Cerebral Edema After Cardiopulmonary Resuscitation: A Therapeutic Target Following Cardiac Arrest?

We sought to review the role that cerebral edema plays in neurologic outcome following cardiac arrest, to understand whether cerebral edema might be an appropriate therapeutic target for neuroprotection in patients who survive cardiopulmonary resuscitation. Articles indexed in PubMed and written in English. Following cardiac arrest, cerebral edema is a cardinal feature of brain injury and is a powerful prognosticator of neurologic outcome. Like other conditions characterized by cerebral ischemia/reperfusion, neuroprotection after cardiac arrest has proven to be difficult to achieve. Neuroprotection after cardiac arrest generally has focused on protecting neurons, not the microvascular endothelium or blood–brain barrier. Limited preclinical data suggest that strategies to reduce cerebral edema may improve neurologic outcome. Ongoing research will be necessary to determine whether targeting cerebral edema will improve patient outcomes after cardiac arrest.     

Hypothermia for neuroprotection after cardiac arrest: mechanisms, clinical trials and patient care

Therapeutic hypothermia is a proven part of cardio-cerebral resuscitation after cardiac arrest as it improves neurologic outcomes after hypoxic brain injury. This article reviews the mechanisms of hypothermic neuroprotection, the clinical trials that support its use after cardiac arrest, as well as the impact of hypothermia on patient management and prognosis. In caring for patients suffering hypoxic brain injury after cardiac arrest, the role of the neurologist is no longer limited to prognosis but is now to become actively involved in clinical management which includes the use of therapeutic hypothermia.     

犬心脏骤停后脑缺血的病理变化

目的：本文旨在观察心肺脑复苏过程中脑缺血的病理变化。方法：16条成年健康杂种犬，随机分为两组，以同法诱颤后复苏，A组诱颤后5分钟而B组诱颤后10分钟开始复苏，复苏成功后，立即取血、脑脊液标本进行脑型肌酸激酶同功酶（CK－BB）检查，72小时后取脑组织标本进行光、电镜检查。结果：A组脑型肌酸激酶同功酶明显低于B组，且其病理改变也明显轻微。结论：心脏骤停后脑复苏成功与否与时间密切相关，时间短则脑病理改变较轻。     

心脏骤停后全脑缺血犬内皮素和脑型肌酸激酶同功酶的变化

目的　脑复苏为心脏骤停后复苏成功与否的关键 ,本文对心脏骤停后全脑缺血犬损害的实验研究 ,旨在为临床心肺脑复苏工作提供一定的实验资料。方法　 16条成年健康杂种犬 ,随机分为两组 ,以同法诱颤后复苏 ,A组诱颤后 5分钟而B组诱颤后 10分钟开始复苏 ,复苏成功后 ,立即取血、脑脊液标本进行内皮素和脑型肌酸激酶同功酶 (CK BB)检查。结果　A组内皮素 (ET)和脑型肌酸激酶同功酶明显低于B组。结论　心脏骤停后脑复苏成功与否与时间密切相关 ,时间短则脑细胞坏死改变较轻     

Thiamine and Parkinson's disease

Cardiac arrest is a leading cause of death that affects more than a million individuals worldwide every year. Despite the recent advancement in the field of cardiac arrest and resuscitation, the management and prognosis of post-cardiac arrest brain injury remain suboptimal. The pathophysiology of post-cardiac arrest brain injury involves a complex cascade of molecular events, most of which remain unknown. Considering that a potentially broad therapeutic window for neuroprotective drug therapy is offered in most successfully resuscitated patient after cardiac arrest, the need for further research is imperative. The aim of this article is to present the major pathophysiological disturbances leading to post-cardiac arrest brain injury, as well as to review the available pharmacological therapies.     

Emergency Neurological Life Support: Resuscitation Following Cardiac Arrest

Cardiac arrest is the most common cause of death in North America. An organized bundle of neurocritical care interventions can improve chances of survival and neurological recovery in patients who are successfully resuscitated from cardiac arrest. Therefore, resuscitation following cardiac arrest was chosen as an Emergency Neurological Life Support protocol. Key aspects of successful early post-arrest management include: prevention of secondary brain injury; identification of treatable causes of arrest in need of emergent intervention; and, delayed neurological prognostication. Secondary brain injury can be attenuated through targeted temperature management (TTM), avoidance of hypoxia and hypotension, avoidance of hyperoxia, hyperventilation or hypoventilation, and treatment of seizures. Most patients remaining comatose after resuscitation from cardiac arrest should undergo TTM. Treatable precipitants of arrest that require emergent intervention include, but are not limited to, acute coronary syndrome, intracranial hemorrhage, pulmonary embolism and major trauma. Accurate neurological prognostication is generally not appropriate for several days after cardiac arrest, so early aggressive care should never be limited based on perceived poor neurological prognosis.     

Prognostic significance of alpha frequency EEG rhythm in coma after cardiac arrest.

Sixty-five patients who remained in coma for more than 24 hours after resuscitation from cardiac arrest were divided into two groups according to their EEGs. Thirteen patients were found to have rhythm of alpha frequency while 52 had the usual EEG findings after cerebral anoxia. Three patients from the group with alpha frequency EEG rhythms regained full consciousness but showed severe sequelae. Our results suggest that the prognosis of comatose patients with EEG rhythm of alpha frequency is no poorer than that of other individuals who are comatose after cardiac arrest.     

Mineralocorticoid receptor mRNA expression is increased in human hippocampus following brief cerebral ischaemia

Background:  We have previously reported that neuronal endangerment in vitro and hypothermic transient global ischaemia in vivo each result in increased mineralocorticoid receptor (MR) expression. In both models MR induction is associated with increased neuronal survival, and blocking MR signalling reduces neuronal survival. Furthermore, transgenic overexpression of human MR promotes neuronal survival both in vitro and in vivo . Aims:  Here we have assessed whether brief periods of cerebral ischaemia in human subjects, such as occurs in cardiac arrest from which successful resuscitation is achieved, are associated with a sustained increase in hippocampal MR mRNA expression. Methods:  Human post-mortem brain sections from patients who had died in the weeks following cardiac arrest were analysed for MR mRNA expression by in situ hybridization. Results:  Sustained upregulation of MR mRNA expression was observed in the dentate gyrus region of human hippocampus following a brief episode of cerebral ischaemia. Conclusions:  This confirms that MR mRNA expression is regulated following neuronal injury in human brain, and suggests that the benefits of increased MR expression seen in animal models of ischaemia may also be observed in humans.     

Biomarkers and neuroimaging of brain injury after cardiac arrest

Unfortunately, it remains a difficult task to predict with certainty which patients will have a poor neurological outcome following cardiac arrest. Finding a quantitative prognostic model of outcome has become the objective of many intensivists to assist grieving families in making early difficult decisions regarding withdrawal of life support. An ideal prognostic test should be readily available, easily reproducible, and associated with a high degree of specificity for poor outcome. The goal is not to define which patients may recover, but rather which patients have no likelihood of meaningful neurological recovery at all to justify early withdrawal of support. The literature and the role of biochemical markers in the blood and in the cerebrospinal fluid will be evaluated as prognosticators following cardiac arrest. Radiological indicators of anoxic cerebral damage are reviewed. Each serum or radiological marker has its pros and cons. To accurately prognosticate following cardiac arrest, a multimodal scale or algorithm that incorporates serum markers, radiological markers, and the neurological exam is clearly needed. As these techniques are being evaluated more closely and as imaging modalities increase in sensitivity and portability, physicians will continue to assist families by providing some guidance as to which patients have no chance of meaningful recovery.     

Sexually Dimorphic Response of TRPM2 Inhibition Following Cardiac Arrest-Induced Global Cerebral Ischemia in Mice

Transient global cerebral ischemia due to cardiac arrest followed by resuscitation (CA/CPR) causes significant neurological damage in vulnerable neuron populations within the brain, such as hippocampal CA1 neurons. In recent years, we have implicated the transient receptor potential M2 (TRPM2) channel as a mediator of ischemic injury to neurons. We previously demonstrated that genetic and pharmacological strategies that reduce TRPM2 function preferentially protect male neurons in vitro and reduce infarct volume following experimental stroke. Due to the narrow therapeutic window for intervention following ischemic stroke, it is important to assess the role of TRPM2 in other models of cerebral ischemia. Therefore, this study utilized a modified mouse model of CA/CPR to mimic more accurately the clinical condition by maintaining body and head temperatures near the physiological range throughout. Here, we report that inhibition of TRPM2 activity with clotrimazole reduces hippocampal CA1 neuronal injury when administered 30 min after resuscitation from cardiac arrest. Consistent with our previous observations, neuroprotection was observed in male mice and no effect on injury was observed in the female. These findings provide further evidence for TRPM2 as a target for protection against cerebral ischemia in the male brain.     

Cerebral resuscitation: state of the art, experimental approaches and clinical perspectives

Neuronal injury following global cerebral ischemia continues to bea central problem of patients in the postresuscitation phase following cardiocirculatory arrest. In addition to measures focusing on rapid restoration of spontaneous circulation, the most effective treatment after cardiac arrest, as shown by large randomized trials,is the use of therapeutic mild hypothermia. Current guidelines of the International Liaison Committee on Resuscitation (ILCOR)are recommending the use of therapeutic mild hypothermia for all unconscious patients after cardiac arrest. At present there is no specific neuroprotective treatment available. Promising animal experimental data concerning the use of thrombolytic agents during cardiopulmonary resuscitation have led to a large European multicenter trial (TROICA trial) that will provide its data in 2006.     

Clinical neurophysiologic monitoring and brain injury from cardiac arrest

Electrophysiologic testing continues to play an important role in injury stratification and prognostication in patients who are comatose after cardiac arrest. As discussed previously, however, the adage about treating whole patients, not just the numbers, is relevant in this situation. EEG and SSEP can offer high specificity for discerning poor prognosis as long as they are applied to appropriate patient populations. As discussed previously, EEG and SSEP patterns change during the first hours to days after cardiac arrest and negative prognostic information should not be based solely on studies performed during the first 24 hours. Both electrophysiologic techniques also are susceptible to artifacts that may worsen the electrical patterns artificially and suggest a falsely poor prognosis. EEG is suppressed by anesthetic agents and hypothermia, both of which may produce ECS and burst suppression. Patients who experience respiratory arrest from a toxic ingestion of narcotics or barbiturates, in particular, may present with high-grade EEG patterns initially. Many patients also receive anesthetic medications at the time of tracheal intubation, which may linger beyond their normal half-life in patients who have hepatic or renal insufficiency or concurrent use of interacting medications. SSEP is much less susceptible to sedative anesthetic agents, but hypothermia is demonstrated to prolong evoked potential latencies. As therapeutic hypothermia becomes more common after cardiac arrest, the effect of temperature on electrophysiologic testing needs to be taken into account. The publications discussed previously also emphasize the need to adjust the prognostic value of electro-physiologic tests to the pretest probability of meaningful neurologic recovery in individual patients. Clearly, grade I EEG patterns and normal N20 potentials indicate a much better prognosis in patients who have a short du-ration of cardiac arrest, short duration of coma after resuscitation, and when the studies are performed within the first few days. In patients who remain in coma days after resuscitation and lack appropriate brainstem reflexes, however, even the most normal appearing electrophysiologic patterns do little to change the overall prognosis. Aside from prognostication, electrophysiologic testing holds great promise in defining the basic anatomy and physiology of coma emergence after cardiac arrest. In addition, quantitative EEG and automated evoked potentials have the potential to render these tools less subjective and arcane and more applicable for monitoring patients in the period during and immediately after resuscitation. Quantitative EEG also has great potential asa tool to define the time window for neuroprotective intervention and the means to track the response to such therapies in real time.     

Prognostic value of myoclonus status in comatose survivors of cardiac arrest

Generalized myoclonus status is common in comatose patients after cardiac resuscitation, but its prognostic value is uncertain. We studied the clinical, radiologic, and pathologic findings in 107 consecutive patients who remained comatose after cardiac resuscitation. Myoclonus status was present in 40 patients (37%). Features more prevalent in patients with myoclonus status were burst suppression on electroencephalograms, cerebral edema or cerebral infarcts on computed tomography scans, and acute ischemic neuronal change in all cortical laminae. All patients with myoclonus status died. Of 67 patients without myoclonus, 20 awakened. We conclude that myoclonus status in postanoxic coma should be considered an agonal phenomenon that indicates devastating neocortical damage. Its presence in comatose patients after cardiac arrest must strongly influence the decision to withdraw life support.     

CHANGES IN CISTERNAL FLUID POTASSIUM CONCENTRATION FOLLOWING CARDIAC ARREST

The purpose of this study was to measure the changes in potassium concentration in human cisternal Cerebrospinal fluid following successful resuscitation after cardiac arrest. We also wished to examine whether or not changes in potassium concentration in the cisternal cerebrospinal fluid could be correlated to the ability to regain normal cerebral function. 41 patients were studied, of whom 20 regained consciousness and 21 did not. In those who did not regain consciousness there mas a significant increase in the potassium concentration found in samples obtained between 40 and 50 min, and between 50 and 60 min after cardiac arrest. The potassium Concentration decreased to normal values during the following hours. Lumbar spinal fluid did not reflect the changes in cisternal fluid. The results suggest that the potassium concentration of cisternal cerebrospinal fluid, obtained soon after cardiac arrest, might give an indication of the degree of cerebral damage caused by cardiac arrest.     

Anoxic-ischemic encephalopathy and strokes causing impaired consciousness

Coma due to global or focal ischemia or hemorrhage is reviewed. Impaired consciousness due to anoxic-ischemic encephalopathy after cardiac arrest is common but prognostically problematic. Recent guidelines need to be refined for those patients who have received therapeutic hypothermia. Strokes, both ischemic and hemorrhagic, can affect the level of consciousness by damaging specific brain structures involved in alertness because of widespread cerebral injury or secondary cerebral or systemic complications.     

Post-anoxic vegetative state: imaging and prognostic perspectives

Prognostic determination of patients in coma after resuscitation from cardiac arrest is a common and difficult requirement with significant ethical, social and legal implications. We set out to seek markers that can be used for the early detection of patients with a poor prognosis, so as to reduce uncertainty over treatment and non-treatment decisions, and to improve relationships with families. We reviewed the medical literature from 1991 to 2010, using key words such as post-anoxic coma, post-anoxic vegetative state, vegetative state prognosis, recovery after cardiac arrest. Neurological examination, electrophysiology, imaging, and biochemical markers are all useful tools for estimating patients' chances of recovery from cardiac arrest. It seems unlikely that any single test will prove to have 100% predictive value for outcome; but the combination of various prognostic markers, as shown in some articles, could increase the reliability of outcome prediction. However, further research is needed.     

Molecular markers of brain damage--clinical and ethical implications with particular focus on cardiac arrest

Although 25-50% of patients suffering from cardiac arrest can be stabilised haemodynamically, the hospital discharge rate is only 2-14%. One of the major causes of this discrepancy is persistent brain damage. Studies to assess the prognostic value of early prediction of neurologic and overall outcome in patients with cardiac arrest have not yet produced precise and generally accepted diagnostic rules. As apparative diagnostic methods often fail to predict neurologic outcome, the role of molecular markers has come a focus of common interest for early outcome prediction. This systematic review article aims to give an overview on the most important molecular markers for neurologic and overall outcome prediction and outline the advantages, clinical implications and ethical issues in patients undergoing cardiopulmonary resuscitation after cardiac arrest. For this purpose, the traditional marker for brain damage, the neuron-specific enolase, a gamma gamma isomer of enolase and cytoplasmatic enzyme of glycolysis, and the astroglial protein S100, a calcium-binding protein regulating neuronal differentiation, outgrowth, and apoptosis, are analysed and their role discussed as a marker for brain damage in general and recovery after cardiopulmonary resuscitation following cardiac arrest. Neuron-specific enolase has been investigated as a neuro-marker after brain damage and for outcome prediction in unconscious patients. Whereas the protein S100 has proven to be a good marker for neuronal damage after isolated brain injury, its role in cardiac surgery is not as clear: at least, in the early postoperative phase S100 is not a sole marker for neurologic damage, as release of S100 from cardiac tissue and other sources has also been demonstrated. However, the persistent elevation of S100 after cardiac surgery is specific for neurologic impairment. Most interestingly, after cardiac arrest the protein S100 has shown to be a good survival marker for overall outcome prediction. Although it cannot be absolutely determined whether cerebral or cardiac release of S100 is predominant in this clinical setting, recent studies have revealed that S100 serum levels are a useful diagnostic tool for outcome prediction. In contrast, after cardiac arrest serum levels of protein S100 did not reach a 100% specificity and sensitivity in clinical studies, and, therefore, elevated S100 in these patients has to be interpreted with caution. Nonetheless, low S100 serum levels have been correlated with good outcome and, therefore, even if all other diagnostic tests indicate poor outcome, all therapeutic efforts must be undertaken, as no single study has shown that normal S100 serum levels were associated with poor prognosis.     

Adult survivors of severe cerebral hypoxia--case series survey and comparative analysis

Over 16 years, Wilson [31] saw and assessed 567 patients, 18 (3.2%) had a primary diagnosis of cerebral hypoxia. The present patient survey includes all referrals for assessment, management/advice and neuropsychological rehabilitation to a part-time clinical neuropsychology service, who were seen by the first author over a five year period (October 1995-2000). Of the total patient sample (n = 168), 13 (7.7%) had incurred hypoxic damage from a variety of causes; [3] carbon monoxide poisoning (smoke inhalation), [3] cardiac arrest, [1] accidental alcohol and drug overdose, [1] near (partial) drowning, [1] near hanging (suffocation), [2] respiratory arrest following prolonged status epilepticus, [1] respiratory arrest following severe pneumonia and [1] following Addisonian crisis. The survey includes a sub-group of patients in vegetative and minimally responsive states on referral. Wilson [31] highlighted that considerable variation in cognitive functioning is likely to be observed depending on (a) nature or cause of the hypoxic insult and (b) the degree of anoxia/hypoxia experienced itself. The results of the present survey when compared with Wilson's earlier work provide a larger total data-set from which to draw conclusions and has implications for practitioners who see such patients and are involved in their multidisciplinary management and rehabilitation.     

Sudden cardiac arrest in a patient with epilepsy induced by chronic inflammation on the cerebral surface

The present study analyzed a patient with epilepsy due to chronic inflammation on the cerebral surface underwent sudden cardiac arrest. Paradoxical brain discharge, which occurred prior to ep-ileptic seizures, induced a sudden cardiac arrest. However, when the focal brain pressure was re-lieved, cardiac arrest disappeared. A 27-year-old male patient underwent pre-surgical vid-eo-electroencephalogram monitoring for 160 hours. During monitoring, secondary tonic-clonic sei-zures occurred five times. A burst of paradoxical brain discharges occurred at 2-19 seconds (mean 8 seconds) prior to epileptic seizures. After 2-3 seconds, sudden cardiac arrest occurred and lasted for 12-22 seconds (average 16 seconds). The heart rate subsequently returned to a normal rate. Results revealed arachnoid pachymenia and adhesions, as well as mucus on the focal cerebral surface, combined with poor circulation and increased pressure. Intracranial electrodes were placed using surgical methods. Following removal of the arachnoid adhesions and mucus on the local ce-rebral surface, paradoxical brain discharge and epileptic seizures occurred three times, but sudden cardiac arrest was not recorded during 150-hour monitoring. Post-surgical histological examination indicated meningitis. Experimental findings suggested that paradoxical brain discharge led to car-diac arrest instead of epileptic seizures; the insult was associated with chronic inflammation on the cerebral surface, which subsequently led to hypertension and poor blood circulation in focal cerebral areas.     

Clinical MRI Interpretation for Outcome Prediction in Cardiac Arrest

Background

In clinical practice, magnetic resonance imaging (MRI) is commonly used to assess the severity of a cardiac arrest patient??s cerebral injury, utilizing treating neurologists?? imaging interpretation. We sought to determine whether clinical interpretation of diffusion-weighted imaging (DWI) helps to determine poor outcome in comatose cardiac arrest patients.

Methods

We analyzed 80 consecutive MRIs from patients in coma following cardiac arrest. Each study was graded as ??normal?? or ??abnormal restricted diffusion?? in pre-specified brain regions by two blinded stroke neurologists. Poor outcome was defined as a modified Rankin Scale (mRS) score >4 at 3?months. Formal interpretations of neuroimaging by non-blinded neuroradiologists were compared with the blinded reviews by the stroke neurologists.

Results

DWI abnormalities were highly sensitive (98.5?%) but only modestly specific (46.2?%) for predicting poor neurological outcome. Inter-observer reliability was moderate (kappa?=?0.49?±?0.32), with 91?% agreement between study observers, and no significant differences in study observers?? interpretations (p?=?0.125). There were, however, significant differences between the study observers and the clinical neuroradiologists in identifying studies showing evidence of global hypoxic-ischemic injury (p?=?0.001).

Conclusions

The qualitative evaluation of imaging abnormalities by stroke physicians in comatose cardiac arrest patients is a highly sensitive method of predicting poor outcome, but with limited specificity.