INT J TUBERC LUNG DIS 14(10):13421346 2010 The Union

Minocycline and talc slurry pleurodesis for patients with secondary spontaneous pneumothorax
C. K. Ng,* F. W. Ko, J. W. Chan,* A. Yeung, W. K. S. Yee, L. K. Y. So, B. Lam,# M. M. L. Wong,** K. L. Choo, A. S. S. Ho, P. Y. Tse, S. L. Fung, C. K. Lo,## W. C. Yu***
* Department of Medicine, Queen Elizabeth Hospital, Hong Kong, Department of Medicine and Therapeutics, Prince of Wales Hospital, Hong Kong, Department of Medicine, Ruttonjee and Tang Shiu Kin Hospital, Hong Kong, Department of Medicine, Kwong Wah Hospital, Hong Kong, Department of Medicine, Pamela Youde Nethersole Eastern Hospital, Hong Kong, # Department of Medicine, Queen Mary Hospital, Hong Kong, ** Department of Medicine, Caritas Medical Centre, Hong Kong, Department of Medicine, North District Hospital, Hong Kong, Department of Medicine, Alice Ho Miu Ling Nethersole Hospital, Hong Kong, Department of Medicine, Tseung Kwan O Hospital, Hong Kong, Respiratory Medical Department, Grantham Hospital, Hong Kong, ## Department of Cardiothoracic Surgery, Queen Elizabeth Hospital, Hong Kong, *** Department of Medicine and Geriatrics, Princess Margaret Hospital, Hong Kong, Hong Kong SAR, China SUMMARY

Few studies have evaluated the sclerosing efficacy of minocycline, and none have specifically compared its sclerosing efficacy and safety profiles with talc slurry in secondary spontaneous pneumothorax (SSP). D E S I G N : A retrospective analysis was conducted in patients with SSP who underwent chemical pleurodesis from January to December 2004 with minocycline or talc slurry in 12 public hospitals of Hong Kong. R E S U LT: There were 121 episodes of minocycline pleurodesis and 64 episodes of talc slurry pleurodesis. Immediate procedural failure were similar in the minocycline and talc slurry groups (21.5% vs. 28.1%, P = 0.31). Presence of interstitial lung disease, 2 previous episodes of pneumothorax, requiring mechanical ventilation during pleurodesis and persistent air leak before
SETTING:

pleurodesis were independently associated with procedural failure. Pain was experienced in respectively 44.6% and 37.5% of the minocycline and the talc slurry groups. Pain was more common in patients receiving high doses of talc (5 g; P = 0.03). Respiratory distress was found in respectively 1.7% and 1.6% of the minocycline and talc slurry groups. C O N C L U S I O N : Minocycline and talc slurry had comparable sclerosing efficacy in SSP, with immediate success rates of >70%. Pain was the most common adverse effect and respiratory distress was uncommon. Both appeared to be effective and safe for chemical pleurodesis in SSP. K E Y W O R D S : minocycline; talc slurry; secondary spontaneous pneumothorax; pleurodesis; adverse effects

PREVENTION OF RECURRENCE is important in patients with secondary spontaneous pneumothorax (SSP), as many of them have poor respiratory reserves, and high mortality rates have been reported with recurrences.1,2 Without pleurodesis, the recurrence rate in SSP was around 4080%.1,3,4 The British Thoracic Society (BTS) and the American College of Chest Physicians (ACCP) advocated pleurodesis in the first occurrence of SSP.5,6 Open thoracotomy with surgical pleurectomy remains the gold standard, but the thoracoscopic approach has comparable success rates.7 Chemical pleurodesis is an alternative when surgical pleurodesis is contraindicated.5,6 Thoracoscopic talc poudrage has reported success rates of >90%,8,9 although that is not widely practised or readily available. The efficacy of talc slurry in the prevention of SSP recurrence in humans was not well explored, and small-scale studies in the 1980s revealed its sclerosing efficacy to be 93100%.10,11 There were no pub-

lished data on its efficacy in the prevention of pneumothorax in comparison to other agents. The sclerosing efficacy of tetracycline in pneumothorax is around 4577%.1214 As tetracycline was no longer available,15 its derivatives, such as oxytetracycline, doxycylcine and minocycline had been used instead. Minocycline and tetracycline had comparable sclerosing efficacies in animal studies.16 The sclerosing efficacy of minocycline in primary spontaneous pneumothorax (PSP) has been evaluated by Chen et al.17,18 Apart from a case report19 and a study that contained a mixture of patients with PSP and SSP,20 no human study had specifically addressed the sclerosing efficacy of minocycline in the prevention of SSP. The primary aim of the present study was to compare the immediate sclerosing efficacy21 of intrapleural minocycline and talc slurry in the prevention of SSP recurrence. Secondary aims included the evaluation of 1) factors that were associated with

Correspondence to: C K Ng, Department of Medicine, Queen Elizabeth Hospital, Hong Kong, 30 Gascoigne Road, Kowloon, Hong Kong, China. Tel: (+852) 2958 2349. Fax: (+852) 2215 1211. e-mail: ngck6@ha.org.hk Article submitted 18 January 2010. Final version accepted 7 April 2010.

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immediate procedural failure and 2) the adverse effects and safety profiles of these two agents in chemical pleurodesis.

Table 1 Clinical characteristics of patients who underwent chemical pleurodesis

Minocycline Talc slurry (n = 121) (n = 64) n (%) n (%) P value Sex, male Age, years, median [IQR] Ever smokers Chronic obstructive pulmonary disease Old tuberculosis Interstitial lung diseases Previous history of pneumothorax 2 previous episodes of pneumothorax Persistent leakage before pleurodesis Large pneumothorax (2 cm) Required >1 intercostal tubes Required suction in the management of pneumothorax Put on ventilatory support
* P < 0.05. IQR = interquartile range.

STUDY POPULATION AND METHODS

Study design and patient selection This is a multicentre retrospective study that involved 10 public hospitals and two university-affiliated hospitals in Hong Kong. The hospital records of patients admitted from January to December 2004 and with discharge diagnoses of spontaneous pneumothorax were retrieved and studied by the investigators. Patients were included if they had SSP and subsequently underwent chemical pleurodesis with either minocycline (300 mg in 100 ml 9% normal saline) or talc slurry (2.55.0 g talc in suspension with 100 ml 9% normal saline) via the intercostal tubes in the same admission. Patients were excluded from the study if 1) their age was <18 years, 2) the diagnosis was not SSP, 3) hospital records could not be retrieved and 4) they underwent surgical pleurodesis or chemical pleurodesis with other agents. Data collection Information collected included demographic data, characteristics of pneumothoraces, dosages and side effects of sclerosants, result of pleurodesis and predefined clinical outcomes. Large pneumothorax was defined as one with distance of visceral pleura to chest wall of 2 cm.6 Immediate failure was defined as having recurrence of pneumothorax within the same hospitalisation after the pleurodesis.21 Approvals from the Institutional Review Boards (IRB) or Hospital Ethics Committees of all the participating hospitals were obtained before the study. Statistical analysis Results were expressed in median (interquartile range) for continuous variables, or number (percentages) for categorical data. Students t-test or Mann-Whitney U test were used to compare the differences between continuous variables, while Pearsons 2 test was used to compare categorical data. Logistic regression was used to determine the independent predictors of clinical outcomes. All statistical tests of significance were two-sided, unless otherwise stated. A P of 0.05 was considered as statistically significant. Statistical analysis was performed using SPSS, Version 11.0 (Statistical Package for the Social Sciences, Chicago, IL, USA).

114 (94.2) 59 (92.2) 0.60 73 [6677] 71 [6375] 0.19 114 (94.2) 58 (90.6) 0.36 95 (78.4) 43 (35.5) 4 (3.3) 43 (35.5) 16 (13.2) 31 (25.6) 75 (62.0) 17 (14.4) 57 (47.1) 5 (4.1) 40 (62.5) 27 (42.2) 4 (6.3) 22 (34.4) 9 (14.1) 21 (32.8) 48 (75.0) 12 (18.8) 42 (65.6) 3 (4.7) 0.02* 0.38 0.35 0.88 0.87 0.30 0.07 0.40 0.02* 1.00

tive pulmonary disease and required suction during pneumothorax drainage in the minocycline and talc slurry groups, respectively (Table 1). Although the median length of hospitalisation was longer in the talc slurry group, other outcomes, such as immediate failure rates, subsequent need for repeated chemical or surgical pleurodesis and median duration of chest drainage, were not significantly different between the two groups (Table 2). Multivariate analysis revealed that having underlying interstitial lung disease, history of 2 previous episodes of pneumothorax, having mechanical ventilation during pleurodesis and having persistent air leakage before pleurodesis were independently associated with failure of chemical pleurodesis in SSP. The choice of chemical sclerosants (talc or minocycline) was not independently associated with immediate procedural failure (adjusted odds ratio [aOR] 0.98, 95%CI 0.442.22, P = 0.97; Table 3). The frequency of pain was not significantly different between the two groups (Table 4). Pain was experienced in 20 patients (47.6%) who received 5 g
Table 2 Clinical outcomes in the minocycline and talc slurry group*
Minocycline (n = 121) n (%) Talc slurry (n = 64) n (%) P value 0.31 0.28 1.00 0.65 0.02

RESULTS
There were 483 episodes of SSP and 215 episodes of subsequent chemical pleurodesis. Minocycline and talc slurry was employed in respectively 121 (56.3%) and 64 episodes (29.8%). The clinical characteristics of the two groups of patients were largely comparable, except that more patients had chronic obstruc-

Immediate procedural failure 26 (21.5) 18 (28.1) Failure and underwent repeated medical pleurodesis 22 (18.2) 16 (25.0) Failure and underwent surgical pleurodesis 1 (0.8) 1 (1.6) Duration on chest drain after pleurodesis, median days [IQR] 2 [1.07.0] 3 [1.05.0] Length of hospital stay, median days [IQR] 15 [828] 20 [1333]
* No death related to pleurodesis recorded. P < 0.05. IQR = interquartile range.

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Table 3

Predictors of pleurodesis failure

Successful pleurodesis (n = 141) n (%) Failed pleurodesis (n = 44) n (%) 41 (93.2) 38 (86.4) 42 (95.5) 32 (72.7) 18 (40.9) 4 (9.1) 9 (20.5) 30 (68.2) 4 (9.1) 23 (52.3) 31 (70.5) 18 (40.9) Crude odds ratio (95%CI) 1.07 (0.284.15) 1.30 (0.493.42) 1.78 (0.388.34) 0.98 (0.462.11) 1.19 (0.592.37) 3.43 (0.8214.31) 2.01 (0.824.93) 1.11 (0.542.28) 3.43 (0.8214.31) 4.23 (2.068.68) 2.56 (1.245.30) 1.43 (0.712.87) Adjusted odds ratio (95%CI) 0.87 (0.184.18) 0.78 (0.232.65) 2.92 (0.4419.13) 1.46 (0.514.18) 1.46 (0.623.41) 9.41 (1.6154.95) 3.40 (1.179.89) 1.89 (0.784.55) 5.76 (1.0531.55) 6.20 (2.5714.94) 2.05 (0.874.80) 0.98 (0.442.22)

P value 0.87 0.69 0.27 0.48 0.39 0.01* 0.03* 0.16 0.04* <0.001 0.10 0.97

Male sex Age > 60 years Smoker Chronic obstructive pulmonary disease Old tuberculosis Interstitial lung diseases 2 previous episodes of pneumothorax Large pneumothorax On mechanical ventilation Persistent air leak before pleurodesis Put on suction Use of minocycline compared to talc as the sclerosant
* P < 0.05. P < 0.001.

132 (93.6) 117 (83.0) 130 (92.2) 103 (73.0) 52 (36.9) 4 (2.8) 16 (11.3) 93 (66.0) 4 (2.8) 29 (20.6) 68 (48.2) 46 (32.6)

talc in comparison to four patients (18.2%) who received <5 g talc (P = 0.03). The frequencies of other side effects, including fever, nausea, vomiting and respiratory distress, were also not significantly different between the two groups (Table 4). Acute respiratory distress syndrome (ARDS), empyema thoracis and death related to pleurodesis were not noted.

DISCUSSION
To the best of our knowledge, this is the first study to specifically compare the sclerosing efficacies and safety profiles of intra-pleural minocycline against talc slurry in patients with SSP. As talc slurry and minocycline are commonly employed sclerosants, such information will be useful for clinicians in making their choices. The sclerosing effectiveness of talc slurry described in the literature was 93100%.10,11 In our study, the immediate success rates of talc slurry were comparable to those of minocycline, and both were under 80%. It is difficult to precisely control the dosage of talc slurry delivered to pleural surfaces. The water solubility of talc is poor and most of it would remain in suspension form.14 A proportion of talc slurry might stick onto the wall of the intercostal tube while it was instilled in the pleural cavity. Rotating patients at different positions did not improve the distribuTable 4 Side effects associated with minocycline and talc slurry
Minocycline Talc slurry (n = 121) (n = 64) n (%) n (%) P value Any pain experienced Mild to moderate pain, requiring non-opioid analgesics Moderate to severe pain, requiring opioid analgesics Fever Nausea or vomiting Respiratory distress with new radiological inltrates 54 (44.6) 27 (22.3) 27 (22.3) 5 (4.1) 0 2 (1.7) 24 (37.5) 14 (21.9) 10 (15.6) 1 (1.6) 1 (1.6) 1 (1.6) 0.35 0.95 0.28 0.67 0.35 1.00

tion onto the mesothelial surface because talc particles would sediment into the dependent parts of the pleural cavity.14 Moreover, it was impossible to ensure the uniform distribution of talc slurry onto pleural surfaces without direct visualisation through thoracoscopy. This might explain its inferiority when compared to talc poudrage. Furthermore, the dose of talc slurry administered in our study was not standardised, as it ranged from 2.5 to 5.0 g, similar to recommendations from international guidelines.6 However, no dose-response relationship between talc and success of pleurodesis has been established.6 No study has specifically addressed the sclerosing efficacy of minocycline in patients with SSP. Minocycline was less efficacious than talc slurry in an animal study.22 The Veterans Administration Cooperative study, with 80% of its subjects being SSP, showed that the 30-day recurrence rate with tetracycline pleurodesis was 19%,13 which was comparable to our 21.5% recurrence rate within the same hospitalisation. This implied that the immediate success rate of minocycline was similar to that of talc slurry and tetracycline.13 Few studies addressed the predictors of pleurodesis failure in SSP. Our logistic regression showed that having interstitial lung diseases, 2 episodes of pneumothorax in the past, persistent air leak before pleurodesis and receiving mechanical ventilation during pleurodesis were independently associated with pleurodesis failure. Failure of pleura apposition and symphysis might be encountered in patients having persistent air-leaks and in patients under mechanical ventilation, where the positive intra-pleural pressure might hinder the closure of pleura-pulmonary fistulas. Patients with multiple previous pneumothoraces might also have more pleural adhesions related to previous pleural manipulations,23 such as tube insertions and aspirations. Thoracoscopic studies have demonstrated that adhesions can prevent the uniform coating of talc onto pleural surfaces, thereby reducing its sclerosing effectiveness.24

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Although the median duration of hospitalisation was longer in the talc slurry group, the duration of intercostal tube drainage after pleurodesis was similar in the two groups. The prolonged hospitalisation may therefore be accounted for by other clinical or social problems. Pain was the most common side effect with minocycline pleurodesis.25 The literature reported that 58.2% of patients with tetracycline pleurodesis suffered from pain, which was attributed to the induced pleural inflammation.26,27 Pain might correlate with the success of tetracycline pleurodesis, and was reduced by the diluting effect of local anaesthesia such as lignocaine.13 Pain was less frequently reported with talc pleurodesis.14 In this study, the prevalence of severe pain in the talc slurry group (15.6%) was higher than the 7% incidence reported in the literature.8,27 The difference might be related to individuals variations in pain perceptions and the dose of talc slurry applied. In this study, patients who received 5 g talc slurry experienced more pain than those who received <5 g. The optimal dose of talc slurry was not well addressed,6 and 210 g of talc slurry had been applied in previous studies involving SSP patients.10,11 As the pleural surfaces in pneumothorax are relatively normal in comparison to those in malignant conditions, a lower dose of talc powder may suffice. The incidence of ARDS was estimated to be 19% in the literature25 and was believed to be related to the particle size of talc.26,27 Mixed talc was shown to produce more lung and systemic inflammation than graded talc with particle size <10 m.26 At the time of the study, only mixed talc was used in Hong Kong and the incidence of respiratory distress after talc pleurodesis was comparable to overseas reports.27 However, a definite association of respiratory distress with the use of talc slurry could not be reliably established by reviewing hospital records alone. Empyema was not found and should not be expected if sterilised talc was used.27 No death related to pleurodesis was reported, which, together with the absence of other serious side effects such as ARDS, suggested that both agents were safe chemical sclerosants. The study was limited by its retrospective nature. It would be difficult to validate the accuracy of data retrieved from hospital notes. As discussed above, the dose of talc applied in our study was not standardised and might possibly confound the observation of its efficacy. The long-term pneumothorax recurrence rates were not explored and we could not explore the possible associations between short-term and longer-term recurrence rates. As it had been suggested that tetracycline exerted its effect mainly at 6 months,13 longterm recurrence rate would be an important element to be included in future studies, and preferably with the presence of a control group to determine the efficacy. However, the definitions of short-term and long-term recurrences have been arbitrary, and an optimal timing to measure the efficacy of pleurodesis

remains unclear since the timing of recurrence might depend on factors such as the severity of the underlying pleural and pulmonary pathologies and the sclerosing agent employed.

CONCLUSION
Intra-pleural minocycline was as effective and safe as talc slurry in preventing pneumothorax recurrence in SSP in the same hospitalisation. Pain was a common adverse effect with both methods, although the pain in talc might be dose-related. Severe adverse reactions such as respiratory distress were uncommon in both. Acknowledgements
The authors thank the following people for their assistance and support in the study: M Lit (Queen Elizabeth Hospital), D Hui and K Lai (Prince of Wales Hospital), D Chui (Caritas Medical Centre), H Kwok and C W Lam (Ruttonjee Hospital), Y-P Lam (Pamela Youde Nethersole Eastern Hospital), W-K Lam, C-M Wong, C-W Yu and H-Y Kwan (North District Hospital), C Poon, J Kwok and C Yui (Princess Margaret Hospital). The authors also thank the Scientific Sub-Committee of the Hong Kong Thoracic Society for its directive and advisory role in conducting this territory-wide research.

References
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tetracycline for the prevention of recurrent spontaneous pneumothorax. Results of a Department of Veterans Affairs cooperative study. JAMA 1990; 264: 22242230. Rodriguez-Panadero F, Antony V B. Pleurodesis: state of the art. Eur Respir J 1997; 10: 16481654. Berger R. Pleurodesis for spontaneous pneumothorax. Will the procedure of choice please stand up? Chest 1994; 106: 992 994. Dryzer S R, Joseph J, Baumann M, Birmingham K, Sahn S A, Strange C. Early inflammatory response of minocycline and tetracycline on the rabbit pleura. Chest 1993; 104: 15851588. Chen J S, Hsu H H, Chen R J, et al. Additional minocycline pleurodesis after thoracoscopic surgery for primary spontaneous pneumothorax. Am J Respir Crit Care Med 2006; 173: 548554. Chen J S, Tsai K T, Hsu H H, Yuan A, Chen W J, Lee Y C. Intrapleural minocycline following simple aspiration for initial treatment of primary spontaneous pneumothorax. Respir Med 2008; 102: 10041010. Liu W L, Wang H C, Luh K T, Yang P C. Recurrent bilateral pneumothoraces: a rare complication of miliary tuberculosis. J Formos Med Assoc 2008; 107: 902906. Luh S P, Tsai T P, Chou M C, Yang P C, Lee C J. Video-assisted

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thoracic surgery for spontaneous pneumothorax: outcome of 189 cases. Int Surg 2004; 89: 185189. Tschopp J M, Brutsche M, Frey J G. Treatment of complicated spontaneous pneumothorax by simple talc pleurodesis under thoracoscopy and local anaesthesia. Thorax 1997; 52: 329332. Whitlow C B, Craig R, Brady K, Hetz S P. Thoracoscopic pleurodesis with minocycline vs talc in the porcine model. Surg Endosc 1996; 10: 10571059. Chung C L, Chen Y C, Chang S C. Effect of repeated thoracenteses on fluid characteristics, cytokines, and fibrinolytic activity in malignant pleural effusion. Chest 2003; 123: 11881195. Wolff A J, Anderson E D, Read C A. Predictors of pleural adhesion formation and success of pleurodesis in patients with pleural effusion. J Bronchol 2004; 11: 611. Janssen J P, Collier G, Astoul P, et al. Safety of pleurodesis with talc poudrage in malignant pleural effusion: a prospective cohort study. Lancet 2007; 369: 15351539. Maskell N A, Lee Y C, Gleeson F V, Hedley E L, Pengelly G, Davies R J. Randomized trials describing lung inflammation after pleurodesis with talc of varying particle size. Am J Respir Crit Care Med 2004; 170: 377382. Sahn S A. Talc should be used for pleurodesis. Am J Respir Crit Care Med 2000; 162: 20232024.

RSUM

Peu dtudes ont valu lefficacit sclrosante de la minocycline dans les pneumothorax spontans secondaires (SSP) et aucune na compar spcifiquement avec le talcage son efficacit sclrosante et son profil de scurit. S C H M A : Une analyse rtrospective a t mene chez des patients souffrant de SSP qui ont subi entre janvier et dcembre 2004 dans 12 hpitaux publics de Hong Kong une pleurodse la minocycline ou par talcage. R S U LTAT S : Il y a eu 121 pisodes de pleurodse par minocycline et 64 pisodes de pleurodse par talcage. Lchec immdiat de lintervention a t du mme ordre de grandeur dans le groupe minocycline et dans le groupe talcage (21,5% vs. 28,1% ; P = 0,31). La prsence dune maladie pulmonaire interstitielle, des pisodes antrieurs de pneumothorax au nombre de deux ou davantage, la
CONTEXTE :

ncessit dune ventilation mcanique durant la pleurodse et une fuite dair persistante avant la pleurodse ont t en association de faon indpendante avec lchec de lintervention. On a not de la douleur respectivement dans 44,6% des groupes sous minocycline et 37,5% des groupes avec talcage. La douleur sest manifeste plus frquemment chez les patients recevant de fortes doses de talc (5 g ; P = 0,03). La dtresse respiratoire a t signale respectivement chez 1,7% et 1,6% des groupes sous minocycline et aprs talcage. C O N C L U S I O N : La minocycline et la boue de talc ont eu des efficacits comparables dans la SSP avec des taux de succs immdiats >70%. Leffet indsirable le plus frquent a t la douleur et la dtresse respiratoire a t peu frquente. Les deux techniques semblent efficaces et sres pour la pleurodse chimique dans les cas de SSP.
RESUMEN

M A R C O D E R E F E R E N C I A : Pocos estudios han evaluado la eficacia de la esclerosis generada por la minociclina en casos de neumotrax y en ningn artculo se ha comparado especficamente su eficacia esclertica y seguridad toxicolgica con la del talco en suspensin en los casos de neumotrax espontneo secundario (SSP). M T O D O S : Se llev a cabo un anlisis retrospectivo de pacientes con SSP, en quienes se practic una pleurodesis qumica con minociclina o talco en suspensin en 12 hospitales pblicos entre enero y diciembre del 2004, en Hong Kong. R E S U LTA D O S : Se encontraron 121 episodios de pleurodesis con minociclina y 64 con suspensin de talco. La tasa de fracaso inmediato del procedimiento fue equivalente en el grupo de minociclina y el grupo tratado con la suspensin de talco (21,5% contra 28,1%; P = 0,31). Los factores asociados en forma independiente con el fracaso fueron la presencia de enfermedad pulmonar in-

tersticial, el antecedente de dos o ms episodios de neumotrax, la necesidad de ventilacin mecnica durante la pleurodesis y una fuga de aire persistente antes del procedimiento. Se present dolor en 44,6% de pacientes del grupo tratado con minociclina y en 37,5% del grupo tratado con talco. El dolor fue ms frecuente en los pacientes que recibieron altas dosis de talco (a partir de 5 g; P = 0,03). Se observ dificultad respiratoria en 1,7% de los casos con minociclina y en 1,6% del grupo tratado con talco. C O N C L U S I N : La minociclina y la suspensin de talco presentaron eficacias esclerticas comparables en los casos de SSP, con una tasa de xito inmediato superior a 70%. El dolor fue la reaccin adversa ms frecuente y la dificultad respiratoria fue infrecuente. Ambos mtodos parecen tcnicas eficaces y seguras de pleurodesis qumica en este tipo de pacientes.