Biomedical subjects
Richard W Light
Publications and source records attributed to Richard W Light.
Apolipoprotein E4 polymorphism as a genetic predisposition to delirium in critically ill patients.
OBJECTIVE: To test for an association between apolipoprotein E (APOE) genotypes and duration of intensive care unit delirium. DESIGN: Prospective, observational cohort study. SETTING: A 541-bed, community-based teaching hospital. PATIENTS: Fifty-three mechanically ventilated intensive care unit patients. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: All patients were managed with standardized sedation and ventilator weaning protocols as part of an ongoing clinical trial and were evaluated prospectively for delirium with the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU). DNA was extracted from whole blood samples obtained on enrollment, and APOE genotype was determined using polymerase chain reaction followed by restriction enzyme digestion by investigators blinded to the clinical information. Delirium occurred in 47 (89%) patients at some point during the intensive care unit stay. Of the 53 patients, 12 (23%) had an APOE4 allele (APOE4+) and 41 (77%) had only APOE2 or APOE3 alleles (APOE4-). APOE4+ patients were younger (53.2 +/- 21.9 vs. 65.4 +/- 13.4, p = .08) and less often admitted for pneumonia (0% vs. 29.3%, p = .05) compared with APOE4- patients, yet they had a duration of delirium that was twice as long: median (interquartile range), 4 (3, 4.5) vs. 2 (1, 4) days (p = .05). No other clinical outcomes were significantly different between the APOE4+ and APOE4- patients. Using multivariable regression analysis to adjust for age, admission diagnosis of sepsis or acute respiratory distress syndrome or pneumonia, severity of illness, and duration of coma, the presence of APOE4 allele was the strongest predictor of delirium duration (odds ratio, 7.32; 95% confidence interval, 1.82-29.51, p = .005). CONCLUSIONS: APOE4 allele represents the first demonstrated genetic predisposition to longer duration of delirium in humans.
The short-term administration of Ketoprofen does not decrease the effect of Pleurodesis induced by talc or Doxycycline in rabbits.
OBJECTIVE: To determine whether the concomitant administration of ketoprofen, a non-steroidal anti-inflammatory drug (NSAID) has any effect on the pleurodesis induced by talc or doxycycline in rabbits. METHODS: Four groups of seven New Zealand rabbits were assigned to receive the following treatments: 400mg/kg of talc intrapleurally only (group 1), 400mg/kg of talc plus 1mg/kg of ketoprofen intramuscularly (group 2), 10mg/kg of doxycycline intrapleurally only (group 3) and 10mg/kg of doxycycline plus 1mg/kg of ketoprofen intramuscularly (group 4). Intramuscular administration of ketoprofen began 4h before the intrapleural administration of the sclerosing agents, followed by twice daily administrations for 1 week. Pleural fluid was collected 24, 48 and 72h after intrapleural injections. Pleurodesis was evaluated macroscopically and microscopically after 14 days. RESULTS: The concomitant use of ketoprofen at 1mg/kg does not decrease the WBC, LDH, and protein in pleural fluid at 24h following intrapleural injection of talc or doxycycline. There were no significant differences in the macroscopic pleurodesis scores, the degree of microscopic pleural fibrosis, the thickness of the pleura or the percent of the pleura occupied with angiogenesis. CONCLUSIONS: The study shows that the short-term systemic administration of NSAIDs does not affect the efficacy of pleurodesis induced by talc or doxycycline in rabbits.
Vascular endothelial growth factor levels in post-CABG pleural effusions are associated with pleural inflammation and permeability.
BACKGROUND: Vascular endothelial growth factor (VEGF) participates in the pathogenesis of exudative pleural effusions (PEs). In the present study, we determined the pleural fluid (PF) and serum VEGF levels in patients with post-coronary artery by-pass grafting (post-CABG) PEs. METHODS: Thirty-eight patients with post-CABG (two with bilateral) PEs were studied. PEs were divided into "early" (occurring earlier than 30 days after surgery) and "late" ones. VEGF levels were measured using ELISA. RESULTS: (i) Serum and PF VEGF levels did not differ significantly when all the patients (P=0.053) or those with late effusions (P=0.6) were analyzed; serum VEGF levels were significantly elevated in comparison to PF VEGF levels in patients with early (P=0.007) effusions. (ii) Serum VEGF levels were significantly higher in patients with early than in those with late effusions (P=0.033), while PF VEGF levels were not significantly different between the two groups (P=0.77). (iii) PF VEGF levels were higher than corresponding serum levels in 4/24 patients with early and in 10/16 patients with late post-CABG PEs (P=0.006). (iv) In PEs VEGF levels significantly correlated with red blood cells (P=0.015), nucleated cells (P=0.003), protein levels (P=0.002) and lactate dehydrogenase (LDH) levels (P=0.04). CONCLUSION: In post-CABG PEs, preferential local production of VEGF in the pleural cavity is most commonly observed a month or later after surgery. The fact that in PEs VEGF levels correlate with markers of pleural inflammation (inflammatory cells and LDH levels) and vascular hyperpermeability (protein levels) suggests that VEGF may be involved in the pathogenesis of post-CABG PEs.
Bayesian analysis using continuous likelihood ratios for identifying pleural exudates.
STUDY OBJECTIVES: To ascertain if equations that calculate continuous likelihood ratios (CLRs) for pleural exudates improve pleural fluid categorization, especially when false positive or false negative test results are obtained by using Light's criteria. DESIGN AND SETTING: Retrospective review of the clinical and pleural fluid data from a consecutive series of patients with pleural effusion who underwent thoracentesis at the University Hospital Arnau de Vilanova (Lleida, Spain) over an 11-year period. PATIENTS AND METHODS: A total of 1490 patients with pleural effusion (298 transudates and 1192 exudates) were recruited into the study. The presence of a transudate or exudate was established by clinical judgment. We examined the comparative diagnostic accuracy of 4 tests (i.e. pleural fluid protein and lactate dehydrogenase (LDH), and pleural fluid to serum protein and LDH ratios) for discriminating between transudates and exudates. Decision thresholds were determined by receiver operating characteristics (ROC) analysis. Equations for calculating CLRs derived from a logistic regression analysis based on a previously described method. RESULTS: Individual pleural fluid tests did not differ in their diagnostic accuracies according to ROC analysis. We calculated CLRs for the elements of Light's criteria and pleural fluid protein, and also illustrated the sequential use of CLRs for determining posttest probabilities. Overall, CLR formulas had marginal performance for the correct categorization of pleural fluid. CONCLUSIONS: CLRs provide a probabilistic statement as to the likelihood an effusion is a transudate or exudate. However, clinical judgment is little changed by the application of CLRs, and in doubtful cases a great amount of uncertainty remains. This Bayesian approach is likely to have no major impact on the clinical practice.
Diagnostic approach to pleural effusion in adults.
The first step in the evaluation of patients with pleural effusion is to determine whether the effusion is a transudate or an exudate. An exudative effusion is diagnosed if the patient meets Light's criteria. The serum to pleural fluid protein or albumin gradients may help better categorize the occasional transudate misidentified as an exudate by these criteria. If the patient has a transudative effusion, therapy should be directed toward the underlying heart failure or cirrhosis. If the patient has an exudative effusion, attempts should be made to define the etiology. Pneumonia, cancer, tuberculosis, and pulmonary embolism account for most exudative effusions. Many pleural fluid tests are useful in the differential diagnosis of exudative effusions. Other tests helpful for diagnosis include helical computed tomography and thoracoscopy.
Intrapleural streptokinase for pleural infection.
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The undiagnosed pleural effusion.
The most common causes for undiagnosed transudative effusions are congestive heart failure and hepatic hydrothorax. Pleural fluid N terminal pro-brain natriuretic peptide levels higher than 1500 pg/mL are virtually diagnostic of congestive heart failure. The most common causes for undiagnosed exudative pleural effusions are malignancy, pulmonary embolism, and tuberculosis. Clinical characteristics of patients with a malignant pleural effusion are symptoms for more than 1 month, absence of fever, blood-tinged pleural fluid, and CT findings suggestive of malignancy. Thoracoscopy is useful to establish the diagnosis of malignancy and tuberculosis.
The superior vena cava syndrome: clinical characteristics and evolving etiology.
Malignancy is the most common cause of the superior vena cava (SVC) syndrome. With the increasing use of intravascular devices, the incidence of the SVC syndrome arising from benign etiologies is increasing. We reviewed the etiology and outcome of 78 patients with SVC syndrome over 5 years. Malignancy was the etiology in 60% of the cases, and bronchogenic carcinoma was the most common malignancy. Small cell and non-small cell lung cancer accounted for 17 (22%) and 19 (24%) cases, respectively, but a higher percentage of patients with small-cell lung cancer developed the syndrome (6% vs 1%). Lymphoma and germ cell tumors were other significant malignant causes (8% and 3% of cases, respectively). An intravascular device was the most common etiology in benign cases (22 of 31 cases; 71%), with fibrosing mediastinitis the second most common benign etiology (6 cases). The most frequent signs and symptoms were face or neck swelling (82%), upper extremity swelling (68%), dyspnea (66%), cough (50%), and dilated chest vein collaterals (38%). Dyspnea at rest, cough, and chest pain were more frequent in the patients with malignancy. Procedures performed for diagnostic or treatment purposes did not increase morbidity or mortality.
Prevalence and characteristics of pleural effusions in superior vena cava syndrome.
OBJECTIVE AND BACKGROUND: The prevalence and characteristics of pleural effusions occurring in adults with the superior vena cava (SVC) syndrome are unknown. The purpose of the present study was to characterize these pleural effusions. METHODS: Charts of patients diagnosed with SVC syndrome at a tertiary care referral centre were reviewed. Radiographs were evaluated for the presence and size of pleural effusions, presence and location of masses and mediastinal width. If a pleural effusion was present, the patient's chart and a pre-existing database on pleural effusions were searched to determine whether the effusion was sampled and the results of any laboratory investigations on the fluid. RESULTS: The SVC syndrome occurred in 78 patients. Malignancy was the aetiology in 60% of the cases and bronchogenic carcinoma was the most common malignancy. An intravascular device was the aetiology in the majority of benign cases. Pleural effusion was found in 70% of patients with a malignant aetiology and 58% of those with a benign cause (P=0.345). The mean size of the effusions was larger in malignant cases (P=0.012). Of the 44 effusions 22 were sampled (17 in malignancy and five with benign processes); none was transudates, 20 (91%) were exudative (four of these were chylous) and the remaining two were reported as exudates but did not have pleural chemistries documented. CONCLUSIONS: More than half of patients with SVC syndrome have pleural effusions, regardless of the aetiology. However, the effusions are larger when associated with malignancy. The majority of these effusions are exudative and occasionally chylous. None was transudates.
Intrapleural heparin or heparin combined with human recombinant DNase is not effective in the treatment of empyema in a rabbit model.
OBJECTIVE AND BACKGROUND: The aim of this study was to investigate the effectiveness of intrapleural heparin or heparin combined with human recombinant DNase in the treatment of empyema. METHODS: Empyema was induced in rabbits with an intrapleural injection of 10(9)Pasteurella multicoda organisms in infusion agar via a surgically placed chest tube. Once empyema was verified, a blinded investigator administered drugs via the chest tube. There were three treatment groups each with six rabbits. One group was given 1000 IU heparin, a second group was given 1000 IU heparin plus 1 mg of human recombinant DNase via chest tube and the control group received saline. The rabbits received treatment every 12 h for a total of six treatments and the volume of each treatment was 3 mL. The animals were sacrificed at day 10 and the amount of empyema and pleural thickening was scored macroscopically on a scale of 0-6. RESULTS: The total volume of pleural effusion aspirated was significantly higher in the heparin group (25.8+/-10.7 mL) compared with either saline (8+/-8.9) or heparin plus human recombinant DNase (6.8+/-6.1) groups (P=0.003). The mean empyema and pleural thickening scores did not differ significantly between the groups (P=0.8, P=0.5 respectively). A weak correlation was found between total volume of aspirated pleural fluid and pleural parameters of white blood cell counts and LDH levels (r=0.546 and P=0.02, r=0.631 and P=0.02 respectively). CONCLUSION: The intrapleural administration of 1000 IU heparin alone or in combination with 1 mg of human recombinant DNase is no more effective than saline in the treatment of empyema in rabbits. Intrapleural heparin significantly increased the drainage of pleural fluid compared with the combination and saline group.
Angiopoietin-2 levels are elevated in exudative pleural effusions.
OBJECTIVE: To examine the pleural fluid (PF) and serum levels of angiopoietin (Ang)-1, Ang-2, and vascular endothelial growth factor (VEGF) in patients with pleural effusions (PEs). METHODS: One hundred fifteen patients, 16 with transudative PEs due to heart failure and 99 with exudative PEs (malignant, 40; para-pneumonic, 24; tuberculous, 13; miscellaneous etiologies, 22) were included in the study. PF and serum levels of the growth factors were measured using enzyme-linked immunosorbent assay. RESULTS: PF Ang-2 and VEGF levels but not Ang-1 levels were higher (p < 0.001) in exudates than in transudates. PF Ang-2 levels were higher in tuberculous PEs than in PEs of any other etiology and were lower in heart failure PEs than in PEs of any other etiology. The highest PF VEGF levels were observed in patients with malignant and parapneumonic PEs. The lowest PF VEGF levels were observed in patients with transudates. In PEs, Ang-2 levels correlate with VEGF levels (p < 0.001), RBC count (p = 0.002), nucleated cell count (p < 0.001), total protein levels (p < 0.001), and lactate dehydrogenase levels (p < 0.001). PF Ang-1 levels were lower than serum Ang-1 levels both in patients with exudates (p < 0.001) and in those with transudates (p = 0.001). PF Ang-2 levels were higher than serum Ang-2 levels both in patients with exudates (p < 0.001) and in those with transudates (p = 0.045). PF VEGF levels were higher than serum VEGF levels in patients with malignant PEs (p < 0.001) and parapneumonic PEs (p = 0.003), but lower than serum VEGF levels in heart failure PEs (p < 0.001). In patients with tuberculous PEs and exudative PEs of miscellaneous etiology, PF and serum VEGF levels did not differ significantly. CONCLUSION: Ang-2 levels but not Ang-1 levels are elevated in exudative PEs, and they correlate with levels of VEGF and markers of pleural inflammation. It is thus possible that Ang-2 along with VEGF participate in pleural inflammation and the pathogenesis of exudative PEs.
Tissue plasminogen activator combined with human recombinant deoxyribonuclease is effective therapy for empyema in a rabbit model.
OBJECTIVES: There have been no controlled studies to test the efficacy of tissue plasminogen activator (tPA) or recombinant human deoxyribonuclease (rhDNase) in the treatment of empyema. In vitro studies show that streptokinase without rhDNase does not liquefy empyemic material from rabbits. However, the combination of streptokinase and streptodornase and rhDNase have been shown to liquefy pus in vitro. The aim of this study was to determine if tPA or rhDNase, or a combination of the two, is more effective than saline solution in the treatment of empyema in rabbits. MATERIALS AND METHODS: Empyema was induced in rabbits using 10(9) Pasteurella multicoda organisms in infusion agar injected via a surgically placed chest tube. Once empyema was verified, a blinded investigator administered one of four treatments via the chest tube: 3 mL of saline solution; 4 mg of alteplase (recombinant tPA); 1 mg of rhDNase; or 4 mg of alteplase and 1 mg of rhDNase. The rabbits received a treatment every 12 h following the initial for a total of six treatments. The animals were killed at day 10, and the degree of empyema and pleural peel was scored macroscopically on a scale of 0 to 4. RESULTS: The combination group had a significantly lower mean empyema score (1.83 +/- 0.75) than did the saline solution group (3.86 +/- 0.38, p = 0.001), rhDNase group (3.17 +/- 0.75, p = 0.012), and alteplase group (3.71 +/- 0.49, p = 0.02) [+/- SD]. The total volume of pleural fluid was markedly higher in the alteplase and rhDNase combination group (142 +/- 79.1 mL) or the alteplase group (231 +/- 78.0 mL) compared to either the rhDNase group (0.8 +/- 1.6 mL) or the saline solution group (5.8 +/- 14.0 mL). CONCLUSION: The combination of alteplase and rhDNase is more effective in the treatment of rabbit empyema than either agent alone. The intrapleural injection of alteplase alone or in combination with rhDNase leads to the production of large amounts of pleural fluid.
Parapneumonic effusions and empyema.
Parapneumonic effusions occur in 20 to 40% of patients who are hospitalized with pneumonia. The mortality rate in patients with a parapneumonic effusion is higher than that in patients with pneumonia without a parapneumonic effusion. Some of the excess mortality is due to mismanagement of the parapneumonic effusion. Characteristics of patients that indicate that an invasive procedure will be necessary for its resolution include the following: an effusion occupying more than 50% of the hemithorax or one that is loculated; a positive Gram stain or culture of the pleural fluid; and a purulent pleural fluid that has a pH below 7.20 or a glucose below 60, or has a lactic acid dehydrogenase level of more than three times the upper normal limit for serum. Patients with pneumonia and an effusion of more than minimal size should have a therapeutic thoracentesis. If the fluid cannot be removed with a therapeutic thoracentesis, a chest tube should be inserted and consideration be given to the intrapleural instillation of fibrinolytics. If the loculated effusion persists, the patient should be subjected to video-assisted thoracoscopic surgery, and if the lung cannot be expanded with this procedure, a full thoracotomy with decortication should be performed. The definitive procedure should be performed within 14 d.
[Effect of anti-vascular endothelial growth factor antibody on pleurodesis induced by transforming growth factor-beta or doxycycline in rabbits].
OBJECTIVE: The intrapleural injection of transforming growth factor-beta (TGF-beta) or doxycycline produces excellent pleurodesis in rabbit models. However, the intrapleural injection of these agents induces large pleural effusion which is possibly related to vascular endothelial growth factor (VEGF). This study investigated whether anti-VEGF antibody has any effect on the fluid production or the pleurodesis induced by TGF-beta or doxycycline in rabbits. METHODS: Two groups of New Zealand white rabbits (7 each) were given TGF-beta 5.0 microg intrapleurally. The TGF-beta treatment group received anti-VEGF antibody 10 mg/kg intravenously 24 h before TGF-beta injection and the TGF-beta control group received no antibody. Another two groups of New Zealand white rabbits (7 each) were given doxycycline 10 mg/kg intrapleurally after chest tube placement. The doxycycline treatment group received 10 mg/kg anti-VEGF antibody intravenously 24 h before doxycycline injection and the doxycycline control group received no Anti-VEGF antibody. The rabbits were sacrificed at 2 weeks and the pleurodesis score was graded macroscopically on a 1-8 scale. The degree of angiogenesis in pleural tissues was assessed by immunohistochemical staining for factor VIII which was assessed by computer-assisted digital analysis. RESULTS: The administration of anti-VEGF antibodies had no effect on pleural fluid volume or the characteristics of the fluid. The mean pleurodesis score of TGF-beta control group (7.7 +/- 0.8) was significantly (P < 0.05) higher than that of the antibody pre-treatment TGF-beta group (4.4 +/- 2.4). The mean pleurodesis score of the doxycycline control group (6.0 +/- 1.7) was significantly (P < 0.05) higher than that of the antibody pre-treatment doxycycline group (2.0 +/- 0.9). The administration of the anti-VEGF antibody also reduced the angiogenesis. The percentage of pleural tissue demonstrating angiogenesis in the TGF-beta control group (4.9 +/- 0.4)% was significantly (P < 0.05) higher than that of the antibody treatment TGF-beta group (2.9 +/- 0.7)%. The percentage of pleural angiogenesis in the doxycycline control group (6.9 +/- 2.2)% was significantly (P < 0.05) higher than the antibody pre-treatment doxycycline group (2.2 +/- 0.9)%. CONCLUSIONS: Anti-VEGF antibody significantly inhibits the pleurodesis induced by doxycycline or TGF-beta. This observation suggests that VEGF and angiogenesis play a pivotal role in the production of pleurodesis.
Nuclear factor-kappaB affects tumor progression in a mouse model of malignant pleural effusion.
We developed a novel mouse model of malignant pleural effusion (MPE) by injecting Lewis lung cancer (LLC) cells directly into the pleural space of syngeneic C57B/6 mice. The pleural effusions in this model share common cellular and biochemical features with human MPEs. Implantation and growth of pleural tumors triggers a host inflammatory response characterized by a mixed inflammatory cell influx into the pleural fluid. LLC cells exhibited high basal nuclear factor (NF)-kappaB activity in vitro and in vivo, which we used to drive expression of a NF-kappaB-dependent green fluorescent protein-firefly luciferase fusion reporter construct. NF-kappaB-dependent reporter expression allowed intravital tracing of pleural tumors. Inhibition of NF-kappaB in LLC cells did not affect cell viability in culture; however, injection of LLC cells expressing a dominant NF-kappaB inhibitor resulted in decreased tumor burden, decreased pleural effusion volume, and decreased pleural effusion TNF-alpha levels. These studies indicate that tumor NF-kappaB activity regulates pleural tumor progression. This reproducible model of MPE can be used to further study the influence of specific host and tumor factors on the pathogenesis of MPE and evaluate new therapeutic strategies.
Etiology and prognostic significance of massive pleural effusions.
It has been stated that malignancy is the most common aetiology of massive pleural effusions. To determine the most frequent causes of massive pleural effusions and to assess the diagnostic yield of different diagnostic procedures and survival, we prospectively studied 1084 patients with pleural effusion. Massive pleural effusions were identified in 121 of 1084 patients (11.2%). Compared with non-massive pleural effusions, massive pleural effusions were significantly more likely to be malignant (53.7% vs. 38.3%, P=0.03) or secondary to cirrhosis (9.9% vs. 2.6%, P=0.0000). On the other hand, massive pleural effusions were significantly less likely to be secondary to infection (10.7% vs. 19.2%, P=0.003) or congestive heart failure (0.8% vs. 6.7%, P=0.03). There was a significant increase in the yield of diagnostic studies in patients with massive malignant pleural effusions (56.9% for cytological studies and 36.9% for biopsies). On the other hand, there was no difference in the diagnostic yield of microbiological and histological studies in the group of tuberculous pleural effusions. In our study population, patients with non-massive malignant pleural effusions had a significantly better survival than those with massive malignant pleural effusions, with a median survival of 8 months (95% confidence interval, 7-9) compared with 5 months (95% confidence interval, 4-6) (P=0.0009). We conclude that malignancy is the most common cause of a massive exudative effusion. Massive malignant pleural effusions are associated with worse survival, independent of age and histologic subgroup, than are non-massive malignant pleural effusions.
Continuous oxygen monitoring--a better way to prescribe long-term oxygen therapy.
STUDY OBJECTIVE: The purpose of this study was to determine if an oxygen prescription based on continuous oximetry monitoring, would result in an increased percentage of time spent within an SpO2 level between 88% and 92%. METHODS: We conducted a prospective, cohort study in an outpatient, pulmonary setting in a tertiary care referral center, on 17 patients with stable chronic obstructive pulmonary disease (COPD) who had previously been prescribed long-term oxygen therapy. The patients were monitored for approximately 24h with a portable oximeter that recorded SpO2 and EKG readings. During the initial 24h of monitoring, the patients were on their previous oxygen prescription. Their oxygen prescription was then altered based on a predetermined protocol described below. The patients were then monitored for an additional 24h. RESULTS: Sixteen patients completed the study. Based on the initial continuous oximetry, the median oxygen prescription was reduced from 2.5 to 1.2 L/min (P < 0.001). The oxygen prescription during exercise, rest, and sleep decreased from 3.0 +/- 0.9 to 1.8 +/- 1.3 L/min (P < 0.001), 2.2+/-0.4 to 0.8 +/- 0.7 L/min (P < 0.001), and 2.2 +/- 0.4 to 0.9 +/- 0.8 L/min (P < 0.001) respectively. After the oxygen prescription was adjusted, the percentage of the time that the SpO2 was between 88 and 92% increased from 24.8 +/- 21.7% to 52.8 +/- 25.0% (P = 0.001), but the percentage of time that the SpO2 was below 88% did not change significantly (2.8 +/- 6.1% to 4.3 +/- 8.1%). CONCLUSIONS: This study demonstrates that an oxygen prescription based on continuous oximetry monitoring results in (1) a significant increase in the percentage of time that the SpO2 is between 88% and 92%, (2) a significant decrease in the amount of oxygen prescribed, (3) a slight increase in the amount of time that the SpO2 is below 88% that was not statistically significant.