Biomedical subjects
D J Dries
Publications and source records attributed to D J Dries.
Dynamic behavior during noninvasive ventilation: chaotic support?
Acute noninvasive ventilation is generally applied via face mask, with modified pressure support used as the initial mode to assist ventilation. Although an adequate seal can usually be obtained, leaks frequently develop between the mask and the patient's face. This leakage presents a theoretical problem, since the inspiratory phase of pressure support terminates when flow falls to a predetermined fraction of peak inspiratory flow. To explore the issue of mask leakage and machine performance, we used a mathematical model to investigate the dynamic behavior of pressure-supported noninvasive ventilation, and confirmed the predicted behavior through use of a test lung. Our mathematical and laboratory analyses indicate that even when subject effort is unvarying, pressure-support ventilation applied in the presence of an inspiratory leak proximal to the airway opening can be accompanied by marked variations in duration of the inspiratory phase and in autoPEEP. The unstable behavior was observed in the simplest plausible mathematical models, and occurred at impedance values and ventilator settings that are clinically realistic.
Sublethal endotoxemia promotes pulmonary cytokine-induced neutrophil chemoattractant expression and neutrophil recruitment but not overt lung injury in neonatal rats.
Gram-negative sepsis and septic shock remain major causes of morbidity and mortality in the newborn. Respiratory failure is a common feature in neonatal sepsis regardless of the presence or absence of associated pneumonia. In adult animal models, cytokine-induced neutrophil chemoattractant (CINC) is a potent chemoattractant for neutrophils and believed to play a role in endotoxin-induced lung injury. We examined this in a neonatal model. Ten-day-old Sprague-Dawley rats were injected with Salmonella enteritidis endotoxin (ETX) 0.03 mg/kg i.p. and sacrificed at baseline, 30 min, 1, 2, 4, 8 and 16 h post-ETX. Blood was collected by cardiac puncture. After bronchoalveolar lavage, lung tissue was collected and evaluated for neutrophil (polymorphonuclear leukocyte) recruitment by myeloperoxidase assay (MPO). Lung CINC expression was measured by Northern blot and ELISA. Peripheral blood leukocytosis was noted at 1 h (p < 0.001) with counts below baseline at 2 and 4 h. Differential counts revealed neutrophilia at 8 h (p < 0.001). MPO revealed pulmonary PMN recruitment peaking at 1 h (p < 0.05) and CINC RNA and protein expression peaked slightly later at 2 h (p < 0. 001). No overt lung injury was noted by bronchoalveolar lavage cell counts or by histology. Therefore, pulmonary CINC expression and neutrophil recruitment follows LPS exposure in neonatal rats. This may represent priming of the lung tissue and a secondary event may be necessary for injury to occur.
Blunt thoracic aortic injury: delayed or early repair?
OBJECTIVE: To evaluate the safety and benefit of delayed repair of blunt thoracic aortic injury (BTAI) in trauma patients with multiple injuries and to assess the financial impact of delayed repair. METHODS: A retrospective review of charts was performed on 55 patients with the diagnosis of BTAI from January 1, 1992, through December 31, 1997, at our Level I trauma center. Early repair was defined as operative repair of BTAI within 12 hours of admission. Seven patients were excluded from analysis due to death before BTAI diagnosis (two deaths were from rupture in the emergency department and five were from massive blunt trauma without rupture). The groups were compared by using a McNemar chi2 test, for which p less than or equal to 0.05 is significant. RESULTS: There were 30 patients in the early repair (ER) group repaired at 5.3+/-2.4 hours, and 18 patients in the delayed repair (DR) group repaired at 8.5 days (range, 17 hours-67 days). There were no significant differences between the ER and DR groups in age (37+/-18 years vs. 41+/-19 years), Injury Severity Score (39+/-15 vs. 45+/-14), intensive care unit days (12+/-14 days vs. 18+/-11 days), hospital length of stay (21+/-19 days vs. 28+/-14 days), or mortality rates (7% vs. 6%). There was a trend toward longer lengths of stay in the DR group. Most DR patients required beta-blocker therapy and/or other antihypertensives for systolic BP more than 120 mm Hg during admission. There were no deaths from aortic rupture in either group. By using financial data that was available from July of 1994 onward, we performed a subset analysis of the direct costs associated with BTAI. Total direct and variable direct costs for patients undergoing delayed repair were over two times the costs for early repair patients (p < 0.05). CONCLUSION: The management of trauma patients with multiple injuries requires prioritization of injuries so that the outcomes from these injuries can be optimized. Although delayed aortic repair was safely practiced in this series, there was not an obvious outcome benefit to delayed repair. The patients undergoing late repair required increased attention to hemodynamics, and there was a trend toward increased length of stay. In addition, analysis of the costs associated with delayed repair demonstrated a twofold increase in the direct costs for delayed repair compared with early repair.
Fibrin sealant inhibits connective tissue deposition in a murine model of peritoneal adhesion formation.
BACKGROUND: Postoperative peritoneal adhesion formation causes a multitude of disorders, including bowel obstruction and infertility. METHODS: To test whether fibrin sealant inhibits adhesion formation, mice were given an intraperitoneal injection of talc (to induce adhesions) after which sealant was administered. Seven and 14 days later, the thickness of connective tissue between the fragmented mesothelium and the abdominal muscle was measured. RESULTS: At both 7 and 14 days after talc administration, talc-treated mice had a 6-fold increase in connective tissue thickness over vehicle alone (P < .05). Although fibrin sealant alone failed to trigger peritoneal pathologic conditions, administration of sealant to talc-treated mice inhibited connective tissue deposition by 80% at 7 and 14 days (P < .05). Additionally, delaying fibrin sealant administration up to and including 72 hours after talc treatment results in comparable inhibition of connective tissue deposition, as does treatment immediately after talc exposure. CONCLUSIONS: This study demonstrates that fibrin sealant inhibits peritoneal inflammation and peritoneal adhesion formation with use of a quantitative assay of connective tissue deposition. In addition, this is the first report to document the administration of fibrin sealant into the closed abdomen. The success of these studies suggests that fibrin sealant will block peritoneal adhesions when administered laparoscopically. Finally, because fibrin sealant is therapeutic even when administered after the initiation of peritoneal inflammation, it suggests that it may be efficacious in patients who present with adhesions or those undergoing multiple operations.
Molecular markers of hemostatic activation and inflammation following major injury: effect of therapy with IFN-gamma.
Interferon-gamma (IFN-gamma) has shown promise in treatment of injured patients. However, reactive states marked by immunologic and inflammatory responses constitute a potential deleterious effect of IFN-gamma administration. IFN-gamma therapy has been associated with high levels of tumor necrosis factor-alpha (TNF-alpha), with potential enhancement of coagulopathy after injury. This study evaluated TNF-alpha production and markers of hemostatic activation in patients receiving IFN-gamma therapy. Seventy-three patients, part of a larger multicenter trial, with severe injuries were randomized to IFN-gamma (100 microg/day s.c. for 21 days) or placebo treatment. Enrollment criteria included injury severity score (ISS) > or = 25 or significant bacterial contamination with ISS > or = 20. TNF-alpha and other cytokine production was assessed at baseline and on days 3, 8, and 22 following injury. Markers of coagulation activation and fibrinolysis were also evaluated. Plasma TNF-alpha and interleukin-6 (IL-6) levels were higher in IFN-treated relative to placebo-treated patients before and after IFN administration. Markers of coagulation and fibrinolysis were elevated at all times studied following injury in both treatment and control groups but did not differ between patients receiving IFN and those receiving placebo. Activation of coagulation and fibrinolysis diminished in a time-related manner following injury. We conclude that (1) IFN-gamma therapy at the dose employed was not associated with a significant increase in TNF-alpha or other inflammatory cytokine production beyond that seen in patients receiving placebo, (2) coagulation and fibrinolytic markers were increased following injury but decreased significantly in surviving patients, and (3) no changes in coagulation and fibrinolytic parameters were noted in relation to IFN-gamma therapy. These findings support previous observations that trauma is associated with hemostatic activation and that treatment of patients at the dose of IFN-gamma studied is safe in the setting of injury.
Interferon-gamma therapy for infectious complications of injury: a called third strike?
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Trauma and thermal injury: comparison of hemostatic and cytokine changes in the acute phase of injury.
BACKGROUND: Initiated either by thermal injury or mechanical trauma, the systemic inflammatory response syndrome stimulates activation of coagulation and fibrinolysis, evolving into a subclinical disseminated intravascular coagulation. METHOD: Hemostatic parameters, interleukin-6, and endothelin plasma levels were compared in burn and trauma patients. Nineteen patients with major burn injury (> or = 40% total body surface area) were compared with 35 trauma patients with Injury Severity Scores > 25 on day 1 and days 5 to 8. RESULTS: Thrombin-antithrombin levels were significantly higher in trauma patients than in burn patients (p < 0.0001) on day 1, and endothelin was significantly higher on days 1 and 5 (p < 0.0001) in trauma patients than in burn patients. Interleukin-6 plasminogen activator inhibitor-1, and tissue plasminogen activator levels were elevated above normal limits on both days in both groups. CONCLUSION: There was a difference in the degree and level to which homeostasis was perturbed between the two groups. The mechanism of injury did not affect the initiation of subclinical disseminated intravascular coagulation and cytokine release, and the physiologic response remained the same.
Prone positioning in acute lung injury.
More than 20 years ago, critical care workers first observed that oxygenation improved when patients with acute respiratory distress syndrome were ventilated in the prone position. In recent reports, on turning prone, from 50 to 100% of patients improve oxygenation to a degree sufficient to allow a reduction in the level of positive end-expiratory pressure or fraction of inspired oxygen. It appears that vascular conductance in lung regions previously in the dorsal position is augmented by an increase in air space volume, with the effect that prone position ventilation will reduce shunt and improve ventilation-perfusion mismatch. Factors determining which patients will respond have not yet been elucidated. Although many questions regarding the role of prone ventilation are unanswered, of greatest importance is whether this technique reduces morbidity and mortality of patients with acute respiratory failure. Only carefully conducted, randomized trials can answer this question.
Weaning from mechanical ventilation.
Use of mechanical ventilation is associated with several major complications despite its lifesaving potential. Timely discontinuation of mechanical ventilation is critical to control of duration of intensive care unit stay and reduction of complications associated with mechanical ventilation. Difficulty in discontinuation (or weaning) of patients from mechanical ventilatory support is in part attributable to inadequate understanding of the mechanisms responsible for unsuccessful outcome and a lack of guidelines regarding the optimal approach to the process of discontinuation of mechanical ventilation. For the first time, results from prospective, randomized, multicenter trials are available comparing common means of discontinuation of mechanical ventilation. In addition, the physiologic basis for a weaning strategy in mechanical ventilation is also coming into better focus. Two recent trials of weaning suggest different optimal modes, one favoring T-piece trials and the other supporting the use of pressure support ventilation. In either case, the above weaning techniques appear to be superior to intermittent mandatory ventilation in separating patients from mechanical ventilatory support. Based on available clinical trials, pressure support ventilation or T-piece trials appear to be the preferred methods for discontinuation of mechanical ventilatory support. A method using a simple T-piece trial technique is described.
Interferon gamma in trauma-related infections.
OBJECTIVE: The efficacy of interferon gamma therapy in reducing infection and improving outcome from infection in patients sustaining major injury was examined. DESIGN: Randomized double-blind placebo control trial SETTING: Nine level one university affiliated trauma centers in the United States. PATIENTS AND PARTICIPANTS: Four hundred sixteen patients with injury severity score (ISS) > or = 25 or ISS > or = 20 with evidence of wound contamination. INTERVENTION: Recombinant human interferon gamma 100 ug or placebo was given subcutaneously daily for up to 21 days in addition to standard antibiotic therapy. MEASUREMENTS AND RESULTS: Comparable rates of major and minor infections were observed. Among the patients treated with interferon gamma there were fewer deaths related to major infection regardless of type [7-(3%) vs 18-(9%)]. The results, however, were dominated by one center which had the highest enrollment, infection and death rates. CONCLUSIONS: Further studies are warranted to investigate the role of interferon gamma therapy in improving outcome with major infection.
Tourniquet-induced exsanguination in patients requiring lower limb surgery. An ischemia-reperfusion model of oxidant and antioxidant metabolism.
BACKGROUND: Surgically induced ischemia and reperfusion is frequently accompanied by local and remote organ injury. It was hypothesized that this procedure may produce injurious oxidants such as hydrogen peroxide (H2O2), which, if unscavenged, will generate the highly toxic hydroxyl radical (.OH). Accordingly, it was proposed that tourniquet-induced exsanguination for limb surgery may be a useful ischemia-reperfusion model to investigate the presence of oxidants, particularly H2O2. METHODS: In ten patients undergoing knee surgery, catheters were placed in the femoral vein of the limb operated on for collection of local blood and in a vein of the arm for sampling of systemic blood. Tourniquet-induced limb exsanguination was induced for about 2 h. After tourniquet release (reperfusion), blood samples were collected during a 2-h period for measurement of H2O2, xanthine oxidase activity, xanthine, uric acid (UA), glutathione, and glutathione disulfide. RESULTS: At 30 s of reperfusion, H2O2 concentrations increased (approximately 90%) from 133 +/- 5 to 248 +/- 8 nmol.ml-1 (P < 0.05) in local blood samples, but no change was evident in systemic blood. However, in both local and systemic blood, xanthine oxidase activity increased approximately 90% (1.91 +/- 0.07 to 3.93 +/- 0.41 and 2.19 +/- 0.07 to 3.57 +/- 0.12 nmol UA.ml-1.min-1, respectively) as did glutathione concentrations (1.27 +/- 0.04 to 2.69 +/- 0.14 and 1.27 +/- 0.03 to 2.43 +/- 0.13 mumol.ml-1, respectively). At 5 min reperfusion, in local blood, H2O2 concentrations and xanthine oxidase activity peaked at 796 +/- 38 nmol.ml-1 (approximately 500%) and 11.69 +/- 1.46 nmol UA.ml-1.min-1 (approximately 520%), respectively. In local blood, xanthine and UA increased from 1.49 +/- 0.07 to 8.36 +/- 0.33 nmol.ml-1 and 2.69 +/- 0.16 to 3.90 +/- 0.18 mumol.ml-1, respectively, whereas glutathione and glutathione disulfide increased to 5.13 +/- 0.36 mumol.ml-1 and 0.514 +/- 0.092 nmol.ml-1, respectively. In systemic blood, xanthine oxidase activity peaked at 4.75 +/- 0.20 UA nmol.ml-1.min-1. At 10 min reperfusion, local blood glutathione and UA peaked at 7.08 +/- 0.46 mumol.ml-1 and 4.67 +/- 0.26 mumol.ml-1, respectively, while the other metabolites decreased significantly toward pretourniquet levels. From 20 to 120 min, most metabolites returned to pretourniquet levels; however, local and systemic blood xanthine oxidase activity remained increased 3.76 +/- 0.29 and 3.57 +/- 0.37 nmol UA.ml-1.min-1, respectively. Systemic blood H2O2 was never increased during the study. During the burst period (approximately 5-10 min), local blood H2O2 concentrations and xanthine oxidase activities were highly correlated (r = 0.999). CONCLUSIONS: These studies suggest that tourniquet-induced exsanguination for limb surgery is a significant source for toxic oxygen production in the form of H2O2 and that xanthine oxidase is probably the H2O2-generating enzyme that is formed during the ischemia-reperfusion event. In contrast to the reperfused leg, the absence of H2O2 in arm blood demonstrated a balanced oxidant scavenging in the systemic circulation, despite the persistent increase in systemic xanthine oxidase activity.
Effect of transfusion on oxygen transport in critically ill patients.
The role of isolated blood transfusion as a means toward improving oxygen transport was evaluated in 19 critically ill patients having sepsis syndrome as defined by standard criteria. ICU therapies were unchanged during transfusion and hemodynamic profiles with serum lactate levels were obtained before and after packed red blood cells were given. Blood transfusions in these patients did not cause a change in hemodynamic status. Arterial lactate determination was normal before and after transfusion was administered. Oxygen uptake failed to increase with transfusion, corresponding to increased arterial and mixed venous oxygen content. In the presence of sepsis, patients having oxygen delivery and uptake above normal without evidence of ischemia (normal lactate) will not increase oxygen consumption by raising the hemoglobin.
Hypotensive resuscitation.
While the mechanism remains unclear, a growing body of experimental and clinical evidence suggests that aggressive crystalloid resuscitation in near fatal uncontrolled hemorrhage is associated with poor outcome. Limited attempts to restore blood pressure improve cardiac output, tissue perfusion, and survival while attempts to restore normal tension with crystalloid result in increased hemorrhage volume and higher mortality. The current standard of therapy for treatment of hemorrhagic shock includes initial aggressive crystalloid resuscitation. This mini-review summarizes some of the experimental and clinical data suggesting that this approach may not be desirable in the presence of uncontrolled hemorrhage following injury.
Assessment of two clinical trials: interferon-gamma therapy in severe injury.
Two recent studies have examined the efficacy of interferon-gamma in reducing infection and death in patients sustaining severe injury. Both included multi-center, randomized, double-blinded placebo-control design. The first trial, conducted at four university trauma centers, enrolled 213 patients, while the second trial involved nine university trauma centers and 416 subjects. Recombinant human interferon-gamma (100 micrograms) was administered subcutaneously daily for 10 days in the first trial and 21 days in the second, in addition to standard supportive therapy. In both trials infection rates were similar in the treatment arms. Although the death rate related to infection was not affected in the first study, the second trial suggested an improved outcome from this complication. The outcome of the larger trial was flawed by dominant findings at one center that had the highest enrollment, infection, and death rates. Confounding variable analysis presented here explains much of the difference between center findings in the larger trial. Thus, the benefit of interferon-gamma as an immune adjuvant in severe injury is clouded by study design flaws evaluating its use and by the inability to identify appropriate subjects using clinical criteria.
Activation of the clotting system and complement after trauma.
The traditional approach to hemostatic disorders in the injured patient has focused on bleeding rather than a hypercoagulable state. This strategy continues despite growing evidence from studies of coagulation disorders in other patient groups highlighting loss of organ function secondary to inappropriate coagulation rather than hemorrhage. While traditional testing is useful in screening for low levels of coagulation factors or platelet dysfunction, only obvious bleeding or significant fibrinolysis is identified. Cellular interactions, in particular those of the vascular endothelium, are not taken into account by these assays. More than 20 years have passed since coagulation abnormalities were reported in patients with severe infection. Despite recognition of this association in sepsis, we are only beginning to understand how coagulation abnormalities develop in injury and to consider strategies to counter them. While hemorrhage may be successfully treated in patients following trauma, thrombosis in the microcirculation often contributes to end-organ damage with irreversible ischemic changes that may lead to death.
Clinical significance of antibiotic endotoxin-releasing properties in trauma patients.
OBJECTIVE: To test the hypothesis that antibiotics leading to greater endotoxin release are associated with greater mortality in septic trauma patients. DESIGN: Post hoc analysis of data from a previously conducted prospective, randomized, multicenter study designed to evaluate the efficacy of interferon gamma in preventing infection and death in trauma patients. SETTING: Nine level I trauma centers. PATIENTS: Severely injured trauma patients at high risk for sepsis. Eighty percent (N = 334) of the enrolled patients developed some manifestation of gram-negative sepsis, defined by the administration of gram-negative specific antibiotics. MAIN OUTCOME MEASURES: The in-hospital mortality rate of patients who received penicillin-binding protein 3/tumor necrosis factor (PBP3/TNF)-specific antibiotics associated with the greatest degree of endotoxin release and TNF production (PBP3/TNF group, n = 78: aztreonam, ceftazidime, and cefotaxime sodium) was compared with that of patients not receiving these agents (non-PBP3/TNF group, n = 256). RESULTS: Mortality in the PBP3/TNF group (17%) was higher than in the non-PBP3/TNF group (8%, P = .02). The two groups were similar in their mean (+/- SD) Injury Severity Scores (34 +/- 9), ages (31 +/- 12 years), and initial degree of bacterial contamination. CONCLUSIONS: Antibiotics that are associated with greater release of endotoxin and production of TNF are also associated with greater mortality in septic trauma patients. Decisions regarding antibiotic administration may need to consider the endotoxin-releasing properties of antibiotics in addition to their antibacterial sensitivity spectrum. Prospective studies of the effect of endotoxin-releasing properties of antibiotics on mortality are warranted.