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Systemic Inflammatory Reaction After Thoracoscopic Talc Poudrage
Original Research INTERVENTIONAL PULMONOLOGY
Systemic Inflammatory Reaction After Thoracoscopic Talc Poudrage* Marios E. Froudarakis, MD, FCCP; Maria Klimathianaki, MD; and Mihalis Pougounias, MD
Background: Recent studies have reported fever as a side effect of talc poudrage during thoracoscopic pleurodesis. However, thoracoscopy itself is likely to induce systemic inflammatory reaction, as it is an interventional procedure. The aim of the study was to investigate whether systemic inflammatory response is due to talc poudrage or to thoracoscopy. Methods: We prospectively studied two groups of patients. The first group (18 patients) underwent thoracoscopic talc poudrage, and the second group (17 patients) underwent only diagnostic thoracoscopy. We measured body temperature, as well as WBC count and C-reactive protein (CRP) levels before the procedure (baseline), and at 24 and 48 h after the procedure. No antiinflammatory medication was permitted to be used before, during, or after the procedure. All patients had a 3-month follow-up. Results: The baseline patient characteristics were similar in both groups. Temperature increased significantly in the thoracoscopic talc poudrage group (overall comparison, p ⴝ 0.005) especially at 9, 12, and 24 h after the procedure. Overall, the WBC count (p ⴝ 0.004), percentage of neutrophils (p ⴝ 0.03), and CRP levels (p < 0.0001) were significantly increased in the group of patients who underwent thoracoscopic talc poudrage. On the contrary, lymphocytes were significantly decreased (overall comparison, p ⴝ 0.01) in the thoracoscopic talc poudrage group during the same period. Mild side effects, such as pain during and after thoracoscopy and subcutaneous emphysema, were noted. No severe complication, such as infection or acute respiratory failure, was noted in either group during the hospitalization or during the follow-up period. Conclusion: According to our results, fever and systemic inflammatory reaction is due to talc poudrage and not to thoracoscopy. (CHEST 2006; 129:356 –361) Key words: fever; inflammation; pleurodesis; talc; thoracoscopy Abbreviations: CRP ⫽ C-reactive protein; IL ⫽ interleukin
is actually the agent of choice for chemical T alcpleurodesis, with an efficacy rate of ⬎ 90%. It may be administered as a powder by insufflation during thoracoscopy,1– 4 inducing fibrosis and inflammation in the pleural cavity.5 Talc pleurodesis is generally well-tolerated. However, reports2,4 have stated that minor side effects, such as pleuritic pain *From the Department of Pneumonology, Medical School, University of Crete, Heraklion, Greece. Manuscript received April 19, 2005; revision accepted June 26, 2005. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal. org/misc/reprints.shtml). Correspondence to: Marios E. Froudarakis, MD, FCCP, Zografou 11, 71201 Heraklion, Greece; e-mail: [email protected] 356
during pleurodesis, nausea and fever after the procedure, and fever after thoracoscopic talc poudrage, occur in about 20% of the patients who have been included in prospective studies.6 Although many authors have reported that fever occurs 1 or 2 days after thoracoscopic talc poudrage,1,6 no clear information exists regarding the characteristics of fever, such as the actual rise in the patient’s baseline temperature, the exact time of its occurrence, or the duration of fever. Also, we have no information about the patient’s tolerance of fever and the possible association with other symptoms such as chills, nausea, and fatigue. Temperature increases in patients who undergo any interventional procedure. Causes include pneuOriginal Research
monia, pulmonary embolus, local infection at the site of entry, and urinary tract infection in catheterized patients. However, fever is more likely to be an acute-phase response that is associated with traumarelated immunologic changes than to postoperative infection.7,8 Thoracoscopy is widely used for the diagnosis and treatment of pleural and lung diseases. Thoracoscopy by itself may result in an elevation of baseline body temperature or may result in fever. However, it has been reported that thoracoscopy induces a lesser degree of acute-phase response compared to more invasive surgery.8,9 In the case of patients who undergo both thoracoscopy and talc poudrage, we cannot know which of the two procedures (maybe both) induces fever. Therefore, we initiated a study to investigate which of the two procedures is responsible for the increasing temperature in patients in this population. Materials and Methods Data Collection From January 2004 to December 2004, all patients who underwent diagnostic thoracoscopy or pleural talc poudrage were monitored in order to evaluate the patient’s temperature after undergoing the procedure. Overall, 35 patients underwent thoracoscopy during that period (thoracoscopy for undiagnosed pleural effusion, 17 patients; thoracoscopic talc poudrage for pleurodesis, 18 patients). Patient characteristics are shown in Table 1. We evaluated inflammation by monitoring leukocytes, neutrophils, and C-reactive protein (CRP) levels in peripheral blood. We also monitored complications and side effects during and after thoracoscopy. If an increase in body temperature to ⬎ 38°C occurred, we systematically evaluated the patient for possible infection, and sent blood and urine to the laboratory for cultures.
Data were collected regarding body temperature before the patient underwent thoracoscopy (baseline) and every 3 h after the procedure. WBC count, the percentage of neutrophils and lymphocytes, and CRP levels were also monitored at baseline, as well as at 24 and 48 h after thoracoscopy. After undergoing thoracoscopy, all patients received baseline treatment for the pain with a fentanyl citrate patch, 25 mg every 72 h. In case of persistent pain, patients received a supplement of parenteral narcotics (morphine) on request. No antiinflammatory or antipyretic medications were permitted to be used before, during, or after the procedure. Thoracoscopy Patients were admitted to the hospital on the same morning of thoracoscopy and were discharged from the hospital on the day of chest tube removal. Thus, the length of hospitalization was equivalent to the number of days required for chest tube drainage. During the procedure, BP, oxygen saturation, and ECG were monitored. Oxygen supplementation was provided if needed. In case of pain during thoracoscopy, patients received supplementary parenteral narcotics (morphine) on request. No general anesthesia was used at any time. Thoracoscopy was performed with the patient in the lateral decubitus position using a single port of entry, under local anesthesia with 1% lignocaine. Morphine, 0.5 mg, was administered to patients as needed. A 7-mm trocar was inserted into the fifth or sixth intercostal space along the midaxillary line. After evacuation of the pleural fluid, a 0o optical telescope was inserted into the patient and connected to a light source. The entire pleural cavity was then inspected, at times requiring supplemental air insufflation. Biopsies were performed with an optical forceps through the single port of entry under direct visualization. No stapling or electrocoagulation was used for parenchymal biopsies.10,11 Sterile asbestos-free talc (Steritalc; Novatech; La Ciotat, France) [4 g for a malignant pleural effusion and 2 g for a pneumothorax] was insufflated into the pleural space of patients who underwent pleurodesis. At the end of the procedure, a chest tube (24F to 28F) was inserted and connected to an underwater seal with a negative suction of 20 cm H2O for at least 2 days. The chest tube was removed when ⬍ 100 mL of pleural fluid was
Table 1—Characteristics of Patients*
Characteristics Age, yr Sex Male Female Diagnosis Malignant Benign Pleural drainage, d Side of thoracoscopy Right Left Pleural fluid during thoracoscopy, L Pleural fluid pH Pleural fluid LDH Pleural protein
Total (n ⫽ 35) 64.6 ⫾ 15 (33–94)
Thoracoscopic Talc Poudrage (n ⫽ 18) 63.1 ⫾ 15.5 (33–93)
Diagnostic Thoracoscopy (n ⫽ 17) 64 ⫾ 14.5 (38–94)
p Value NS
26 (74.3) 9 (25.7)
12 (66.6) 6 (33.3)
14 (82.3) 3 (17.7)
NS
26 (74.3) 9 (25.7) 2.8 ⫾ 1.3 (1–7)
16 (88.9) 2 (11.1) 3.4 ⫾ 1.4 (2–7)
10 (58.8) 7 (31.2) 2.2 ⫾ 0.8 (1–4)
0.05
19 (54.3) 16 (45.7) 1.52 ⫾ 1.1 (0.2–4.4) 7.39 ⫾ 0.08 (7.19–7.49) 330 ⫾ 249 (89–1286) 4.47 ⫾ 0.83 (3.1–7.2)
9 (50) 9 (50) 1.52 ⫾ 1.1 (0.2–4.2) 7.37 ⫾ 0.09 (7.19–7.49) 332 ⫾ 280 (104–1286) 4.45 ⫾ 0.96 (3.1–7.2)
10 (58.8) 7 (41.2) 1.51 ⫾ 1.1 (0.35–4.4) 7.41 ⫾ 0.07 (7.20–7.49) 328 ⫾ 216 (89–857) 4.51 ⫾ 0.67 (3.5–5.7)
0.006 NS NS NS NS NS
*Values are given as the mean ⫾ SD (range) or No. (%), unless otherwise indicated. LDH ⫽ lactate dehydrogenase (LDH ⫽ units/L); NS ⫽ not significant; protein ⫽ gr/dl. www.chestjournal.org
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drained over a 24-h period from patients who had undergone pleurodesis. The thoracic drain was removed from patients who had undergone diagnostic thoracoscopy after the complete reexpansion of the lung to the thoracic wall.1,10,11 A chest radiograph was performed on hospital admission, immediately after thoracoscopy, 24 h later, on hospital discharge, and as needed based on the patient’s clinical status. A clinical evaluation with chest radiograph was also performed by the respiratory physician at 1 week after the procedure, when the stitches were removed, at 1 month after the procedure, and at 3 months after the procedure. All patients had a 3-month follow-up after the procedure. Statistical Analysis We used a statistical software package (StatView, version 4.5; Abacus Concepts Inc; Berkeley, CA) for the statistical evaluation of our data. The mean values and SD were calculated for continuous data in both groups. Continuous data were compared between the two groups studied using the Student t test. Analysis of variance was used to evaluate differences in repeated measurements in the same group of patients. The 2 test was used to determine whether a difference existed between demographic parameters such as diagnosis and gender. The Fisher exact test was used to compare significant difference in proportions. A p value of ⬍ 0.05 was considered to be statistically significant.
Results Temperature Overall, the temperature rise was more significant in the talc poudrage group than in the diagnostic thoracoscopy group (p ⫽ 0.005). A significant increase in temperature was noted in the talc poudrage group at 9, 12, 24 h after patients had undergone the procedure compared to that in the diagnostic thoracoscopy group (Fig 1). Of the 17 patients who underwent diagnostic thoracoscopy, only 1 patient (5.8%) achieved a temperature of ⬎ 38°C. Of the
18 patients who underwent thoracoscopic talc poudrage, 9 patients (50%) had at least one temperature measured of ⬎ 38°C (p ⫽ 0.007 [Fisher exact test]). Six patients (33.3%) had two temperature measurements of ⬎ 38°C (p ⫽ 0.019 [Fisher exact test]). Infection was not identified despite the intensive evaluation of febrile patients after the procedure or during the follow-up period. Inflammatory Parameters We found a significant increase in the values for mean overall WBC count (p ⫽ 0.004) and the percentage of neutrophils (p ⫽ 0.03) in the group of patients who had undergone talc poudrage compare to those values in the group of patients who had undergone diagnostic thoracoscopy. At the same time, we found a significant decrease in the overall percentage of lymphocytes (p ⫽ 0.01) in the group that had undergone talc poudrage compared to that in the group that had undergone diagnostic thoracoscopy (Fig 2). These significant modifications were reproduced when we compared the differences from baseline between the two groups in mean WBC count (p ⫽ 0.005 and p ⫽ 0.004, respectively), percentage of neutrophils (p ⫽ 0.001 and p ⫽ 0.005, respectively), and percentage of lymphocytes (p ⫽ 0.001 and p ⫽ 0.003, respectively) at 24 and 48 h after the procedure. Also, we observed a significant increase in the overall mean CRP level (p ⬍ 0.0001) in the group that had undergone talc poudrage compared to that in the group that had undergone diagnostic thoracoscopy (Fig 3). A significant increase in mean CRP levels was also noted when we compared the differences from baseline values between the groups (p ⫽ 0.001 and p ⫽ 0.006, respectively) at 24 and 48 h after the procedure. Diagnostic thoracoscopy, as an interventional procedure in our report, had an effect on WBC count and the percentage of neutrophils (Fig 2). Patients who underwent diagnostic thoracoscopy had a significant increase in mean WBC count (p ⫽ 0.0002) and neutrophil percentage (p ⬍ 0.001) at 24 and 48 h after undergoing the procedure. At the same time, the mean serum CRP level in this group of patients was significantly increased from baseline at 24 h (p ⬍ 0.0001) and at 48 h (p ⫽ 0.0003) after the procedure (Fig 3). Complications
Figure 1. The mean temperatures of patients who have undergone diagnostic thoracoscopy and thoracoscopic talc poudrage. Values are expressed as the mean. Error bars show the SE. * ⫽ p ⫽ 0.01; ** ⫽ p ⫽ 0.008; *** ⫽ p ⫽ 0.001. 358
All patients were followed up for at least 3 months after undergoing the procedure. Pleurodesis was successful in all but one patient after hospital discharge (94.4%). Complications that were noted in both groups, during and after the procedure, are Original Research
Figure 3. Evolution of serum mean values of CRP (in milligrams per deciliter) at baseline, and at 24 and 48 h after thoracoscopy for both groups. Error bars show the SE. Overall comparison, p ⬍ 0.0001.
antibiotics were prescribed to any patient. One patient developed bradycardia during talc poudrage, which was easily reversed with the IV administration of atropine (Table 2). Discussion
Figure 2. Evolution of WBC count (top, A), of the percentage of blood neutrophils (middle, B), and of the percentage of blood lymphocytes (bottom, C) at baseline, and at 24 and 48 h after undergoing thoracoscopy for both groups. Values are expressed as the mean. Error bars indicate the SE. Top, A: evolution of the WBC count (mean No. of cells per cubic millimeter). Overall comparison, p ⫽ 0.004. * ⫽ p ⫽ 0.0003; ** ⫽ p ⫽ 0.0002. Middle, B: evolution of the mean percentage of blood neutrophils. Overall comparison, p ⫽ 0.03. * ⫽ p ⬍ 0.0001; ** ⫽ p ⫽ 0.0007. Bottom, C: evolution of the mean percentage of blood lymphocytes. Overall comparison, p ⫽ 0.01. * ⫽ p ⬍ 0.0001; ** ⫽ p ⫽ 0.0004.
shown in Table 2. None of the patients experienced respiratory insufficiency requiring oxygen supplementation during or after thoracoscopy. Also, none of the patients experienced an infection. Thus, no www.chestjournal.org
This study demonstrates that the temperature rise is significantly higher in patients who undergo thoracoscopic talc poudrage than in patients who undergo diagnostic thoracoscopy. According to our results, based on the rise in WBC count, percentage of neutrophils, and CRP levels, fever is due to a systemic inflammation that is produced after talc insufflation. To the best of our knowledge, this is the first report distinguishing talc-induced inflammatory reaction from the presumed postthoracoscopy response. Fever has been reported as a side effect after thoracoscopic talc poudrage in many series ranging from 2.7%12 to 9.8% of cases.4 However, these reports were retrospective studies. It is well-known that retrospective studies always underestimate complications. No prospective comparative study has been performed evaluating the effect of talc poudrage on temperature in patients who undergo thoracoscopy. Our data demonstrate that temperature rises in patients who undergo thoracoscopic talc poudrage within 3 h of the procedure. This temperature rise is not significant compared to that in patients who undergo diagnostic thoracoscopy alone (Fig 1). The temperature rise in the group of patients who underwent diagnostic thoracoscopy, ceasing within 6 h of procedure, was mild. The fever in patients who had undergone thoracoscopic talc CHEST / 129 / 2 / FEBRUARY, 2006
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Table 2—Complications of Thoracoscopy*
Side Effects
Thoracoscopic Talc Poudrage (n ⫽ 18)
Diagnostic Thoracoscopy (n ⫽ 17)
p Value
Pain during thoracoscopy requiring morphine supplementation Pain after thoracoscopy requiring morphine supplementation Subcutaneous emphysema Nausea/vomiting Bradyarrythmia
6 (33.3) 8 (44.4) 2 (11.1) 1 (5.5) 1 (5.5)
5 (29.4) 6 (35.3) 3 (17.6) 0 0
NS NS NS NS NS
*Values are given as No. (%). See Table 1 for abbreviation not used in the text.
poudrage became significant at 9 h after the procedure and remained significantly higher until 24 h after the procedure. The higher prevalence of fever in our report (43.75% of the patients with pleurodesis) was likely due to the fact that our study was prospective. Our results are in agreement with another prospective study13 that reported fever in 21 of 47 patients (45%) after they had undergone thoracoscopic talc poudrage under local anesthesia. According to our results, diagnostic thoracoscopy also increases WBC count and the percentage of neutrophils at 24 h after the procedure. These mean values returned to normal 48 h after the procedure. During the same time period, the mean serum CRP level in this group of patients significantly increased from baseline at 24 h and remained elevated at 48 h. There are a number of reports in the literature8,9,14 demonstrating the systemic inflammatory effects of video-assisted thoracoscopic surgery and minimally invasive thoracic surgery. All studies compared the effects of minimally invasive techniques to thoracotomy. There has been no report concerning medical thoracoscopy that was performed through a single port of entry by respiratory physicians. The same results and curve patterns concerning WBC count and the percentage of neutrophils have been observed by Andres et al7 in patients after total knee arthroplasty. The increases in the percentages of leukocytes and neutrophils in peripheral blood is significant in patients who have undergone thoracoscopic talc poudrage compared to those who have undergone diagnostic thoracoscopy only at 24 and 48 h after the procedure. At the same time, we found an increase in serum values of CRP, which is an acute-phase protein. This rise in serum values in the pleurodesis group may indicate a greater degree of inflammatory reaction in this population. This may be due to talc insufflation in the pleural cavity. It is well-known that talc induces inflammation to the pleural cavity.5,15 One study16 measured WBC count and the percentage of neutrophils in the blood of rabbits after talc pleurodesis. The authors reported16 that 360
talc had induced a significant increase in both WBC count and the percentage of neutrophils by 6 h after pleurodesis. There is a significant decrease in lymphocyte percentage in the peripheral blood of patients who have undergone thoracoscopic talc poudrage compared to those who have undergone diagnostic thoracoscopy. This observation, in association with the increases in WBC count and neutrophil percentage, leads to the hypothesis that the inflammatory reaction induced by talc in the pleural cavity may stimulate the bone marrow, resulting in neutrophil recruitment. This hypothesis is supported by the findings of other authors15,17 who have reported that during talc-induced inflammation there are a number of mediators released into the pleural cavity, such as tumor necrosis factor-␣, interleukin (IL)-1, IL-8, and IL-6. These cytokines may result in the induction of IL-3 and granulocyte-macrophage colony-stimulating factor, which act in the bone marrow and stimulate the production and maturity of leukocytes.18,19 Also, granulocyte-macrophage colonystimulating factor and granulocyte colony-stimulating factor control the expression of specific adhesion molecules and enable an increased rate of migration from the blood to the site of tissue inflammation.19 Thus, these cytokines could contribute to talc-induced inflammation, which may explain the pathophysiologic mechanism of talc-induced ARDS.20,21 Procedures such as pleural abrasion during thoracoscopy, in addition to the insufflation of high doses of talc, may increase the risk of the systemic dissemination of talc particles, leading to ARDS.3,22 However, in an animal study Fraticelli and coworkers23 did not find any systemic dispersion of talc particles ⬎ 15 m in size used in their clinical practice, despite the use of high doses of talc. The significance of the size of talc particles was also shown by Maskell and coworkers,24 in a study in humans. Their goal was to compare the incidence of inflammation after using pleurodesis with various sizes of talc particles and to the use of tetracycline. They found that the use of talc with large particles (ie, ⬎ 15 m) proOriginal Research
duced less inflammation than the use of talc with small particles (ie, ⬍ 15 m) and tetracycline. We used the same talc as used by Fraticelli and coworkers23 and did not have any respiratory complications develop in our patients. Medical thoracoscopy is a well-tolerated interventional procedure. The incidence of complications between the two groups in our study was not significantly different. The overall relative higher occurrence of those side effects compared to that in the literature, again, is common for prospective studies.6,25 No case of fever was related to any postthoracoscopic infection in our study. None of our 35 patients received antibiotic therapy during or after undergoing thoracoscopy. Thus, a systematic test, such as a blood culture or urinary culture, may not be required in those patients in order to evaluate any possible infection during the period of temperature rise, in accordance with the results of other reports.7,8 Fever, especially in patients who have undergone talc poudrage, is only due to a short-term inflammatory reaction. This observation should decrease significantly the overall cost of thoracoscopy. The length of hospital stay, in our study, was similar to that in other reports.1,25 Other complications such as pain, nausea, subcutaneous emphysema, and bradyarrythmia were minimal, and, in all cases, were well-controlled. In conclusion, the results of this study suggest that a more significant temperature rise is induced from talc insufflation during medical thoracoscopy than from diagnostic thoracoscopy alone. This temperature rise is significant from 9 until 24 h after the procedure. In patients who have undergone thoracoscopic talc poudrage, fever is associated with a significant systemic inflammatory reaction. References 1 Rodriguez-Panadero F, Antony VB. Pleurodesis: state of the art. Eur Respir J 1997; 10:1648 –1654 2 Lee YC, Baumann MH, Maskell NA, et al. Pleurodesis practice for malignant pleural effusions in five Englishspeaking countries: survey of pulmonologists. Chest 2003; 124:2229 –2238 3 Bouros D, Froudarakis M, Siafakas NM. Pleurodesis: everything flows. Chest 2000; 118:577–579 4 Viallat JR, Rey F, Astoul P, et al. Thoracoscopic talc poudrage pleurodesis for malignant effusions: a review of 360 cases. Chest 1996; 110:1387–1393 5 Colt HG, Russack V, Chiu Y, et al. A comparison of thoracoscopic talc insufflation, slurry, and mechanical abrasion pleurodesis. Chest 1997; 111:442– 448 6 Tschopp JM, Boutin C, Astoul P, et al. Talcage by medical thoracoscopy for primary spontaneous pneumothorax is more
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7 8 9 10 11 12 13 14
15 16
17
18
19 20 21
22 23 24
25
cost-effective than drainage: a randomised study. Eur Respir J 2002; 20:1003–1009 Andres BM, Taub DD, Gurkan I, et al. Postoperative fever after total knee arthroplasty: the role of cytokines. Clin Orthop Relat Res 2003; 415:221–231 Craig SR, Leaver HA, Yap PL, et al. Acute phase responses following minimal access and conventional thoracic surgery. Eur J Cardiothorac Surg 2001; 20:455– 463 Yim AP, Wan S, Lee TW, et al. VATS lobectomy reduces cytokine responses compared with conventional surgery. Ann Thorac Surg 2000; 70:243–247 Boutin C, Astoul P. Diagnostic thoracoscopy. Clin Chest Med 1998; 19:295–309 Loddenkemper R. Thoracoscopy: state of the art. Eur Respir J 1998; 11:213–221 Milanez de Campos JR, Vargas FS, de Campos Werebe E, et al. Thoracoscopy talc poudrage: a 15-year experience. Chest 2001; 119:801– 806 Aelony Y, King R, Boutin C. Thoracoscopic talc poudrage pleurodesis for chronic recurrent pleural effusions. Ann Intern Med 1991; 115:778 –782 Nagahiro I, Andou A, Aoe M, et al. Pulmonary function, postoperative pain, and serum cytokine level after lobectomy: a comparison of VATS and conventional procedure. Ann Thorac Surg 2001; 72:362–365 van den Heuvel MM, Smit HJ, Barbierato SB, et al. Talcinduced inflammation in the pleural cavity. Eur Respir J 1998; 12:1419 –1423 Marchi E, Vargas FS, Acencio MM, et al. Talc and silver nitrate induce systemic inflammatory effects during the acute phase of experimental pleurodesis in rabbits. Chest 2004; 125:2268 –2277 Montes-Worboys A, Gomez-Izquierdo L, Martin-Juan J, et al. Comparison of production of interleukin-8 (IL-8) after stimulation of human mesothelial cells “in vitro” with different types of talc [abstract]. Eur Respir J 2003; 22(suppl):P3380 Katschinski DM, Wiedemann GJ, Longo W, et al. Whole body hyperthermia cytokine induction: a review, and unifying hypothesis for myeloprotection in the setting of cytotoxic therapy. Cytokine Growth Factor Rev 1999; 10:93–97 Nussler AK, Wittel UA, Nussler NC, et al. Leukocytes, the Janus cells in inflammatory disease. Langenbecks Arch Surg 1999; 384:222–232 Brant A, Eaton T. Serious complications with talc slurry pleurodesis. Respirology 2001; 6:181–185 Bondoc AY, Bach PB, Sklarin NT, et al. Arterial desaturation syndrome following pleurodesis with talc slurry: incidence, clinical features, and outcome. Cancer Invest 2003; 21:848 – 854 Montes JF, Ferrer J, Villarino MA, et al. Influence of talc dose on extrapleural talc dissemination after talc pleurodesis. Am J Respir Crit Care Med 2003; 168:348 –355 Fraticelli A, Robaglia-Schlupp A, Riera H, et al. Distribution of calibrated talc after intrapleural administration: an experimental study in rats. Chest 2002; 122:1737–1741 Maskell NA, Lee YC, Gleeson FV, et al. Randomized trials describing lung inflammation after pleurodesis with talc of varying particle size. Am J Respir Crit Care Med 2004; 170:377–382 Noppen M, Meysman M, d’Haese J, et al. Comparison of video-assisted thoracoscopic talcage for recurrent primary versus persistent secondary spontaneous pneumothorax. Eur Respir J 1997; 10:412– 416
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Systemic Inflammatory Reaction After Thoracoscopic Talc Poudrage* Marios E. Froudarakis, MD, FCCP; Maria Klimathianaki, MD; and Mihalis Pougounias, MD
Background: Recent studies have reported fever as a side effect of talc poudrage during thoracoscopic pleurodesis. However, thoracoscopy itself is likely to induce systemic inflammatory reaction, as it is an interventional procedure. The aim of the study was to investigate whether systemic inflammatory response is due to talc poudrage or to thoracoscopy. Methods: We prospectively studied two groups of patients. The first group (18 patients) underwent thoracoscopic talc poudrage, and the second group (17 patients) underwent only diagnostic thoracoscopy. We measured body temperature, as well as WBC count and C-reactive protein (CRP) levels before the procedure (baseline), and at 24 and 48 h after the procedure. No antiinflammatory medication was permitted to be used before, during, or after the procedure. All patients had a 3-month follow-up. Results: The baseline patient characteristics were similar in both groups. Temperature increased significantly in the thoracoscopic talc poudrage group (overall comparison, p ⴝ 0.005) especially at 9, 12, and 24 h after the procedure. Overall, the WBC count (p ⴝ 0.004), percentage of neutrophils (p ⴝ 0.03), and CRP levels (p < 0.0001) were significantly increased in the group of patients who underwent thoracoscopic talc poudrage. On the contrary, lymphocytes were significantly decreased (overall comparison, p ⴝ 0.01) in the thoracoscopic talc poudrage group during the same period. Mild side effects, such as pain during and after thoracoscopy and subcutaneous emphysema, were noted. No severe complication, such as infection or acute respiratory failure, was noted in either group during the hospitalization or during the follow-up period. Conclusion: According to our results, fever and systemic inflammatory reaction is due to talc poudrage and not to thoracoscopy. (CHEST 2006; 129:356 –361) Key words: fever; inflammation; pleurodesis; talc; thoracoscopy Abbreviations: CRP ⫽ C-reactive protein; IL ⫽ interleukin
is actually the agent of choice for chemical T alcpleurodesis, with an efficacy rate of ⬎ 90%. It may be administered as a powder by insufflation during thoracoscopy,1– 4 inducing fibrosis and inflammation in the pleural cavity.5 Talc pleurodesis is generally well-tolerated. However, reports2,4 have stated that minor side effects, such as pleuritic pain *From the Department of Pneumonology, Medical School, University of Crete, Heraklion, Greece. Manuscript received April 19, 2005; revision accepted June 26, 2005. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal. org/misc/reprints.shtml). Correspondence to: Marios E. Froudarakis, MD, FCCP, Zografou 11, 71201 Heraklion, Greece; e-mail: [email protected] 356
during pleurodesis, nausea and fever after the procedure, and fever after thoracoscopic talc poudrage, occur in about 20% of the patients who have been included in prospective studies.6 Although many authors have reported that fever occurs 1 or 2 days after thoracoscopic talc poudrage,1,6 no clear information exists regarding the characteristics of fever, such as the actual rise in the patient’s baseline temperature, the exact time of its occurrence, or the duration of fever. Also, we have no information about the patient’s tolerance of fever and the possible association with other symptoms such as chills, nausea, and fatigue. Temperature increases in patients who undergo any interventional procedure. Causes include pneuOriginal Research
monia, pulmonary embolus, local infection at the site of entry, and urinary tract infection in catheterized patients. However, fever is more likely to be an acute-phase response that is associated with traumarelated immunologic changes than to postoperative infection.7,8 Thoracoscopy is widely used for the diagnosis and treatment of pleural and lung diseases. Thoracoscopy by itself may result in an elevation of baseline body temperature or may result in fever. However, it has been reported that thoracoscopy induces a lesser degree of acute-phase response compared to more invasive surgery.8,9 In the case of patients who undergo both thoracoscopy and talc poudrage, we cannot know which of the two procedures (maybe both) induces fever. Therefore, we initiated a study to investigate which of the two procedures is responsible for the increasing temperature in patients in this population. Materials and Methods Data Collection From January 2004 to December 2004, all patients who underwent diagnostic thoracoscopy or pleural talc poudrage were monitored in order to evaluate the patient’s temperature after undergoing the procedure. Overall, 35 patients underwent thoracoscopy during that period (thoracoscopy for undiagnosed pleural effusion, 17 patients; thoracoscopic talc poudrage for pleurodesis, 18 patients). Patient characteristics are shown in Table 1. We evaluated inflammation by monitoring leukocytes, neutrophils, and C-reactive protein (CRP) levels in peripheral blood. We also monitored complications and side effects during and after thoracoscopy. If an increase in body temperature to ⬎ 38°C occurred, we systematically evaluated the patient for possible infection, and sent blood and urine to the laboratory for cultures.
Data were collected regarding body temperature before the patient underwent thoracoscopy (baseline) and every 3 h after the procedure. WBC count, the percentage of neutrophils and lymphocytes, and CRP levels were also monitored at baseline, as well as at 24 and 48 h after thoracoscopy. After undergoing thoracoscopy, all patients received baseline treatment for the pain with a fentanyl citrate patch, 25 mg every 72 h. In case of persistent pain, patients received a supplement of parenteral narcotics (morphine) on request. No antiinflammatory or antipyretic medications were permitted to be used before, during, or after the procedure. Thoracoscopy Patients were admitted to the hospital on the same morning of thoracoscopy and were discharged from the hospital on the day of chest tube removal. Thus, the length of hospitalization was equivalent to the number of days required for chest tube drainage. During the procedure, BP, oxygen saturation, and ECG were monitored. Oxygen supplementation was provided if needed. In case of pain during thoracoscopy, patients received supplementary parenteral narcotics (morphine) on request. No general anesthesia was used at any time. Thoracoscopy was performed with the patient in the lateral decubitus position using a single port of entry, under local anesthesia with 1% lignocaine. Morphine, 0.5 mg, was administered to patients as needed. A 7-mm trocar was inserted into the fifth or sixth intercostal space along the midaxillary line. After evacuation of the pleural fluid, a 0o optical telescope was inserted into the patient and connected to a light source. The entire pleural cavity was then inspected, at times requiring supplemental air insufflation. Biopsies were performed with an optical forceps through the single port of entry under direct visualization. No stapling or electrocoagulation was used for parenchymal biopsies.10,11 Sterile asbestos-free talc (Steritalc; Novatech; La Ciotat, France) [4 g for a malignant pleural effusion and 2 g for a pneumothorax] was insufflated into the pleural space of patients who underwent pleurodesis. At the end of the procedure, a chest tube (24F to 28F) was inserted and connected to an underwater seal with a negative suction of 20 cm H2O for at least 2 days. The chest tube was removed when ⬍ 100 mL of pleural fluid was
Table 1—Characteristics of Patients*
Characteristics Age, yr Sex Male Female Diagnosis Malignant Benign Pleural drainage, d Side of thoracoscopy Right Left Pleural fluid during thoracoscopy, L Pleural fluid pH Pleural fluid LDH Pleural protein
Total (n ⫽ 35) 64.6 ⫾ 15 (33–94)
Thoracoscopic Talc Poudrage (n ⫽ 18) 63.1 ⫾ 15.5 (33–93)
Diagnostic Thoracoscopy (n ⫽ 17) 64 ⫾ 14.5 (38–94)
p Value NS
26 (74.3) 9 (25.7)
12 (66.6) 6 (33.3)
14 (82.3) 3 (17.7)
NS
26 (74.3) 9 (25.7) 2.8 ⫾ 1.3 (1–7)
16 (88.9) 2 (11.1) 3.4 ⫾ 1.4 (2–7)
10 (58.8) 7 (31.2) 2.2 ⫾ 0.8 (1–4)
0.05
19 (54.3) 16 (45.7) 1.52 ⫾ 1.1 (0.2–4.4) 7.39 ⫾ 0.08 (7.19–7.49) 330 ⫾ 249 (89–1286) 4.47 ⫾ 0.83 (3.1–7.2)
9 (50) 9 (50) 1.52 ⫾ 1.1 (0.2–4.2) 7.37 ⫾ 0.09 (7.19–7.49) 332 ⫾ 280 (104–1286) 4.45 ⫾ 0.96 (3.1–7.2)
10 (58.8) 7 (41.2) 1.51 ⫾ 1.1 (0.35–4.4) 7.41 ⫾ 0.07 (7.20–7.49) 328 ⫾ 216 (89–857) 4.51 ⫾ 0.67 (3.5–5.7)
0.006 NS NS NS NS NS
*Values are given as the mean ⫾ SD (range) or No. (%), unless otherwise indicated. LDH ⫽ lactate dehydrogenase (LDH ⫽ units/L); NS ⫽ not significant; protein ⫽ gr/dl. www.chestjournal.org
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drained over a 24-h period from patients who had undergone pleurodesis. The thoracic drain was removed from patients who had undergone diagnostic thoracoscopy after the complete reexpansion of the lung to the thoracic wall.1,10,11 A chest radiograph was performed on hospital admission, immediately after thoracoscopy, 24 h later, on hospital discharge, and as needed based on the patient’s clinical status. A clinical evaluation with chest radiograph was also performed by the respiratory physician at 1 week after the procedure, when the stitches were removed, at 1 month after the procedure, and at 3 months after the procedure. All patients had a 3-month follow-up after the procedure. Statistical Analysis We used a statistical software package (StatView, version 4.5; Abacus Concepts Inc; Berkeley, CA) for the statistical evaluation of our data. The mean values and SD were calculated for continuous data in both groups. Continuous data were compared between the two groups studied using the Student t test. Analysis of variance was used to evaluate differences in repeated measurements in the same group of patients. The 2 test was used to determine whether a difference existed between demographic parameters such as diagnosis and gender. The Fisher exact test was used to compare significant difference in proportions. A p value of ⬍ 0.05 was considered to be statistically significant.
Results Temperature Overall, the temperature rise was more significant in the talc poudrage group than in the diagnostic thoracoscopy group (p ⫽ 0.005). A significant increase in temperature was noted in the talc poudrage group at 9, 12, 24 h after patients had undergone the procedure compared to that in the diagnostic thoracoscopy group (Fig 1). Of the 17 patients who underwent diagnostic thoracoscopy, only 1 patient (5.8%) achieved a temperature of ⬎ 38°C. Of the
18 patients who underwent thoracoscopic talc poudrage, 9 patients (50%) had at least one temperature measured of ⬎ 38°C (p ⫽ 0.007 [Fisher exact test]). Six patients (33.3%) had two temperature measurements of ⬎ 38°C (p ⫽ 0.019 [Fisher exact test]). Infection was not identified despite the intensive evaluation of febrile patients after the procedure or during the follow-up period. Inflammatory Parameters We found a significant increase in the values for mean overall WBC count (p ⫽ 0.004) and the percentage of neutrophils (p ⫽ 0.03) in the group of patients who had undergone talc poudrage compare to those values in the group of patients who had undergone diagnostic thoracoscopy. At the same time, we found a significant decrease in the overall percentage of lymphocytes (p ⫽ 0.01) in the group that had undergone talc poudrage compared to that in the group that had undergone diagnostic thoracoscopy (Fig 2). These significant modifications were reproduced when we compared the differences from baseline between the two groups in mean WBC count (p ⫽ 0.005 and p ⫽ 0.004, respectively), percentage of neutrophils (p ⫽ 0.001 and p ⫽ 0.005, respectively), and percentage of lymphocytes (p ⫽ 0.001 and p ⫽ 0.003, respectively) at 24 and 48 h after the procedure. Also, we observed a significant increase in the overall mean CRP level (p ⬍ 0.0001) in the group that had undergone talc poudrage compared to that in the group that had undergone diagnostic thoracoscopy (Fig 3). A significant increase in mean CRP levels was also noted when we compared the differences from baseline values between the groups (p ⫽ 0.001 and p ⫽ 0.006, respectively) at 24 and 48 h after the procedure. Diagnostic thoracoscopy, as an interventional procedure in our report, had an effect on WBC count and the percentage of neutrophils (Fig 2). Patients who underwent diagnostic thoracoscopy had a significant increase in mean WBC count (p ⫽ 0.0002) and neutrophil percentage (p ⬍ 0.001) at 24 and 48 h after undergoing the procedure. At the same time, the mean serum CRP level in this group of patients was significantly increased from baseline at 24 h (p ⬍ 0.0001) and at 48 h (p ⫽ 0.0003) after the procedure (Fig 3). Complications
Figure 1. The mean temperatures of patients who have undergone diagnostic thoracoscopy and thoracoscopic talc poudrage. Values are expressed as the mean. Error bars show the SE. * ⫽ p ⫽ 0.01; ** ⫽ p ⫽ 0.008; *** ⫽ p ⫽ 0.001. 358
All patients were followed up for at least 3 months after undergoing the procedure. Pleurodesis was successful in all but one patient after hospital discharge (94.4%). Complications that were noted in both groups, during and after the procedure, are Original Research
Figure 3. Evolution of serum mean values of CRP (in milligrams per deciliter) at baseline, and at 24 and 48 h after thoracoscopy for both groups. Error bars show the SE. Overall comparison, p ⬍ 0.0001.
antibiotics were prescribed to any patient. One patient developed bradycardia during talc poudrage, which was easily reversed with the IV administration of atropine (Table 2). Discussion
Figure 2. Evolution of WBC count (top, A), of the percentage of blood neutrophils (middle, B), and of the percentage of blood lymphocytes (bottom, C) at baseline, and at 24 and 48 h after undergoing thoracoscopy for both groups. Values are expressed as the mean. Error bars indicate the SE. Top, A: evolution of the WBC count (mean No. of cells per cubic millimeter). Overall comparison, p ⫽ 0.004. * ⫽ p ⫽ 0.0003; ** ⫽ p ⫽ 0.0002. Middle, B: evolution of the mean percentage of blood neutrophils. Overall comparison, p ⫽ 0.03. * ⫽ p ⬍ 0.0001; ** ⫽ p ⫽ 0.0007. Bottom, C: evolution of the mean percentage of blood lymphocytes. Overall comparison, p ⫽ 0.01. * ⫽ p ⬍ 0.0001; ** ⫽ p ⫽ 0.0004.
shown in Table 2. None of the patients experienced respiratory insufficiency requiring oxygen supplementation during or after thoracoscopy. Also, none of the patients experienced an infection. Thus, no www.chestjournal.org
This study demonstrates that the temperature rise is significantly higher in patients who undergo thoracoscopic talc poudrage than in patients who undergo diagnostic thoracoscopy. According to our results, based on the rise in WBC count, percentage of neutrophils, and CRP levels, fever is due to a systemic inflammation that is produced after talc insufflation. To the best of our knowledge, this is the first report distinguishing talc-induced inflammatory reaction from the presumed postthoracoscopy response. Fever has been reported as a side effect after thoracoscopic talc poudrage in many series ranging from 2.7%12 to 9.8% of cases.4 However, these reports were retrospective studies. It is well-known that retrospective studies always underestimate complications. No prospective comparative study has been performed evaluating the effect of talc poudrage on temperature in patients who undergo thoracoscopy. Our data demonstrate that temperature rises in patients who undergo thoracoscopic talc poudrage within 3 h of the procedure. This temperature rise is not significant compared to that in patients who undergo diagnostic thoracoscopy alone (Fig 1). The temperature rise in the group of patients who underwent diagnostic thoracoscopy, ceasing within 6 h of procedure, was mild. The fever in patients who had undergone thoracoscopic talc CHEST / 129 / 2 / FEBRUARY, 2006
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Table 2—Complications of Thoracoscopy*
Side Effects
Thoracoscopic Talc Poudrage (n ⫽ 18)
Diagnostic Thoracoscopy (n ⫽ 17)
p Value
Pain during thoracoscopy requiring morphine supplementation Pain after thoracoscopy requiring morphine supplementation Subcutaneous emphysema Nausea/vomiting Bradyarrythmia
6 (33.3) 8 (44.4) 2 (11.1) 1 (5.5) 1 (5.5)
5 (29.4) 6 (35.3) 3 (17.6) 0 0
NS NS NS NS NS
*Values are given as No. (%). See Table 1 for abbreviation not used in the text.
poudrage became significant at 9 h after the procedure and remained significantly higher until 24 h after the procedure. The higher prevalence of fever in our report (43.75% of the patients with pleurodesis) was likely due to the fact that our study was prospective. Our results are in agreement with another prospective study13 that reported fever in 21 of 47 patients (45%) after they had undergone thoracoscopic talc poudrage under local anesthesia. According to our results, diagnostic thoracoscopy also increases WBC count and the percentage of neutrophils at 24 h after the procedure. These mean values returned to normal 48 h after the procedure. During the same time period, the mean serum CRP level in this group of patients significantly increased from baseline at 24 h and remained elevated at 48 h. There are a number of reports in the literature8,9,14 demonstrating the systemic inflammatory effects of video-assisted thoracoscopic surgery and minimally invasive thoracic surgery. All studies compared the effects of minimally invasive techniques to thoracotomy. There has been no report concerning medical thoracoscopy that was performed through a single port of entry by respiratory physicians. The same results and curve patterns concerning WBC count and the percentage of neutrophils have been observed by Andres et al7 in patients after total knee arthroplasty. The increases in the percentages of leukocytes and neutrophils in peripheral blood is significant in patients who have undergone thoracoscopic talc poudrage compared to those who have undergone diagnostic thoracoscopy only at 24 and 48 h after the procedure. At the same time, we found an increase in serum values of CRP, which is an acute-phase protein. This rise in serum values in the pleurodesis group may indicate a greater degree of inflammatory reaction in this population. This may be due to talc insufflation in the pleural cavity. It is well-known that talc induces inflammation to the pleural cavity.5,15 One study16 measured WBC count and the percentage of neutrophils in the blood of rabbits after talc pleurodesis. The authors reported16 that 360
talc had induced a significant increase in both WBC count and the percentage of neutrophils by 6 h after pleurodesis. There is a significant decrease in lymphocyte percentage in the peripheral blood of patients who have undergone thoracoscopic talc poudrage compared to those who have undergone diagnostic thoracoscopy. This observation, in association with the increases in WBC count and neutrophil percentage, leads to the hypothesis that the inflammatory reaction induced by talc in the pleural cavity may stimulate the bone marrow, resulting in neutrophil recruitment. This hypothesis is supported by the findings of other authors15,17 who have reported that during talc-induced inflammation there are a number of mediators released into the pleural cavity, such as tumor necrosis factor-␣, interleukin (IL)-1, IL-8, and IL-6. These cytokines may result in the induction of IL-3 and granulocyte-macrophage colony-stimulating factor, which act in the bone marrow and stimulate the production and maturity of leukocytes.18,19 Also, granulocyte-macrophage colonystimulating factor and granulocyte colony-stimulating factor control the expression of specific adhesion molecules and enable an increased rate of migration from the blood to the site of tissue inflammation.19 Thus, these cytokines could contribute to talc-induced inflammation, which may explain the pathophysiologic mechanism of talc-induced ARDS.20,21 Procedures such as pleural abrasion during thoracoscopy, in addition to the insufflation of high doses of talc, may increase the risk of the systemic dissemination of talc particles, leading to ARDS.3,22 However, in an animal study Fraticelli and coworkers23 did not find any systemic dispersion of talc particles ⬎ 15 m in size used in their clinical practice, despite the use of high doses of talc. The significance of the size of talc particles was also shown by Maskell and coworkers,24 in a study in humans. Their goal was to compare the incidence of inflammation after using pleurodesis with various sizes of talc particles and to the use of tetracycline. They found that the use of talc with large particles (ie, ⬎ 15 m) proOriginal Research
duced less inflammation than the use of talc with small particles (ie, ⬍ 15 m) and tetracycline. We used the same talc as used by Fraticelli and coworkers23 and did not have any respiratory complications develop in our patients. Medical thoracoscopy is a well-tolerated interventional procedure. The incidence of complications between the two groups in our study was not significantly different. The overall relative higher occurrence of those side effects compared to that in the literature, again, is common for prospective studies.6,25 No case of fever was related to any postthoracoscopic infection in our study. None of our 35 patients received antibiotic therapy during or after undergoing thoracoscopy. Thus, a systematic test, such as a blood culture or urinary culture, may not be required in those patients in order to evaluate any possible infection during the period of temperature rise, in accordance with the results of other reports.7,8 Fever, especially in patients who have undergone talc poudrage, is only due to a short-term inflammatory reaction. This observation should decrease significantly the overall cost of thoracoscopy. The length of hospital stay, in our study, was similar to that in other reports.1,25 Other complications such as pain, nausea, subcutaneous emphysema, and bradyarrythmia were minimal, and, in all cases, were well-controlled. In conclusion, the results of this study suggest that a more significant temperature rise is induced from talc insufflation during medical thoracoscopy than from diagnostic thoracoscopy alone. This temperature rise is significant from 9 until 24 h after the procedure. In patients who have undergone thoracoscopic talc poudrage, fever is associated with a significant systemic inflammatory reaction. References 1 Rodriguez-Panadero F, Antony VB. Pleurodesis: state of the art. Eur Respir J 1997; 10:1648 –1654 2 Lee YC, Baumann MH, Maskell NA, et al. Pleurodesis practice for malignant pleural effusions in five Englishspeaking countries: survey of pulmonologists. Chest 2003; 124:2229 –2238 3 Bouros D, Froudarakis M, Siafakas NM. Pleurodesis: everything flows. Chest 2000; 118:577–579 4 Viallat JR, Rey F, Astoul P, et al. Thoracoscopic talc poudrage pleurodesis for malignant effusions: a review of 360 cases. Chest 1996; 110:1387–1393 5 Colt HG, Russack V, Chiu Y, et al. A comparison of thoracoscopic talc insufflation, slurry, and mechanical abrasion pleurodesis. Chest 1997; 111:442– 448 6 Tschopp JM, Boutin C, Astoul P, et al. Talcage by medical thoracoscopy for primary spontaneous pneumothorax is more
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cost-effective than drainage: a randomised study. Eur Respir J 2002; 20:1003–1009 Andres BM, Taub DD, Gurkan I, et al. Postoperative fever after total knee arthroplasty: the role of cytokines. Clin Orthop Relat Res 2003; 415:221–231 Craig SR, Leaver HA, Yap PL, et al. Acute phase responses following minimal access and conventional thoracic surgery. Eur J Cardiothorac Surg 2001; 20:455– 463 Yim AP, Wan S, Lee TW, et al. VATS lobectomy reduces cytokine responses compared with conventional surgery. Ann Thorac Surg 2000; 70:243–247 Boutin C, Astoul P. Diagnostic thoracoscopy. Clin Chest Med 1998; 19:295–309 Loddenkemper R. Thoracoscopy: state of the art. Eur Respir J 1998; 11:213–221 Milanez de Campos JR, Vargas FS, de Campos Werebe E, et al. Thoracoscopy talc poudrage: a 15-year experience. Chest 2001; 119:801– 806 Aelony Y, King R, Boutin C. Thoracoscopic talc poudrage pleurodesis for chronic recurrent pleural effusions. Ann Intern Med 1991; 115:778 –782 Nagahiro I, Andou A, Aoe M, et al. Pulmonary function, postoperative pain, and serum cytokine level after lobectomy: a comparison of VATS and conventional procedure. Ann Thorac Surg 2001; 72:362–365 van den Heuvel MM, Smit HJ, Barbierato SB, et al. Talcinduced inflammation in the pleural cavity. Eur Respir J 1998; 12:1419 –1423 Marchi E, Vargas FS, Acencio MM, et al. Talc and silver nitrate induce systemic inflammatory effects during the acute phase of experimental pleurodesis in rabbits. Chest 2004; 125:2268 –2277 Montes-Worboys A, Gomez-Izquierdo L, Martin-Juan J, et al. Comparison of production of interleukin-8 (IL-8) after stimulation of human mesothelial cells “in vitro” with different types of talc [abstract]. Eur Respir J 2003; 22(suppl):P3380 Katschinski DM, Wiedemann GJ, Longo W, et al. Whole body hyperthermia cytokine induction: a review, and unifying hypothesis for myeloprotection in the setting of cytotoxic therapy. Cytokine Growth Factor Rev 1999; 10:93–97 Nussler AK, Wittel UA, Nussler NC, et al. Leukocytes, the Janus cells in inflammatory disease. Langenbecks Arch Surg 1999; 384:222–232 Brant A, Eaton T. Serious complications with talc slurry pleurodesis. Respirology 2001; 6:181–185 Bondoc AY, Bach PB, Sklarin NT, et al. Arterial desaturation syndrome following pleurodesis with talc slurry: incidence, clinical features, and outcome. Cancer Invest 2003; 21:848 – 854 Montes JF, Ferrer J, Villarino MA, et al. Influence of talc dose on extrapleural talc dissemination after talc pleurodesis. Am J Respir Crit Care Med 2003; 168:348 –355 Fraticelli A, Robaglia-Schlupp A, Riera H, et al. Distribution of calibrated talc after intrapleural administration: an experimental study in rats. Chest 2002; 122:1737–1741 Maskell NA, Lee YC, Gleeson FV, et al. Randomized trials describing lung inflammation after pleurodesis with talc of varying particle size. Am J Respir Crit Care Med 2004; 170:377–382 Noppen M, Meysman M, d’Haese J, et al. Comparison of video-assisted thoracoscopic talcage for recurrent primary versus persistent secondary spontaneous pneumothorax. Eur Respir J 1997; 10:412– 416
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