Kenji Nishio

Increased plasma concentrations of adrenomedullin correlate with relaxation of vascular tone in patients with septic shock

OBJECTIVE To investigate plasma concentrations of adrenomedullin in patients with septic shock and the potential association of these concentrations with relaxation of vascular tone. DESIGN Prospective, case series. SETTING Department of Emergency and Critical Care Medicine, Nara Medical University. PATIENTS Twelve patients who fulfilled the clinical criteria for severe sepsis or septic shock (as defined by the Members of the American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference Committee) and 13 healthy volunteers. INTERVENTIONS Arterial blood samples were obtained via a 20-gauge cannula inserted into each patients radial artery. MEASUREMENTS AND MAIN RESULTS After extraction and purification, plasma adrenomedullin was measured by radioimmunoassay. Systemic vascular resistance index, pulmonary vascular resistance, cardiac index, and stroke volume index were determined with a thermodilution catheter. The mean plasma concentration of adrenomedullin was markedly higher in patients than in controls (226.1 +/- 66.4 [SEM] vs. 5.05 +/- 0.21 fmol/mL, p < .01). Moreover, these concentrations correlated significantly with cardiac index, stroke volume index, and heart rate values, and correlated significantly with decreases in diastolic blood pressure, systemic vascular resistance index, and pulmonary vascular resistance index values. CONCLUSIONS Enhanced production of adrenomedullin in patients with septic shock may contribute to reduced vascular tone, hypotension, or both. More data are needed to clarify the role of adrenomedullin in the regulation of vascular tone in this patient population.

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.

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.

Significance of increased plasma adrenomedullin concentration in patients with cirrhosis

BACKGROUND/AIMS Adrenomedullin recently discovered in human pheochromocytoma is a potent vasodilatory peptide mainly derived from vascular endothelial and smooth muscle cells. Hyperdynamic circulation, ultimately leading to ascites formation, has been attributed to peripheral vasodilatation in liver cirrhosis. However, little is known about the role of adrenomedullin in this condition. METHODS Plasma adrenomedullin concentrations were measured by radioimmunoassay after extraction and purification in 28 cirrhotic patients without ascites, 12 cirrhotic patients with ascites and 10 healthy subjects. RESULTS Plasma adrenomedullin concentrations in cirrhotic patients with ascites (12.7+/-4.5 fmol/ml) were significantly higher than those in cirrhotic patients without ascites (8.2+/-2.3 fmol/ml, p<0.005) and healthy subjects (5.8+/-0.8 fmol/ml, p<0.005). Interestingly, plasma adrenomedullin concentrations were highest in patients with refractory ascites (n=5, 15.8+/-3.0 fmol/ml) and were positively correlated with the Child-Pugh score (r=0.44, p<0.01). Moreover, plasma adrenomedullin concentrations were positively correlated with plasma renin activity (r=0.63, p<0.0001), plasma aldosterone (r=0.60, p<0.0001) and plasma norepinephrine concentrations (r=0.60, p<0.0001), and negatively correlated with creatinine clearance (r=-0.61, p<0.0005) and urinary sodium excretion (r=-0.44, p<0.02). Stepwise multiple regression analysis using certain independent variables, including Pughs score, vasoactive substances, renal function and hemodynamic parameters, showed that the adjusted R square was highest when plasma renin activity and creatinine clearance (standard coefficient=0.53, -0.49, respectively) were considered (adjusted R square=0.61, p<0.0001). CONCLUSIONS Plasma adrenomedullin concentrations increased with the progression of liver cirrhosis and were highest in cirrhotic patients with refractory ascites. In addition, elevated adrenomedullin was associated with activation of the renin-angiotensin-aldosterone and sympathetic nervous systems, and with functional renal impairment in cirrhosis. Considering the potent vasodilatory action of adrenomedullin, increased adrenomedullin may participate in the hyperdynamic circulation, ultimately leading to ascites formation, in patients with liver cirrhosis.

Thrombelastgram as a Hemostatic Monitor during Recombinant Factor VIla Treatment in Hemophilia A Patients with Inhibitor to Factor VIII

Thrombelastgram (TEG) is an old but automated instrument that demonstrates changes occurring during blood coagulation and fibrinolysis. TEG was evaluated to be better than activated partial thromboplastin time (APTT) as a monitor of hemostatic effects when using recombinant factor VIIa (65-80 mu g/kg) in 3 hemophilia A patients with a high titer of factor VIII inhibitors. TEG was more suitable than APTT, because r, r + k and ma values of TEG were normalized at least for 4 h after the infusion, whereas APTT was variably shortened and was not always maintained at a normal level for 4 h.

Abnormal breathing of sudden cardiac arrest victims described by laypersons and its association with emergency medical service dispatcher-assisted cardiopulmonary resuscitation instruction.

Background Current guidelines for cardiopulmonary resuscitation (CPR) emphasise that emergency medical service (EMS) dispatchers should identify sudden cardiac arrest (CA) with abnormal breathing and assist lay rescuers performing CPR. However, lay rescuers description of abnormal breathing may be inconsistent, and it is unclear how EMS dispatchers provide instruction for CPR based on the breathing status of the CA victims described by laypersons. Methods and results To investigate the incidence of abnormal breathing and the association between the EMS dispatcher-assisted CPR instruction and layperson CPR, we retrospectively analysed 283 witnessed CA cases whose information regarding breathing status of CA victims was available from population-based prospective cohort data. In 169 cases (59.7%), laypersons described that the CA victims were breathing in various ways, and that the victims were ‘not breathing’ in 114 cases (40.3%). Victims described as breathing in various ways were provided EMS dispatch-instruction for CPR less frequently than victims described as ‘not breathing’ (27.8% (47/169) vs 84.2% (96/114); p<0.001). Multivariate logistic regression showed that EMS dispatch-instruction for CPR was associated significantly with layperson CPR (adjusted OR, 11.0; 95% CI, 5.72 to 21.2). Conclusions This population-based study indicates that 60% of CA victims showed agonal respiration, which was described as breathing in various ways at the time of EMS call. Although EMS dispatch-instruction was associated significantly with an increase in layperson CPR, abnormal breathing was associated with a much lower rate of CPR instruction and, in turn, was related to a much lower rate of bystander CPR.

Ratio of von Willebrand factor propeptide to ADAMTS13 is associated with severity of sepsis.

ABSTRACT Von Willebrand factor (VWF)–cleaving protease (ADAMTS13) cleaves ultralarge VWF (ULVWF) secreted from endothelium and by which is regulating its physiologic function. An imbalance between ULVWF secretion and ADAMTS13 level occurs in sepsis and may cause multiple organ dysfunction. We evaluated the association between the VWF-propeptide (VWF-pp)/ADAMTS13 ratio and disease severity in patients with severe sepsis or septic shock. In 27 patients with severe sepsis or septic shock and platelet count less than 120 000/&mgr;L, we measured plasma VWF, VWF-pp, and ADAMTS13 levels on hospital days 1, 3, 5, and 7. The VWF-pp/ADAMTS13 ratio was increased greater than 12-fold in patients with severe sepsis or septic shock on day 1 and remained markedly high on days 3, 5, and 7 compared with normal control subjects. The VWF-pp/ADAMTS13 ratio significantly correlated with Acute Physiology and Chronic Health Evaluation II score on days 1 and 5; Sepsis-related Organ Failure Assessment score on days 1, 3, and 5; maximum Sepsis-related Organ Failure Assessment score and tumor necrosis factor &agr; level on days 1, 3, 5, and 7; and creatinine level on days 1, 5, and 7. Patients with greater than stage 1 acute kidney injury had significantly higher VWF-pp/ADAMTS13 ratio than patients without acute kidney injury. In summary, the VWF-pp/ADAMTS13 ratio was associated with disease severity in patients with severe sepsis or septic shock and may help identify patients at risk for multiple organ dysfunction by detecting severe imbalance between ULVWF secretion and ADAMTS13 level.

ADAMTS13 safeguards the myocardium in a mouse model of acute myocardial infarction

Masaaki Doi1,2; Hideto Matsui1; Yukiji Takeda3; Yoshihiko Saito3; Maiko Takeda4; Yasunori Matsunari1,5; Kenji Nishio6; Midori Shima2; Fumiaki Banno7; Masashi Akiyama7; Koichi Kokame7; Toshiyuki Miyata7; Mitsuhiko Sugimoto1 1Department of Regulatory Medicine for Thrombosis, Nara Medical University, Kashihara, Japan; 2Department of Pediatrics, Nara Medical University, Kashihara, Japan; 3Department of Internal Medicine, Nara Medical University, Kashihara, Japan; 4Department of Pathology, Nara Medical University, Kashihara, Japan; 5Department of Anesthesiology, Nara Medical University, Kashihara, Japan; 6Department of General Medicine, Nara Medical University, Kashihara, Japan; 7Department of Molecular Pathogenesis, National Cerebral and Cardiovascular Center, Osaka, Japan

Acute pulmonary edema associated with naphazoline ingestion

In published reports of naphazoline ingestion, clinical effects are hypertension, bradycardia, pallor, diaphoresis, and respiratory distress. We report three cases of acute pulmonary edema after the intentional ingestion of naphazoline-containing antiseptic first aid liquid. These cases presented with altered mental status, hypertension, bradycardia, and diaphoresis. Chest x-ray on admission revealed acute pulmonary edema. Two cases required mechanical ventilation. All of these clinical effects resolved within 24 hours and the patients were discharged with no sequelae. Since naphazoline stimulates the peripheral alpha-2 adrenergic receptor, we speculate that intense vasoconstriction may have elevated cardiac afterload and left atrial-ventricular blood volume and caused acute pulmonary edema.