INT J TUBERC LUNG DIS 14(10):1342–1346© 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

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

S E T T I N G : Few studies have evaluated the sclerosing ef-

fi cacy of minocycline, and none have specifi cally com-

pared its sclerosing effi cacy and safety profi les with talc

slurry in secondary spontaneous pneumothorax (SSP).

D E S I G N : A retrospective analysis was conducted in pa-

tients 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 pleu-

rodesis and 64 episodes of talc slurry pleurodesis. Im-

mediate procedural failure were similar in the mino-

cycline and talc slurry groups (21.5% vs. 28.1%, P =

0.31). Presence of interstitial lung disease, ⩾2 previous

episodes of pneumothorax, requiring mechanical venti-

lation during pleurodesis and persistent air leak before

pleurodesis were independently associated with proce-

dural 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 compa-

rable sclerosing effi cacy in SSP, with immediate success

rates of >70%. Pain was the most common adverse ef-

fect and respiratory distress was uncommon. Both ap-

peared to be effective and safe for chemical pleurodesis

in SSP.

K E Y W O R D S : minocycline; talc slurry; secondary spon-taneous 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 re-currences.1,2 Without pleurodesis, the recurrence rate in SSP was around 40–80%.1,3,4 The British Thoracic Society (BTS) and the American College of Chest Phy-sicians (ACCP) advocated pleurodesis in the fi rst oc-currence of SSP.5,6 Open thoracotomy with surgical pleurectomy remains the gold standard, but the tho-racoscopic 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 al-though that is not widely practised or readily avail-able. The effi cacy of talc slurry in the prevention of SSP recurrence in humans was not well explored, and small-scale studies in the 1980s revealed its scleros-ing effi cacy to be 93–100%.10,11 There were no pub-

lished data on its effi cacy in the prevention of pneu-mothorax in comparison to other agents.

The sclerosing effi cacy of tetracycline in pneumo-thorax is around 45–77%.12–14 As tetracycline was no longer available,15 its derivatives, such as oxytetracy-cline, doxycylcine and minocycline had been used in-stead. Minocycline and tetracycline had comparable sclerosing effi cacies in animal studies.16 The scleros-ing effi cacy 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 specifi cally addressed the scleros-ing effi cacy of minocycline in the prevention of SSP.

The primary aim of the present study was to com-pare the immediate sclerosing effi cacy21 of intra-pleural minocycline and talc slurry in the preven-tion of SSP recurrence. Secondary aims included the evaluation of 1) factors that were associated with

S U M M A R Y

Talc slurry and minocycline for pleurodesis 1343

im mediate procedural failure and 2) the adverse ef-fects and safety profi les of these two agents in chem-ical pleurodesis.

STUDY POPULATION AND METHODS

Study design and patient selectionThis is a multicentre retrospective study that involved 10 public hospitals and two university-affi liated hos-pitals 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. Pa-tients were included if they had SSP and subsequently underwent chemical pleurodesis with either minocy-cline (300 mg in 100 ml 9% normal saline) or talc slurry (2.5–5.0 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 collectionInformation collected included demographic data, characteristics of pneumothoraces, dosages and side effects of sclerosants, result of pleurodesis and pre-defi ned clinical outcomes. ‘Large’ pneumothorax was defi ned as one with distance of visceral pleura to chest wall of ⩾2 cm.6 Immediate failure was defi ned 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 analysisResults were expressed in median (interquartile range) for continuous variables, or number (percentages) for categorical data. Student’s t-test or Mann-Whitney U test were used to compare the differences between continuous variables, while Pearson’s χ2 test was used to compare categorical data. Logistic regression was used to determine the independent predictors of clini-cal outcomes. All statistical tests of signifi cance were two-sided, unless otherwise stated. A P of ⩽0.05 was considered as statistically signifi cant. Statistical anal-ysis was performed using SPSS, Version 11.0 (Statisti-cal Package for the Social Sciences, Chicago, IL, USA).

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 compara-ble, except that more patients had chronic obstruc-

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 re-peated chemical or surgical pleurodesis and median duration of chest drainage, were not signifi cantly dif-ferent between the two groups (Table 2).

Multivariate analysis revealed that having under-lying interstitial lung disease, history of ⩾2 previous episodes of pneumothorax, having mechanical venti-lation during pleurodesis and having persistent air leakage before pleurodesis were independently asso-ciated 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 0.44–2.22, P = 0.97; Table 3).

The frequency of pain was not signifi cantly differ-ent between the two groups (Table 4). Pain was expe-rienced in 20 patients (47.6%) who received ⩾5 g

Table 1 Clinical characteristics of patients who underwent chemical pleurodesis

Minocycline (n = 121)

n (%)

Talc slurry (n = 64)

n (%) P value

Sex, male 114 (94.2) 59 (92.2) 0.60Age, years, median [IQR] 73 [66–77] 71 [63–75] 0.19Ever smokers 114 (94.2) 58 (90.6) 0.36Chronic obstructive pulmonary

disease 95 (78.4) 40 (62.5) 0.02*Old tuberculosis 43 (35.5) 27 (42.2) 0.38Interstitial lung diseases 4 (3.3) 4 (6.3) 0.35Previous history of pneumothorax 43 (35.5) 22 (34.4) 0.88⩾2 previous episodes of

pneumothorax 16 (13.2) 9 (14.1) 0.87Persistent leakage before

pleurodesis 31 (25.6) 21 (32.8) 0.30Large pneumothorax (⩾2 cm) 75 (62.0) 48 (75.0) 0.07Required >1 intercostal tubes 17 (14.4) 12 (18.8) 0.40Required suction in the

management of pneumothorax 57 (47.1) 42 (65.6) 0.02*Put on ventilatory support 5 (4.1) 3 (4.7) 1.00

* P < 0.05.IQR = interquartile range.

Table 2 Clinical outcomes in the minocycline and talc slurry group*

Minocycline (n = 121)

n (%)

Talc slurry (n = 64)

n (%) P value

Immediate procedural failure 26 (21.5) 18 (28.1) 0.31Failure and underwent repeated

medical pleurodesis 22 (18.2) 16 (25.0) 0.28Failure and underwent surgical

pleurodesis 1 (0.8) 1 (1.6) 1.00Duration on chest drain after

pleurodesis, median days [IQR] 2 [1.0–7.0] 3 [1.0–5.0] 0.65Length of hospital stay,

median days [IQR] 15 [8–28] 20 [13–33] 0.02†

* No death related to pleurodesis recorded.† P < 0.05.IQR = interquartile range.

1344 The International Journal of Tuberculosis and Lung Disease

talc in comparison to four patients (18.2%) who re-ceived <5 g talc (P = 0.03). The frequencies of other side effects, including fever, nausea, vomiting and re-spiratory distress, were also not signifi cantly 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 fi rst study to specifi cally compare the sclerosing effi cacies and safety profi les 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 93–100%.10,11 In our study, the immediate success rates of talc slurry were compa-rable to those of minocycline, and both were under 80%. It is diffi cult 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 distribu-

tion onto the mesothelial surface because talc parti-cles would sediment into the dependent parts of the pleural cavity.14 Moreover, it was impossible to en-sure the uniform distribution of talc slurry onto pleu-ral surfaces without direct visualisation through tho-racoscopy. This might explain its inferiority when compared to talc poudrage. Furthermore, the dose of talc slurry administered in our study was not stan-dardised, 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 specifi cally addressed the sclerosing effi cacy of minocycline in patients with SSP. Mino-cycline was less effi cacious than talc slurry in an ani-mal study.22 The Veterans Administration Cooperative study, with 80% of its subjects being SSP, showed that the 30-day recurrence rate with tetracycline pleu-rodesis was 19%,13 which was comparable to our 21.5% recurrence rate within the same hospitalisa-tion. 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 pleuro-desis 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 dur-ing 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 fi stu-las. Patients with multiple previous pneumothoraces might also have more pleural adhesions related to previous pleural manipulations,23 such as tube in-sertions and aspirations. Thoracoscopic studies have demonstrated that adhesions can prevent the uniform coating of talc onto pleural surfaces, thereby reduc-ing its sclerosing effectiveness.24

Table 3 Predictors of pleurodesis failure

Successful pleurodesis(n = 141)

n (%)

Failed pleurodesis

(n = 44)n (%)

Crude odds ratio(95%CI)

Adjusted odds ratio(95%CI) P value

Male sex 132 (93.6) 41 (93.2) 1.07 (0.28–4.15) 0.87 (0.18–4.18) 0.87Age > 60 years 117 (83.0) 38 (86.4) 1.30 (0.49–3.42) 0.78 (0.23–2.65) 0.69Smoker 130 (92.2) 42 (95.5) 1.78 (0.38–8.34) 2.92 (0.44–19.13) 0.27Chronic obstructive pulmonary disease 103 (73.0) 32 (72.7) 0.98 (0.46–2.11) 1.46 (0.51–4.18) 0.48Old tuberculosis 52 (36.9) 18 (40.9) 1.19 (0.59–2.37) 1.46 (0.62–3.41) 0.39Interstitial lung diseases 4 (2.8) 4 (9.1) 3.43 (0.82–14.31) 9.41 (1.61–54.95) 0.01*⩾2 previous episodes of pneumothorax 16 (11.3) 9 (20.5) 2.01 (0.82–4.93) 3.40 (1.17–9.89) 0.03*Large pneumothorax 93 (66.0) 30 (68.2) 1.11 (0.54–2.28) 1.89 (0.78–4.55) 0.16On mechanical ventilation 4 (2.8) 4 (9.1) 3.43 (0.82–14.31) 5.76 (1.05–31.55) 0.04*Persistent air leak before pleurodesis 29 (20.6) 23 (52.3) 4.23 (2.06–8.68) 6.20 (2.57–14.94) <0.001†

Put on suction 68 (48.2) 31 (70.5) 2.56 (1.24–5.30) 2.05 (0.87–4.80) 0.10Use of minocycline compared to talc as

the sclerosant 46 (32.6) 18 (40.9) 1.43 (0.71–2.87) 0.98 (0.44–2.22) 0.97

* P < 0.05.† P < 0.001.

Table 4 Side effects associated with minocycline and talc slurry

Minocycline(n = 121)

n (%)

Talc slurry(n = 64)

n (%) P value

Any pain experienced 54 (44.6) 24 (37.5) 0.35Mild to moderate pain, requiring

non-opioid analgesics 27 (22.3) 14 (21.9) 0.95Moderate to severe pain, requiring

opioid analgesics 27 (22.3) 10 (15.6) 0.28Fever 5 (4.1) 1 (1.6) 0.67Nausea or vomiting 0 1 (1.6) 0.35Respiratory distress with new

radiological infi ltrates 2 (1.7) 1 (1.6) 1.00

Talc slurry and minocycline for pleurodesis 1345

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 mino-cycline pleurodesis.25 The literature reported that 58.2% of patients with tetracycline pleurodesis suf-fered from pain, which was attributed to the induced pleural infl ammation.26,27 Pain might correlate with the success of tetracycline pleurodesis, and was re-duced 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 se-vere 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’ varia-tions 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 re-ceived <5 g. The optimal dose of talc slurry was not well addressed,6 and 2–10 g of talc slurry had been applied in previous studies involving SSP patients.10,11 As the pleural surfaces in pneumothorax are rela-tively normal in comparison to those in malignant conditions, a lower dose of talc powder may suffi ce.

The incidence of ARDS was estimated to be 1–9% 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 infl ammation than ‘graded talc’ with particle size <10 μm.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 defi nite association of respiratory distress with the use of talc slurry could not be reliably estab-lished by reviewing hospital records alone. Empyema was not found and should not be expected if sterilised talc was used.27 No death related to pleu rodesis was reported, which, together with the absence of other se-rious side effects such as ARDS, suggested that both agents were safe chemical sclerosants.

The study was limited by its retrospective nature. It would be diffi cult 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 effi cacy. The long-term pneumothorax recurrence rates were not explored and we could not explore the pos-sible associations between short-term and longer-term recurrence rates. As it had been suggested that tetra-cycline exerted its effect mainly at 6 months,13 long-term 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 ef-fi cacy. However, the defi nitions of ‘short-term’ and ‘long-term’ recurrences have been arbitrary, and an optimal timing to measure the effi cacy of pleurodesis

remains unclear since the timing of recurrence might depend on factors such as the severity of the under-lying pleural and pulmonary pathologies and the scle-rosing 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.

AcknowledgementsThe 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 Scientifi c Sub-Committee of the Hong Kong Thoracic Society for its directive and advisory role in conducting this territory-wide research.

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17 Chen J S, Hsu H H, Chen R J, et al. Additional minocycline pleurodesis after thoracoscopic surgery for primary spontane-ous pneumothorax. Am J Respir Crit Care Med 2006; 173: 548–554.

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R É S U M É

C O N T E X T E : Peu d’études ont évalué l’effi cacité sclé-

rosante de la minocycline dans les pneumothorax spon-

tanés secondaires (SSP) et aucune n’a comparé spéci-

fi quement avec le talcage son effi cacité sclérosante et son

profi l de sécurité.

S C H É M A : Une analyse rétrospective a été menée chez

des patients souffrant de SSP qui ont subi entre janvier

et décembre 2004 dans 12 hôpitaux publics de Hong

Kong une pleurodèse à la minocycline ou par talcage.

R É S U LTAT S : Il y a eu 121 épisodes de pleurodèse par

minocycline et 64 épisodes de pleurodèse par talcage.

L’échec immédiat de l’intervention a été du même ordre

de grandeur dans le groupe minocycline et dans le groupe

talcage (21,5% vs. 28,1% ; P = 0,31). La présence d’une

maladie pulmonaire interstitielle, des épisodes antérieurs

de pneumothorax au nombre de deux ou davantage, la

nécessité d’une ventilation mécanique durant la pleuro-

dèse et une fuite d’air persistante avant la pleurodèse

ont été en association de façon indépendante avec l’échec

de l’intervention. On a noté de la douleur respectivement

dans 44,6% des groupes sous minocycline et 37,5% des

groupes avec talcage. La douleur s’est manifestée plus

fréquemment chez les patients recevant de fortes doses

de talc (⩾5 g ; P = 0,03). La détresse respiratoire a été

signalée respectivement chez 1,7% et 1,6% des groupes

sous minocycline et après talcage.

C O N C L U S I O N : La minocycline et la boue de talc ont eu

des effi cacités comparables dans la SSP avec des taux de

succès immédiats >70%. L’effet indésirable le plus

fréquent a été la douleur et la détresse respiratoire a été

peu fréquente. Les deux techniques semblent effi caces et

sûres pour la pleurodèse chimique dans les cas de SSP.

R E S U M E N

M A R C O D E R E F E R E N C I A : Pocos estudios han evaluado

la efi cacia de la esclerosis generada por la minociclina en

casos de neumotórax y en ningún artículo se ha com-

parado específi camente su efi cacia esclerótica y seguri-

dad toxicológica con la del talco en suspensión en los

casos de neumotórax espontáneo secundario (SSP).

M É T O D O S : Se llevó a cabo un análisis retrospectivo de

pacientes con SSP, en quienes se practicó una pleuro-

desis química con minociclina o talco en suspensión en

12 hospitales públicos entre enero y diciembre del 2004,

en Hong Kong.

R E S U LTA D O S : Se encontraron 121 episodios de pleuro-

desis con minociclina y 64 con suspensión de talco. La

tasa de fracaso inmediato del procedimiento fue equiva-

lente en el grupo de minociclina y el grupo tratado con

la suspensión 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 más episodios de neu-

motórax, la necesidad de ventilación mecánica durante

la pleurodesis y una fuga de aire persistente antes del

procedimiento. Se presentó dolor en 44,6% de pacientes

del grupo tratado con minociclina y en 37,5% del grupo

tratado con talco. El dolor fue más frecuente en los pa-

cientes que recibieron altas dosis de talco (a partir de

5 g; P = 0,03). Se observó difi cultad 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 Ó N : La minociclina y la suspensión de talco

presentaron efi cacias escleróticas comparables en los ca-

sos de SSP, con una tasa de éxito inmediato superior a

70%. El dolor fue la reacción adversa más frecuente y la

difi cultad respiratoria fue infrecuente. Ambos métodos

parecen técnicas efi caces y seguras de pleurodesis química

en este tipo de pacientes.