Karen E. Lynch

Depressed Bronchoalveolar Urokinase Activity in Patients with Adult Respiratory Distress Syndrome

Abundant deposition of bronchoalveolar fibrin and fibronectin occurs during the exudative phase of the adult respiratory distress syndrome (ARDS), promoting hyaline-membrane formation and subsequent alveolar fibrosis. To explore the mechanisms that account for the persistence of bronchoalveolar fibrin and fibronectin, we compared the activity of urokinase, which is necessary for plasminogen activation and fibrin degradation, in cell-free bronchoalveolar-lavage fluid from 8 patients with ARDS, 9 patients with acute pulmonary diseases other than ARDS, and 10 normal subjects. The mean level of urokinase activity in the lavage fluid from the patients with ARDS was 0.003 IU per milliliter of fluid (range, 0 to 0.008), which was significantly lower (P = 0.001) than the level in the fluid from either the patients with pulmonary diseases other than ARDS (0.118 IU per milliliter [range, 0.032 to 0.295]) or the normal subjects (0.129 IU per milliliter [range, 0.045 to 0.198]). The lavage fluid from all the patients with ARDS also had antiplasmin activity, which would promote the persistence of fibrin. A true decrease in urokinase activity was confirmed by the failure of the lavage fluid from the patients with ARDS to convert [125I]plasminogen to plasmin. Despite the low urokinase activity, immunochemical assays revealed normal levels of urokinase antigen in the fluid from the patients with ARDS, suggesting the presence of urokinase inhibitors. Inhibitors were demonstrated directly by a fibrin gel-underlay assay that detects complexes of urokinase with inhibitors. Plasminogen-activator inhibitor type 1 was the principal inhibitor identified. We conclude that increased antifibrinolytic activity due to both urokinase inhibitors and antiplasmins in the bronchoalveolar compartment of patients with ARDS contributes to the formation and persistence of hyaline membranes, a key component of alveolar histopathology in ARDS.

Myocardial Perfusion as Assessed by Thallium-201 Scintigraphy during the Discontinuation of Mechanical Ventilation in Ventilator-dependent Patients

Patients who cannot be separated from mechanical ventilation (MV) after an episode of acute respiratory failure often have coexisting coronary artery disease. The authors hypothesized that increased left ventricular (LV) wall stress during periods of spontaneous ventilation (SV) could alter myocardial perfusion in these patients. Using thallium-201 (201TI) myocardial scintigraphy, the authors studied the occurrence of myocardial perfusion abnormalities during periods of SV in 15 MV-dependent patients (nine women, six men; aged 71 +/- 7 yr, mean +/- SD). Fourteen of these patients were studied once with 201TI myocardial scintigraphy during intermittent mechanical ventilation (IMV) and again on another day, after at least 10 min of SV through a T-piece. One patient was studied during SV only. Thirteen of 14 of the patients (93%) studied during MV had abnormal patterns of initial myocardial 201TI uptake, but only 1 patient demonstrated redistribution of 201TI on delayed images. The remainder of the abnormalities observed during MV were fixed defects. SV produced significant alterations of myocardial 201TI distribution or transient LV dilation, or both, in 7 of the 15 patients (47%). Four patients demonstrated new regional decreases of LV myocardial thallium concentration with redistribution of the isotope on delayed images. The patient studied only during SV also had myocardial 201TI defects with redistribution. Five patients (3 also having areas of 201TI redistribution) had transient LV dilation during SV.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of Recombinant Human Erythropoietin on Transfusion Risk in Coronary Bypass Patients

BACKGROUND Patients having a cardiac operation frequently require allogeneic blood transfusions despite surgical blood-conservation techniques. Recombinant human erythropoietin (Epoetin alfa) may augment this conservation by stimulating erythropoiesis. The safety and efficacy of perioperative use of Epoetin alfa to reduce the need of allogeneic transfusion was studied. METHODS A multicenter double-blind, placebo-controlled, parallel-group study involved 182 patients having coronary artery bypass grafting and randomized to receive Epoetin alfa (300 or 150 IU/kg) or placebo subcutaneously for 5 days before, on the day of, and for 2 days after operation. RESULTS Perioperative Epoetin alfa resulted in greater increases in baseline to preoperative hemoglobin levels and hematocrit (300 IU/kg) and in presurgery to postsurgical day 1 reticulocyte counts versus placebo (p < or = 0.05). However, there was no significant difference in transfusion requirements. Incidences of adverse events were similar in all study groups. CONCLUSIONS Lower incidences of allogeneic blood exposure were observed in both Epoetin alfa-treated groups; however, the differences between all treatment groups were not significant. This was probably due to the relatively short 5-day preoperative course of Epoetin alfa therapy. There were no significant differences between the three groups relative to safety. Epoetin alfa was well tolerated in this population.

Bedside Measurement of Pulmonary Capillary Pressure in Patients with Acute Respiratory Failure

In this report, the authors present the results of 34 estimates of pulmonary capillary pressure (Pcap) in 15 adult patients receiving intensive care for acute respiratory failure (ARF). Within the pulmonary artery pressure profile during transient balloon occlusion, the authors identified two exponential pressure decay components-the slower one representing the discharge of the pulmonary capillary pressure through the pulmonary venous resistance. By extrapolating this exponential to its origin at the moment of pulmonary artery occlusion, a pressure within the pulmonary vascular bed which approximates pulmonary capillary pressure (Pcap) was identified. Pcap, and not the pulmonary artery occlusion pressure (PAOP), is the major driving pressure forcing fluid from the pulmonary microvasculature. The results indicate that a discrete value for pulmonary capillary pressure can be reproducibly measured in paralyzed ventilated patients. The data report that mean pulmonary artery pressure, pulmonary capillary pressure, and total pulmonary vascular resistance (PVR) are increased in acute respiratory failure, but there is considerable variation in the distribution of pulmonary vascular resistance between the arterial and venous beds. The data suggest that there is unequal and variable partitioning of the increased PVR during acute respiratory failure. Bedside pressure profile Pcap measurements will allow optimum reduction of Pcap during ARF by infusing vasoactive agents to modify the distribution of PVR or reducing the PAOP.

Aprotinin in primary valve replacement and reconstruction : A multicenter, double-blind, placebo-controlled trial

BACKGROUND Patients having cardiac operations often require blood transfusions. Aprotinin reduces the need for blood transfusions during coronary artery bypass graft operations. To determine the safety and effectiveness of aprotinin in reducing the use of allogeneic blood and postoperative mediastinal chest tube drainage, we studied 212 patients undergoing primary sternotomy for valve replacement or repair. METHODS This study was multicenter, randomized, prospective, double-blind, and placebo-controlled. Patients received high-dose aprotinin (n = 71), low-dose aprotinin (n = 70), or placebo (n = 71). The study medication was given as a loading dose followed by a continuous infusion and pump prime dose. Heparin administration was standardized. Transfusions, postoperative mediastinal shed blood, and adverse events were tracked. RESULTS Demographic profiles were similar among the treatment groups. Aprotinin did not decrease the percentage of patients receiving transfusions when compared with placebo (high-dose aprotinin, 63%, p = 0.092; low-dose aprotinin, 52%, p = 0.592; placebo, 48%). Aprotinin was associated with a reduction in the volume of mediastinal shed blood (high-dose aprotinin vs placebo, p = 0.002; low-dose aprotinin vs placebo, p = 0.017). Adverse events were equally distributed among the treatment groups except for postoperative renal dysfunction (high-dose aprotinin, 11%; low-dose aprotinin, 7%; placebo, 0%; p = 0.01). A disproportionate number of patients in the high-dose aprotinin group with postoperative renal dysfunction also had diabetes mellitus. CONCLUSIONS Aprotinin treatment in this population did not reduce allogeneic blood use, although there were significant reductions in the volume of mediastinal shed blood.

Recombinant platelet factor 4 reversal of heparin in human cardiopulmonary bypass blood

The ability of recombinant platelet factor 4, a protein of human origin with high heparin affinity, and the present clinical heparin reversal agent, protamine, to neutralize heparin in human whole blood was studied by means of three standard whole blood coagulation tests: whole blood clotting time, heparin assay, and activated clotting time. Ten subjects were chosen at random among patients undergoing cardiopulmonary bypass operations. Heparinized blood, free of protamine, was obtained from the bypass reservoir for testing. Whole blood aliquots, without reversal agents (controls) or with either protamine (10, 20, 30, or 40 micrograms/ml) or recombinant platelet factor 4 (10, 20, 40, or 80 micrograms/ml), were analyzed. The quantity of each agent required to reverse the ten samples, using 95% upper confidence bounds (t distribution) was determined for each method. Recombinant platelet factor 4 reversed heparin at 40 micrograms/ml and protamine at 20 micrograms/ml, suggesting a reversal ratio for recombinant platelet factor 4/protamine of 2:1 on a milligram basis. Further, currently available methods for testing coagulation should be reliable, without modification, to monitor the restoration of normal coagulation parameters with recombinant platelet factor 4 after cardiopulmonary bypass.

The influence of positive end-expiratory pressure on pulmonary blood volume changes in adult respiratory distress syndrome

Pathophysiologic changes associated with the Adult Respiratory Distress Syndrome (ARDS), such as the presence of pulmonary vascular occlusions, decreased vascular compressibility, or inceased intrapulmonary shunting, could limit the effect of positive end-expiratory pressure (PEEP) upon pulmonary blood volume (PBV). Accordingly, we determined the effect of 5 and 15 cm H2O PEEP upon the PBV changes of normal volunteers (n = 9) and patients with moderate or severe ARDS associated with acute pulmonary hypertension (n = 10). Changes of PBV were estimated from equilibrium blood pool scans using Technetium-99m-labeled erythrocytes. The change of PBV induced by PEEP was assessed by measuring the count density over a region of the left lung during 0, 5, and 15 cm H2O continuous positive airway pressure in the volunteers and during mechanic ventilation with 5 and 15 cm H2O PEEP in the ARDS patients. Biventricular ejection fractions using gated blood pool angiocardiography and central hemodynamics were also measured in the ARDS patients. In volunteers, 5 and 15 cm H2O continuous positive airway pressure decreased pulmonary activity by 10% ± 4% and 24% ± 9%, respectively (mean ± SD, P = .0001). In ARDS patients, PBV appeared to be unaffected by decreasing PEEP from 15 to 5 cm H2O, despite an increased stroke volume, biventricular end-diastolic volume, and venous admixture. Pulmonary vascular resistance and right and left ventricular ejection fraction were unchanged. The ability of PEEP to reduce PBV appears to be decreased during acute lung injury.

Antithrombin III in Critically Ill Patients

To assess the role of antithrombin III (ATIII) in the thrombotic complications of acutely ill patients who suffered from septicemia or trauma, with or without evidence of acute lung injury, we measured the plasma concentration of ATIII-related antigen (ATIII:Ag) in 146 patients with acute lung injury and in 43 critically ill patients without lung injury. We found plasma ATIII:Ag levels of both groups of acutely ill patients to be significantly lower than those of normal subjects (n = 21). The plasma ATIII:Ag levels of patients with acute lung injury, however, were significantly higher than those without lung injury (P < .01). By separating post-trauma acutely ill patients with lung injury from those with septicemia, we noted that their plasma ATIII:Ag levels were identical to those of normal subjects despite activation of blood coagulation. This finding led us to examine ATIII functional activity (ATIII:Fn) and search for ATIII-enzyme(s) complexes in 46 patients with acute lung injury (30 patients with sepsis and 16 post-trauma patients) and in 12 acutely ill patients without lung injury (eight patients with sepsis and four post-trauma patients). These 58 patients were representative of the groups studied and had no evidence of hepatic or renal dysfunction. We found significantly reduced ATIII:Ag and ATIII:Fn in septic patients, with or without lung injury, as compared with the normal levels (P < .05). After trauma, patients with or without lung injury had normal ATIII:Ag, but the ATIII:Fn levels were disproportionately lower. Following trauma, the ATIII:Ag/ATIII:Fn ratio was significantly higher than in septicemia patients or in normal patients. Patients who died from septicemia and post-trauma had higher ATIII:Ag to ATIII:Fn ratios, while surviving patients had ATIII:Ag to ATIII:Fn ratios closer to normal. In addition, in all post-trauma or septicemia patients, there was evidence of ATIII-enzyme(s) complex formation by cross-immunoelectrophoresis despite ATIII levels and the presence or absence of acute lung injury. High ATIII:Ag to ATIII:Fn ratios and the presence of circulating ATIII:enzyme(s) complexes were associated with high mortality. The ATIII alterations, however, did not allow us to determine the presence of acute lung injury. The ATIII changes observed in our patients appeared to be primarily influenced by the differing pathways of blood activation that occurred in septicemia and trauma.