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To investigate whether pyrrolidinone derivative (N2733), an inhibitor of nuclear factor (NF)-kappaB activation, improves altered metabolic and hemodynamic changes and organ dysfunctions caused by endotoxic shock.Prospective, randomized, animal study in a laboratory at a university hospital.Twenty-three anesthetized male beagle dogs (10-14 kg).Dogs were mechanically ventilated and monitored with a pulmonary arterial catheter and a gastric tonometer. A central venous catheter was inserted into the femoral vein, and lactated Ringer's solution (10 ml/kg per hour) was administered throughout the study period. Three groups of animals were studied: (a) the lipopolysaccharide (LPS) group (n=8), which received LPS (250 ng/kg per minute for 2 h); (b) the LPS plus N2733 group (n=8), which received N2733 (30 mg/kg intravenously and 10 mg/kg hour for 6 h) after the start of LPS; and (c) the N2733 group (n=7), which received N2733 (30 mg/kg intravenously and 10 mg/kg per hour for 6 h).Changes in hemodynamics, blood gas, gastric intramural pH, and renal and hepatic function were measured for 6 h. Coadministration of N2733 increased oxygen delivery index and prevented the LPS-induced hypotension, metabolic acidosis, and gastric mucosal acidosis but did not affect renal or hepatic function.Administration of N2733 increased oxygen delivery index and prevented the LPS-induced hypotension and metabolic and gastric mucosal acidosis in an anesthetized canine endotoxic shock model, suggesting its beneficial effect on local blood flow against tissue hypoxia. These findings suggest that blockade of NF-kappaB activation prevents hypodynamic shock and gastric hypoperfusin in endotoxic shock.

To test the hypotheses (1) that nitric oxide (NO) production is stimulated after cardiovascular surgery and is related to the hyperdynamic state and (2) that NO production is more prominent in patients with cardiopulmonary bypass.Prospective, clinical study.Intensive care unit in a university hospital.One hundred patients after cardiovascular surgery: coronary artery bypass graft with (n=53) and without (n=17) cardiopulmonary bypass, valve surgery with cardiopulmonary bypass (n=23) and thoracic aortic replacement with cardiopulmonary bypass (n=7).None.Urinary nitrite/nitrate (NOx) excretion was measured by the high-performance liquid chromatography-Griess system as an index of endogenous NO production during the first 2 postoperative days. Hemodynamic variables, hematologic variables and serum C-reactive protein concentrations were measured after the operation. Urinary NOx concentrations were 146+/-70 and 190+/-93 micro mol/l, and the amounts of NOx excreted in the urine were 23+/-10 and 18+/-8 micro mol/h on the 1st and 2nd days, respectively. Urinary NOx excretions were positively correlated with the cardiac index (P0.01), but inversely correlated with the systemic vascular resistance index (P0.01). Urinary NOx concentrations were positively correlated with serum C-reactive protein concentrations (P0.01), but inversely correlated with the cardiopulmonary bypass time (P0.01). The urinary NOx concentration was highest in patients undergoing coronary artery bypass graft without cardiopulmonary bypass.These findings suggest, firstly, that NO production is stimulated by a surgical inflammatory response and, secondly, that the endogenous NO contributes to the increase in cardiac output that accompanies the reduced systemic vascular resistance after cardiovascular surgery.

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.Prospective, comparable, experimental study.Laboratory at a university hospital.Eighteen male beagle dogs were studied under mechanical ventilation with pentobarbital anesthesia.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 microg x kg(-1) x min(-1) for 5 hrs), and furosemide group (n = 6) receiving furosemide (1 mg x kg(-1) x hr(-1) for 5 hrs).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.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.

Objective: The purpose of this study was to investigate the effects of aerosolized prostacyclin (A-PGI2) and intratracheally instilled prostacyclin (I-PGI2) during partial liquid ventilation (PLV) on gas exchange and pulmonary circulation in rabbits with acute respiratory distress. Design: Prospective control study. Setting: A research laboratory at a university medical centre. Subjects: Sixty-nine Japanese white rabbits. Intervention: Lung injury was induced by oleic acid and the animals were divided into five groups of ten each: a mechanical gas ventilation (GV) group, an A-PGI2 group, a PLV group, an A-PGI2+PLV group and an I-PGI2+PLV group. PLV, A-PGI2+PLV and I-PGI2+PLV groups received 15 ml/kg perflubron intratracheally while receiving mechanical GV. A-PGI2 and A-PGI2+PLV groups received aerosolized PGI2 (50 ng/kg/min) in combination with GV or PLV, respectively. The I-PGI2+PLV group was instilled 50 ng/kg/min PGI2 intratracheally in combination with PLV. Result: After lung injury, all animals developed hypoxia, hypercarbia and pulmonary hypertension. The improvement of partial pressure of arterial oxygen (PaO2) in the A-PGI2 and PLV groups was transient, whereas the A-PGI2+PLV and I-PGI2+PLV groups showed consistent improvement throughout the experiment. The PaO2 values of the I-PGI2+PLV group were significantly higher than those of the other groups 120 min after treatment. The mean pulmonary artery pressure (PAP) significantly decreased after treatment in the A-PGI2, A-PGI2+PLV and I-PGI2+PLV groups. Conclusions: The results suggest that both aerosolized and intratracheally instilled PGI2 improve oxygenation and reduce PAP during PLV in oleic acid lung injury.

Objective: To investigate the regional partial pressure of oxygen (PO2) and partial pressure of carbon dioxide (PCO2) of the perfluorocarbon liquid (PpfcO2, PpfcCO2) during partial liquid ventilation (PLV). Design: Prospective, controlled study. Setting: A research laboratory at a university medical center. Subjects: Thirteen Japanese white rabbits. Interventions: After the tracheostomy, PLV was started with perflubron (15 ml/kg) following saline lung lavage. Fractional inspired oxygen (FIO2) was 1.0, respiratory rate was 30 bpm and tidal volume (VT) was 30 ml. Two epidural catheters (18 gauge) were inserted from the rubber diaphragm interposed in the respiratory circuit to sample perflubron. One catheter was inserted into the left lower lobe bronchus and placed at 5–6 cm distal from the carina (DISTAL). The other one was inserted at the tip of the endotracheal tube (PROXIMAL). Then the effect of the larger VT (50 ml) or positive end-expiratory pressure (PEEP; 10 cmH2O) to the gas tension in perflubron was examined. Measurements and main results: (1) In the lower VT (30 ml) with 0 cmH2O PEEP, DISTAL PpfcO2 was significantly lower than PROXIMAL PpfcO2 (265±72 vs 386±47 mmHg, p

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.

Study objectives To elucidate the efficacy of the combination of inhaled nitric oxide (NO) and partial liquid ventilation (PLV) in ARDS. Design Prospective, randomized, controlled study. Setting A research laboratory at a university medical center. Subjects Thirty-two rabbits. Interventions Animals were anesthetized and ventilated via tracheostomy (tidal volume=40 mL; respiratory rate=25 breaths/min; fraction of inspired oxygen=0.99). After 0.08 mL/kg (0.071 g/kg) oleic acid was administered via the central venous route, animals were randomly divided into the following four groups depending on the ventilatory mode: (1) Gas ventilation (GV)control group: GV was continued throughout the study; (2) GV-NO group: NO inhalation (10 ppm) was performed under GV; (3) PLV-control group: PLV using perflubron (15 mL/kg) was continued until the end of the study; and (4) PLV-NO group: NO inhalation (10 ppm) was performed under PLV. Measurements and results NO inhalation improved PaO 2 in the PLV-NO group (from 133±20 to 167±23 mm Hg; p=0.0008), but not in the GV-NO group (from 67±6 to 63±9 mm Hg), although pulmonary vascular resistance decreased both in the GV-NO (from 4,604±328 to 4,337±322 dyne·s·cm −5 ; p=0.0116) and the PLV-NO group (from 4,727±665 to 4,112±560 dyne·s·cm −5 ; p=0.0036). (Data were expressed as mean±SEM.) Conclusion PLV augmented the effect of inhaled NO on pulmonary gas exchange. The combination of PLV and NO inhalation could be effective in severe ARDS.

The 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.Prospective, comparative, experimental study.Laboratory at a university hospital.Twelve male beagle dogs (10-13 kg) with mechanical ventilation under pentobarbital anesthesia.A 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 microg/kg/min) for 5 hrs, starting from 10 mins before suprarenal abdominal aortic cross-clamping until the end of procedure.Changes 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.The 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.

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 microM/L, ranging from 8.1 to 186.2 microM/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 microM/L) and septic shock (94.5 +/- 53.7 microM/L) were significantly (P < 0.01) higher than those in patients with noninfectious SIRS (25.8 +/- 16.9 microM/L) and healthy subjects (29.6 +/- 8.9 microM/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.

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.

Objective: To elucidate the relationship between airway pressure (Paw) and the distribution of gas-liquid interface during partial liquid ventilation (PLV). Design: Prospective, controlled study. Setting: A research laboratory at a university medical center. Subjects: Ten Japanese white rabbits. Interventions: Ten rabbits were tracheostomized and mechanically ventilated (FIO 2 = 1.0, tidal volume = 40 mL, respiratory rate = 25 breaths/min) under general anesthesia. In the oleic acid lung injury group (n = 5), oleic acid (0.10-0.12 mUkg) was intravenously administered to make a lung injury model. When PaO 2 became

Fourteen mongrel dogs were anaesthetized and mechanically ventilated with oxygen. After oleic acid was administered intravenously, amrinone 1 mg/kg was intravenously administered to one group followed by a continuous infusion of 10 μg/kg/min for one hour (amrinone group, n = 7). Isovolumetric saline was administered to the control group (n = 7). Amrinone slightly lowered PaO2 but significantly increased oxygen delivery and improved gastric intramucosal pH (pHi) during the first 30 minutes (7.33±0.13) compared with the control group (7.21 ±0.06, P

Background: Nitric oxide (NO) production following bacterial infection may play a physiological role in the host defense mechanism due to its antimicrobial activity. However, excess production of NO in severe infection such as sepsis has been implicated in the pathogenesis of septic shock. To determine whether a nitronyl nitroxide NO scavenger compound could prevent the hemodynamic and blood gas alterations in sepsis, bacterial lipopolysaccharide (LPS: 250ng/kg/min) was administered for 2 h in anesthetized dogs with or without infusion of carboxy-2-phenyl-4, 4, 5, 5-tetramethylimidazoline-1-oxyl3-oxide (carboxy-PTIO: 0.1 mg/kg/min) for 1 h. Control animals received isotonic saline instead of LPS with or without carboxy-PTIO. Results: Infusion of LPS caused a marked decrease in mean arterial pressure (MAP), metabolic acidosis, and hypoxia. These effects were reversed by co-administration of carboxy-PTIO, without affecting other hemodynamic parameters. In control animals, neither hemodynamic nor blood gas parameters changed with or without carboxy-PTIO. Conclusion: These results indicate that carboxy-PTIO attenuates LPS-induced hypotension, metabolic acidosis, and hypoxia by scavenging excess NO from the circulation without affecting NO synthase (NOS) activity. An NO scavenger, carboxy-PTIO, may be preferable to non-selective NOS inhibitors for the treatment of human septic shock.

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.