MATERIAL AND METHODS Critical review of device manufacturers specifications, current research and expert opinions. RESULTS The spectrum of available MCS procedures include mechanical chest compression devices, catheter-based micropumps and complete artificial hearts. Device selection depends on the severity of heart failure (monoventricular or biventricular pump failure), the expected duration of treatment and the degree of lung function impairment. The decision between minimally invasive and open surgical procedures depends on the options established at the specific healthcare institution and whether the heart function is to be temporarily or permanently replaced. Compliance with the anticoagulation regimens defined by the manufacturer is especially important as they differ vastly between devices and are critical to avoid bleeding or thromboembolic complications. CONCLUSION Due to the increasing number of patients on long-term mechanical circulatory support, the chances are that physicians in the initial emergency admission are unfamiliar with these devices but need to operate them in emergency cases. Therefore, knowledge of these procedures and their complications becomes increasingly important.