Kuninori Yokoyama

The pathogenesis of carbon monoxide encephalopathy in the acute phase—Physiological and morphological correlation

SummaryExperimental studies were performed to elucidate the significance of various physiological factors contributing to the pathogenesis of carbon monoxide (CO) encephalopathy, such as systemic blood pressure (BP), common carotid artery blood flow (CF), local blood flow (LBF) of the brain and blood gas including pH, and to analyse the morphological character of the cerebral white matter lesions in the acute phases with light and electron microscopes; 14 adult cats were exposed to 0.3% CO/air gas under respiratory control for 1 h and 17 min to 2 h and 50 min and killed 1.5 h to 3 weeks later.During the 1st h the CF and LBF increased along with the concentration of CO haemoglobin and the BP showed slight decrease in all the CO-exposed cats. After the 1st h, the BP dropped progressively as well as the CF and LBF. The LBF of the cortex and white matter changed in parallel, but often that of the latter approximated or exceeded that of the former in the cerebrum. During CO exposure, acidosis occurred in all the cats and haemoconcentration resulted in almost all of the cats. In all the cats except one which showed the least BP drop, lesions occurred selectively in the cerebral white matter and in six or seven cats focal coagulation necrosis or ischaemic changes occurred in the nerve cells in the bilateral pallidum, substantia nigra, and hippocampus similar to human patients. The cerebral white matter lesions were suggestive of those caused by circulatory disturbance. The severity of the white matter damage showed a good positive correlation with the intensity of the BP drop, but not with other factors, such as the duration of CO-exposure, CO-haemoglobin level, acidosis, or haemoconcentration. On the basis of such physiological and morphological findings, we have found the following to be essential for the selective damage of the cerebral white matter rather than the cerebral cortex or white matter of other regions of the CNS: (1) the coexistence of the initial phase of increase in and the succeeding decrease in the cerebral blood flow and (2) the anatomical finding that the cerebral white matter is supplied by its own long nourishing arteries with small amounts of capillary beds and a thinner media compared with that of the subarach-noidal artery.

Comparative study on pathogenesis of selective cerebral lesions in carbon monoxide poisoning and nitrogen hypoxia in cats

SummarySince in a previous study hypoxia and subsequent hypotension were considered to be essential for the pathogenesis of carbon monoxide encephalopathy (CO-encephalopathy), experiments were conducted to see whether a combination of nitrogen hypoxia and subsequent systemic hypotension of similar degree and duration as in the previous experimental CO poisoning could induce the same lesion in the CNS of cats. The partial pressure of blood oxygen was reduced to less than 26 mm Hg by increasing the concentration of nitrogen in N2/O2 gas to be inhaled in 1.5 h and then the aortic blood pressure (BP) was reduced to 60–80 mm Hg by blood depletion and ganglion-blockage for 1 h. In 11 of the 15 cats, lesions were produced in the CNS which were similar by light and electron microscopy to those in CO-encephalopathy. In control groups which were treated by hypoxemia only, hypotension only or a combination of CO2-gas inhalation and hypotension without hypoxemia, such lesions were not found in the cerebral white matter.Considering the pathogenesis of lesions in the cerebral white matter in both nitrogen hypoxia and CO-poisoning, two factors, i.e., hypoxemia and subsequent systemic hypotension, are common and essential. Further, the enormous vasodilation in the cerebral white matter induced by hypoxemia and subsequent drop in BP seem to cause a more severe circulatory disturbance in the cerebral white matter than in the cortex.

Improvement of renal dysfunction in dogs with endotoxemia by a nonselective endothelin receptor antagonist

OBJECTIVES During endotoxemia, there is a marked and intractable decrease in systemic blood pressure, as well as profound vasoconstriction of the renal artery, thereby leading to septic shock and acute renal failure. The purpose of this study was to elucidate the effect of endothelin-1, a potent endothelium-derived vasoconstrictor peptide, on the hemodynamic and renal vascular changes seen in endotoxemia. DESIGN Prospective, comparative, experimental study. SETTING Laboratory at a university hospital. SUBJECTS Thirty-two male mongrel dogs (12.1+/-0.4 kg) under pentobarbital anesthesia. INTERVENTIONS Four groups of animals were studied: a) the lipopolysaccharide (LPS) group (n = 10), which received LPS (250 ng/kg/min for 2 hrs); b) the TAK-044 (a nonselective endothelinA/ endothelinB receptor antagonist) plus LPS group (n = 12), which received a bolus of TAK-044 (5 mg/kg) 0.5 hr before the start of LPS infusion; c) the TAK-044 plus vehicle group (n = 5), which received the same dose of TAK-044 0.5 hr before the start of vehicle infusion; and d) the control group (n = 5), which received only vehicle infusion. MEASUREMENTS AND MAIN RESULTS Changes in systemic and renal hemodynamics, blood gas, and renal function were measured at baseline, and at 0.5, 1, 2, 3, and 4 hrs. Infusion of LPS resulted in significant decreases in mean arterial pressure, arterial pH, Pao2, base excess, urine volume, renal blood flow, creatinine clearance, and urine osmolality. The administration of TAK-044 before LPS infusion did not affect the LPS-induced hypotension. In contrast, the receptor antagonist prevented LPS-induced metabolic acidosis and hypoxemia, and improved LPS-induced decreases in urine volume, renal blood flow, creatinine clearance, and urine osmolality, whereas TAK-044 or vehicle administered alone resulted in no significant hemodynamic or blood gas changes. Plasma endothelin-1 concentrations significantly increased after LPS infusion, with or without TAK-044. CONCLUSIONS The present study suggests that endothelin-1 plays an important role in the impaired renal hemodynamics and renal function associated with endotoxemia, and that endothelin receptor antagonists may be useful as therapeutic agents for acute renal failure during endotoxemia.

Relationships of circulating nitrite/nitrate levels to severity and multiple organ dysfunction syndrome in systemic inflammatory response syndrome

Excessive nitric oxide (NO) production has been implicated to be responsible for the development of septic shock. To determine whether plasma nitrite/nitrate (NOx) levels are related to the severity of systemic inflammatory response syndrome (SIRS) and the degree of multiple organ dysfunction, we studied plasma NOx levels in 70 patients with SIRS consisting of noninfectious SIRS (n = 32), sepsis (n = 23), and septic shock (n = 15). Infection is a microbial phenomenon characterized by an inflammatory response to the presence of microorganism. Positive culture for microorganism is regarded as infectious SIRS (sepsis and septic shock) and negative culture is regarded as noninfectious SIRS. Plasma samples collected from each patient within 24 h from admission to the intensive care unit were subjected for measurement of NOx levels, the stable end products of NO, by the high performance liquid chromatography-Greiss system. Mean plasma NOx levels in patients with SIRS were 52.8 ± 44 &mgr;M/L, ranging from 8.1 to 186.2 &mgr;M/L. Plasma NOx levels were positively correlated with Acute Physiology, Age, and Chronic Health Evaluation (APACHE) III score (r = 0.414, P < 0.01) and sequential organ failure assessment (SOFA) score (r = 0.433, P < 0.01). Plasma NOx levels in patients with sepsis (51.0 ± 38.5 &mgr;M/L) and septic shock (94.5 ± 53.7 &mgr;M/L) were significantly (P < 0.01) higher than those in patients with noninfectious SIRS (25.8 ± 16.9 &mgr;M/L) and healthy subjects (29.6 ± 8.9 &mgr;M/L). Our study shows that plasma NOx levels are increased in patients with infectious, but not noninfectious SIRS, which increase as the severity of SIRS and the development of multiple organ dysfunction syndrome, suggesting its possible pathogenic role in SIRS.

EFFECTS OF CONTINUOUS POSITIVE – PRESSURE VENTILATION ON HEPATIC BLOOD FLOW AND INTRAHEPATIC OXYGEN DELIVERY IN DOGS

The effect of mechanical ventilation with PEEP of 0, 10, and 20 cm H2O (continuous positive-pressure ventilation [CPPV]) on hepatic blood flow (HBF) and intrahepatic oxygen delivery was studied in 26 mongrel dogs anesthetized with fentanyl. Hepatic arterial and portal venous blood flow was measured by an electromagnetic flowmeter. CPPV caused a significant decrease in HBF, which was related to the PEEP level. A linear correlation was seen between HBF and cardiac output. Intrahepatic oxygen delivery decreased more than HBF and cardiac output. The reduced oxygen delivery was due mainly to the decrease in portal venous oxygen content.

Atrial natriuretic peptide infusion improves ischemic renal failure after suprarenal abdominal aortic cross-clamping in dogs.

ObjectiveThe suprarenal abdominal aortic cross-clamping during aortic aneurysm repair causes renal dysfunction after surgery. Atrial natriuretic peptide (ANP), a hormone synthesized by the cardiac atria, induces diuresis-natriuresis and increases glomerular filtration rate. Therefore, we tested the hypothesis that prophylactic ANP infusion could limit the development of acute renal failure after aortic cross-clamping. DesignProspective, comparative, experimental study. SettingLaboratory at a university hospital. SubjectsTwelve male beagle dogs (10–13 kg) with mechanical ventilation under pentobarbital anesthesia. InterventionsA catheter was inserted into the femoral vein, and lactated Ringer solution (10 mL/kg/hr) was administered throughout the study period. Two groups of animals were studied: the control group (n = 6), which received saline vehicle before and after suprarenal abdominal aortic cross-clamping for 1.5 hrs; and the ANP group (n = 6), which received ANP (1 &mgr;g/kg/min) for 5 hrs, starting from 10 mins before suprarenal abdominal aortic cross-clamping until the end of procedure. Measurements and Main ResultsChanges in systemic and renal hemodynamics, blood gases, and renal function were measured at baseline and 1, 2, 3, 4, and 5 hrs after aortic cross-clamping. After aortic cross-clamping, urine volume, renal blood flow, and creatinine clearance significantly (p < .01) decreased, and serum creatinine concentrations significantly (p < .01) increased, but these effects were limited by continuous ANP infusion. ConclusionsThe present study shows that ANP infusion preserved renal function after suprarenal abdominal aortic cross-clamping in dogs. These results justify a trial of ANP infusion in humans during aortic aneurysm repair.

A selective inhibitor for inducible nitric oxide synthase improves hypotension and lactic acidosis in canine endotoxic shock.

Objective To investigate whether ONO-1714, a putative selective inhibitor for inducible nitric oxide synthase, modulates systemic hemodynamics, arterial blood gases, lactate concentrations, gastric mucosal perfusion, and renal and hepatic functions in endotoxic shock. Design Prospective, randomized, controlled animal study. Setting Laboratory at a university hospital. Subjects Eighteen male beagle dogs (12–19 kg) under pentobarbital anesthesia. Interventions Dogs were mechanically ventilated and monitored with a pulmonary arterial catheter and a gastric tonometer. They were divided in three groups: a) lipopolysaccharide (LPS) plus vehicle group (n = 6), which received LPS (250 ng/kg/min for 2 hrs) and saline 1 hr later; b) LPS plus ONO (0.05) group (n = 6), which received ONO-1714 (0.05 mg/kg) 1 hr after the start of LPS; c) LPS plus ONO (0.1) group (n = 6), which received ONO-1714 (0.1 mg/kg) 1 hr after the start of LPS. Measurements and Main Results Hemodynamics, blood gas parameters, gastric intramural pH, urine output, and serum levels of lactate, transaminases, bilirubin, and creatinine were measured during a 6-hr observation period. LPS induced hypotension, lactic acidosis, gastric mucosal acidosis, and renal and hepatic dysfunction. ONO-1714 reversed the LPS-induced hypotension and lactic acidosis without deteriorating cardiac output, oxygen delivery, or gastric mucosal acidosis. Conclusions These findings suggest that ONO-1714 is a useful agent to reverse hypotension and lactic acidosis in a canine endotoxic shock model.

Atrial natriuretic peptide improves pulmonary gas exchange by reducing extravascular lung water in canine model with oleic acid-induced pulmonary edema.

Objective The purpose of this study was to examine and compare the effects of atrial natriuretic peptide and furosemide on pulmonary gas exchange, hemodynamics, extravascular lung water, and renal function in a dog model of oleic acid-induced pulmonary edema. Design Prospective, comparable, experimental study. Setting Laboratory at a university hospital. Subjects Eighteen male beagle dogs were studied under mechanical ventilation with pentobarbital anesthesia. Interventions Oleic acid (0.08 mL/kg) was injected and allowed for 1 hr to achieve pulmonary edema with hypoxemia at Fio2 of 0.3. After lung injury, dogs were divided into three groups; control group (n = 6) receiving saline (2.5 mL/hr for 5 hrs), atrial natriuretic peptide group (n = 6) receiving atrial natriuretic peptide (1 &mgr;g·kg−1·min−1 for 5 hrs), and furosemide group (n = 6) receiving furosemide (1 mg·kg−1·hr−1 for 5 hrs). Measurements and Main Results Hemodynamics, arterial blood gases, extravascular lung water, and renal function were measured hourly for 7 hrs after injury. Oleic acid increased extravascular lung water and induced hypoxemia. In the atrial natriuretic peptide group, extravascular lung water was significantly (p < .05) lower and Pao2 was significantly (p < .05) higher than in the control and furosemide groups, respectively. Pulmonary hypertension induced by oleic acid was attenuated by atrial natriuretic peptide infusion but not by saline or furosemide. Increased natriuresis/diuresis did not significantly differ between the atrial natriuretic peptide and the furosemide group, whereas creatinine clearance in the atrial natriuretic peptide group was significantly higher than that in the furosemide group. Conclusions These findings suggest that atrial natriuretic peptide improves pulmonary gas exchange by reducing extravascular lung water and pulmonary arterial pressure, possibly independently from natriuresis/diuresis in oleic acid-induced pulmonary edema.

Phenylephrine ameliorates cerebral cytotoxic edema and reduces cerebral infarction volume in a rat model of complete unilateral carotid artery occlusion with severe hypotension.

BACKGROUND: Phenylephrine is a selective &agr;1 adrenergic receptor agonist that increases arterial blood pressure by peripheral vasoconstriction. However, whether phenylephrine improves the outcome of cerebral ischemia in patients with internal carotid artery disease during hemorrhagic shock is unclear. METHODS: (Experiment 1) Twenty-one adult male Sprague-Dawley rats were anesthetized with isoflurane and their lungs mechanically ventilated. After the right common carotid artery was ligated, arterial blood was withdrawn until mean arterial blood pressure (MAP) reached 30 mm Hg to induce cerebral ischemia. After MAP was maintained at 30 mm Hg for 10 min, the animals were randomly allocated to three groups (n = 7 each). In the phenylephrine group, phenylephrine was administered IV to maintain a MAP of 70 ± 3 mm Hg for 5 min. In the saline group, an identical volume of normal physiologic saline was continuously administered for 5 min. In the control group, neither phenylephrine nor saline was administered and MAP was maintained at 30 mm Hg. At 30 min of exsanguination, the withdrawn blood was reinfused IV at a rate of 0.25 mL/min. Diffusion-weighted magnetic resonance images were serially acquired and apparent diffusion coefficient maps were created to determine the volume of cytotoxic edema. (Experiment 2) To analyze the effect of phenylephrine on the regional cerebral blood flow (rCBF) in the right middle cerebral artery territory, rCBF was measured using laser Doppler flowmetry in 15 additional rats (n = 5 each). RESULTS: (Experiment 1) At 10 min of exsanguination, there were no significant differences in the volume of cytotoxic edema among the phenylephrine (357.5 ± 93.5 mm3), saline (333.5 ± 69.6 mm3), and control (303.1 ± 85.8 mm3) groups. Low apparent diffusion coefficient regions significantly expanded with time in the control group, whereas they started to decrease just after phenylephrine infusion and almost all had disappeared within 30 min in the phenylephrine group. The final infarction volume in the phenylephrine group (3.9 ± 2.6 mm3, P < 0.01) was significantly lower than that in the saline group (341.5 ± 213.7 mm3) and control group (509.1 ± 197.0 mm3). (Experiment 2) Although rCBF decreased to 40%–50% of the baseline at 10 min of exsanguination, phenylephrine immediately increased rCBF over the baseline level. In the saline group, rCBF increased significantly, but there was some delay compared with the phenylephrine group. CONCLUSIONS: Phenylephrine ameliorated cytotoxic edema and decreased the infarction volume in a rat model of complete unilateral carotid artery occlusion with severe hypotension. These findings suggest that phenylephrine transiently increased CBF without increasing the tonus of cerebral vasculature during hemorrhagic shock.

S-methylisothiourea sulfate improves renal, but not hepatic dysfunction in canine endotoxic shock model

Objective: Excess production of nitric oxide (NO) by inducible NO synthase (iNOS) has been implicated in the pathophysiology of septic shock. This study was designed to see whether S-methylisothiourea sulfate (SMT), a selective inhibitor for iNOS, prevents cardiovascular changes and multiple organ damage in the canine endotoxic shock model.¶Design: Prospective, comparable, experimental study.¶Setting: Laboratory at a university hospital.¶Subjects: Twenty male mongrel dogs were studied under pentobarbital anesthesia.¶Interventions: Dogs were divided into three groups: bacterial lipopolysaccharide (LPS) group (n = 7) receiving continuous infusion of LPS (2 mg/kg/h for 1 h); LPS plus SMT group (n = 7) receiving LPS and SMT (1 mg/kg, bolus i. v., followed by continuous infusion of 1 mg/kg/h for 1 h); and vehicle plus SMT group (n = 6).¶Measurements and results: Hemodynamics, blood gas parameters, and urine output were measured during 6 h observation periods. Serum levels of lactate, transaminases, and bilirubin were measured at baseline, 1 and 6 h. Creatinine and free water clearance, urine sodium excretion and fractional excretion of sodium were calculated. LPS caused a profound hypotension associated with decreases in cardiac output and oxygen delivery, lactic acidosis, renal and liver dysfunction, and thrombocytopenia. SMT prevented the LPS-induced hypotension and renal dysfunction, whereas it did not affect the LPS-induced decreases in cardiac output or oxygen delivery, hyperlactatemia, liver dysfunction, or thrombocytopenia. SMT alone had no appreciable effects on hemodynamics, blood gases, liver or renal functions.¶Conclusions: These findings show that SMT improves renal, but not hepatic dysfunction, in dogs with endotoxic shock, suggesting that iNOS-derived NO plays differential roles in sepsis-associated multiple organ dysfunction.