Chest.publicaciones.saludcastillayleon.es

Oral Forms of Tetracycline and
Doxycycline Are Effective in Producing
Pleurodesis*
Semra Bilaceroglu, MD, FCCP; Yubiao Guo, MD; Michael L. Hawthorne, MD;Zhiwen Zhu, MD; Georgios T. Stathopoulos, MD; Kirk B. Lane, PhD; andRichard W. Light, MD, FCCP Purpose: We investigated whether oral tetracyclines could produce an efficient and safe
pleurodesis as does parenteral doxycycline, which is currently unavailable in many countries.
Methods: Parenteral doxycycline (10 mg/kg), oral tetracycline (35 mg/kg), or doxycycline (10
mg/kg) was injected intrapleurally through a right chest tube in rabbits. The oral forms were
dissolved in saline solution and passed through a sterile membrane filter. When daily aspirated
pleural fluid was < 5 mL/24 h, the chest tube was removed. Fluid WBC, lactate dehydrogenase
(LDH), and protein levels were measured 24 h after the injection. After the death of the animals
on day 14, pleurodesis was graded from 1 (none) to 8 (> 50% symphysis) by two observers blinded
to treatment groups.
Results: The right pleurodesis score of the combined oral groups (median, 7.0; interquartile range
[IQR], 4.0; n ؍ 26) did not differ significantly (p ؍ 0.349) from that of the parenteral group
(median, 7.5; IQR, 6.0; n ؍ 10). Oral tetracycline (capsule or tablet, n ؍ 6 in each group) and
doxycycline (capsule or tablet, n ؍ 7 in each group) were as effective as parenteral doxycycline in
producing pleurodesis: tetracycline capsule (median, 7.50; IQR, 6.00); tetracycline tablet (me-
dian, 6.50; IQR, 6.00); doxycycline capsule (median, 4.00; IQR, 1.00); doxycycline tablet (median,
8.00; IQR, 5.00), and parenteral doxycycline (median, 7.50; IQR, 6.00) [p ؍ 0.235]. The left
pleurodesis scores were 1.00 in all 36 rabbits. Fluid total volume, WBC, LDH, and protein levels
were comparable between each oral and parenteral group, excluding WBCs in the tetracycline
tablet group (p ؍ 0.047). The complications were nonfatal (right hemothorax: tetracycline
capsule [n ؍ 3]/tetracycline tablet [n ؍ 2], doxycycline tablet [n ؍ 2], parenteral doxycycline
[n ؍ 2]; left hemothorax: tetracycline capsule [n ؍ 1]; ascites: parenteral doxycycline [n ؍ 1]).
There was no growth on all filtrate cultures. Oral forms cost less than parenteral doxycycline (<$1
vs $4.72 per rabbit). Filtering costs were $1.12 per rabbit.
Conclusion: Oral tetracycline or doxycycline is as effective and safe as parenteral doxycycline in
producing pleurodesis in rabbits; thus, they may also be used in humans.
(CHEST 2005; 128:3750 –3756)
Key words: capsule; doxycycline; pleurodesis; tablet; tetracycline
Abbreviations: IQR ϭ intraquartile range; LDH ϭ lactate dehydrogenase; MMP ϭ matrix degrading metalloproteinase
Pleurodesis is the obliteration of the pleural space pleurodesis. Most of the agents used for pleurodesis
by fusion of the visceral and parietal pleurae with injure the pleura and cause an inflammatory reaction fibrous tissue. Recurrent and symptomatic pleural together with a pleural effusion. Subsequently, the effusions and pneumothoraces are indications for local activation of the coagulation system and theproduction of fibrogenic cytokines such as trans- *From the Department of Pulmonary Medicine (Dr. Bilacero-glu), Izmir Training and Research Hospital for Thoracic Medi- This study was supported by the Saint Thomas Foundation, cine and Surgery, Izmir, Turkey; Department of Pulmonary Medicine (Drs. Hawthorne and Light), Vanderbilt University and Manuscript received March 31, 2005; revision accepted June 24, St. Thomas Hospital, Nashville, TN; Department of Respiratory and Critical Care Medicine (Drs. Guo and Zhu), First Affiliated Reproduction of this article is prohibited without written permission Hospital of Sun Yatsen University, Guangzhou, PR China; and from the American College of Chest Physicians (www.chestjournal.
Department of Pulmonary Medicine (Drs. Stathopoulos and Lane), Vanderbilt University, Nashville, TN.
Correspondence to: Semra Bilaceroglu, MD, FCCP, Associate This study was presented as a poster at the ACCP Congress, Professor of Pulmonology, 6026 Sokak, No. 197/22, 35560 Bostanli, Izmir, Turkey; e-mail: [email protected] Downloaded From: http://journal.publications.chestnet.org/ on 03/10/2014
forming growth factor ␤ lead to the production of through the one-way valve. A local anesthetic was applied into the collagen that can result in a pleurodesis.1 incision area before it was sutured since the rabbits were not Currently talc,2 tetracycline derivatives,3–5 and given full general anesthesia. The left pleural cavity was used forcontrol.
bleomycin5,6 are the most frequently used sclerosingagents. A survey study by Lee et al7 questioning pleurodesis practice for malignant pleural effusionsin five English-speaking countries reported that talc Thirty-six rabbits were allocated into tetracycline capsule was the most commonly used agent, followed by (n ϭ 6), tetracycline tablet (n ϭ 6), doxycycline capsule (n ϭ 7), tetracycline derivatives and bleomycin. Bleomycin is doxycycline tablet (n ϭ 7), and parenteral doxycycline (n ϭ 10)groups. Oral forms of tetracycline (35 mg/kg) or doxycycline (10 more expensive1,6 and less efficient than tetracycline mg /kg), or parenteral doxycycline (10 mg/kg) dissolved in 2 mL derivatives1 or talc.1,2 The intrapleural injection of 0.9% sodium chloride were injected intrapleurally immediately talc can cause ARDS and death.7,8 Although tetracy- after chest tube placement. Injection of tetracycline or doxycy- cline (35 mg/kg) was the most effective compound cline was followed by an injection of 1 mL of 0.9% sodium when original animal experiments on producing chloride solution to clear the dead space of the chest tube.
The tetracycline and doxycycline capsule contents and all of pleurodesis in rabbits were performed,9,10 the par- the tetracycline and doxycycline tablets were previously dissolved enteral form of tetracycline is currently not available in 0.9% normal saline solution using sterile methods. Subse- in most countries. Subsequently, parenteral doxycy- quently, the solution was filtered through a 0.2-␮m sterile and cline was used for pleurodesis at an approximate nonpyrogenic polyethersulfone membrane (Puradisc 25 AS, 25 dose of 10 mg/kg and was shown to have comparable mm in diameter; Whatman; Clifton, NJ) to remove infectiousmaterials and other particulate matter. The sterility of the filtered effectiveness with tetracycline at 35 mg/kg.3,5,11,12 solutions was assessed by bacterial culture. The total amount of However, parenteral doxycycline is also not available inactive ingredients in each tablet or capsule was determined by currently in many parts of the world. In contrast, weighing the tablet or the contents of the capsule and then tetracycline and doxycycline capsules and tablets are subtracting the stated amount of the tetracycline derivative.
available worldwide but (to our knowledge) havenever been tested for their efficacy and safety in Measurements for Pleural Fluid and Follow-up producing pleurodesis. We hypothesized that they After the intrapleural injection, the chest tube was aspirated at can produce pleurodesis as efficaciously, safely, and 24-h intervals for any pleural fluid that had accumulated. The cost effectively as their parenteral forms.
volumes of the aspirated fluids were recorded. The levels ofprotein, lactate dehydrogenase (LDH), and WBC were measuredin the fluid collected 24 h after the injection. The protein and LDH levels were determined with an automated analyzer (John-son & Johnson; Rochester, NY). The lower and upper limits of The study protocol was approved by the Vanderbilt University normal serum LDH are 120 IU/L and 200 IU/L, respectively, by Institutional Animal Care and Use Committee. The methods this method. The total WBC count was measured using an used were similar to those described in our previous studies.13,14 automated counter (Coulter Electronics; Luton, UK) that wascalibrated daily. The first reading was ignored, and the mean ofthe next three readings was recorded.
Gentamicin (2 mg/kg) was administered IM every 24 h until New Zealand white rabbits weighing 2.5 to 3 kg were anesthe- the removal of the chest tubes. The chest tube was removed tized with an IM injection of 35 mg/kg of ketamine hydrochloride under light sedation when the pleural fluid drainage was Ͻ 5 mL (Fort Dodge Animal Health Laboratories; Fort Dodge, IA) and 5 mg/kg of xylazine hydrochloride (Fermenta; Kansas City, MO).
The chest was shaved, and the skin was sterilized with 10% povidone iodine (Baxter; Deerfield, IL). The rabbit was placed inthe left lateral decubitus position, and a skin incision Ͻ 3 cm was Rabbits were killed on day 14 by carbon dioxide euthanasia made midway between the tip of the right scapula and the following sedation. The thorax was removed en bloc. The lungs sternum, approximately 2 cm above the costal margin. A chest were expanded by the injection of 50 mL of 10% neutral- tube (silicone tube, 0.062-inch internal diameter and 0.125-inch buffered formalin into the exposed trachea. The trachea was then outer diameter; Braintree Scientific; Braintree, MA) with three ligated, and the entire thorax was submerged into 10% neutral- extra openings near the distal end to enhance drainage was then buffered formalin solution for at least 48 h. To assess the inserted by blunt dissection into the right pleural cavity and was pleurodesis, the pleural cavity was carefully exposed as previously secured at the muscle layers with purse-string sutures. The described.13,14 Using a semiquantitative scheme, a consensus proximal end of the chest tube was tunneled underneath the skin grading on the degree of macroscopic pleurodesis was reached by and drawn out through the skin posteriorly and superiorly two investigators (K.B.L. and R.W.L.) blinded to the treatment between the two scapulae. A three-way stopcock (Medex; Dublin, group. The degree of pleurodesis was graded using the following OH) was attached to the end of the chest tube via an adapter scale: 1 ϭ no adhesions between the visceral and parietal pleura; through which pleural air was evacuated from the pleural space.
2 ϭ rare adhesions between the visceral and parietal pleura with The three-way stopcock was then removed from the chest tube, no symphysis; 3 ϭ a few scattered adhesions between the visceral and the exterior end of the chest tube was sealed with a one-way and parietal pleura with no symphysis; 4 ϭ many adhesions valve with a cap (Medex) via the adapter and was sutured to the between the visceral and parietal pleura with no symphysis; skin. Any pleural fluid or air that accumulated could be aspirated 5 ϭ many adhesions between the visceral and parietal pleura Downloaded From: http://journal.publications.chestnet.org/ on 03/10/2014
with symphysis involving Ͻ 5% of the hemithorax; 6 ϭ many difference in the 24-h pleural fluid volume achieved adhesions between the visceral and parietal pleura with symphy- statistical significance (p ϭ 0.024). When the four sis involving 5 to 25% of the hemithorax; 7 ϭ many adhesions oral groups were compared regarding all parameters, between the visceral and parietal pleura with symphysis involving25 to 50% of the hemithorax; and 8 ϭ many adhesions between the only significant difference was that the 72-h the visceral and parietal pleura with symphysis involving Ͼ 50% pleural fluid volume was significantly higher in the of the hemithorax. Adhesions were defined as fibrous connec- tetracycline capsule group than in the doxycycline tions between the visceral and parietal pleura. Symphysis was capsule group (p ϭ 0.032) [Table 2].
present if the visceral and parietal pleura were difficult to There were no significant differences in the pleu- ral fluid LDH or protein levels between the groupsor when the four groups that received the oral preparations were combined and compared with the The data were expressed as mean Ϯ SD when they were group that received the parenteral doxycycline. The normally distributed, and as median (intraquartile range [IQR]) pleural fluid WBC level was significantly lower in the when they were not normally distributed. One-way analysis of group that received parenteral doxycycline than variance was used to compare the means, and the Kruskal-Wallistest was used to compare the medians between the groups. The in the group that received tetracycline tablet correlations were assessed by the Pearson product moment (p ϭ 0.047), and the combined oral group (p ϭ 0.036) correlation test. All data were analyzed with statistical software [Table 1]. However, pleural fluid WBC levels of the (Sigma Stat; SPSS; Chicago, IL). A p value Ͻ 0.05 was considered parenteral group (median, 2,564/␮L; IQR, 1,784/␮L; n ϭ 10) and the combined oral group excluding thetetracycline tablet group (median, 9,077/␮L; IQR,2,722/␮L; n ϭ 20) were comparable (p ϭ 0.144).
Each of the oral forms of tetracycline or doxycy- The intrapleural injection of each of the five cline was as efficacious as parenteral doxycycline in preparations elicited an exudative pleural effusion producing pleurodesis in rabbits (p ϭ 0.235) [Fig 1].
(Table 1). Thirty of the effusions (83%) were bloody Furthermore, the right pleurodesis score of the four oral groups combined (median, 7.0; IQR, 4.0; The volumes of aspirated pleural fluids at 24 h, n ϭ 26) did not differ significantly (p ϭ 0.349) from 48 h, and 72 h after pleural instillation and the total that of the parenteral doxycycline group (median, volumes were comparable between each group re- 7.5; IQR, 6.0; n ϭ 10). The combined oral group ceiving an oral form and receiving parenteral doxy- excluding the tetracycline tablet group (median, 7.0; cycline (p Ͼ 0.05). These volumes tended to be less IQR, 3.0; n ϭ 20) was also comparable (p ϭ 0.415) in the combined oral group (n ϭ 26) than in the to the parenteral group regarding the right pleurode- parenteral doxycycline group (n ϭ 10), but only the sis score. The left pleural score in each rabbit in allfive groups was 1.
A significantly positive correlation existed between the right pleurodesis score and total, 24-h, 48-h, or Table 1—Pleural Fluid WBC, LDH, and Protein Levels
72-h pleural fluid volume, and the fluid protein level.
in Each of the Oral Groups, the Combined Oral
Thus, efficiency of pleurodesis tended to be better in Group, and the Parenteral Doxycycline Group*
the presence of larger fluid volume or higher fluid protein level. However, no significant correlation was found for fluid WBC or LDH levels and thepleurodesis scores (Table 3).
All 36 rabbits survived without any major distress until death. Right hemothoraces occupying 20 to 90% of the hemithorax were observed at autopsy in three rabbits in the tetracycline capsule group, and in two rabbits in each of the tetracycline tablet, doxycycline tablet, and parenteral doxycycline groups, while one 5% left hemothorax was observed TETcap ϭ tetracycline capsule; TETtab ϭ tetracycline tablet;DOXcap ϭ doxycycline capsule; DOXtab ϭ doxycycline tablet; in the tetracycline capsule group. This left hemotho- rax accompanied one of the above-mentioned right hemothoraces. In the rabbits with hemothoraces, the pleurodesis scores ranged between 6 and 8. One rabbit from the parenteral doxycycline group was ʈp ϭ 0.036 vs DOXpe group.
¶p ϭ 0.322 vs DOXpe group.
noted to have moderate ascites at death but no hemothorax. This rabbit had a pleurodesis score of 6.
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Table 2—Volumes of Aspirated Pleural Fluid in Each of the Oral Groups, the Combined Oral Group, and the
Parenteral Doxycycline Group*
*Data are presented as median (IQR) or mean Ϯ SD. See Table 1 for expansion of abbreviations.
†p ϭ 0.649 vs DOXpe group.
‡p ϭ 0.394 vs DOXpe group.
§p ϭ 0.032 vs DOXpe group.
ʈp ϭ 0.097 vs DOXpe group.
¶p ϭ 0.024 vs DOXpe group.
#p ϭ 0.090 vs DOXpe group.
**p ϭ 0.367 vs DOXpe group.
††p ϭ 0.087 vs DOXpe group.
There was no growth on microbiological culture of tablet ($0.10), and doxycycline capsule ($0.48) and the filtered oral tetracycline or doxycycline solutions.
tablet ($0.95) were lower than that of parenteral When a 100-mg doxycycline capsule was dissolved in doxycycline ($4.72). The cost of each filter used in 10 mL of saline solution and then filtered, the prefiltration and postfiltration concentrations of thedoxycycline capsule solution did not differ signifi-cantly (10 mg/mL vs 11.8 mg/mL, respectively).
Based on the per-tablet costs of a tetracycline 250-mg capsule ($0.25) or tablet ($0.23), doxycycline Our study demonstrates that oral forms of tetracy- 100-mg capsule ($1.44) or tablet ($3.16), and per vial cline or doxycycline are as effective and safe as paren- cost of doxycycline 100 mg injectable ($15.73), the teral doxycycline in producing pleurodesis in rabbits.
per -rabbit cost of tetracycline capsule ($0.10) and The oral forms are less expensive and more widely Figure 1. Individual pleurodesis scores in oral tetracycline (n ϭ 6 in each) and doxycycline groups (n ϭ 7 in each) compared with those in parenteral doxycycline group (n ϭ 10) [p ϭ 0.235]. See Table Downloaded From: http://journal.publications.chestnet.org/ on 03/10/2014
Table 3—Correlation of Pleural Fluid Features With
bined oral group with or without tetracycline tablet Right Pleurodesis Scores in All 36 Rabbits*
group was comparable to that of the parenteraldoxycycline group.
The median right pleurodesis scores obtained with the oral forms of tetracycline and doxycycline ranged from 4.0 to 8.0, being Ն 6.5 in three of the four groups. Thus, 70% (18 of 26 animals) of the oral group had a pleurodesis with many adhesions and accompanying symphysis involving Ն 5% of the hemithorax. The doxycycline capsule group had the *Pearson product moment correlation test.
lowest mean score, which was 4.0. It can be seen inFigure 1 that the pleurodesis score was 1.0 in threeof the rabbits in this group. Furthermore, in these available than the parenteral forms. It is likely that three cases, pleural fluid total volumes (Յ 1.5 mL), these results can be extrapolated to human subjects and protein (Յ 2.82 g/dL), LDH (Յ 3,102 IU/L), since parenteral tetracycline4,6,15 and doxycycline3,5,15 and WBC (Յ 10,370/␮L) levels tended to be lower have been extensively studied and shown to be effective than those of the other rabbits with higher pleurode- and safe in producing pleurodesis in patients.
sis scores in the same and other groups. We believe The ingredients other than tetracycline or doxycy- that technical problems with the pleurodesis explain cline in tablets or capsules are in small amounts.
these three low scores. Although we cannot prove it, There is 10-mg filling in a 250-mg tetracycline tablet, we believe that the chest tubes were misplaced in 100-mg filling in a 500-mg tetracycline capsule, 25- these three rabbits such that the doxycycline partly to 50-mg filling in a 100-mg doxycycline tablet, and or never entered the pleural space. Another possible 100- to 350-mg filling in a 100-mg doxycycline explanation for the lower score in the doxycycline capsule. Depending on the form (capsule/tablet) and capsule group could be that the doxycycline was also the product from different producers, these incompletely dissolved or that it was removed by the inactive ingredients may include anhydrous lactose, filter. However, when we dissolved the contents of colloidal silicone dioxide, magnesium stearate, meth- one 100-mg doxycycline capsule in 10 mL of saline ylcellulose, microcrystalline cellulose, polyethylene solution and then filtered, the measured concentra- glycol, sodium starch glycolate, stearic acid, titanium tion of doxycycline in the solution was 11.8 mg/mL dioxide, FD&C Yellow No. 6, FD&C Red No. 40, with an expected concentration of 10.0 mg/mL.
hydroxypropyl methylcellulose, propylene glycol, po- Accordingly, the poorer results with the doxycycline vidone, talc, triacetin, aluminum lake, polyparaben, capsule cannot be blamed on lower concentrations of methylparaben sodium citrate, potassium sorbate, xanthan gum, progyl paraben, and polyethylene gly- To create a pleurodesis, usually the pleura is injured with a sclerosing agent that leads to an One might question whether one of these other inflammatory response that can result in pleurodesis.
substances might be responsible for the pleurodesis.
After instillation of a sclerosing agent, the pleural The only two substances in the above list that have inflammation is indicated by the accumulating exu- been shown to produce pleurodesis are talc2,8,11 and dative pleural fluid with high WBC, protein, and povidone.17 However, in the current study, we did LDH levels.12,18–20 In all of the 36 rabbits in the not use any product containing talc, and povidone is current study, the aspirated pleural fluid was an present only in the tetracycline tablets we used.
exudate with total volumes of 9.21 to 26.10 mL, and Povidone is not likely to have a role in the pleurode- high LDH (Ͼ 1,900 U/L), WBC (Ͼ 2,500/␮L), and sis score of the tetracycline tablet group considering protein levels (Ͼ 2.90 g/dL). It also was bloody the minute amount administered (Ͻ 10 mg per appearing in 83% of the rabbits. The positive corre- 250-mg tetracycline tablet that equates to Ͻ 4.2 mg lation between the pleural score and fluid volume or per rabbit). Moreover, the tetracycline capsule group protein level in the current study supports the that did not receive any povidone had a higher importance of inflammation in pleurodesis. A posi- pleurodesis score than the tetracycline tablet group.
tive correlation would also be expected for fluid Previous studies have shown that only larger doses of LDH and WBC levels since they also are surrogates povidone in humans (20 mg/kg)17 or rabbits (40 mg of inflammation. However, in the present study, in total) produce an effective pleurodesis (Yubiao pleural fluid LDH and WBC were not significantly Guo, MD; personal communication; December correlated with the pleurodesis score.
2003). In addition to all of the above, the pleurodesis There were some differences between the groups score of the tetracycline tablet group, or the com- regarding the features of the pleural fluid. The Downloaded From: http://journal.publications.chestnet.org/ on 03/10/2014
pleural fluid WBC in the parenteral doxycycline Right hemothoraces occurred in a total of nine group was significantly lower than that in the com- rabbits receiving intrapleural tetracycline deriva- bined oral group with the highest pleural fluid WBC tives. Although a high incidence of hemothorax10,12 occurring in the tetracycline tablet group. One pos- and substantial mortality10 was reported in rabbits sible explanation for the higher WBC (8,623 to administered intrapleural tetracycline derivatives 17,998 cells/␮L) in the oral groups than the paren- without chest tube drainage, in a more recent teral group (2,564/␮L) could be additional inflam- study,18 insertion of a chest tube and daily aspirations mation due to the fillers present in the oral forms. It of the accumulating fluid have prevented hemotho- is noteworthy that the group with the highest WBC rax and led to a better pleurodesis in rabbits. Simi- level, the tetracycline tablet group, was the only larly, hemothorax or mortality has not been reported group that received povidone as a filler. However, if in human subjects receiving intrapleural tetracycline this were the explanation, one would also expect the or its derivatives and also being drained with chest fluid volume, LDH, and protein levels to be signif- tube.2–6,15,24–28 In the current study, the complica- icantly higher; however, they were all comparable.
tions including right or bilateral hemothorax and Furthermore, tetracycline tablet did not induce ascites did not have a significantly adverse effect on the highest pleurodesis score. In fact, it induced the the pleurodesis efficiency since the pleurodesis second lowest among the other scores. Thus, the scores ranged between 6 and 8 in these rabbits daily highest WBC level in the tetracycline tablet group aspirated for pleural fluid. Furthermore, there was did not result in a significantly higher pleurodesis no major morbidity or mortality due to these com- plications. No infectious complication was observed Tetracycline and doxycycline are dose-dependent in any of the rabbits. This may be at least partly due effective inhibitors of matrix-degrading metallopro- to the fact that the solutions prepared with the oral teinase (MMP) activity in pleural fluid. They may forms were filtered to eliminate any infectious also reduce the synthesis of MMP via nonspecific agents. Moreover, antibiotic treatment until removal cell injury. At a concentration of Ն 1 mg/mL, both of the chest tube, removal of the chest tube right drugs reduce MMP activity by Ͼ 75%. These data after pleural fluid is Ͻ 5 mL, meticulous care for suggest one possible mechanism for tetracycline or sterility during and after surgery, and the antibiotic doxycycline pleurodesis.21 Thus, the pleural fibrotic nature of the sclerosing agents used might have process needed for pleurodesis is augmented by the prevented infection. As evidenced by animal9–12,18,19 reduction of MMP activity that favors remodeling and human studies,2–6,15,24–28 infectious complica- through normal repair of the tissue rather than tions due to use of tetracycline and its derivatives in fibrosis.22 Another proposed mechanism is that tet- pleurodesis are not as frequent as those with other racyclines stimulate mesothelial cells to release a agents such as talc,29 Corynebacterium parvum,30 growth factor-like activity for fibroblasts.23 Further- and cytotoxic agents30 (almost none vs 3%).
more, both tetracycline24 and doxycycline12 pleu- Intense pleural pain caused by the intrapleural rodesis is effective at neutral pH, suggesting a injection of tetracycline or its derivatives is a well- mechanism of action independent of acid injury to known complication of pleurodesis. Usually, con- scious sedation with benzodiazepines or analgesia That most of the aspirated pleural fluids (83%) with a narcotic drug is recommended before starting after intrapleural injections of tetracyclines were pleurodesis with tetracycline and its derivatives.3– bloody appearing might have produced a positive 6,25–28 In our study, we did not observe signs of pain effect on pleurodesis since bloody fluids may lead to in any rabbit, but this is probably due to the fact that formation of adhesions and, thus, augment pleurode- the tetracycline compounds were injected while the sis. Previously, tetracyclines have been shown to cause bloody effusions and hemothoraces in animal The cost of oral forms of tetracycline or doxycy- studies.10,12,18 These bloody effusions may be a com- cline for each rabbit is approximately 1/50 to 1/5 of ponent in the natural course of pleurodesis by parenteral doxycycline: Ͻ $1 vs nearly $5. When tetracyclines (intense pleural inflammation3 exuda- proportioned to a 60-kg human, these costs are tive pleural effusion ϩ neovascularization ϩ increas- Ͻ $20 vs nearly $100. The cost of the filter we used ing negative intrapleural pressure due to fibrosis3 for each rabbit in filtering oral tetracycline and rupture of newly formed fragile capillaries3 bloody doxycycline is $1.12. Thus, the total expense of effusions). The critical point is that excess of these pleurodesis increases to Ͻ $2.2 per rabbit and $21.2 fluids should be aspirated to bring visceral and per human. However, the cost of oral forms of tetra- parietal pleurae to apposition for an effective pleu- cycline or doxycycline combined with that of filter rodesis. In the current study, appropriate daily aspi- still remains considerably lower than the cost of rations of the pleural fluids were performed.
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In conclusion, the present study demonstrates that 14 Gary Lee YC, Teixeira LR, Devin CJ, et al. Transforming the intrapleural injection of the oral forms of tetra- growth factor-␤2 induces pleurodesis significantly faster than cycline and doxycycline dissolved in sterile saline talc. Am J Respir Crit Care Med 2001; 163:640 – 644 15 Dryzer SR, Allen ML, Strange C, et al. A comparison of solution produces a pleurodesis that is comparable to rotation and nonrotation in tetracycline pleurodesis. Chest that produced by the intrapleural injection of paren- teral doxycycline in rabbits. Thus, in countries where 16 Medical Economics Staff, ed. Physicians’ desk reference parenteral tetracycline and doxycycline are not avail- 2003, 57th ed. Montvale, NJ: Thomson PDR, 2003; 2194, able, oral forms of these drugs may also be used in humans for pleurodesis provided that meticulous 17 Olivares-Torres CA, Laniado-Laborin R, Chavez-Garcia C, et care for avoiding infection is exercised.
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