Nariyuki Hayashi

Cardiopulmonary cerebral resuscitation using emergency cardiopulmonary bypass, coronary reperfusion therapy and mild hypothermia in patients with cardiac arrest outside the hospital

OBJECTIVES The purpose of this study was to evaluate the efficacy of an alternative cardiopulmonary cerebral resuscitation (CPCR) using emergency cardiopulmonary bypass (CPB), coronary reperfusion therapy and mild hypothermia. BACKGROUND Good recovery of patients with out-of-hospital cardiac arrest is still inadequate. An alternative therapeutic method for patients who do not respond to conventional CPCR is required. METHODS A prospective preliminary study was performed in 50 patients with out-of-hospital cardiac arrest meeting the inclusion criteria. Patients were treated with standard CPCR and, if there was no response, by emergency CPB plus intra-aortic balloon pumping. Immediate coronary angiography for coronary reperfusion therapy was performed in patients with suspected acute coronary syndrome. Subsequently, in patients with systolic blood pressure above 90 mm Hg and Glasgow coma scale score of 3 to 5, mild hypothermia (34 C for at least two days) was induced by coil cooling. Neurologic outcome was assessed by cerebral performance categories at hospital discharge. RESULTS Thirty-six of the 50 patients were treated with emergency CPB, and 30 of 39 patients who underwent angiography suffered acute coronary artery occlusion. Return of spontaneous circulation and successful coronary reperfusion were achieved in 92% and 87%, respectively. Mild hypothermia could be induced in 23 patients, and 12 (52%) of them showed good recovery. Factors related to a good recovery were cardiac index in hypothermia and the presence of serious complications with hypothermia or CPB. CONCLUSIONS The alternative CPCR demonstrated an improvement in the incidence of good recovery. Based upon these findings, randomized studies of this hypothermia are needed.

Systemic Management of Cerebral Edema Based on a New Concept in Severe Head Injury Patients

Cerebral hypothermia treatment of critical brain injury patients was studied based on the management and control of cerebral thermo-pooling, synaptic excitation, hypermetabolic demand, and the systemic critical condition of the metabolic reserve. The initial pathophysiological changes after trauma included a progressive increase in brain tissue temperature. Such cerebral thermo-pooling, which reached a maximum of 43.8 degrees C, can change or damage the vascular proteins directly. The brain tissue temperature was influenced by four factors: 1. the cerebral metabolism, 2. the systemic excess energy metabolism, 3. the CPP that carries the systemic energy to the brain tissue, and 4. the cerebral blood flow that leads to washout of brain tissue temperature. Mild cerebral hypothermia (32-33 degrees C) managed by the whole body compartment cooling technique in the critical conditions of diffuse brain injury patients (GCS < 4) produced a good recovery in 8 of 10 patients. Continuous monitoring of the jugular venous oxygen saturation and BTT/TMT was effective for evaluating cerebral ischemia and oxygen metabolic disturbances even during cerebral hypothermia treatment.

The Clinical Issue and Effectiveness of Brain Hypothermia Treatment for Severely Brain-Injured Patients

Treatment for brain injury has focused on neuroprotection against brain edema, brain ischemia, and control of intracranial hypertension in animal studies. However, these concepts are not successful in the management of in severely brain-injured patients, because animal studies do not include information about the influence of the excess response of systemic circulatory-metabolic changes and hypothalamus-pituitary endocrine axis dysfunction caused by anesthesia. In our recent clinical studies of severe brain injury, the management of restoration therapy of dying neurons in injured brain tissue before neuroprotection therapy produced successful clinical results. Three major targets of treatment are important: Adequate administration of oxygen and metabolic substrates, control of excess release of vasopressin and growth hormone for prevention of blood-brain barrier dysfunction and cytokine encephalitis, and preclusion of selective neuronal radical damage of the dopamine A 10 nervous system for prevention of vegetation. Management of intensive care is focused on three subsequent targets: Initial care management is to maintain sufficient cerebral oxygenation and adequate brain metabolism by control of PaO2/FiO2above 300, systolic blood pressure above l00 mmHg, serum glucose at 120–140mg/dl, brain temperature at 34°-32°C, ICP below 20 mmHg, antithrombin-III (AT-III) above 100%, hemoglobin 2,3 diphosphoglycerate at 12–15 mmol/mL, serum pH above 7.3, oxygen delivery above 800ml/min, and fluid resuscitation. The second target is control of hypothalamus-pituitary axis activation by management of brain tissue temperature at 34°C with 120–140 mg/d serum glucose, 9% saline followed by 4% saline fluid resuscitation, AT-III above 100% followed by replacement of albumin drip, and maintaining serum albumin higher than 3.5g/dl within 2–3 h after injury. The third target is to prevent the selective neuronal damage of the dopamine A 10 nervous system by controlling brain tissue temperature at 32°-33°C with management of Hb above 11 g/dl and administration of vitamin E and C. However, in brain hypothermia treatment, there are five major pitfalls: hemoglobin dysfunction associated with masking brain hypoxia, inadequate management of brain tissue temperature with hyperglycemia, undesirable duration of brain hypothermia, inadequate care management of systemic infections, and misunderstanding of nutritional issues in the management of brain injury. These pitfalls are discussed in this chapter. A novel technique for control of these clinical issues, the success of adequate neuronal oxygenation and brain metabolism, neurohormonal control of the blood-brain barrier dysfunction, and preservation of the dopamine A 10 nervous system are explained. Prevention of brain edema, elevation of ICP, and neuroexcitaion are not mechanisms of brain hypothermia. The effectiveness of brain hypothermia treatment was studied by comparing the clinical results of brain hypothermia (99 cases) and normothermia (65 cases) of head injury with Glascow Coma Scale (GCS) less than 6. Patients with initial GCS scores of 3 did not benefit from brain hypothermia treatment, but with GCS 4, 5, and 6, clinical benefit was observed. As clinical signs, memory, intelhgence, and personality were not much disturbed in the brain hypothermia-treated group.

L-8 is a key mediator of neuroinflammation in severe traumatic brain injuries

The subjects were 22 patients with severe head injury. The average age was 45 ± 18.3 years. There were 13 survivors and 9 fatalities. Samples of peripheral blood and cerebrospinal fluid (CSF) were taken four times, at the time of admission and at 24, 72, and 168 hours later. IL-6: For the survivor group, peripheral blood levels were 181, 105, 37, and 26 pg/ml, respectively (median values). CSF levels were 5376, 3565, 328, and 764 pg/ml, respectively. For the fatality group, peripheral blood levels were 102, 176, 873, and 3059 pg/ml, respectively, whereas CSF levels were 15241, 97384, 548225, and 366500 pg/ml, respectively. IL-8: For the survivor group, peripheral blood levels were 36, 15, 15, and 15 pg/ml, respectively, whereas CSF levels were 23736, 4074, 355, and 1509 pg/ml, respectively. For the fatality group, peripheral blood levels were 21, 28, 43, and 77 pg/ml, respectively, whereas CSF levels were 29003, 8906, 5852, and 8220 pg/ml, respectively. IL-6 and IL-8 levels were significantly higher after 72 hours in the fatality group. The fact that CSF IL-8 was 1000 times that in the peripheral blood at the time of admission, and decreased thereafter, indicates that IL-8 is a key mediator of neuroinflammation.

Moderate low temperature preserves the stemness of neural stem cells and suppresses apoptosis of the cells via activation of the cold-inducible RNA binding protein

We hypothesized that one of the mechanisms underlying the protection of brain injury by therapeutic hypothermia is associated with preservation of neural stem cells. We investigated effects of moderate low temperature and the contribution of a cold-inducible molecule for the stemness of neural stem cells. The MEB5 mouse neural stem cell line was cultured in the presence or absence of EGF, and apoptosis, mRNA expression, and immunocytochemistry of the differentiation markers nestin and GFAP were evaluated at 37 or 32°C. We investigated the contribution of the cold-inducible RNA binding protein (CIRP) on apoptosis and differentiation of MEB5 cells at 32°C. EGF deprivation increased the number of apoptotic cells, decreased expression of nestin, and increased expression of GFAP. The moderate low temperature prevented apoptosis and decreases in expression of GFAP in MEB5 by EGF deprivation. The moderate low temperature significantly increased expression of CIRP. siRNA against CIRP significantly increased the apoptotic cell population of MEB5 cells via EGF deprivation at 32°C. These findings suggest that moderate low temperature preserved stemness of neural stem cells and prevented cell apoptosis via the stimulation of CIRP, and one of the mechanisms of rescue of brain injury by the moderate hypothermia is associated with preservation of neural stem cells.

Enhanced Neuronal Damage in Severely Brain-Injured Patients by Hypothalamus, Pituitary, and Adrenal Axis Neurohormonal Changes

Brain edema, brain ischemia, and elevation of intracranial pressure have been considered major brain injury mechanisms. Therefore, factors that promote these pathophysiological changes, such as hypotension, hypoxia, free radicals, blood-brain barrier dysfunction, excitatory amino acid, and increased intracellular Ca++, have been considered targets of treatment. This concept of brain injury mechanism has long been supported by many animal studies. Information from animal studies was obtained under conditions of anesthesia with body temperature controlled at 37°C. Therefore, harmful stress induced by pathophysiological changes from stimulation of the hypothalamus-pituitary axis have not been included. A new concept of brain injury mechanisms in severe brain-injured patients is presented in this chapter. When the brain is injured, progression of its pathophysiological state typically exhibits a certain time window. The initial stages of brain injury involve destruction of the brain tissue, localized brain ischemia, cytokine inflammation, and synaptic dysfunction with release of vascular agonists, catecholamines, dopamine, neurogenous agonists such as choline, excitatory amino acids, and K+ ions. However, the prognosis of dying neurons in injured tissue is strictly influenced by two other extracerebral factors. One is the change in systemic circulation and metabolism associated with catecholamine surge, and the other is the inflammatory reaction associated with release of hypothalamus-pituitary axis hormones. The dying neurons need enough oxygen and an adequate metabolic substitute to make a neuronal recovery. Three types of brain hypoxia and energy crisis occur in the primarily injured neurons. One is rapid consumption of residual oxygen for maintaining intracellular homeostasis and neuroexcitation. Second, the catecholamine surge produces unstable cardiopulmonary dysfunction, hyperglycemia, and difficulty in washing out the elevated brain tissue temperature. The elevation of brain tissue temperature by brain thermopooling, hemoglobin dysfunction (difficulty in releasing oxygen from hemoglobin), reduced oxygen delivery, and intestinal blood shift produce neuronal hypoxia even with normal intracranial pressure, cerebral perfusion pressure, and PaO2. This is specific neuronal hypoxia, masking brain hypoxia, has not been monitored previously. High temperature (above 38°C) and systolic blood pressure lower than 90–100 mmHg after reperfusion were the clinical conditions for producing brain thermopooling. This new pathophysiological change, brain thermopooling, masking brain hypoxia, progresses within 3–6 h after insult. Such specific pathophysiological conditions generally precede cerebral edema and intracranial hypertension. After 6h, the third stage of brain hypoxia occurs with blood-brain barrier dysfunction and cytokine encephalitis associated with stimulation of the hypothalamus-pituitary axis, such as excess release of vasopressin and growth hormone. Hyperglycemia activates the release of vasopressin, blood-brain barrier dysfunction, and cytokine encephalitis by a feedback mechanism of macronutrient intake. Damage to the hypothalamus is important in understanding the brain injury mechanism. The hypothalamus is also important as the site for control of the mind—thinking, volition, emotion, love and anxiety—by means of the function of the dopamine A10 nervous system. After severe brain injury, dopamine leak from the dopamine nervous system permits selective radical damage to the dopamine A10 nervous system and facilitates development of a vegetative state or mental retardation. These entirely new brain injury mechanisms are triggered by a harmful stress response. The many neurons in primary injured brain tissue need restoration therapy before the start of neuroprotection therapy. Systemic neurohormonal pathophysiological changes are the most important initial target for neuronal restoration in injured brain tissue.

Changes in local cerebral blood flow and neuronal activity during sensory stimulation in normal and sympathectomized cats

Activities of neurons of the thalamic relay nucleus and cortical somatosensory area which are capable of producing excitatory potentials in response to stimulation of the sciatic nerve were recorded, and local cerebral blood flow was measured simultaneously using a double microelectrode under local anesthesia in both non-pretreated cats and cats undergoing chemical denervation of the vasoadrenergic nerves by intraventricular injection of 6-hydroxydopamine (6-OHDA), in order to unmask the neural control on the cerebral vessels during increase of local metabolic rate. The results obtained may be summarized as follows. (1) A positive correlation was found between an increase in firing rate of a single neuron in the thalamic relay nucleus and somatosensory area and an increase in local cerebral blood flow following stimulation of the sciatic nerve. A distinct spatial and quantitative correlation was thus observed between neural activity and cerebral blood flow. (2) In 6-OHDA-pretreated cats, an increase in neuronal firing rate was observed following stimulation of the sciatic nerve, as it was in non-pretreated cats, but the concurrent response of local cerebral blood flow was seriously impaired. All these findings indicate that the increase in local cerebral blood flow occurring in association with increased neural activity does not result solely from increased local metabolism and a consequent increase in CO2 production, but requires for its occurrence that certain basic conditions be satisfied and maintained by the vasoadrenergic innervation.

Traumatic Axonal Injury

Diffuse axonal injury (DAI) leads to disconnection of various brain regions, a condition which translates into much of the morbidity seen with head injury [1, 2, 3, 7, 8]. Following spinal cord injury (Table 2), damage to major white matter tracts disrupts sensory and motor circuits. Moderate hypothermia has recently been reported to reduce axonal injury after experimental traumatic brain injury (TBI) [4,5]. Marion and White [5] first reported that posttraumatic hypothermia delayed up to 24 min after cortical impact injury significantly decreased the frequency of immunoreactive damaged axons. Using an impact acceleration rat model, Koizumi and Povlishock [4] reported that postinjury hypothermia delayed for 1h (32°C/1h) reduced beta-amyloid precursor protein (beta-APP) damaged axons at 24h compared to non-treated controls. Reduced axonal swelling and abnormal beta-APP immunoreactivity was also reported with hypoth ermia treatment after severe spinal cord compression [10].

A case of posterior cerebral artery aneurysm associated with idiopathic bilateral internal carotid artery occlusion: case report

BACKGROUND Aneurysms of the posterior circulation are challenging lesions to neurosurgeons, despite improvements in microsurgical techniques and advances in skull base approaches. We present a rare case of a posterior cerebral artery (PCA)-posterior communicating artery (PcomA) junction aneurysm associated with bilateral internal carotid artery (ICA) occlusion successfully treated with an endovascular procedure. CASE DESCRIPTION A 57-year-old female presented with sudden onset of severe headache and loss of consciousness. CT scan showed diffuse subarachnoid hemorrhage and acute hydrocephalus. The patient developed severe neurogenic pulmonary edema and shock. Although her neurogenic pulmonary edema did not resolve, she recovered from shock. However, her general condition was so critical and her vital signs so unstable, that direct surgery under general anesthesia was considered too risky. A cerebral angiogram showed complete occlusion of both internal carotid arteries without any Moyamoya vessels. A saccular aneurysm located at the right PCA-PcomA junction was seen. To obliterate the aneurysm and prevent rerupture, the patient underwent coil embolization via an endovascular approach under sedation with local anesthesia. The balloon remodeling technique was useful to prevent occlusion of parent arteries. Finally, four interlocking detachable coils (IDC) with a total length of 44 cm were used to completely obliterate the aneurysm using the balloon remodeling technique. The patient made a full recovery after treatment and the aneurysm remained obliterated 2 years after coil embolization. CONCLUSIONS We emphasize the advantages of the endovascular approach for the patient in critical condition. We believe that this is the first report of a PCA-Pcom junction aneurysm associated with bilateral ICA occlusion without moyamoya disease.

Development of Pyrrole-Imidazole Polyamide for Specific Regulation of Human Aurora Kinase-A and -B Gene Expression

Pyrrole-imidazole polyamide (PIP) is a nuclease-resistant novel compound that inhibits gene expression through binding to the minor groove of DNA. Human aurora kinase-A (AURKA) and -B (AURKB) are important regulators in mitosis during the cell cycle. In this study, two specific PIPs (PIP-A and PIP-B) targeting AURKA and AURKB promoter regions were designed and synthesized, and their biological effects were investigated by several in vitro assays. PIP-A and PIP-B significantly inhibited the promoter activities, mRNA expression, and protein levels of AURKA and AURKB, respectively, in a concentration-dependent manner. Moreover, 1:1 combination treatment with both PIPs demonstrated prominent antiproliferative synergy (CI value [ED(50)] = 0.256) to HeLa cells as a result of inducing apoptosis-mediated severe catastrophe of cell-cycle progression. The novel synthesized PIP-A and PIP-B are potent and specific gene-silencing agents for AURKA and AURKB.