Akira Utagawa

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.

Effects of Bag-mask versus Advanced Airway Ventilation for Patients Undergoing Prolonged Cardiopulmonary Resuscitation in Pre-hospital Setting

BACKGROUND There is no evidence that the advanced airway ventilation (AAV) method improves patient outcome in the pre-hospital cardiac arrest setting. OBJECTIVE The aim of this study was to estimate the effectiveness of AAV vs. bag-mask ventilation (BMV) for cardiopulmonary arrest (CPA) patients, when administered by a licensed emergency medical technician in the pre-hospital setting. METHODS The study used the database of patients who suffered out-of-hospital cardiogenic CPA from 2006 to 2007 in our hospital. Patient records were searched for the method of pre-hospital airway management (BMV or AAV) and the patients outcomes were compared between groups. The primary endpoint was a favorable neurological outcome; the secondary endpoints were rate of return of spontaneous circulation (ROSC) and rate of admission to the intensive care unit (ICU). RESULTS A total of 355 CPA patients (156 BMV and 199 AAV) were retrospectively enrolled. There was no significant difference in demographics between the two groups. The transportation time exceeded 30 min in both groups. The overall ROSC rate and ICU admission rate were significantly higher in the AAV group (p = 0.0352 and p = 0.0089, respectively). The data showed that AAV (odds ratio 1.960; 95% confidence interval 1.015-3.785) resulted in a higher overall ROSC rate than BMV, but there were no significant differences in either the rate of pre-hospital ROSC or in favorable neurological outcome. CONCLUSION AAV may yield advantages over BMV in the overall rate of ROSC in CPA patients, but both approaches for airway management in this study resulted in a comparably favorable neurological outcome. Earlier ROSC would be required for improved overall outcome.

Prevention of Cerebral Thermo-Pooling, Free Radical Reactions, and Protection of A10 Nervous System by Control of Brain Tissue Temperature in Severely Brain Injured Patients

Based on our recent clinical studies, we have presented new concepts for the regulation of brain tissue temperature, a cerebral thermo-pooling brain damage mechanism and prolonged A10 nerve dysfunction in severe head injury patients (6,7,8,9). This understanding of the brain tissue temperature alteration mechanism let to the development of an advanced technique for controlling the brain tissue temperature precisely (6, 7). The results obtained with our cerebral hypothermia treatment and activation of the A10 nervous system indicate that several patients who had been considered difficult to treat by previous methods were saved, and many patients who had clinical signs of brain stem disturbance and vegetative conditions recovered without leaving serious sequelae (4, 7). In this paper, we present new concepts for a secondary brain injury mechanism by elevation of the brain tissue temperature, a protection mechanism through cerebral hypothermia and management of the A10 nervous system in head injury patients.

Application of a Novel Technique for Clinical Evaluation of Nitric Oxide-Induced Free Radical Reactions in ICU Patients

Abstract1. We recently developed a new technique for measuring serum NO2 and NO3 levels precisely, and we examined these parameters in severely brain-injured ICU patients who could not take nutrition intestinally.2. Our results demonstrated that NO increased rapidly after stroke, trauma, and the occurrence of infection in all ICU patients. Elevation of NO2/NO3 was most pronounced 24 to 48 hr after trauma or ischemic stroke. This dysregulation of free radical elimination closely correlated with hemoglobin levels.3. In most ICU patients,with the exception of those with complications of infection, the free radical potentials were maximal at 24 to 48 hr and continued to remain high for 4 to 5 days after trauma or stroke. The level of free radical potentials was closely correlated with the severity and prognosis of critically injured patients. None with radical potential values higher than 0.4 μM survived.4.Clinically, the maintenance of hemoglobin at >12 g/dl and lower body temperature were demonstrated to be successful in the management of these free radical reactions.

Change in brain glucose after enteral nutrition in subarachnoid hemorrhage.

BACKGROUND The alteration of brain extracellular glucose after enteral nutrition (EN) remains unclear. In this study, we used brain microdialysis methods to estimate whether the physiologic elevation of plasma glucose following EN affects brain glucose metabolism of aneurysmal subarachnoid hemorrhage (SAH) patients. METHODS Brain extracellular glucose, lactate, glycerol, glutamate, and pyruvate were measured with a brain microdialysis probe in 12 patients (mean age: 60.0 y+/-7.8 y) after SAH. The EN was initially administered a mean of 3.2 d after the onset of SAH. All of the measured parameters were estimated before and after EN. RESULTS Cerebral perfusion pressure did not significantly change after SAH during the study period. Plasma glucose rose significantly after EN (141.4+/-11.6mg/dL before EN versus 183.8+/-26.2mg/dL immediately after EN (P=0.0006), 177.7+/-30.2mg/dL at 2h after EN (P=0.0033)). The brain extracellular glucose before EN (2.5+/-0.92mmol/L) was significantly lower than the levels measured just after (3.49+/-1.0mmol/L, P=0.0186) and 2h after the end of EN (3.70+/-1.0mmol/L, P=0.0053). Brain extracellular concentrations of lactate, glutamate, pyruvate, and glycerol showed no significant changes. CONCLUSIONS Brain extracellular glucose increased after the transient elevation of plasma glucose following EN. These results suggest that brief, physiologic elevations in plasma glucose after EN produced no changes in brain extracellular glutamate concentration or lactate/pyruvate ratio. These data may help determine the plasma glucose levels most effective for avoiding brain metabolic acidosis in patients after SAH. It remains unclear, however, how SAH itself influences these findings.

Serum Pentosidine, An Advanced Glycation End Product, Indicates Poor Outcomes After Acute Ischemic Stroke

BACKGROUND An advanced glycation end product has been implicated in a wide range of pathologic conditions, including diabetes mellitus, chronic kidney diseases, cardiovascular diseases, and arteriosclerosis. Little is known about its relationship with cerebral ischemia. The authors investigated serum levels of pentosidine and outcomes of patients with acute ischemic stroke METHODS Serum pentosidine levels were measured in 83 patients with acute ischemic stroke at initial hospitalization and other risk factors of stroke. Outcomes of patients at 30 days from hospitalization were assessed by using modified Rankin Scale (mRS) score. Univariate and multivariate logistic regression analyses were performed to analyze the relationship between pentosidine and patient outcomes. RESULTS In the univariate logistic regression analyses, poor outcomes, defined as mRS scores of >2, at 30 days were significantly related to high serum pentosidine (P = .001), type of stroke (P = .045), old age (P = .02), male sex (P = .042), and the absence of dyslipidemia (P = .02). Deterioration of mRS was significantly correlated with high serum pentosidine (P = .003) and creatinine (P = .02). Multivariate logistic regression analysis showed that a high level of serum pentosidine was the only independent risk factor for poor outcomes (P = .004) and deterioration of mRS (P = .01) at 30 days. CONCLUSIONS A high level of serum pentosidine indicates poor and worse outcomes 30 days after acute ischemic stroke. This new biomarker is useful for risk stratification of patients with acute ischemic stroke.

Changes in coagulative and fibrinolytic activities in patients with intracranial hemorrhage

OBJECTIVE To investigate whether any changes occur in the coagulative/fibrinolytic cascade in patients with subarachnoid hemorrhage (SAH) or hypertensive intracerebral hemorrhage (HICH). DESIGN AND METHODS Subjects included 143 patients with intracranial hemorrhage (SAH, n = 50; HICH, n = 82; ROSC-SAH [return of spontaneous circulation after cardiopulmonary arrest due to SAH], n = 11). Coagulative and fibrinolytic factors were measured in blood samples taken on admission. RESULTS The prothrombin fragment 1+2 level was significantly higher (p < 0.005) in SAH patients than in HICH patients. The fibrinolytic factors (plasmin alpha 2-plasmin inhibitor complex, D-dimer, or fibrinogen degradation products) in SAH and ROSC-SAH were both significantly higher than those in HICH, but the significance of difference was stronger in the case of ROSC-SAH (p < 0.05). DISCUSSION Both coagulative and fibrinolytic activities were altered after the onset of SAH. These results demonstrate that the coagulative/fibrinolytic cascade might be activated via different mechanisms in different types of stroke. It remains unclear, however, whether a significant alteration of the fibrinolytic cascade in patients with ROSC-SAH might be a nonspecific phenomenon attributable to the reperfusion after collapse.

Importance of cerebral perfusion pressure management using cerebrospinal drainage in severe traumatic brain injury

OBJECTIVE To evaluate hemodynamics in patients with severe traumatic brain injury (TBI) after cerebral perfusion pressure (CPP) management using cerebrospinal fluid (CSF) drainage. METHODS Twenty-six patients with TBI (Glasgow Coma Score = 8 or less) were investigated. Mean arterial blood pressure, CPP, cardiac index (CI), systemic vascular resistance index (SVRI), and central venous pressure were measured. The patients were divided into 2 groups after craniotomy: the intraparenchymal ICP (IP-ICP) monitoring group (n = 14) and ventricular ICP (V-ICP) monitoring group (n = 12). Patient hemodynamics were investigated on the second hospital day to identify differences. Measurements indicated a target CPP above 70 mmHg and a central venous pressure of 8 10 mmHg in both groups. Mannitol administration (IP-ICP group) or CSF drainage (V-ICP group) was performed whenever the CPP remained below 70 mmHg. RESULTS High SVRI and low CI (p < 0.05) were observed in the IP-ICP group. The V-ICP group exhibited a reduction in the total fluid infusion volume of crystalloid (p < 0.01) and a reduction in the frequency of hypotensive episodes after the mannitol infusion. CONCLUSIONS CPP management using CSF drainage decreases the total infusion volume of crystalloid and may reduce the risk of aggravated brain edema after excess fluid resuscitation.

Importance of hemodynamics management in patients with severe head injury and during hypothermia

OBJECTIVE To evaluate the hemodynamics in patients with traumatic brain injury (TBI) during therapeutic hypothermia. METHODS Subjects were 25 patients with TBI (GCS; 8 or less). Mean arterial blood pressure (MAP), cerebral perfusion pressure (CPP), cardiac index (CI), systemic oxygen delivery (DO2), systemic vascular resistance index (SVRI), and pulmonary capillary wedge pressure (PCWP) were measured. Patients were retrospectively divided into 3 groups: normothermia (n = 5; NT), and survivors (n = 14; HT-S) and non-survivors (n = 6; HT-Non-S) after hypothermia. and hemodynamics were investigated for difference among groups at 24 hours from induction of normothermia or hypothermia. RESULTS CPP target was above 70 mmHg, however, HT-Non-S could not maintain CPP above 70 mmHg. The low CPP was the result of elevated ICP, low MAP (P < .05), or both during hypothermia. In HT-Non-S, significantly high SVRI and low CI (P < .05) causing dehydration were observed during cooling. DO2 could not be maintained in HT-Non-S during hypothermia. CONCLUSIONS These results suggest that patients run the risk of impairing hemodynamics during therapeutic hypothermia. Hemodynamic management is essential during hypothermia. If dehydration occurs during hypothermia. MAP may be reduced due to inadequate sedation, analgesia, and excess use of diuretic agents.

Relation between brain oxygen metabolism and temperature gradient between brain and bladder

Brain temperature is slightly higher than systemic core temperature normally. Fluctuations of a temperature gradient between brain and core body have recently been reported after a severe brain insult. The pathophysiological significance of the gradient fluctuations is unclear. This study aims to identify the gradient fluctuations between brain and core temperatures after a brain insult. Temperature gradient (brain temperature minus bladder temperature: degrees C) was measured in 11 patients (125 points) with severe brain injury (4 patients with subarachnoid hemorrhage, 4 with cerebral hemorrhage. and 3 with traumatic brain injury). Cerebral perfusion pressure (CPP; mmHg) and jugular venous blood saturation (SjO2; %) was also measured. The average gradient was 0.29 +/- 0.285 degrees C when CPP was above 50 mmHg. SjO2 was inversely related to the temperature gradient in a significant manner (r = 0.472; P < 0.0001). Temperature gradients tended to increase and then decrease when CPP < 50 mmHg. This study demonstrates that increased temperature gradient has a significant inverse correlation with SjO2 at CPP > 50 mmHg. The current results suggest that the fluctuations in temperature gradient in critical conditions reflect brain ischemia.