Kazuo Okuchi

Specific Changes in Human Brain After Hypoglycemic Injury

BACKGROUND AND PURPOSE Very few reports are available on serial changes in the human brain after severe hypoglycemic injury. The aim of this study was to investigate sequential neuroradiological changes in brains of patients after hypoglycemic coma compared with those after cardiac arrest previously studied with the same methods. METHODS We repeatedly studied CT scans and MR images obtained at 1.5 T in four vegetative patients after profound hypoglycemia associated with diabetes mellitus. RESULTS In all patients, consecutive CT scans showed symmetrical, persistent low-density lesions with transient enhancement in the caudate and lenticular nuclei and transient enhancement in the cerebral cortex 7 to 14 days after onset. Serial MR images consistently revealed symmetrical lesions of persistent hyperintensity and hypointensity on T1- and T2-weighted images, respectively, in the caudate and lenticular nuclei, cerebral cortex, substantia nigra, and/or hippocampus from 8 days to 12 months after onset. CONCLUSIONS Repeated MR images revealed specific lesions in the bilateral basal ganglia, cerebral cortex, substantia nigra, and hippocampus, which suggests the particular vulnerability of these areas to hypoglycemia in the human brain. We speculate that the localized lesions represent tissue degeneration, including some combination of selective neuronal death, proliferation of astrocytic glial cells, paramagnetic substance deposition, and/or lipid accumulation. The absence of localized hemorrhages on MR images in hypoglycemic encephalopathy is in marked contrast to the presence of regional minor hemorrhages in postischemic-anoxic encephalopathy.

Wound Therapy by Marrow Mesenchymal Cell Transplantation

Background: Marrow mesenchymal cells are useful in regenerative medicine because they contain stem cells, but there have been few reports of clinical applications. The authors developed a new wound treatment technique by improving marrow mesenchymal cell culture methods and placing cultured cells in an artificial skin material. This new treatment was useful for tissue regeneration in 20 patients with skin wounds. Methods: Marrow mesenchymal cells from a 46-year-old man were cultured and placed in artificial dermis made of collagen sponge. This composite graft was implanted subcutaneously into the back of a nude mouse and removed 10 days later; immunohistological analysis confirmed regeneration of subcutaneous tissue using human marrow mesenchymal cells. Next, in 20 patients (nine men and 11 women; average age, 64.8 years; range, 22 to 91 years) with intractable dermatopathies, 10 to 20 ml of bone marrow fluid was aspirated from the ilium and cultured in medium containing either fetal calf or autologous serum. The resulting cultured cells were placed in artificial dermis made of collagen sponge, and this composite graft was used to treat skin wounds. Results: The wound mostly healed in 18 of the 20 patients; the remaining two patients died of causes unrelated to transplantation. In all patients, autologous marrow mesenchymal cell transplantation was shown to be therapeutically effective. Conclusions: In skin regeneration therapy using a marrow mesenchymal cell/artificial dermis composite graft, skin regeneration is possible with bone marrow aspiration, a minimally invasive procedure. Compared with existing skin grafting techniques, the present technique is practical and much less invasive.

Improving clinical outcomes from acute subdural hematomas with the emergency preoperative administration of high doses of mannitol: a randomized trial.

OBJECTIVETo evaluate clinical outcomes and postoperative physiological findings for comatose patients with acute subdural hematomas who received preoperative high-dose mannitol (HDM) versus conventional-dose mannitol treatment. METHODSOne hundred seventy-eight adult patients with non-missile, traumatic, acute, subdural hematomas were prospectively and randomly assigned to receive emergency, preoperative, intravenous HDM treatment (91 patients), compared with a control group treated with a lower preoperative mannitol dose (87 patients). RESULTSPreoperative improvement of abnormal pupillary widening was significantly more frequent in the study group than in the control group of patients (P < 0.0001). Preoperative HDM treatment was also associated with significantly better clinical outcomes at 6-month follow-up evaluations (P < 0.01). Postoperative physiological findings revealed statistically significant between-group differences, with higher intracranial pressure and lower cerebral extraction of oxygen (relative cerebral hyperperfusion) in the control group, compared with the HDM group. Postoperative global brain ischemia (abnormally low arteriojugular lactate difference values) was rare and was detected in 2.2 and 3.4% of the patients in the study and control groups, respectively. CONCLUSIONEmergency preoperative HDM administration was associated with improved clinical outcomes for patients with acute subdural hematomas. Preoperative improvement of abnormal pupillary widening and better postoperative control of intracranial hypertension and associated relative cerebral hyperperfusion seemed to be relevant factors associated with improved outcomes.

Specific changes in human brain following reperfusion after cardiac arrest.

Very few reports are available on serial changes in human brain after cardiac arrest. The pri-mary objective of this study is to investigate sequential neuro-radiological changes in patients remaining in a persistent vegetative state following resuscitation after cardiac arrest. Methods We repeatedly studied eight vegetative patients resuscitated from unexpected out-of-hospital cardiac arrest using computed tomographic (CT) scanning and high-field magnetic resonance (MR) imaging at 1.5 T. Results In seven of the eight patients, CT scans obtained between days 2 and 6 featured symmetrical low-density lesions in the bilateral caudate, lenticular, and/or thalamic nuclei. These ischemic lesions were persistently of low density on serial CT scans. In these seven patients, MR images demon-strated what were thought to be hemoglobin degradation products derived from minor hemorrhages localized in the bilateral basal ganglia, thalami, and/or substantia nigra. Dif-fuse brain edema in the acute stage and diffuse brain atrophy in the chronic stage were consistent neuroradiological findings. No abnormal enhanced lesions were demonstrated by CT scans. Conclusions The most characteristic findings on high-field MR images were symmetrical lesions in the bilateral basal ganglia, thalami, and/or substantia nigra with specific changes suggestive of minor hemorrhages that were not evident on CT scans. We speculate that these minor hemorrhages result from diapedesis of red blood cells in these regions during the reperfusion period through the endothelium disrupted by ischemia-reperfusion insult.

ADAMTS13 gene deletion aggravates ischemic brain damage: a possible neuroprotective role of ADAMTS13 by ameliorating postischemic hypoperfusion.

Reperfusion after brain ischemia causes thrombus formation and microcirculatory disturbances, which are dependent on the platelet glycoprotein Ib-von Willebrand factor (VWF) axis. Because ADAMTS13 cleaves VWF and limits platelet-dependent thrombus growth, ADAMTS13 may ameliorate ischemic brain damage in acute stroke. We investigated the effects of ADAMTS13 on ischemia-reperfusion injury using a 30-minute middle cerebral artery occlusion model in Adamts13(-/-) and wild-type mice. After reperfusion for 0.5 hours, the regional cerebral blood flow in the ischemic cortex was decreased markedly in Adamts13(-/-) mice compared with wild-type mice (P < .05), which also resulted in a larger infarct volume after 24 hours for Adamts13(-/-) compared with wild-type mice (P < .01). Thus, Adamts13 gene deletion aggravated ischemic brain damage, suggesting that ADAMTS13 may protect the brain from ischemia by regulating VWF-platelet interactions after reperfusion. These results indicate that ADAMTS13 may be a useful therapeutic agent for stroke.

Hypertonic saline resuscitation reduces apoptosis and tissue damage of the small intestine in a mouse model of hemorrhagic shock.

&NA; The effect of hypertonic saline resuscitation on intestinal damage and the incidence of apoptosis after hemorrhagic shock were investigated. After anesthesia, male BALB/c mice weighing 24‐34 g were hemorrhaged to the mean arterial pressure of 40 ± 5 mmHg for 90 min. Animals were randomly assigned to four groups: 1) resuscitation with 4 mL/kg of 7.5% NaCl (hypertonic saline; HS) + shed blood (SB); 2) resuscitation with two times the volume of shed blood of lactated Ringers solution (2LR) + SB; 3) sham (catheter only); or 4) control (no treatment). Intestinal damage was graded based on the extent of the vacuolation at the basal area of the intestinal villi. Apoptosis of the small intestines was examined with the terminal deoxynucleotidyl transferase‐mediated deoxyuridine 5‐triphosphate nick‐end labeling method and with DNA laddering. Caspase‐3 activation, heat shock protein (HSP) 70, and HSP40 were assessed by western blotting. Apoptosis of the small intestine and intestinal damage were significantly lower (P < 0.01) in the HS+SB group compared with the 2LR+SB group 2 h and 6 h after hemorrhagic shock and resuscitation, respectively. This corresponded with more DNA fragmentation in the small intestine of the 2LR+SB group compared with the HS+SB group 2 h after hemorrhage and resuscitation. In addition, we observed less caspase‐3 activation in the small intestine of the HS+SB group compared with the 2LR+SB group at 2 h after resuscitation. The content of HSP40 and HSP70 in the HS+SB group was similar to that in controls, but slightly decreased in the 2LR+SB group. HS resuscitation reduced intestinal damage and apoptosis after hemorrhagic shock, suggesting that HS resuscitation may improve the outcome after hemorrhagic shock by reducing apoptosis and damage to the small intestine.

Major clinical and physiological benefits of early high doses of mannitol for intraparenchymal temporal lobe hemorrhages with abnormal pupillary widening: A randomized trial

OBJECTIVE We evaluated long-term clinical outcomes and postoperative physiological findings in acutely comatose patients with nonmissile surgical intraparenchymal temporal lobe hemorrhages and abnormal pupillary widening who received early preoperative high-dose mannitol (HDM) versus conventional dose mannitol treatment in the emergency room. METHODS One hundred forty-one adult patients with traumatic, nonmissile, acute, intraparenchymal temporal lobe hemorrhages associated with early abnormal pupillary widening were prospectively and randomly assigned to receive emergency preoperative intravenous HDM treatment (approximately 1.4 g/kg; 72 patients) and were compared with a control group that was treated with a lower preoperative mannitol dose (approximately 0.7 g/kg; 69 patients). RESULTS Early preoperative improvement of abnormal bilateral pupillary widening was significantly more frequent in the study group than in the control group (P < 0.03). The same was true for abnormal unilateral pupillary widening (P < 0.01). Early HDM treatment in the emergency room was also associated with significantly better 6-month clinical outcomes (P < 0.005). The two groups of patients were well matched with respect to diameter of the temporal lobe hemorrhages (approximately 4 cm) as well as timing of clot removal (approximately 2.5 hours after injury). Postoperative physiological findings revealed statistically significant between-group differences, with higher intracranial pressure and lower cerebral extraction of oxygen (global relative cerebral hyperperfusion) in the control group than in the HDM group. Postoperative global brain ischemia (abnormally low arteriojugular lactate difference values) was rare and was found for less than 3% of the patients in both groups. CONCLUSION Early preoperative HDM administration in the emergency room was associated with improved clinical outcomes for adult comatose patients with acute, nonmissile, intraparenchymal temporal lobe hemorrhages and associated abnormal pupillary widening. Early improvement of bilateral or unilateral pupillary abnormalities and better postoperative control of intracranial hypertension and associated global relative cerebral hyperperfusion seemed to be relevant factors that were related to improved outcomes.

Hippocampal Damage in the Human Brain after Cardiac Arrest

Background and Purpose: Very few reports are available on changes in the human hippocampus after cardiac arrest. The objective of this study was to investigate if specific hippocampal volume losses can be demonstrated in the human brain following reperfusion after cardiac arrest. Methods: We assessed the volumes of the hippocampal formation (HF) and temporal lobe excluding HF (TL) as the contrast using magnetic resonance (MR)-imaging-based volumetry in 11 vegetative patients after cardiac arrest and in 22 healthy controls of similar age, sex and body size distribution. The measured volumes were normalized for differences in the head size among subjects by dividing by the total intracranial volume (TICV). The MR images of the 11 patients were obtained between days 8 and 21 after cardiac arrest. Results: The observed volumes of HFs and TLs of both patient and control groups were as follows: right HF volume (HFV): 2.67 ± 0.19 (mean ± SD, cm3) in patients versus 3.89 ± 0.44 in controls; left HFV: 2.72 ± 0.17 versus 3.74 ± 0.35; right TL volume (TLV): 73.37 ± 6.54 versus 80.08 ± 7.62, and left TLV: 72.45 ± 6.77 versus 78.59 ± 6.68. The normalized indices (HFV/TICV and TLV/TICV) were as follows: right HF: 0.0021 ± 0.0002 (mean ± SD) in patients versus 0.0031 ± 0.0001 in controls, p < 0.0001, left HF: 0.0022 ± 0.0002 versus 0.0030 ± 0.0001, p < 0.0001, right TL: 0.058 ± 0.002 versus 0.064 ± 0.004, p = 0.0007, and left TL: 0.058 ± 0.002 versus 0.062 ± 0.004, p = 0.0014. The HFV-TLV ratios (HFV/TICV divided by TLV/TICV) of both groups were: right HFV-TLV ratio: 0.037 ± 0.004 in patients versus 0.049 ± 0.004 in controls, p < 0.0001, left HFV-TLV ratio: 0.038 ± 0.004 versus 0.048 ± 0.004, p < 0.0001. Conclusions: The patient group had HFs that were 26.8–30.6% smaller than those of the control group, but in the patient group, the TLs slightly decreased in size by only 7.8–8.2% of the volume of those in the control group within 21 days after cardiac arrest. The volume reductions in the bilateral HFs of patients after cardiac arrest were significantly larger than those in the bilateral TLs. We speculate that this specific rapid hippocampal shrinkage reflects its greater vulnerability to global brain ischemia.

Prognostic value of increased plasma levels of brain natriuretic peptide in patients with septic shock.

ABSTRACT Our objective was to investigate the plasma levels of brain and atrial natriuretic peptides (BNP and ANP, respectively) in patients with septic shock/severe sepsis and to study the association of BNP and ANP levels with hemodynamic parameters, severity of the disease, and prognosis of those patients. This is a prospective case series study of 22 patients with septic shock, 11 patients with severe sepsis, and 20 healthy volunteers at the Department of Emergency and Critical Care Medicine, Nara Medical University Hospital, Japan. Blood collection was performed on admission and on days 1, 2, and 4. Plasma BNP and ANP levels were measured by radioimmunoassay. Right atrial pressure, mean pulmonary arterial pressure, pulmonary arterial wedge pressure, and left ventricular stroke work index were determined using a thermodilution catheter. Acute Physiological and Chronic Health Evaluation II scores were calculated. Plasma levels of BNP and ANP were markedly elevated in patients with septic shock/severe sepsis compared with controls (BNP, 7 ± 0.3 pg mL−1; ANP, 13 ± 1 pg mL−1). In patients with septic shock, both BNP and ANP peaked on day 2 (BNP, 987 ± 160 pg mL−1; ANP, 103 ± 17 pg mL−1). Plasma levels of BNP on day 2 in patients with septic shock significantly correlated with right atrial pressure (r = 0.744, P < 0.01), mean pulmonary arterial pressure (r = 0.670, P < 0.01), pulmonary arterial wedge pressure (r = 0.709, P < 0.01), left ventricular stroke work index (r = −0.552, P < 0.05), Acute Physiological and Chronic Health Evaluation II score (r = 0.581, P < 0.01), and poor prognosis (P < 0.05). The optimal cutoff point for predicting mortality in patients with septic shock was a BNP level of 650 pg mL−1 on day 2, in which sensitivity and specificity were 92% and 80%, respectively. Increased plasma levels of BNP may reflect not only the severity of myocardial depression but also the disease severity and could be of prognostic value in patients with septic shock.

Relationship between extravascular lung water and severity categories of acute respiratory distress syndrome by the Berlin definition

IntroductionThe Berlin definition divides acute respiratory distress syndrome (ARDS) into three severity categories. The relationship between these categories and pulmonary microvascular permeability as well as extravascular lung water content, which is the hallmark of lung pathophysiology, remains to be elucidated. The aim of this study was to evaluate the relationship between extravascular lung water, pulmonary vascular permeability, and the severity categories as defined by the Berlin definition, and to confirm the associated predictive validity for severity.MethodsThe extravascular lung water index (EVLWi) and pulmonary vascular permeability index (PVPI) were measured using a transpulmonary thermodilution method for three consecutive days in 195 patients with an EVLWi of ≥10 mL/kg and who fulfilled the Berlin definition of ARDS. Collectively, these patients were seen at 23 ICUs. Using the Berlin definition, patients were classified into three categories: mild, moderate, and severe.ResultsCompared to patients with mild ARDS, patients with moderate and severe ARDS had higher acute physiology and chronic health evaluation II and sequential organ failure assessment scores on the day of enrollment. Patients with severe ARDS had higher EVLWi (mild, 16.1; moderate, 17.2; severe, 19.1; P <0.05) and PVPI (2.7; 3.0; 3.2; P <0.05). When categories were defined by the minimum PaO2/FIO2 ratio observed during the study period, the 28-day mortality rate increased with severity categories: moderate, odds ratio: 3.125 relative to mild; and severe, odds ratio: 4.167 relative to mild. On independent evaluation of 495 measurements from 195 patients over three days, negative and moderate correlations were observed between EVLWi and the PaO2/FIO2 ratio (r = -0.355, P<0.001) as well as between PVPI and the PaO2/FIO2 ratio (r = -0.345, P <0.001). ARDS severity was associated with an increase in EVLWi with the categories (mild, 14.7; moderate, 16.2; severe, 20.0; P <0.001) in all data sets. The value of PVPI followed the same pattern (2.6; 2.7; 3.5; P <0.001).ConclusionsSeverity categories of ARDS described by the Berlin definition have good predictive validity and may be associated with increased extravascular lung water and pulmonary vascular permeability.Trial registrationUMIN-CTR ID UMIN000003627