Chemically modified tetracycline 3 prevents acute respiratory distress syndrome in a porcine model of sepsis + ischemia/reperfusion-induced lung injury.

Experimental pharmacotherapies for the acute respiratory distress syndrome (ARDS) have not met with success in the clinical realm. We hypothesized that chemically modified tetracycline 3 (CMT-3), an anti-inflammatory agent that blocks multiple proteases and cytokines, would prevent ARDS and injury in other organs in a clinically applicable, porcine model of inflammation-induced lung injury. Pigs (n = 15) were anesthetized and instrumented for monitoring. A "2-hit" injury was induced: (a) peritoneal sepsis-by placement of a fecal clot in the peritoneum, and (b) ischemia/reperfusion-by clamping the superior mesenteric artery for 30 min. Animals were randomized into two groups: CMT-3 group (n = 7) received CMT-3 (200 mg/kg); placebo group (n = 9) received the same dose of a CMT-3 vehicle (carboxymethylcellulose). Experiment duration was 48 h or until early mortality. Animals in both groups developed polymicrobial bacteremia. Chemically modified tetracycline 3 treatment prevented ARDS as indicated by PaO(2)/FIO(2) ratio, static compliance, and plateau airway pressure (P < 0.05 vs. placebo). It improved all histological lesions of ARDS (P < 0.05 vs. placebo). The placebo group developed severe ARDS, coagulopathy, and histological injury to the bowel. Chemically modified tetracycline 3 treatment prevented coagulopathy and protected against bowel injury. It significantly lowered plasma concentrations of interleukin 1ß (IL-1ß), tumor necrosis factor α, IL-6, IL-8, and IL-10. This study presents a clinically relevant model of lung injury in which CMT-3 treatment prevented the development of ARDS due in part to reduction of multiple plasma cytokines. Treatment of sepsis patients with CMT-3 could significantly reduce progression from sepsis into ARDS.

Transverse sinus thrombosis after internal jugular vein ligation.

BACKGROUND: Cerebral vein and dural sinus thrombosis is a rare condition with a wide range of causes and a highly variable presentation. It can lead to significant morbidity, but scant literature is available describing diagnosis and treatment when this occurs after ligation of the internal jugular vein. OBJECTIVES: To discuss potential risk factors for cerebral vein and dural sinus thrombosis after ligation of the internal jugular vein, and present current options for diagnosis and treatment. CASE REPORT: A 23-year-old male construction worker was brought to the Emergency Department by Emergency Medical Services after sustaining a severe neck laceration from a hand-held grinder. He was treated with ligation of the left internal jugular vein, but subsequently developed severe headaches and symptoms of increased intracranial pressure. A magnetic resonance venogram of the head revealed a left transverse sinus thrombosis requiring treatment with anticoagulation. The placement of a lumboperitoneal shunt was ultimately needed for relief of his symptoms. CONCLUSIONS: Early diagnosis and aggressive therapeutic interventions are critical to prevent further morbidity in patients who develop cerebral vein and dural sinus thrombosis after ligation of the internal jugular vein.

Comparison of "open lung" modes with low tidal volumes in a porcine lung injury model.

BACKGROUND: Ventilator strategies that maintain an "open lung" have shown promise in treating hypoxemic patients. We compared three "open lung" strategies with standard of care low tidal volume ventilation and hypothesized that each would diminish physiologic and histopathologic evidence of ventilator induced lung injury (VILI). MATERIALS AND METHODS: Acute lung injury (ALI) was induced in 22 pigs via 5% Tween and 30-min of injurious ventilation. Animals were separated into four groups: (1) low tidal volume ventilation (LowVt -6 mL/kg); (2) high-frequency oscillatory ventilation (HFOV); (3) airway pressure release ventilation (APRV); or (4) recruitment and decremental positive-end expiratory pressure (PEEP) titration (RM+OP) and followed for 6 h. Lung and hemodynamic function was assessed on the half-hour. Bronchoalveolar lavage fluid (BALF) was analyzed for cytokines. Lung tissue was harvested for histologic analysis. RESULTS: APRV and HFOV increased PaO(2)/FiO(2) ratio and improved ventilation. APRV reduced BALF TNF-α and IL-8. HFOV caused an increase in airway hemorrhage. RM+OP decreased SvO(2), increased PaCO(2), with increased inflammation of lung tissue. CONCLUSION: None of the "open lung" techniques were definitively superior to LowVt with respect to VILI; however, APRV oxygenated and ventilated more effectively and reduced cytokine concentration compared with LowVt with nearly indistinguishable histopathology. These data suggest that APRV may be of potential benefit to critically ill patients but other "open lung" strategies may exacerbate injury.

A clinically applicable porcine model of septic and ischemia/reperfusion-induced shock and multiple organ injury.

BACKGROUND: Although many sepsis treatments have shown efficacy in acute animal models, at present only activated protein C is effective in humans. The likely reason for this discrepancy is that most of the animal models used for preclinical testing do not accurately replicate the complex pathogenesis of human sepsis. Our objective in this study was to develop a clinically applicable model of severe sepsis and gut ischemia/reperfusion (I/R) that would cause multiple organ injury over a period of 48 h. MATERIALS AND METHODS: Anesthetized, instrumented, and ventilated pigs were subjected to a "two-hit" injury by placement of a fecal clot through a laparotomy and by clamping the superior mesenteric artery (SMA) for 30 min. The animals were monitored for 48 h. Wide spectrum antibiotics and intravenous fluids were given to maintain hemodynamic status. FiO(2) was increased in response to oxygen desaturation. Twelve hours following injury, a drain was placed in the laparotomy wound. Extensive hemodynamic, lung, kidney, liver, and renal function measurements and serial measurements of arterial and mixed venous blood gases were made. Bladder pressure was measured as a surrogate for intra-peritoneal pressure to identify the development of the abdominal compartment syndrome (ACS). Plasma and peritoneal ascites cytokine concentration were measured at regular intervals. Tissues were harvested and fixed at necropsy for detailed morphometric analysis. RESULTS: Polymicrobial sepsis developed in all animals. There was a progressive deterioration of organ function over the 48 h. The lung, kidney, liver, and intestine all demonstrated clinical and histopathologic injury. Acute lung injury (ALI) and ACS developed by consensus definitions. Increases in multiple cytokines in serum and peritoneal fluid paralleled the dysfunction found in major organs. CONCLUSION: This animal model of Sepsis+I/R replicates the systemic inflammation and dysfunction of the major organ systems that is typically seen in human sepsis and trauma patients. The model should be useful in deciphering the complex pathophysiology of septic shock as it transitions to end-organ injury thus allowing sophisticated preclinical studies on potential treatments.

Titration of mean airway pressure and FiO2 during high frequency oscillatory ventilation in a porcine model of acute lung injury.

BACKGROUND: High frequency oscillatory ventilation (HFOV) is frequently utilized for patients with acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). However, precise criteria to titrate mean airway pressure (mPaw) and FiO(2) as the patient's condition improves are lacking. We hypothesized that reducing mPaw and FiO(2) too quickly after reaching target arterial oxygen saturation levels would promote ventilator induced lung injury (VILI). MATERIALS AND METHODS: ALI was induced by instilling 3% Tween 20. Pigs were placed supine and received 30 min of nonprotective ventilation. Pigs were separated into two groups: HFOV constant (HFOVC, n = 3) = constant mPaw and FiO(2) for the duration; HFOV titrated (HFOVT, n = 4) = FiO(2) and/or mPaw were reduced every 30 min if the oxygen saturation remained between 88%-95%. Hemodynamic and pulmonary measurements were made at baseline, after lung injury, and every 30 min during the 6-h study. Lung histopathology was determined by quantifying alveolar hyperdistension, fibrin, congestion, atelectasis, and polymorphonuclear leukocyte (PMN) infiltration. RESULTS: Oxygenation was significantly lower in the HFOVT group compared to the HFOVC group after 6 h. Lung histopathology was significantly increased in the HFOVT group in the following categories: PMN infiltration, alveolar hyperdistension, congestion, and fibrin deposition. CONCLUSIONS: Rapid reduction of mPaw and FiO(2) in our ALI model significantly reduced oxygenation, but, more importantly, caused VILI as evidenced by increased lung inflammation and alveolar hyperdistension. Specific criteria for titration of mPaw and inspired oxygen are needed to maximize the lung protective effects of HFOV while maintaining adequate gas exchange.

Peritoneal negative pressure therapy prevents multiple organ injury in a chronic porcine sepsis and ischemia/reperfusion model.

Sepsis and hemorrhage can result in injury to multiple organs and is associated with an extremely high rate of mortality. We hypothesized that peritoneal negative pressure therapy (NPT) would reduce systemic inflammation and organ damage. Pigs (n = 12) were anesthetized and surgically instrumented for hemodynamic monitoring. Through a laparotomy, the superior mesenteric artery was clamped for 30 min. Feces was mixed with blood to form a fecal clot that was placed into the peritoneum, and the abdomen was closed. All subjects were treated with standard isotonic fluid resuscitation, wide spectrum antibiotics, and mechanical ventilation, and were monitored for 48 h. Animals were separated into two groups 12 h (T12) after injury: for NPT (n = 6), an abdominal wound vacuum dressing was placed in the laparotomy, and negative pressure (-125 mmHg) was applied (T12 - T48), whereas passive drainage (n = 6) was identical to the NPT group except the abdomen was allowed to passively drain. Negative pressure therapy removed a significantly greater volume of ascites (860 ± 134 mL) than did passive drainage (88 ± 56 mL). Systemic inflammation (e.g. TNF-α, IL-1ß, IL-6) was significantly reduced in the NPT group and was associated with significant improvement in intestine, lung, kidney, and liver histopathology. Our data suggest NPT efficacy is partially due to an attenuation of peritoneal inflammation by the removal of ascites. However, the exact mechanism needs further elucidation. The clinical implication of this study is that sepsis/trauma can result in an inflammatory ascites that may perpetuate organ injury; removal of the ascites can break the cycle and reduce organ damage.

Loss of airway pressure during HFOV results in an extended loss of oxygenation: a retrospective animal study.

BACKGROUND: Patients with acute respiratory distress syndrome (ARDS) are often ventilated with high airway pressure. Brief loss of airway pressure may lead to an extended loss of oxygenation. While using high frequency oscillatory ventilation (HFOV) in a porcine acute lung injury model, two animals became disconnected from the ventilator with subsequent loss of airway pressure. We compared the two disconnected animals to the two animals that remained connected to determine causes for the extended reduction in oxygenation. METHODS: ARDS was induced using 5% Tween. Thirty min of nonprotective ventilation (NPV) followed before placing the pigs on HFOV. Measurements were made at baseline, after lung injury, and every 30min during the 6-h study. Disconnections were treated by hand-ventilation and a recruitment maneuver before being placed back on HFOV. The lungs were histologically analyzed and wet/dry weights were measured to determine lung edema. RESULTS: Hemodynamics and lung function were similar in all pigs at baseline, after injury, and following NPV. The animals that remained connected to the oscillator showed a continued improvement in PaO(2)/FiO(2) (P/F) ratio throughout the study. The animals that experienced the disconnection had a significant loss of lung function that never recovered. The disconnect animals had more diffuse alveolar disease on histologic analysis. CONCLUSIONS: A significant fall in lung function results following disconnection from HFOV, which remains depressed for a substantial period of time despite efforts to reopen the lung. Dispersion of edema fluid is a possible mechanism for the protracted loss of lung function.

Plateau and transpulmonary pressure with elevated intra-abdominal pressure or atelectasis.

BACKGROUND: ARDSnet standards limit plateau pressure (Pplat) to reduce ventilator induced lung injury (VILI). Transpulmonary pressure (Ptp) [Pplat-pleural pressure (Ppl)], not Pplat, is the distending pressure of the lung. Lung distention can be affected by increased intra-abdominal pressure (IAP) and atelectasis. We hypothesized that the changes in distention caused by increases in IAP and atelectasis would be reflected by Ptp but independent of Pplat. METHODS: In Yorkshire pigs, esophageal pressure (Pes) was measured with a balloon catheter as a surrogate for Ppl under two experimental conditions: (1) high IAP group (n=5), where IAP was elevated by CO2 insufflation in 5 mm Hg steps from 0 to 30 mm Hg; and (2) Atelectasis group (n=5), where a double lumen endotracheal tube allowed clamping and degassing of either lung by O2 absorption. Lung collapse was estimated by increases in pulmonary shunt fraction. RESULTS: High IAP: Sequential increments in IAP caused a linear increase in Pplat (r2=0.754, P<0.0001). Ptp did not increase (r2=0.014, P=0.404) with IAP due to the concomitant increase in Pes (r2=0.726, P<0.0001). Partial Lung Collapse: There was no significant difference in Pplat between the atelectatic (21.83+/-0.63 cm H2O) and inflated lung (22.06+/-0.61 cmH2O, P<0.05). Partial lung collapse caused a significant decrease in Pes (11.32+/-1.11 mm Hg) compared with inflation (15.89+/-0.72 mm Hg, P<0.05) resulting in a significant increase in Ptp (inflated=5.97+/-0.72 mm Hg; collapsed=10.55+/-1.53 mm Hg, P<0.05). CONCLUSIONS: Use of Pplat to set ventilation may under-ventilate patients with intra-abdominal hypertension and over-distend the lungs of patients with atelectasis. Thus, Ptp must be used to accurately set mechanical ventilation in the critically ill.

The role of time and pressure on alveolar recruitment.

Inappropriate mechanical ventilation in patients with acute respiratory distress syndrome can lead to ventilator-induced lung injury (VILI) and increase the morbidity and mortality. Reopening collapsed lung units may significantly reduce VILI, but the mechanisms governing lung recruitment are unclear. We thus investigated the dynamics of lung recruitment at the alveolar level. Rats (n = 6) were anesthetized and mechanically ventilated. The lungs were then lavaged with saline to simulate acute respiratory distress syndrome (ARDS). A left thoracotomy was performed, and an in vivo microscope was placed on the lung surface. The lung was recruited to three recruitment pressures (RP) of 20, 30, or 40 cmH(2)O for 40 s while subpleural alveoli were continuously filmed. Following measurement of microscopic alveolar recruitment, the lungs were excised, and macroscopic gross lung recruitment was digitally filmed. Recruitment was quantified by computer image analysis, and data were interpreted using a mathematical model. The majority of alveolar recruitment (78.3 +/- 7.4 and 84.6 +/- 5.1%) occurred in the first 2 s (T2) following application of RP 30 and 40, respectively. Only 51.9 +/- 5.4% of the microscopic field was recruited by T2 with RP 20. There was limited recruitment from T2 to T40 at all RPs. The majority of gross lung recruitment also occurred by T2 with gradual recruitment to T40. The data were accurately predicted by a mathematical model incorporating the effects of both pressure and time. Alveolar recruitment is determined by the magnitude of recruiting pressure and length of time pressure is applied, a concept supported by our mathematical model. Such a temporal dependence of alveolar recruitment needs to be considered when recruitment maneuvers for clinical application are designed.