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Critical Care 04/2012; 11:1-1. · 4.93 Impact Factor
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Critical Care 04/2012; 12:1-1. · 4.93 Impact Factor
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Critical Care 04/2012; 12:1-1. · 4.93 Impact Factor
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Shock (Augusta, Ga.) 09/2009; 33(6):668-9. · 2.87 Impact Factor
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ABSTRACT: In the current issue of Critical Care, Simon and coworkers investigated the effects of first-line arginine vasopressin (AVP) on organ function and systemic metabolism compared with norepinephrine in a pig model of fecal peritonitis. AVP was titrated according to the mean arterial pressure suggesting a vasopressor rather than a hormone replacement therapy. The study provides some evidence for the safety of this therapeutic approach. It needs to be determined whether AVP is most beneficial as a constant low-dose infusion to supplement norepinephrine or in higher doses than currently recommended to substitute norepinephrine. In addition, future studies are warranted to evaluate whether a first-line therapy of AVP is superior to a last-resort administration.
Critical care (London, England) 09/2009; 13(4):178. · 4.61 Impact Factor
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Collette C Jonkam,
Kamna Bansal, Daniel L Traber,
Atsumori Hamahata,
Marc O Maybauer,
Dirk M Maybauer,
Robert A Cox,
Matthias Lange,
Rhykka L Connelly,
Lillian D Traber,
Clarisse D Djukom,
John R Salsbury,
David N Herndon,
Perenlei Enkhbaatar
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ABSTRACT: Endothelial dysfunction is a hallmark of sepsis, associated with lung transvascular fluid flux and pulmonary dysfunction in septic patients. We tested the hypothesis that methicillin-resistant Staphylococcus aureus (MRSA) sepsis following smoke inhalation increases pulmonary transvascular fluid flux via excessive nitric oxide (NO) production.
Ewes were chronically instrumented, and randomised into either a control or MRSA sepsis (MRSA and smoke inhalation) group.
Pulmonary function remained stable in the control group, whereas the MRSA sepsis group developed impaired gas exchange and significantly increased lung lymph flow, permeability index and bloodless wet-to-dry weight-ratio (W/D ratio). The plasma nitrate/nitrite (NOx) levels, lung inducible nitric oxide synthases (iNOS) and endothelial nitric oxide synthases (eNOS), vascular endothelial growth factor (VEGF) protein expressions and poly-(ADP)-ribose (PAR) were significantly increased by MRSA challenge.
These results provide evidence that excessive NO production may mediate pulmonary vascular hyperpermeability in MRSA sepsis via up regulation of reactive radicals and VEGF.
Critical care (London, England) 03/2009; 13(1):R19. · 4.61 Impact Factor
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ABSTRACT: Impairment of the protein C pathway plays a central role in the pathogenesis of sepsis. Treatment with recombinant human activated protein C (rhAPC) has been reported to increase survival from severe sepsis. Protein C levels also decrease markedly in acute lung injury, of both septic and nonseptic origin. Low levels of protein C in acute lung injury are associated with poor clinical outcome. The present article discusses the beneficial effects of rhAPC in oleic acid-induced lung injury as well as the controversies between different animal models and the timing of drug administration. The unique bronchial circulation in ovine models seems to be responsible for the beneficial effects of rhAPC when given simultaneously to the injury.
Critical care (London, England) 02/2009; 13(1):112. · 4.61 Impact Factor
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Journal of burn care & research: official publication of the American Burn Association 01/2009; · 1.37 Impact Factor
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Journal of burn care & research: official publication of the American Burn Association 01/2009; 30(1):164-5. · 1.37 Impact Factor
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Journal of burn care & research: official publication of the American Burn Association 01/2009; 30(1):169-71. · 1.37 Impact Factor
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ABSTRACT: Smoke inhalation injury is often complicated with pneumonia, which frequently leads to subsequent development of sepsis. Excessive NO has been shown to mediate many sepsis-related pathological responses. In the present study, we used our well-established ovine smoke inhalation and pneumonia/sepsis model to examine the hypothesis that neuronal NO synthase (NOS) may be primarily responsible for these pathological alterations. We report the beneficial effects of the specific neuronal NOS (nNOS) inhibitor ZK234238. Adult female sheep were surgically prepared for the study. After 5 to 7 days' recovery, sheep were anesthetized and given double injury: insufflation of 48 breaths of cotton smoke (<40 degrees C) into the airway of each animal and subsequent instillation of live Pseudomonas aeruginosa (5 x 10(11) colony-forming units) into each sheep's lung via tracheostomy tube. All sheep were mechanically ventilated and fluid resuscitated by lactated Ringer's solution. Sheep were randomly allocated into groups: control (injured not treated, n = 6) and treated (injured, but treated with ZK234238, n = 4). Continuous infusion of ZK234238 (100 microg x kg(-1) x h(-1)) was started 1 h after insult. ZK234238 attenuated the hypotension (at 18 and 24 h) and fall in systemic vascular resistance (at 24 h) seen in control animals. ZK234238 significantly inhibited increased fluid accumulation as well as increased plasma nitrate/nitrite 24 h after injury. Neuronal NOS inhibition significantly reduced lung water content and attenuated inflammatory indices such as lung tissue myeloperoxidase activity, IL-6 mRNA, and reactive nitrogen species. The above results suggest that the nNOS-derived NO may be involved in the pathophysiology of sepsis-related multiorgan dysfunction.
Shock (Augusta, Ga.) 12/2008; 32(3):253-7. · 2.87 Impact Factor
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Perenlei Enkhbaatar,
Rhykka Connelly,
Jianpu Wang,
Yoshimitsu Nakano,
Matthias Lange,
Atsumori Hamahata,
Eszter Horvath,
Csaba Szabo,
Stefan Jaroch,
Peter Hölscher,
Margrit Hillmann,
Lillian D Traber,
Frank C Schmalstieg,
David N Herndon, Daniel L Traber
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ABSTRACT: Acute respiratory distress syndrome/acute lung injury is a serious complication of burn patients with concomitant smoke inhalation injury. Nitric oxide has been shown to play a major role in pulmonary dysfunction from thermal damage. In this study, we have tested the hypothesis that inhibition of neuronal nitric oxide synthase could ameliorate the severity of acute lung injury using our well-established ovine model of cutaneous burn and smoke inhalation.
Prospective, randomized, controlled, experimental animals study.
Investigational intensive care unit at university hospital.
Adult female sheep.
Female sheep (n = 16) were surgically prepared for the study. Seven days after surgery, all sheep were randomly allocated into three study groups: sham (noninjured, nontreated, n = 6); control (injured, treated with saline, n = 6); and neuronal nitric oxide synthase (injured, treated with specific neuronal nitric oxide synthase inhibitor, ZK 234238 (n = 4). Control and neuronal nitric oxide synthase groups were given a cutaneous burn (40% of total body surface, third degree) and insufflated with cotton smoke (48 breaths, <40 degrees C) under halothane anesthesia. Animals in sham group received fake injury also under halothane anesthesia. After injury or fake injury procedure, all sheep were placed on ventilators and resuscitated with lactated Ringer's solution. Neuronal nitric oxide synthase group was administered with continuous infusion of ZK 234238 started 1 hr postinjury with a dose of 100 microg/kg/hr. Sham and control groups received same amount of saline.
Cardiopulmonary hemodynamics monitored during the 24-hr experimental time period was stable in the sham group. Control sheep developed multiple signs of acute lung injury. This pathophysiology included decreased pulmonary gas exchange and lung compliance, increased pulmonary edema, and inflammatory indices, such as interleukin-8. Treatment of injured sheep with neuronal nitric oxide synthase inhibitor attenuated all the observed pulmonary pathophysiology.
The results provide definitive evidence that inhibition of neuronal nitric oxide synthase-derived excessive nitric oxide may be a novel and beneficial treatment strategy for pulmonary pathology in burn victims with smoke inhalation injury.
Critical care medicine 12/2008; 37(1):208-14. · 6.37 Impact Factor
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ABSTRACT: Activation of the coagulation cascade resulting in alveolar fibrin deposition is recognized as a hallmark of acute lung injury (ALI). Anticoagulant treatment with recombinant human activated protein C (rhAPC) appears promising, because - like in sepsis - there is a deficiency of protein C in ALI, which is correlated with poor outcome in both syndromes. Recently in Critical Care, Waerhaug and colleagues confirmed the beneficial effects of rhAPC on pulmonary function in ovine endotoxin-induced ALI. Notably, the authors reported no differences in hemorrhage in histologic analyses between rhAPC-treated and untreated animals. However, a recently reported randomized, placebo-controlled, multicenter trial in ALI patients without severe sepsis failed to identify any differences in the number of ventilator-free days or 60 day-mortality between the rhAPC and placebo group. In addition to (or perhaps because of) the complex pathogenesis, the discrepancy between clinical and experimental results in ALI is another common feature with sepsis. The future challenge will be to transfer our theoretical knowledge adequately into daily clinical practice. Anticoagulant therapy might be a useful tool in the treatment of ALI; however the proper operating instruction remains to be defined.
Critical care (London, England) 10/2008; 12(5):179. · 4.61 Impact Factor
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Perenlei Enkhbaatar,
Collette Joncam,
Lillian Traber,
Yoshimitsu Nakano,
Jianpu Wang,
Matthias Lange,
Rhykka Connelly,
Gabriela Kulp,
Fiona Saunders,
Ruksana Huda,
Robert Cox,
Frank Schmalstieg,
David Herndon, Daniel Traber
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ABSTRACT: Methicillin-resistant Staphylococcus aureus (MRSA)-related pneumonia and/or sepsis are a frequent serious menace. The aim of the study was to establish a standardized and reproducible model of MRSA-induced septic pneumonia to evaluate new therapies. Sheep were operatively prepared for chronic study. After 5 days' recovery, tracheostomy was performed under anesthesia, and smoke injury was induced by inhalation of cotton smoke (48 breaths, <40 degrees C). Methicillin-resistant S. aureus (AW6) (approximately 2.5x10(11) colony-forming units) was instilled into the airway by a bronchoscope. After the injury, animals were awakened and maintained on mechanical ventilation by 100% oxygen for first 3 h, and thereafter, oxygen concentration was adjusted according to blood gases. The sheep were resuscitated by lactated Ringer solution with an initial rate of 2 mL kg(-1) h(-1) that was further adjusted according to hematocrit. Study groups include (1) sham (noninjured, nontreated; n=6), (2) S+MRSA (exposed to smoke inhalation and MRSA, nontreated; n=6), and (3) smoke (exposed to smoke inhalation alone; n=6). Injured (S+MRSA) animals showed the signs of severe sepsis-related multiple organ failure 3 h after insult. Cardiovascular morbidity was evidenced by severe hypotension, with increased heart rate, cardiac output, left atrial pressure and severely decreased systemic vascular resistance index, and left ventricle stroke work index. Pulmonary dysfunction was characterized by deteriorated gas exchange (PaO2/FIO2 and pulmonary shunt) and increased ventilatory pressures. The S+MRSA group showed significantly greater lung tissue water content, myeloperoxidase activity, and cytokine production compared with uninjured sham animals. Microvascular hyperpermeability was evidenced by marked fluid retention (fluid net balance), decreased plasma protein with decreased plasma oncotic pressure, and increased pulmonary microvascular pressure. All these changes were accompanied by 6- to 7-fold increase in plasma nitrite/nitrate and increased production of reactive nitrogen species in lung. The smoke inhalation alone had a little or no effect on these variables. This model closely mimics hyperdynamic human sepsis. The excessive production of NO may be extensively involved in the pathogenic process.
Shock 05/2008; 29(5):642-9. · 2.85 Impact Factor
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Perenlei Enkhbaatar,
Collette Joncam,
Lillian Traber,
Yoshimitsu Nakano,
Jianpu Wang,
Matthias Lange,
Rhykka Connelly,
Gabriela Kulp,
Fiona Saunders,
Ruksana Huda,
Robert Cox,
Frank Schmalstieg,
David Herndon, Daniel Traber
[show abstract]
[hide abstract]
ABSTRACT: Methicillin-resistant Staphylococcus aureus (MRSA)-related pneumonia and/or sepsis are a frequent serious menace. The aim of the study was to establish a standardized and reproducible model of MRSA-induced septic pneumonia to evaluate new therapies. Sheep were operatively prepared for chronic study. After 5 days' recovery, tracheostomy was performed under anesthesia, and smoke injury was induced by inhalation of cotton smoke (48 breaths, <40°C). Methicillin-resistant S. aureus (AW6) (~2.5 × 1011 colony-forming units) was instilled into the airway by a bronchoscope. After the injury, animals were awakened and maintained on mechanical ventilation by 100% oxygen for first 3 h, and thereafter, oxygen concentration was adjusted according to blood gases. The sheep were resuscitated by lactated Ringer solution with an initial rate of 2 mL kg-1 h-1 that was further adjusted according to hematocrit. Study groups include (1) sham (noninjured, nontreated; n = 6), (2) S + MRSA (exposed to smoke inhalation and MRSA, nontreated; n = 6), and (3) smoke (exposed to smoke inhalation alone; n = 6). Injured (S + MRSA) animals showed the signs of severe sepsis-related multiple organ failure 3 h after insult. Cardiovascular morbidity was evidenced by severe hypotension, with increased heart rate, cardiac output, left atrial pressure and severely decreased systemic vascular resistance index, and left ventricle stroke work index. Pulmonary dysfunction was characterized by deteriorated gas exchange (PaO2/FIO2 and pulmonary shunt) and increased ventilatory pressures. The S + MRSA group showed significantly greater lung tissue water content, myeloperoxidase activity, and cytokine production compared with uninjured sham animals. Microvascular hyperpermeability was evidenced by marked fluid retention (fluid net balance), decreased plasma protein with decreased plasma oncotic pressure, and increased pulmonary microvascular pressure. All these changes were accompanied by 6- to 7-fold increase in plasma nitrite/nitrate and increased production of reactive nitrogen species in lung. The smoke inhalation alone had a little or no effect on these variables. This model closely mimics hyperdynamic human sepsis. The excessive production of NO may be extensively involved in the pathogenic process.
Shock 04/2008; 29(5):642-649. · 2.85 Impact Factor
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ABSTRACT: OBJECTIVE:: Acute lung injury is a detrimental complication for victims of burn accidents. Airway obstruction plays an important role in pulmonary dysfunction in these patients. In this study, we tested the hypothesis that aerosolized anticoagulants will reduce the degree of airway obstruction and improve pulmonary function in sheep with severe combined burn and smoke inhalation injury by preventing the formation of airway fibrin clots. DESIGN:: Prospective, randomized, controlled, experimental animal study. SETTING:: Investigational intensive care unit at a university hospital. SUBJECTS:: Adult female sheep. INTERVENTIONS:: After 7 days of surgical recovery, sheep were given a cutaneous burn (40% of total body surface, third degree) and insufflated with cotton smoke (48 breaths, <40 degrees C) under halothane anesthesia. After injury, sheep were placed on ventilators and resuscitated with lactated Ringer's solution. Sheep were randomly divided into five groups: sham, noninjured and nontreated (n = 6); control, injured and aerosolized with saline (n = 6); recombinant human antithrombin (rhAT) + heparin, injured and aerosolized with rhAT (290 units for each) and heparin (10,000 units for each) (n = 6); rhAT, injured and aerosolized with rhAT alone (290 units for each; n = 5); and heparin, injured and aerosolized with heparin alone (10,000 units for each; n = 5). rhAT and heparin were aerosolized every 4 hrs, starting at 2 hrs postinjury. MEASUREMENTS AND MAIN RESULTS:: Cardiopulmonary hemodynamics were monitored during 48-hr experimental time period. Control sheep developed multiple signs of acute lung injury. This pathophysiology included decreased pulmonary gas exchange and lung compliance, increased pulmonary edema, and extensive airway obstruction. These variables were stable in sham animals. The aerosolization of rhAT or heparin alone did not significantly improve deteriorated pulmonary gas exchange. However, aerosolization of these anticoagulants in combination significantly attenuated all the observed pulmonary pathophysiology. CONCLUSIONS:: The results provide definitive evidence that aerosolized rhAT and heparin in combination may be a novel treatment strategy for pulmonary pathology in burn victims with smoke inhalation injury.
Critical care medicine 10/2007; · 6.37 Impact Factor
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Critical Care Medicine 05/2007; 35(4):1212-3. · 6.33 Impact Factor
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Critical Care Medicine 05/2006; 34(4):1280-1. · 6.33 Impact Factor
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ABSTRACT: Introduction: A decrease in ?-tocopherol (vitamin E) plasma levels in burn patients is typically associated with increased mortality. We hypothesized that vitamin E supplementation (?-tocopherol) would attenuate acute lung injury induced by burn and smoke inhalation injury.Materials and Methods: Under deep anesthesia, sheep (33 ± 5 kg) were subjected to a flame burn (40% total body surface area, third degree) and inhalation injury (48 breaths of cotton smoke, < 40°C). Half of the injured group received ?-tocopherol (1000 IU vitamin E) orally, 24 h prior to injury. The sham group was neither injured nor given vitamin E. All three groups (n = 5 per group) were resuscitated with Ringer's lactate solution (4 ml/kg/%burn/24 h), and placed on a ventilator (PEEP = 5 cmH2O; tidal volume = 15 ml/kg) for 48 h.Results: Plasma ?-tocopherol per lipids doubled in the vitamin E treated sheep. Vitamin E treatment prior to injury largely prevented the increase in pulmonary permeability index and moderated the increase in lung lymph flow (52.6 ± 6.2 ml/min, compared with 27.3 ± 6.0 ml/min, respectively), increased the PaO2/FiO2 ratio, ameliorated both peak and pause airway pressure increases, and decreased plasma conjugated dienes and nitrotyrosine.Conclusions: Pretreatment with vitamin E ameliorated the acute lung injury caused by burn and smoke inhalation exposure.Introduction: A decrease in ?-tocopherol (vitamin E) plasma levels in burn patients is typically associated with increased mortality. We hypothesized that vitamin E supplementation (?-tocopherol) would attenuate acute lung injury induced by burn and smoke inhalation injury.Materials and Methods: Under deep anesthesia, sheep (33 ± 5 kg) were subjected to a flame burn (40% total body surface area, third degree) and inhalation injury (48 breaths of cotton smoke, < 40°C). Half of the injured group received ?-tocopherol (1000 IU vitamin E) orally, 24 h prior to injury. The sham group was neither injured nor given vitamin E. All three groups (n = 5 per group) were resuscitated with Ringer's lactate solution (4 ml/kg/%burn/24 h), and placed on a ventilator (PEEP = 5 cmH2O; tidal volume = 15 ml/kg) for 48 h.Results: Plasma ?-tocopherol per lipids doubled in the vitamin E treated sheep. Vitamin E treatment prior to injury largely prevented the increase in pulmonary permeability index and moderated the increase in lung lymph flow (52.6 ± 6.2 ml/min, compared with 27.3 ± 6.0 ml/min, respectively), increased the PaO2/FiO2 ratio, ameliorated both peak and pause airway pressure increases, and decreased plasma conjugated dienes and nitrotyrosine.Conclusions: Pretreatment with vitamin E ameliorated the acute lung injury caused by burn and smoke inhalation exposure.
Redox Report 03/2006; 11(2):61-70. · 1.73 Impact Factor
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Gisele V Oliveira,
Katsumi Shimoda,
Perenlei Enkhbaatar,
Jeff Jodoin,
A S Burke,
D L Chinkes,
Hal K Hawkins,
David N Herndon,
Lillian Traber, Daniel Traber,
Kazunori Murakami
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ABSTRACT: Local and systemic inflammation can lead to progression of burn wounds, converting second- to third-degree wounds or extending the burn to adjacent areas. Previous studies have suggested that the skin is an important site of production of nitric oxide (NO), synthesized by inducible nitric oxide synthase (iNOS) activation after injury. NO increases in burned wounds, but its formation in noninjured skin has not been investigated. We hypothesized that after severe burns, NO and cytotoxic peroxynitrite would increase in noninjured skin. We also tested the hypothesis that BBS-2, a specific inhibitor of iNOS, would impair NO formation after burn. Thirteen female sheep were randomized into burn injury and smoke inhalation (n = 5, group 1), burn and smoke treated with BBS-2 (n = 3, group 2), and sham (saline treatment, no injury) (n = 5, group 3). All the animals, including the sham-injury group, were mechanically ventilated for 48 h. Samples of nonburned skin and plasma were collected from each animal, and levels of NO and its metabolites were evaluated using a NO chemiluminescent detector. Nitrotyrosine and iNOS expression were determined in the skin by Immunoperoxidase staining, and scoring of masked slides (epidermis, hair follicles, vessels, glands, and stroma) was performed. Skin NO and metabolites significantly increased in the burn and smoke injury group, and this was inhibited by BBS-2. Nitrotyrosine expression also increased significantly in the skin of burned animals. BBS-2 prevented the increase of NOx but not the increase of nitrotyrosine expression in skin. Plasma levels of NO increased in burned animals when compared with sham, but this increase was not significant. The increase of NO and its metabolites after burn in noninjured skin is followed by a significant increase in peroxynitrite, a potent cytotoxic mediator.
Shock 10/2004; 22(3):278-82. · 2.85 Impact Factor
