Elimination of micropollutants and hazardous substances at the source in the chemical and pharmaceutical industry.

Industrial wastewater, especially from chemical and pharmaceutical production, often contains substances that need to be eliminated before being discharged into a biological treatment plant and following water bodies. This can be done within the production itself, in selected waste water streams or in a central treatment plant. Each of these approaches has certain advantages and disadvantages. Furthermore, a variety of wastewater treatment processes exist that can be applied at each stage, making it a challenging task to choose the best one in economic and ecological terms. In this work a general approach for that and examples from practice are discussed.

Hybrid flotation--membrane filtration process for the removal of heavy metal ions from wastewater.

A promising process for the removal of heavy metal ions from aqueous solutions involves bonding the metals firstly to a special bonding agent and then separating the loaded bonding agents from the wastewater stream by separation processes. For the separation stage, a new hybrid process of flotation and membrane separation has been developed in this work by integrating specially designed submerged microfiltration modules directly into a flotation reactor. This made it possible to combine the advantages of both flotation and membrane separation while overcoming the limitations. The feasibility of this hybrid process was proven using powdered synthetic zeolites as bonding agents. Stable fluxes of up to 80l m(-2)h(-1) were achieved with the ceramic flat-sheet multi-channel membranes applied at low transmembrane pressure (<100 mbar). The process was applied in lab-scale to treat wastewater from the electronics industry. All toxic metals in question, namely copper, nickel and zinc, were reduced from initial concentrations of 474, 3.3 and 167mg x l(-1), respectively, to below 0.05 mg x l(-1), consistently meeting the discharge limits.

Continuous negative abdominal pressure device to treat pseudotumor cerebri.

OBJECTIVE: To study the effects of an externally applied negative abdominal pressure device designed to lower the effects of intra-abdominal pressure (IAP) on headaches and pulsatile tinnitus in severely obese women with pseudotumor cerebri (PTC). DESIGN: Short-term clinical intervention trial in the Clinical Research Center. Days 1 and 3 were 'control' days; on days 2 and 4-6 patients were in the device from 8:00 am to noon and from 1:00 to 5:00 pm, and on nights 7-11 they were in the device from 10:00 pm to 8:00 am. The last four patients were treated in a device with a counter-traction mechanism. SUBJECTS: Seven centrally obese women with PTC. MEASUREMENTS: Headache and pulsatile tinnitus severity were graded by the patient using visual analog scale (1-10) and averaged for the time that the device was in use or not in use. IAP was estimated from urinary bladder pressure (UBP) before and during device use. The internal jugular vein (IJV) elliptical cross-sectional area was measured with B-mode ultrasonography; the timed average velocity was measured by Doppler. RESULTS: There was a decrease in both headache (6.8+/-0.8 to 4.2+/-0.8, P<0.05) and pulsatile tinnitus (4.2+/-0.5 to 1.8+/-0.5, P<0.02) within 5 min, and in headache (to 2.2+/-0.8, P<0.01) and tinnitus (to 1.7+/-0.5, P<0.01) within 1 h of device activation. UBP decreased (P<0.001) from 19.1+/-3 to 12.5+/-2.8 cmH2O. Headache remained improved throughout time that the device was used. During the second week, five of seven patients slept in the device without difficulty and four awoke without headache. There was a progressive decrease (P<0.01) in headache during the day after sleeping in the device at night as compared with days 1 and 3 when it was not used (6.5+/-0.5, day 1; 4.1+/-0.7, day 3; 3.1+/-0.8, day 8; 2.3+/-0.8, day 10). Headaches returned late in the afternoon in two patients; the device was reactivated and headache again improved. Five patients underwent IJV sonography; the IJV area decreased (129+/-53 to 100+/-44 mm2, P=0.06) without a change in IJV flow (1004+/-802 to 1000+/-589 ml/min) with the device. When activated, the device was pulled into the patient, creating discomfort that was alleviated with the counter-traction mechanism in the last four patients. One patient developed a 5 cm area of blisters that resolved when the device was worn over a hospital gown. CONCLUSIONS: Decreasing IAP relieved headaches and pulsatile tinnitus in PTC. When patients slept in the device, they awoke without headache or tinnitus, which remained markedly improved throughout most of the following day. This study supports the hypothesis that PTC in obese women is secondary to an increased IAP.

Chronically increased intra-abdominal pressure produces systemic hypertension in dogs.

OBJECTIVE: Determine if increased intra-abdominal pressure (IAP) alone can cause systemic hypertension in a chronic canine model. DESIGN: Evaluate effects of increase in IAP with progressive inflation and deflation of an intra-abdominal balloon on systemic blood pressure in experimental and control animals. SUBJECTS: Male dogs weighing 15-25 kg underwent placement of an intra-abdominal balloon which was progressively inflated on a weekly basis in the experimental animals (5) over 4 weeks to 25 mmHg above baseline and kept there for an additional 2 weeks before gradual deflation over 2 weeks. Control animals (5) had the balloon placed but not inflated. Pain was controlled with osmotic analgesic pumps. MEASUREMENTS: The animals were anesthetized, blood pressure (BP) measured and blood drawn for plasma renin activity (PRA), aldosterone, atrial naturetic peptide (ANP), catecholamines, and serum sodium (Na). A right heart catheter was inserted for measuring cardiac output (CO) and pulmonary artery occlusion pressure (PAOP) at baseline, week 5 (maximal IAP) and week 7 (after balloon deflation). The animals were weighed and urinary bladder pressures recorded weekly before and after abdominal balloon inflation. RESULTS: Systolic (122+/-3 to 155+/-5 mmHg, P<0.05) and diastolic (82+/-4 mmHg to 107+/-7 mmHg, P<0.05) BP rose at 5 weeks at 25 mmHg IAP>baseline and returned to control with balloon deflation. Both systolic and diastolic BP rose (P<0.05) above control animals BP at 15 mmHg IAP at 2 weeks and remained elevated until abdominal decompression, at week 7. There were no significant changes in net animal weight, PRA, aldosterone, ANF, catecholamines, Na, CO or PAOP. CONCLUSION: Increased IAP from progressively inflating an intra-abdominal balloon in dogs was associated with significant increases in systolic and diastolic BP that resolved with balloon deflation. Increased IAP may be a cause for systemic hypertension in central obesity and pre-eclampsia.

Effects of increased renal parenchymal pressure on renal function.

OBJECTIVE: Acute renal failure is seen with the acute abdominal compartment syndrome (AACS). The cause of acute renal failure in AACS is thought to be multifactorial, including increased renal venous pressure, renal parenchymal pressure (RPP), and decreased cardiac output. Previous studies have established the role of renal venous pressure as an important mediator of this renal derangement. In this study, we evaluate the role of renal parenchymal compression on renal function. METHODS: Two groups of swine (20-26 kg) were studied after left nephrectomy and placement of a renal artery flow probe and ureteral cannula. Two hours were allowed for equilibration, and an inulin infusion was begun to calculate inulin clearance as a measurement of glomerular filtration. In group 1 animals (n = 6), RPP was elevated by 30 mm Hg for 2 hours with renal parenchymal compression. RPP then returned to baseline for 1 hour. In group 2 (n = 6), the RPP was not elevated. The cardiac index, preload, and mean arterial pressure remained stable. Blood samples for plasma renin activity and plasma aldosterone were taken at baseline and at hourly intervals. RESULTS: Elevation of RPP in the experimental group showed no significant decrease in renal blood flow index or glomerular filtration when compared with control animals. There were no significant elevations of plasma aldosterone or plasma renin activity in the experimental animals when compared with control. CONCLUSION: Elevated renal compression alone did not create the pathophysiologic derangements seen in AACS. However, prior data from this laboratory found that renal vein compression alone caused a decreased renal blood flow and glomerular filtration and an increased plasma renin activity, plasma aldosterone, and urinary protein leak. These changes are partially or completely reversed by decreasing renal venous pressure as occurs with abdominal decompression for AACS. These data strengthen the proposal that renal vein compression, and not renal parenchymal compression, is the primary mediator of the renal derangements seen in AACS.

Effect of increased renal venous pressure on renal function.

OBJECTIVE: Acute renal failure is seen with the acute abdominal compartment syndrome (AACS). Although the cause of acute renal failure in AACS may be multifactorial, renal vein compression alone has not been investigated. This study evaluated the effects of elevated renal vein pressure (RVP) on renal function. METHODS: Two groups of swine (18-22 kg) were studied after left nephrectomy and placement of a renal artery flow probe to measure renal artery blood flow, renal vein catheter, and ureteral cannula. Two hours were allowed for equilibration and an inulin infusion was begun to calculate inulin clearance for measurement of glomerular filtration rate. Group 1 animals (n = 4) had RVP elevated by 30 mm Hg for 2 hours with renal vein constriction. RVP was then returned to baseline for 1 hour. In group 2 (n = 4), the RVP was not elevated. The cardiac index (2.9 +/- 0.5 L/min/m2) and mean arterial pressure (101 +/- 9 mm Hg) remained stable. Plasma renin activity and serum aldosterone were measured every 60 minutes. RESULTS: Elevation of RVP (0-30 mm Hg above baseline) in the experimental group showed a significant decrease in renal artery blood flow index (2.7 to 1.5 mL/min per g) and glomerular filtration rate (26 to 8 mL/min) compared with control. In addition, there was significant elevation of plasma serum aldosterone (14 to 25 microng/dL) and plasma renin activity (2.6 to 9.5 microng/mL per h) as well as urinary protein leak in the experimental animals compared with control. These changes were partially or completely reversible as RVP returned toward baseline. CONCLUSION: Elevated RVP alone leads to decreased renal artery blood flow and glomerular filtration rate and increased plasma renin activity, serum aldosterone, and urinary protein leak. These changes are consistent with the renal pathophysiology seen in AACS, morbid obesity, and preeclampsia. The changes are partially or completely reversed by decreasing renal venous pressure as occurs with abdominal decompression for AACS.

Physiologic effects of externally applied continuous negative abdominal pressure for intra-abdominal hypertension.

BACKGROUND: To determine the ability of an externally applied continuous negative abdominal pressure device (CNAP) to reverse the effects of elevated intra-abdominal pressure on the central nervous and cardiovascular systems. METHODS: Anesthetized, ventilated swine had catheters placed for measurement of intra-abdominal (IAP), intracranial (ICP), central venous, pulmonary artery, pulmonary artery occlusion, mean arterial, peak inspiratory, inferior vena cava, and femoral vein pressures. After the animals stabilized, baseline measurements were obtained. IAP was increased by incrementally instilling an isosmotic polyethylene glycol solution into the peritoneal cavity until it was 25 mm Hg above baseline. IAP was maintained at 25 mm Hg above baseline for 2 hours. CNAP was then applied for 2 hours. All parameters were remeasured 30 minutes after each increase in IAP, at 2 hours after attaining maximum IAP, and lastly at 2 hours after abdominal decompression. Cardiac index was maintained near baseline by volume expansion. RESULTS: Elevation of IAP to 25 mm Hg above baseline for 2 hours caused increases (p<0.05) in central venous pressure (10.3+/-0.9 to 15.2+/-1.7), inferior vena cava pressure (13.0+/-1.0 to 29.5+/-1.5), femoral vein pressure (13.5+/-0.5 to 33.3+/-1.3), ICP (10.6+/-1.5 to 21.0+/-1.5), and peak inspiratory pressure (18.3+/-0.3 to 34.2+/-1.0). The mean arterial pressure (106.3+/-3.5 to 125.8+/-3.4), pulmonary artery pressure (24.3+/-2.3 to 31.3+/-1.7), and pulmonary artery occlusion pressure rose (12.3+/-0.9 to 17.5+/-3.5), but not significantly. Cardiac index (3.3+/-0.5 to 3.4+/-0.4) remained essentially unchanged. CNAP significantly (p<0.05) decreased IAP (30.7+/-1.3 to 18.2+/-1.3), central venous pressure (15.2+/-1.7 to 12.4+/-2.1), inferior vena cava (29.5+/-1.5 to 19.2+/-1.3), and ICP (21.0+/-1.5 to 16.2+/-1.3). Pulmonary artery occlusion pressure (17.5+/-3.5 to 15.0+/-3.1) and peak inspiratory pressure (34.2+/-1.0 to 29.7+/-1.1) decreased, but not significantly. CONCLUSION: Acutely elevated IAP causes a significant increase in ICP and impaired cardiovascular and pulmonary function. Abdominal decompression remains the standard of care for abdominal compartment syndrome. However, in patients in whom an increased IAP does not require surgical decompression, the results of this study suggest that externally applied CNAP may be of value.

Treatment of intracranial hypertension using nonsurgical abdominal decompression.

BACKGROUND: Elevated intra-abdominal pressure (IAP) increases intracranial pressure (ICP) and reduces cerebral perfusion pressure (CPP). We evaluated a nonsurgical means of reducing IAP to reverse this process. METHODS: Swine with a baseline ICP of 25 mm Hg produced by an intracranial balloon catheter were studied. In group 1 (n = 5), IAP was increased by 25 mm Hg. Continuous negative abdominal pressure (CNAP) was then applied. Group 2 (n = 4) had neither IAP elevation nor CNAP. Group 3 (n = 4) had CNAP without IAP elevation. RESULTS: Elevation of IAP by 25 mm Hg above baseline led to deleterious changes in ICP (25.8+/-0.8 to 39.0+/-2.8; p < 0.05) and CPP (85.2+/-2.0 to 64.8+/-2.6; p < 0.05). CNAP led to a reduction in IAP (30.2+/-1.2 to 20.4+/-1.3; p < 0.05) and improvements in cerebral perfusion (ICP, 33+/-2.7; CPP, 74.4+/-1.2; both p < 0.05). Group 2 had stable ICP (25.8+/-0.25 to 28.7+/-1.7; p > 0.05) and CPP (80.8+/-1.4 to 80.5+/-1.8; p > 0.05). In group 3, CNAP decreased cardiac index (2.9+/-0.2 to 1.1+/-0.4; p < 0.05), mean arterial pressure (105.2+/-4.0 to 38.2+/-12.0; p < 0.05), and CPP (74.2+/-4.7 to 14.5+/-12.2; p < 0.05). CONCLUSION: Elevations in IAP led to increased ICP and decreased CPP. CNAP ameliorated these intracranial disturbances. With normal IAP, CNAP impaired cerebral perfusion.

OPC-6535, a superoxide anion production inhibitor, attenuates acute lung injury.

A large body of evidence has demonstrated that inhibition of the neutrophil's oxidant burst attenuates sepsis-induced acute lung injury. The present study sought to evaluate the ability of OPC-6535, a superoxide anion production inhibitor, to attenuate sepsis-induced acute lung injury. Four groups of swine were anesthetized, ventilated, and studied for 5 hr. Following surgical preparation, control (n = 10) and OPC-control (n = 2) animals received a 1-hr infusion of sterile saline. Sepsis was induced with a 1-hr intravenous infusion of live Pseudomonas aeruginosa. Untreated septic animals (n = 10) received no treatment. Animals treated with OPC-6535 (n = 6) received a 1 mg/kg bolus of OPC-6535 15 min prior to initiation of the bacterial infusion. Changes in systemic and pulmonary hemodynamics, arterial oxygen tension, bronchoalveolar lavage protein and neutrophil content, neutrophil integrin expression, neutrophil oxidant burst, and lung myeloperoxidase content were used as outcome measures. Treatment with OPC-6535 significantly reduced acute lung injury, as indicated by improved bronchoalveolar lavage protein and neutrophil content, resulting in a significant improvement in arterial oxygenation. Treatment with OPC-6535 failed to prevent the development of pulmonary hypertension and systemic hypotension. Neutrophils from animals with both treated and untreated sepsis exhibited significant up-regulation of CD18 and production of increased levels of oxidants, indicating significant activation when compared to neutrophils from control animals. Although animals treated with OPC-6535 produced 25% less superoxide anion than untreated septic animals, this decrease was not statistically significant. Treatment of animals with OPC-6535 prior to the onset of sepsis produced significant protection against acute lung injury but failed to attenuate hemodynamic derangements associated with sepsis.

Elevated intra-abdominal pressure increases plasma renin activity and aldosterone levels.

OBJECTIVE: To study the effects of elevated intra-abdominal pressure upon renal function and the renin-angiotensin-aldosterone system. MATERIALS AND METHODS: Two groups of anesthetized, ventilated swine were studied. Intra-abdominal pressure was increased in experimental animals (n = 6) by incrementally instilling an isosmotic ethylene glycol solution into the peritoneal cavity until intra-abdominal pressure was 25 mm Hg above baseline. The intravascular volume was then expanded until cardiac index returned to baseline. Lastly, the solution was drained to decompress the abdomen. Control animals underwent surgical preparation but did not have their intra-abdominal pressure raised. Changes in systemic and pulmonary hemodynamic parameters, renal venous pressure, and urine output were recorded. Venous samples for plasma renin activity, aldosterone, and atrial natriuretic factor were drawn after each change in either intra-abdominal pressure or intravascular volume in experimental animals, and at the same time points in control animals. MEASUREMENTS AND MAIN RESULTS: Elevated intra-abdominal pressure significantly (p < 0.05, analysis of variance) increased renal venous pressure, pleural pressure, wedge pressure, and pulmonary artery pressure compared to both baseline and control animals; whereas cardiac index and urine output decreased significantly. Both plasma renin and aldosterone levels increased significantly compared with baseline and controls. Intravascular volume expansion significantly increased urine output and decreased significantly both plasma renin activity and aldosterone levels. Abdominal decompression further significantly decreased both plasma renin activity and aldosterone levels. There were no significant changes in atrial natriuretic factor at any time point. CONCLUSIONS: Elevated intra-abdominal pressure decreases urine output and significantly up-regulates the hormonal output of the renin-angiotensin-aldosterone system. Intravascular volume expansion in combination with abdominal decompression reverses the effects of acutely elevated intra-abdominal pressure upon renal function and the renin-angiotensin-aldosterone system.

Pretreatment with inhaled nitric oxide inhibits neutrophil migration and oxidative activity resulting in attenuated sepsis-induced acute lung injury.

OBJECTIVE: To determine if, and by what mechanisms, inhaled nitric oxide attenuates acute lung injury in a porcine model of adult respiratory distress syndrome induced by Gram-negative sepsis. DESIGN: Nonrandomized, controlled study. SETTING: Laboratory at a university medical center. SUBJECTS: Thirty pathogen-free Yorkshire swine (15 to 20 kg). INTERVENTIONS: Four groups of swine were anesthetized, mechanically ventilated, and studied for 5 hrs. Both control-nitric oxide and septic-nitric oxide animals received inhaled nitric oxide at 20 parts per million throughout the study. Control (n = 10) and control-nitric oxide (n = 5) animals received a 1-hr infusion of sterile saline. Sepsis was induced in septic (n = 10) and septic-nitric oxide (n = 5) animals with a 1-hr intravenous infusion of live Pseudomonas aeruginosa. MEASUREMENTS AND MAIN RESULTS: Untreated septic animals developed a progressive decrease in Pao2 that was prevented in septic-nitric oxide animals (73 +/- 4 vs. 214 +/- 23 torr [9.7 +/- 0.5 vs. 28.5 +/- 3.1 kPa], respectively, at 5 hrs, p < .05). Untreated septic animals showed a significant increase in bronchoalveolar lavage protein and neutrophil count at 5 hrs, compared with the baseline value, indicating acute lung injury. Septic-nitric oxide animals showed no significant increase in these parameters. Peripheral blood neutrophils from untreated septic animals and septic-nitric oxide animals exhibited significant (p < .05) up-regulation of CD18 receptor expression and oxidant activity (10.5 +/- 0.9 and 5.0 +/- 0.9 nmol of superoxide anion/10(6) neutrophils/10 mins, respectively) compared with both control and control-nitric oxide animals (3.0 +/- 0.6 and 2.6 +/- 0.2 nmol of superoxide anion/10(6) neutrophils/10 mins, respectively). Also, priming for the oxidant burst at 5 hrs was decreased by 50% in septic-nitric oxide animals compared with untreated septic animals. Both untreated septic and septic-nitric oxide animals showed a significant increase in pulmonary arterial pressure at 30 mins (47.5 +/- 2.4 and 51.0 +/- 3.0 mm Hg, respectively), followed by a progressive decrease (32.8 +/- 2.6 and 31.3 +/- 5.4 mm Hg, respectively, at 5 hrs). Both of these changes were significant (p < .05) compared with baseline values and compared with the control groups. There was no significant difference in pulmonary arterial pressure or systemic arterial pressure at any time between untreated septic and septic-nitric oxide animals. CONCLUSIONS: These results demonstrate that inhaled nitric oxide attenuates alveolar-capillary membrane injury in this porcine model of Gram-negative sepsis but does not adversely affect systemic hemodynamics. The data suggest that inhaled nitric oxide preserves alveolar-capillary membrane integrity by the following means: a) inhibiting transendothelial migration of activated, tightly adherent neutrophils; and b) possibly by attenuating the neutrophil oxidant burst.

A proposed relationship between increased intra-abdominal, intrathoracic, and intracranial pressure.

OBJECTIVES: To determine the effect of acutely increased intra-abdominal pressure on pleural pressure, intracranial pressure, and cerebral perfusion pressure, and to clarify the relationship between these parameters. DESIGN: Nonrandomized, controlled study. SETTING: Laboratory at a university medical center. SUBJECTS: Yorkshire swine, weighing 15 to 20 kg. INTERVENTIONS: Anesthetized, ventilated swine had a balloon inserted into the peritoneal cavity and catheters placed for measurement of intracranial pressure, pleural pressure, central venous pressure, pulmonary artery occlusion pressure, and mean arterial pressure. Following baseline measurements, intra-abdominal pressure was increased by incrementally inflating the intraperitoneal balloon. All parameters were remeasured 30 mins after each increase in intra-abdominal pressure. Two groups were studied: a) group 1 (n = 9) animals had intra-abdominal pressure increased to 25 mm Hg above baseline, then released; b) group 2 (n = 3) animals underwent sternotomy and pleuropericardotomy to prevent an increase in pleural pressure with increasing intra-abdominal pressure. MEASUREMENTS AND MAIN RESULTS: Increase of intra-abdominal pressure to 25 mm Hg above baseline caused significant (p < .05) increases in intracranial pressure (7.3 +/- 0.6 [SEM] to 16.4 +/- 1.9 mm Hg), pleural pressure (4.3 +/- 1.3 to 11.8 +/- 1.9 mm Hg), pulmonary artery occlusion pressure (9.0 +/- 0.6 to 14.3 +/- 0.8 mm Hg), and central venous pressure (6.6 +/- 0.7 to 10.7 +/- 0.9 mm Hg). The cardiac index (3.4 +/- 0.3 to 1.6 +/- 0.1 L/min/m2) and cerebral perfusion pressure (75.6 +/- 3.6 to 62.0 +/- 6.8 mm Hg) deceased significantly (p < .05), whereas mean arterial pressure (82.8 +/- 3.2 to 78.4 +/- 6.6 mm Hg) remained essentially constant. Sternotomy and pleuro-pericardotomy negated all effects of increased intra-abdominal pressure except the decreased cardiac index (1.6 +/- 0.1 to 2.5 +/- 0.2 L/min/m2). CONCLUSIONS: Acutely increased intra-abdominal pressure causes a significant increase in intracranial pressure and a decrease in cerebral perfusion pressure. Increased intra-abdominal pressure appears to produce this effect by augmenting pleural and other intrathoracic pressures and causing a functional obstruction to cerebral venous outflow via the jugular venous system. It is possible that the same phenomenon may be why persons with chronically increased intra-abdominal pressure, such as the morbidly obese, suffer from a high frequency rate of idiopathic intracranial hypertension.

Protective role of synthetic sialylated oligosaccharide in sepsis-induced acute lung injury.

Proper engagement of leukocyte and endothelial cell selectins with their counterreceptors is an initial step in neutrophil trafficking to sites of inflammation. Certain fucosylated carbohydrate determinants such as sialyl Lewis-x are proposed to act as these counterreceptors. We studied the effects of a synthetic sialyl Lewis-x analog, CY-1503, on the course of hemodynamic derangements and acute lung injury during experimental gram-negative sepsis. Anesthetized ventilated swine were made septic with an infusion of live Pseudomonas aeruginosa. A treatment group received an initial bolus of CY-1503 (60 mg/kg) before sepsis, followed by continuous infusion of CY-1503 (15 mg.kg-1.h-1). Treatment with CY-1503 did not prevent the development of pulmonary hypertension, systemic hypotension, decline in cardiac output, or severe neutropenia. However, CY-1503 significantly attenuated lung injury, demonstrated by decreased bronchoalveolar lavage protein content and neutrophil influx, lowered lung myeloperoxidase activity, and improved arterial oxygenation. Neutrophils from septic and CY-1503 animals showed significant activation, reflected by upregulated CD18 expression and priming for oxidant burst compared with control animals. This study suggests blockade of selectin interactions as a potential therapeutic intervention in sepsis-induced lung injury.

Delayed administration of inhaled nitric oxide preserves alveolar-capillary membrane integrity in porcine gram-negative sepsis.

OBJECTIVE: To determine the effect of delayed administration of inhaled nitric oxide (NO) on acute lung injury after the onset of gram-negative sepsis. DESIGN: Nonrandomized controlled study. SETTING: University medical center laboratory. SUBJECTS: Yorkshire swine. INTERVENTIONS: Five groups of swine were anesthetized, mechanically ventilated, and studied for 5 hours. After surgical preparation, control (n = 10) and NO-treated control (n = 6) animals received a 1-hour infusion of sterile saline solution. Sepsis was induced with a 1-hour intravenous infusion of live Pseudomonas aeruginosa. Untreated animals with sepsis (n = 10) received no treatment. Inhaled NO at 20 ppm was administered to NO30-treated animals with sepsis (n = 7) and NO60-treated animals with sepsis (n = 8) beginning at 30 and 60 minutes after bacterial infusion was begun, respectively. MAIN OUTCOME MEASURES: Systemic and pulmonary hemodynamics, arterial blood gas determination, bronchoalveolar lavage protein and neutrophil content, neutrophil oxidant burst, lung myeloperoxidase content, and scanning electron micrographic studies. RESULTS: A progressive, significant (P < .05) decline in PaO2 developed in untreated animals with sepsis, which was prevented in NO30- and NO60-treated animals with sepsis. A significant (P < .05) increase in bronchoalveolar lavage protein and neutrophil counts compared with baseline values was observed in untreated animals with sepsis, indicating acute lung injury. These variables exhibited no notable increase in NO30- and NO60-treated animals with sepsis and were significantly (P < .05) reduced compared with untreated animals with sepsis. The lung myeloperoxidase content was significantly (P < .05) elevated at 5 hours in all groups with sepsis compared with baseline values and the control and NO-treated control groups. The total phorbol myristate acetate-induced polymorphonuclear leukocyte oxidant burst at 5 hours was significantly (P < .05) decreased in the NO30- and NO60-treated animals with sepsis compared with untreated animals with sepsis. Untreated and NO30- and NO60-treated animals with sepsis showed a significant (P < .05) increase in pulmonary artery pressure at 30 minutes, followed by a progressive decline. These changes were significant (P < .05) compared with baseline values and the control groups. No significant (P < .05) difference in pulmonary artery pressure or systemic arterial pressure was found at any time between untreated and NO30- and NO60-treated animals with sepsis. CONCLUSIONS: The delayed administration of inhaled NO preserves alveolar-capillary membrane integrity in this porcine model of gram-negative sepsis. The inhibition of neutrophil transendothelial migration, rather than neutrophil rolling or tight adhesion, may be a critical mechanism by which inhaled NO produces this effect. Decreased oxidant production by activated neutrophils may be a secondary mechanism by which inhaled NO reduces acute lung injury.

Effects of increased intra-abdominal pressure upon intracranial and cerebral perfusion pressure before and after volume expansion.

OBJECTIVE: To study the effects of elevated intra-abdominal pressure (IAP) upon intracranial (ICP) and cerebral perfusion pressure (CPP) before and after intravascular volume resuscitation. MATERIALS AND METHODS: Intra-abdominal pressure was increased in five anesthetized swine by inflating an intraperitoneal balloon until the IAP was 25 mm Hg above baseline. Intravascular volume was then expanded and finally abdominal decompression was performed. Changes in ICP and systemic and pulmonary hemodynamic parameters secondary to increasing IAP were measured. The effect upon CPP was derived from these measurements. PaO2 and PaCO2 were maintained relatively constant by increasing ventilatory rate. MEASUREMENTS AND MAIN RESULTS: Elevated IAP significantly increased ICP (7.6 +/- 1.2 vs. 21.4 +/- 1.0), pleural pressure and central venous pressure; whereas cardiac index and CPP (82.2 +/- 6.3 vs. 62.0 +/- 10.0) decreased significantly. Intravascular volume expansion further significantly increased ICP (27.8 +/- 1.0), and significantly increased both mean arterial pressure (83.4 +/- 14.0 versus 103.4 +/- 8.9) and CPP (75.6 +/- 9.0). Abdominal decompression returned ICP (11.2 +/- 1.8) toward baseline and further increased CPP (79.8 +/- 9.7). CONCLUSIONS: Elevated IAP increases ICP and decreases CPP and cardiac index. Volume expansion further increases ICP yet improves CPP via its greater positive effect upon mean arterial pressure (*p < 0.05, analysis of variance. All measurements are mean +/- SEM in mm Hg).

Cardiopulmonary effects of raised intra-abdominal pressure before and after intravascular volume expansion.

The cardiopulmonary effects of acutely elevated intra-abdominal pressure (IAP) were studied in a porcine model to help define more clearly IAP effects in patients with trauma. IAP was increased in six anesthetized swine by intra-abdominal instillation of isotonic ethylene glycol up to an IAP of 25 mm Hg above baseline. Systemic and pulmonary hemodynamic parameters were measured, as well as the effects on bladder pressure, pleural pressure, and pulmonary function. At IAP of 25 mm Hg above baseline, intravascular volume expansion with saline was administered to return the cardiac index (CI) to baseline. Raising IAP correlated with measured bladder pressures (r = 0.9, p = 0.001). At IAP of 25 mm Hg, CI was significantly decreased (p < 0.05, analysis of variance (ANOVA); 3.6 +/- 0.3 vs. 2.2 +/- 0.3 L/min/m2); whereas wedge, pulmonary arterial, and pleural pressures were all elevated (p < 0.05, ANOVA). However, transarterial wedge pressure (wedge--pleural pressure) declined nonsignificantly with increasing IAP. Raised IAP caused impaired pulmonary function with a decreased (p < 0.05, ANOVA) PaO2 and increased (p < 0.05, ANOVA) PaCO2. Despite the elevated wedge pressure, fluid resuscitation returned CI to baseline. These data clarify the hemodynamic changes associated with raised IAP and indicate that care must be taken in interpreting hemodynamic measurements to determine intravascular fluid status in patients with elevated IAP.

A dual-binding antibody to E- and L-selectin attenuates sepsis-induced lung injury.

Many studies indicate a pivotal role for neutrophil adhesion in sepsis-associated lung injury. Neutrophil adhesion to endothelium depends on activation and expression of selectin and integrin adhesion receptors. We studied the effects of pretreatment with a dual-binding porcine anti-E- and anti-L-selectin monoclonal antibody (EL-246) on a porcine model of sepsis-induced lung injury. Four groups were studied for 5 h. Group 1 (control animals) received intravenous saline only. Group 2 (septic) received a 1-h infusion of Pseudomonas aeruginosa. Group 3 (EL-246 pretreatment) received EL-246 (1 mg/kg) prior to Pseudomonas infusion. Group 4 (EL-246 controls) received EL-246 infusion only. Group 2 animals showed rapid, significant decline in arterial pH and oxygen tension whereas, in Group 3, physiologic deterioration was significantly attenuated. Bronchoalveolar lavage at 5 h showed a significant increase in neutrophil count and protein content in Group 2. Group 3, however, showed no significant differences in these parameters compared with control animals. Despite severe neutropenia, lung myeloperoxidase content at 5 h was significantly reduced in Group 3 compared with Group 2. There was no significant difference in pulmonary and systemic hemodynamics between Groups 2 and 3. Group 4 animals exhibited a transient neutropenia, but otherwise no other differences in measured parameters were found compared with Group 1 control animals. In conclusion, EL-246 significantly reduced neutrophil accumulation in lung and attenuated sepsis-induced lung injury, but failed to attenuate deranged pulmonary and systemic hemodynamics.(ABSTRACT TRUNCATED AT 250 WORDS)

Beneficial effects of a bradykinin antagonist in a model of gram-negative sepsis.

UNLABELLED: Activation of the kallikrein-kinin system in sepsis has long been recognized, but its role, beneficial or pathologic, has not been determined. Recently, however, specific bradykinin (BK) antagonists have become available and we sought to determine the effects of a BK antagonist, NPC17731, in a model of sepsis-induced acute lung injury (ALI). METHODS: Anesthetized swine were studied for 5 hours, receiving a 1-hour infusion of saline (Controls) or live Pseudomonas aeruginosa (Septic untreated). Treatment groups received a 5 mg/kg bolus of NPC17731 followed by a 1 mg/kg bolus hourly commencing either just before sepsis (Pretreatment) or 30 minutes following the onset of sepsis (Posttreatment). RESULTS: Septic untreated animals showed a rapid, progressive decline in arterial PaO2 compared to controls, and this was significantly improved in both treatment groups. Bronchoalveolar lavage at 5 hours in both treatment groups also showed significant decreases in neutrophil (PMN) counts and protein content compared to untreated septic animals, indicating decreased PMN migration and alveolar-capillary membrane damage. Both treatment groups also showed reduced PMN sequestration in the lung compared to untreated animals, although PMNs did exhibit significant upregulation of PMN CD18 receptor expression and superoxide generation. CONCLUSIONS: These data imply a significant role for BK in the pathogenesis of sepsis-induced ALI. Use of a competitive BK antagonist significantly attenuated the development of ALI without inhibiting PMN activation. BK antagonists may be a useful adjunct in the armamentarium against sepsis-induced ALI.

Hemodynamic effects of bradykinin antagonism in porcine gram-negative sepsis.

Activation of the kallikrein-kinin system in sepsis has long been recognized, but its role, beneficial or pathologic, has not been defined. Recently, however, specific bradykinin (BK) antagonists have become available and this study investigated the effects of a BK antagonist, NPC17731 (Scios-Nova) on systemic and pulmonary hemodynamics in a model of gram-negative sepsis. Anesthetized swine were studied for 5 h receiving a 1-h infusion of saline (controls, group 1, N = 8) or live Pseudomonas aeruginosa (septic, group 2, N = 8). Group 3 (treatment, N = 6) received NPC17731 (5 mg/kg initial bolus followed by 1 mg/kg hourly) just prior to the onset of sepsis. Group 2 animals showed a rapid decrease in systemic arterial pressure (SAP) from 30 min onward, and sustained significant hypotension from 2 h onward. In group 3, SAP fell similarly until 2 h then progressively rose, returning to baseline levels by 5 h. In contrast, cardiac index fell progressively from 3 h onward in groups 2 and 3. Systemic vascular resistance index (SVRI) fell significantly by 2 h in group 2 animals, recovering to baseline by 5 h. Group 3 showed a similar initial fall followed by a rebound increase in SVRI, which, at 5 h was significantly raised above the other groups. Group 2 developed significant, persistent pulmonary artery hypertension which was not reduced by NPC17731. The data imply a significant role for bradykinin in the pathogenesis of hypotension in septic shock in this model. Septic shock was reversed by a BK antagonist which increased peripheral resistance without affecting cardiac output.(ABSTRACT TRUNCATED AT 250 WORDS)

Beneficial cardiopulmonary effects of pentoxifylline in experimental sepsis are lost once septic shock is established.

OBJECTIVE: To determine the effects of pretreatment and posttreatment with pentoxifylline in a porcine model of gram-negative sepsis. DESIGN: Nonrandomized controlled trial. STUDY SUBJECTS: Young Yorkshire swine. INTERVENTIONS: Six groups of ventilated swine were studied for 5 hours. Group 1 swine (control, n = 8) received saline solution only. Group 2 swine (sepsis, n = 8) received a 1-hour infusion of Pseudomonas aeruginosa. Groups 3, 4, and 5 swine received the P aeruginosa infusion and a 20 mg/kg bolus followed by a 6 mg/kg per hour infusion of pentoxifylline. Group 3 swine (n = 6) received pentoxifylline prior to the onset of sepsis; group 4 swine (n = 6) received pentoxifylline at 1 hour and group 5 swine (n = 4) at 2 hours after the onset of the P aeruginosa infusion. Group 6 swine (control pentoxifylline, n = 3) received pentoxifylline only. OUTCOME MEASURES: Hemodynamic variables, neutrophil counts and CD18 expression, tumor necrosis factor activity, and arterial blood gases were measured hourly. Bronchoalveolar lavage was performed at 0 and 5 hours to measure neutrophil and protein content. RESULTS: All variables remained unchanged in the control and control pentoxifylline groups. Both pretreatment and posttreatment with pentoxifylline significantly attenuated lung injury and improved arterial PaO2. The cardiac index was significantly improved by administration of pentoxifylline in groups 3 and 4. Administration of pentoxifylline to group 5 animals in established septic shock caused uncontrolled, fatal systemic hypotension in two of the four animals. Plasma tumor necrosis factor activity, blood polymorphonuclear leukocyte counts, and CD18 expression were unaffected by the administration of pentoxifylline. CONCLUSIONS: Pentoxifylline protects against pulmonary and systemic hemodynamic derangements in fulminant sepsis and protects against pulmonary dysfunction. Pentoxifylline has a "therapeutic window" when given in established sepsis; if administration is delayed until overt septic shock occurs, it may then have deleterious effects.