Metalloproteinase inhibition prevents acute respiratory distress syndrome.

BACKGROUND: The acute respiratory distress syndrome (ARDS) occurs in patients with clearly identifiable risk factors, and its treatment remains merely supportive. We postulated that patients at risk for ARDS can be protected against lung injury by a prophylactic treatment strategy that targets neutrophil-derived proteases. We hypothesized that a chemically modified tetracycline 3 (COL-3), a potent inhibitor of neutrophil matrix metalloproteinases (MMPs) and neutrophil elastase (NE) with minimal toxicity, would prevent ARDS in our porcine endotoxin-induced ARDS model. METHODS: Yorkshire pigs were anesthetized, intubated, surgically instrumented for hemodynamic monitoring, and randomized into three groups: (1) control (n = 4), surgical instrumentation only; (2) lipopolysaccharide (LPS) (n = 4), infusion of Escherichia coli lipopolysaccharide at 100 microg/kg; and (3) COL-3 + LPS (n = 5), ingestion of COL-3 (100 mg/kg) 12 h before LPS infusion. All animals were monitored for 6 h following LPS or sham LPS infusion. Serial bronchoalveolar lavage (BAL) samples were analyzed for MMP concentration by gelatin zymography. Lung tissue was fixed for morphometric assessment at necropsy. RESULTS: LPS infusion was marked by significant (P < 0.05) physiological deterioration as compared with the control group, including increased plateau airway pressure (P(plat)) (control = 15.7 +/- 0.4 mm Hg, LPS = 23.0 +/- 1.5 mm Hg) and a decrement in arterial oxygen partial pressure (P(a)O(2)) (LPS = 66 +/- 15 mm Hg, Control = 263 +/- 25 mm Hg) 6 h following LPS or sham LPS infusion, respectively. Pretreatment with COL-3 reduced the above pathophysiological changes 6 h following LPS infusion (P(plat) = 18.5 +/- 1.7 mm Hg, P(a)O(2) = 199 +/- 35 mm Hg; P = NS vs control). MMP-9 and MMP-2 concentration in BAL fluid was significantly increased between 2 and 4 h post-LPS infusion; COL-3 reduced the increase in MMP-9 and MMP-2 concentration at all time periods. Morphometrically LPS caused a significant sequestration of neutrophils and monocytes into pulmonary tissue. Pretreatment with COL-3 ameliorated this response. The wet/dry lung weight ratio was significantly greater (P < 0.05) in the LPS group (10.1 +/- 1.0 ratio) than in either the control (6.4 +/- 0.5 ratio) or LPS+COL-3 (7.4 +/- 0.6 ratio) group. CONCLUSIONS: A single prophylactic treatment with COL-3 prevented lung injury in our model of endotoxin-induced ARDS. The proposed mechanism of COL-3 is a synergistic inhibition of the terminal neutrophil effectors MMPs and NE. Similar to the universal practice of prophylaxis against gastric stress ulceration and deep venous thromboses in trauma patients, chemically modified tetracyclines may likewise be administered to prevent acute lung injury in critically injured patients at risk of developing ARDS.

Complex reconstruction of the aortic and mitral annuli: a simplification.

Simultaneous reconstruction of the aortic and mitral annuli is a useful but complex procedure. Implantation of a bovine pericardial gusset can be facilitated by ex vivo attachment to the sewing ring of the mitral valve prosthesis.

The mechanism of lung volume change during mechanical ventilation.

To understand ventilator-induced lung injury (VILI) during positive pressure ventilation, mechanisms of normal alveolar mechanics must first be established. Isotropic "balloonlike" alveolar volume (VA) change has been viewed as the prevailing mechanism of normal lung volume (VL) changes. We hypothesized that change in VL is predominantly caused by alveolar recruitment-derecruitment (R/D). Fifteen mongrel dogs were anesthetized and intubated with a tracheal divider. Through a thoracotomy incision, in vivo microscopy of subpleural alveoli was performed as the degassed lung was inflated to 80% TLC, and then deflated to residual volume (RV). Still photomicrographs were evaluated to determine if change in VL is due to change in VA or R/D of alveoli. We noted a steady, significant increase in alveolar recruitment as VL increased to 80% TLC (p < 0.05). However, VA increased significantly, but only to 20% TLC (p < 0.05). Once recruited, alveoli did not demonstrate any further volume change, whereas the lung as a whole maintained a normal pressure/volume relationship. In our model, changes in VL predominantly are caused by R/D.

Matrix metalloproteinase inhibitor prevents acute lung injury after cardiopulmonary bypass.

BACKGROUND: Acute lung injury (ALI) after cardiopulmonary bypass (CPB) results from sequential priming and activation of neutrophils. Activated neutrophils release neutral serine, elastase, and matrix metalloproteinases (MMPs) and oxygen radical species, which damage alveolar-capillary basement membranes and the extracellular matrix, resulting in an ALI clinically defined as adult respiratory distress syndrome (ARDS). We hypothesized that treatment with a potent MMP and elastase inhibitor, a chemically modified tetracycline (CMT-3), would prevent ALI in our sequential insult model of ALI after CPB. METHODS AND RESULTS: Anesthetized Yorkshire pigs were randomized to 1 of 5 groups: control (n=3); CPB (n=5), femoral-femoral hypothermic bypass for 1 hour; LPS (n=7), sham bypass followed by infusion of low-dose Escherichia coli lipopolysaccharide (LPS; 1 microgram/kg); CPB+LPS (n=6), both insults; and CPB+LPS+CMT-3 (n=5), both insults plus intravenous CMT-3 dosed to obtain a 25-micromol/L blood concentration. CPB+LPS caused severe lung injury, as demonstrated by a significant fall in PaO(2) and an increase in intrapulmonary shunt compared with all groups (P<0.05). These changes were associated with significant pulmonary infiltration of neutrophils and an increase in elastase and MMP-9 activity. CONCLUSIONS: All pathological changes typical of ALI after CPB were prevented by CMT-3. Prevention of lung dysfunction followed an attenuation of both elastase and MMP-2 activity. This study suggests that strategies to combat ARDS should target terminal neutrophil effectors.

Reconstruction of the mitral and aortic annuli for advanced management of the Shone complex.

Shone's complex is a congenital cardiac abnormality which consists of surpravalvular mitral ring, parachute mitral valve, subaortic stenosis and aortic coarctation. Initial operative management has traditionally proven difficult, with multiple procedures often necessary to control symptoms. Advanced management had required a careful, individual approach based on both clinical and anatomic patient presentation. We present the first patient in whom mitral and aortic annular reconstruction with bovine pericardial gussets was successful in managing the late sequelae of Shone complex.

Videomicroscopy provides accurate in vivo assessment of pulmonary microvascular reactivity in rabbits.

When defining the mechanism of hypoxic pulmonary vasoconstriction (HPV), investigators have employed ex vivo preparations because of the belief that accurate, quantitative assessment of pulmonary microvessels could not be obtained in vivo. We hypothesize that accurate, quantitative assessment of pulmonary microvascular reactivity can be performed using a simple, in vivo preparation. Our aim was to provide this quantitative assessment in a defined animal model, and to confirm that the chosen preparation could discriminate changes in microvascular reactivity as influenced by endogenous mediators. New Zealand rabbits were instrumented for in vivo microscopy and direct measurement of subpleural arterioles. Rabbits were first randomized to either control (n = 7) or endotoxin (n = 5), infusion of Escherichia coli lipopolysaccharide (200 Fg/kg). All rabbits were then exposed to a repeated protocol of normoxia (21% O2) for 20 min and then hypoxia (15% O2) for 10 min over 2 h. The changes in arteriole diameter were measured at the end of each interval. Normal pulmonary arterioles repeatedly constrict 15+/-3.5% during hypoxia. Altering endogenous vasoactive mediators, as with infusion of endotoxin, caused a loss of hypoxia-induced vasoconstriction. The results of our study validate this experimental preparation for the reliable quantification of pulmonary microvascular reactivity and investigation of hypoxic pulmonary vasoconstriction under both normal and pathologic conditions.

Multiple sequential insults cause post-pump syndrome.

BACKGROUND: We hypothesize that post-pump syndrome (PPS) following cardiopulmonary bypass (CPB) can be caused by multiple minor insults and that the mechanism of PPS is a priming and subsequent activation of polymorphonuclear (PMN) leukocytes. In this study extensive pathophysiologic and morphometric assessment was undertaken in a porcine model of sequential insult PPS. METHODS: Pigs were anesthetized, placed on a ventilator, instrumented for measurements of hemodynamic function, and separated into five groups: (1) Control (n = 4)--surgery only, (2) CPB (n = 4)--placed on femoral-femoral hypothermic (28 degrees C) bypass for 1 h, (3) LPS (n = 6)--underwent sham CPB followed by infusion of low dose endotoxin [E. coli lipopolysaccharide (LPS-1 microg/kg)], (4) Heparin + protamine + LPS (HP + LPS, n = 4)--were heparinized without CPB for 1 h, following which protamine and LPS were infused and (5) CPB + LPS (n = 8)--subjected to both CPB and LPS. RESULTS: Only CPB + LPS resulted in acute respiratory distress typical of PPS as indicated by a significant decrease in PaO2 and increase in intrapulmonary shunt fraction (p<0.05). CPB + LPS significantly increased tissue density and the number of sequestered monocytes and PMNs (p<0.05) above all other groups. Alveolar macrophages (AM) increased equally in all groups receiving LPS. CONCLUSIONS: CPB primes the inflammatory system causing pulmonary PMN sequestration without lung injury. Exposure to an otherwise benign dose of endotoxin results in activation of the sequestered PMNs causing PPS. This study confirms that PPS can be caused by multiple minor insults.

Soluble tumor necrosis factor receptor prevents post-pump syndrome.

Post-pump syndrome is an acute lung injury following cardiopulmonary bypass (CPB) which is indistinguishable from the adult respiratory distress syndrome (ARDS). Tumor necrosis factor (TNF) is central to the inflammatory process and is capable of triggering the entire pathophysiologic response leading to ARDS. We hypothesized that treatment with a soluble TNF receptor-binding protein (TNFbp) would reduce the increase in serum TNF and prevent acute lung injury in our sequential insult model of ARDS following CPB. Anesthetized pigs were randomized to one of three groups: Control (n = 3), surgical preparation only; CPB + LPS (n = 6), femoral-femoral hypothermic bypass for 1 h followed by infusion of low dose Escherichia coli lipopolysaccharide (LPS; 1 microg/kg); and TNFbp + CPB + LPS (n = 4), pretreatment with intravenous TNFbp (2 mg/kg) followed immediately by both insults. CPB + LPS caused severe lung injury demonstrated by a significant fall in PaO2 and an increase in both intrapulmonary shunt and peak airway pressure as compared to all groups (P < 0.05). These changes were associated with a significant increase in plasma TNF level and pulmonary neutrophil sequestration. TNFbp significantly reduced plasma levels of TNF and prevented the lung injury typically observed with this ARDS model, but did not reduce pulmonary neutrophil sequestration. Thus, elevated serum TNF is not responsible for neutrophil sequestration but does play a role in neutrophil activation which causes lung injury. Prophylactic use of TNFbp in CPB patients may prevent neutrophil activation and reduce the incidence of post-pump ARDS.

Matrix metalloproteinase inhibitor: differential effects on pulmonary neutrophil and monocyte sequestration following cardiopulmonary bypass.

UNLABELLED: Acute respiratory distress syndrome (ARDS) following cardiopulmonary bypass (CPB), also known as "post-pump" or "post-perfusion syndrome" (PPS), results from sequential priming and activation of neutrophils. We hypothesized that chemically modified tetracycline (CMT-3) an inhibitor of neutrophil matrix metalloproteinase (MMP) and elastase, would prevent PPS. We performed histometric analysis of lung tissue from our porcine PPS model to correlate cellular sequestration and histologic injury with CMT-3 treatment. METHODS: Yorkshire pigs were randomized into five groups: Control (n = 3); CPB (n = 5); femoral-femoral bypass 1 hour; LPS (n = 7), Escherichia coli lipopolysaccharide (1 microgram/kg); CPB + LPS (n = 6); and CPB + LPS + CMT (n = 5), sequential insults and CMT-3. Protocol histometric analysis defined cellular and tissue components of lung injury. RESULTS: CMT-3 decreased neutrophil sequestration in the CPB + LPS + CMT-3 group (p < 0.0001 vs. CPB + LPS). There were no differences in monocytes between CPB + LPS and CPB + LPS + CMT treatment groups. CONCLUSIONS: CMT-3 attenuates neutrophil sequestration but has no effect on mononuclear sequestration in our PPS model. This finding supports current research on leukocyte chemokines and has important implications regarding mechanisms of CMT-3. Despite lack of monocyte response to CMT-3, PPS was prevented by inhibiting neutrophils alone; confirming the primary role of neutrophils in PPS.

Endotoxin-stimulated alveolar macrophage recruitment of neutrophils and modulation with exogenous surfactant.

OBJECTIVE: To determine whether endotoxin-stimulated alveolar macrophages would attract neutrophils and whether exogenous surfactant treatment would modulate this chemoattraction. DESIGN: Alveolar macrophages were harvested from bronchoalveolar lavage fluid and neutrophils from the blood of anesthetized guinea pigs. SUBJECTS: Hartley guinea pigs. INTERVENTIONS: Alveolar macrophages were suspended in RPMI 1640 and stimulated with 1 microg/mL of lipopolysaccharide (LPS), the supernatant removed and the alveolar macrophages were incubated in either RPMI or RPMI with surfactant at two different doses (292 microg/mL or 875 microg/mL) for 16 hrs. MEASUREMENTS AND MAIN RESULTS: The supernatant was extracted from the alveolar macrophages and placed in a chemotaxis plate and the migration of neutrophils was measured. Chemotaxis of all cell types to be tested was measured by a change of absorbance on a microplate reader set at 492 nm. Results were compared with alveolar macrophages not stimulated with LPS, RPMI alone, and N formyl-methionyl-leucyl-phenylalanine (FMLP). The supernatant of the stimulated alveolar macrophages increased neutrophil chemotaxis as compared with unstimulated alveolar macrophages, and RPMI (p < .05). Surfactant treatment with 292 microg/mL significantly decreased LPS-stimulated alveolar macrophages induced neutrophil chemotaxis. Treatment with 875 microg/mL of surfactant did not alter neutrophil chemotaxis. CONCLUSIONS: Alveolar macrophages stimulation with LPS increased the chemotaxis of neutrophils. Treatment with surfactant at a concentration of 875 microg/mL did not alter neutrophil migration; however, treatment with 292 microg/mL significantly decreased neutrophil chemotaxis suggesting that at low concentrations, surfactant inhibits chemokine release and may reduce pulmonary neutrophil sequestration in vivo.

Obstructed tracheal bronchus as a cause of post-obstructive pneumonia.

This article describes a case of obstructed supernumerary tracheal bronchus with partial atelectasis and pneumonia of the right upper lobe, diagnosed using trispiral tomograms. An obstructing broncholith, a supernumerary tracheal bronchus, and granulation tissue mass extruding from the bronchus were confirmed by resection of the pulmonary segment.

Paranasal sinusitis: cryptic sepsis after coronary artery bypass operations.

Infections occurred in 52 of 400 patients (13%) undergoing coronary artery bypass operations from January 1987 to December 1990. The hospital courses of 5 patients (1.3%) in whom occult infections of the paranasal sinuses developed were reviewed. Only 1 patient had specific clinical findings of acute sinusitis (purulent nasal discharge). Computed tomography showed wall thickening, opacification, or air-fluid levels in one or more paranasal sinuses in each patient. All patients were successfully treated with surgical drainage and antibiotics. Risk factors for development of postoperative acute sinusitis include: prolonged tracheal intubation, airway colonization with nosocomial bacteria, inability to clear nasal secretions, sinus ostial obstruction, and critical organ system dysfunction. Physical examination and roentgenographic evaluation of the paranasal sinuses should be considered when postoperative sepsis of obscure etiology occurs.

Role of autogenous tissue factors in hemolysis during cardiopulmonary bypass operations.

Pericardial fluid has been implicated as a causative factor in hemolysis during cardiopulmonary bypass operations. Preoperative blood samples were obtained from 10 patients undergoing coronary artery bypass grafting for ischemic myocardial disease. Whole blood samples were separately incubated with autogenous pericardial fluid, pericardium, pleura, vein, skeletal muscle, and fat harvested during the operative intervention. The plasma fraction was separated by centrifugation and assayed for serum free hemoglobin. Statistical analysis was accomplished by the Bonferroni technique to adjust for multiple comparisons. Pericardial fluid-induced hemolysis was least (20.7 mg/dL). Pleura and muscle contributed significantly to the serum free hemoglobin level (56.3 and 112.3 mg/dL, respectively; p < 0.05). Pericardium, vein, and fat did not cause significant elevations of the serum free hemoglobin level. Postbypass hemolysis is an important management consideration that may be minimized by delicate tissue manipulation and attention to minimizing tissue trauma. Avoidance of aspiration of pericardial fluid into the autotransfusion system is not supported.

Sepsis after coronary bypass grafting: evidence for loss of the gut mucosal barrier.

Postoperative infections may originate from a patient's gastrointestinal tract. We studied infections after coronary artery revascularization. Three hundred twenty-nine patients underwent coronary artery revascularization from January 1987 to March 1990. Eight of the 329 (2.4%) died; none of the deaths were infection related. Fifty-five culture-proven infections were identified in 22 of 321 survivors (6.8%); 9 infections (16%) were gram-positive, 5 (9%) were fungal, and 41 (75%) were gram-negative. Site of infections were respiratory tract, 58%; urinary tract, 18%; blood, 13%; and mediastinum, 11%. Ninety-six percent of respiratory tract and all urinary tract infections were gram-negative or fungal. There was no significant difference between infected and noninfected groups in sex, age, smoking history, preoperative hematocrit or leukocyte count, serum albumin level, or time on extracorporeal bypass. The infected group required intubation and nasogastric suction for a significantly longer time than the noninfected group (p less than 0.001). Time to enteral alimentation was significantly longer in the infected group (p less than 0.02). We were unable to correlate the number of infections with the lengths of intubation, nasogastric suction, or time to enteral alimentation. This study supports the concept of postoperative infections arising from bacterial translocation across the patient's gastrointestinal tract. The most significant risk factor is the length of the gastrointestinal tract disuse.

Cardiac missiles. A review of the literature and personal experience.

The management of retained missiles in the heart is still controversial. In an attempt to define the issue more clearly, the reported cases in the English literature from 1940 to 1988 (group 1) and our experience from 1968 to 1988 (group 2) were reviewed. In group 1 there were 222 missiles retained in the hearts of 201 patients. The retained missiles were 45 bullets in 45 patients, 109 shrapnel in 99 patients, 18 pellets in 7 patients, and 50 unidentified missiles in 50 patients. Thirteen of the missiles were completely embedded intramyocardial missiles, 122 were partially intramyocardial, 47 were free in a cardiac chamber, and 40 were intrapericardial. One hundred four of the missiles were removed and 118 were left in place. In group 2 there were 24 missiles, 18 bullets, 1 bullet fragment, and 5 pellets retained in the hearts of 24 patients. Ten missiles were removed, no attempt was made in 13 patients, and an unsuccessful attempt was made to remove one other. From group 1 patients, 6 died, 2 with intracavitary missiles, 3 patients with partially intramyocardial, and 1 patient with an intrapericardial missile, all of whom had either unsuccessful or no attempt to remove the missile. Twenty-seven patients had symptoms, all of whom, except two, had either unsuccessful or no attempt to remove the missile. All group 2 patients did well and had been free of symptoms related to the missiles. This review suggests that the management of missiles in the heart should be individualized according to the patient's clinical course, the site, shape, and size of the missile, and that in selected patients missiles in the heart are tolerated well.

Surgery for high cervical esophageal carcinoma: experience with 11 patients.

The treatment of carcinoma of the cervical esophagus remains controversial. Eleven patients with carcinoma of the high cervical esophagus were encountered over the past 7 years at our institution. There were 6 men and 5 women whose ages ranged from 51 to 72 years. Six patients had tracheal or laryngeal invasion. In all instances one-stage pharyngolaryngoesophagectomy with pharyngogastric (6 patients) or pharyngocolic (5 patients) reconstruction was performed. There was one hospital death. Six patients died 6 to 35 months postoperatively: 1 from recurrence, 2 from generalized metastases, and 3 with both local recurrent and metastatic disease. One other patient died free of disease 6 weeks postoperatively of pneumonia. The remaining 3 patients are alive 12 to 84 months after operation with excellent rehabilitation and good quality of life. We conclude that one-stage surgical resection and reconstruction for high cervical carcinoma of the esophagus offers good palliation and possible long-term survival with acceptable operative risk.

Missiles in the heart.

The records of 24 patients who had a missile retained in the heart and who were treated at Grady Memorial Hospital from 1968 to 1987 were reviewed. In 22, the missile lodged in the heart after its direct injury and in the remaining 2, after the bullet injured a systemic vein. Immediately after the cardiac injury, 7 of the 22 patients were seen with cardiac tamponade (3 also had hemothorax), 11 were seen with hemothorax, 5 were asymptomatic, and 1 was in shock. Seven patients underwent emergency thoracotomy; the bullet was removed in 3, but in the remaining 4 patients, it was not located. In the other 17 patients and in the 4 in whom the bullet could not be found during emergency thoracotomy, the diagnosis was suspected from the chest roentgenograms and confirmed by cardiac fluoroscopy or angiocardiography. Eight patients with retained bullets underwent elective operation; the bullet was removed from 7 and in 1 it was left embedded in the right ventricular septum. All 10 patients who underwent excision of the missile recovered without complication except 1 in whom pericarditis developed, and all were followed for up to 17 years. All 14 patients with a retained missile in the heart had no cardiac symptoms referable to the bullet and were followed for up to 15 years. This experience suggests that the management of patients with a bullet of .38 caliber or smaller that is retained in the heart should be individualized according to the patient's clinical course and the site of the bullet and that in select patients, bullets left in the heart are tolerated well.