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Three Part Question

In [patients undergoing pleurodesis] is the use of [NSAIDs] detrimental in terms of [successful pleurodesis].

Clinical Scenario

A 25 year old man with his second spontaneous right-sided pneumothorax has undergone VATS bullectomy and talc pleurodesis this morning. Patient controlled analgesia (PCA) was set up at completion of surgery and oral paracetamol prescribed. You are asked to see him on the ward later that evening because he is in a lot of pain, and his morphine PCA is making him feel very sick. You think the pain is likely to be muscular and aggravated by his chest drain, and you think he would benefit from a NSAID such as diclofenac, but the thoracic surgical nurse looking after him is unhappy to give it. She was told that it may reduce the chances of a successful pleurodesis.

Search Strategy

Medline 1950 – Apr 2006 and Embase 1974 – Apr 2006 using the Dialog Datastar interface
[Pleurodesis.W..DE.OR Pleurodesis] AND [Voltarol OR Diclofenac OR Diclofenac.W..DE. OR Anti-Inflammatory-Agents-Non-Steroidal.DE. OR NSAIDS or non-steroids$ ADJ ant-inflammatory OR nonsteroid$ ADJ antiinflammtory OR Nonsteroid-Antinflammatory-Agent.DE. OR Ibuprofen.W..DE. OR Ibuprofen-Arginine.DE.OR Ibuprofen-Lysine.DE.OR Ibuprofen-Plus-Oxycodone.DE.OR ibuprofen]. Limit to English. This search was repeated in Cochrane Central Register of Controlled Trials

Search Outcome

A total of 17 papers were identified. No human studies were found and all the animal studies were small prospective histopathological assessments of pleurodesis using different agents or mechanical abrasion. Three were deemed to be relevant.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Lardinois et al, 2004, Switzerland	10 VLS pigs underwent VATS & apical mechanical abrasion: 2 groups postop diclofenac 2mg/kg po for 3 weeks vs. Control (no NSAIDS)	Experimental study (level 4)	After 21 days macroscopic pleurodesis scored (5-point pleurodesis score & 4-point obliteration score)	Macroscopic pleurodesis (using 5-point scoring, 0=normal pleural space no adhesions to 4=severe dense adhesions): 3.67+/-1.0 vs. 2.0+/-2.2 (control) (p=0.01) Distribution of adhesions comparable	Small animal study with short term outcome Extrapolation to humans different scoring systems from 2 other studies
			Microscopic pleurodesis scored (4-point fibrosis score) by 3 blinded reviewers	Microscopic pleurodesis: No significant difference but higher amount of organized collagen fibres in control group
			Complications	Post-operative complications: One death from GI bleed & one D&V
Teixeira et al, 2005, Brazil	60 male NZ rabbits 2 groups Silver nitrate pleurodesis vs. talc pleurodesis Further subgroups: -sclerosing agent alone vs. sclerosing agent + Pred IM vs. sclerosing agent + Dic 1mg/kg IM	Experimental study (level 4)	After 28 days scored for macroscopic pleurodesis	Macroscopic Pleural adhesions: Silver nitrate 3.2+/-1.1 & Talc 2.2+/-0.8 (p=0.019). In subgroup test Silver nitrate with Pred 3.5+/-0.5 or Dic 3.3+/-1.0 . Talc with Pred 1.3+/-0.7 or Dic 1.2+/-0.7. (0-4 scoring score used ranging from 0=normal pleural space to 4=complete obliteration of pleural space by adhesions.)	Animal study with short term outcome Extrapolation to humans Neither silver nitrate or prednisolone are part of standard clinical practice
			After 28 days scored for microscopic pleurodesis	Microscopic Pleural inflammation: Silver nitrate with Pred 1.3+/-0.5 or Dic 2.2+/-1.6. Talc with Pred 0.9+/-0.3 or Dic 0.7+/-0.5 Microscopic Pleural fibrosis: Silver nitrate with Pred 3.4+/-0.5 or Dic 3.2+/-1.0. Talc with Pred 1.5+/-1.0 or Dic 1.4+/-0.8 Microscopic process scored using scoring system ranging from 0=equivocal to 4=marked changes
Ors et al, 2005, Turkey	12 male NZ rabbits – given tetracycline pleurodesis: 2 groups – 2mg/kg diclofenac IM for 10/7 - 30mg/kg acetaminophen (Paracetamol) po for 0/7	Experimental study (level 4)	After 28 days: Scored for macroscopic pleurodesis (gross inspection)	Mean macroscopic score Dic 2.16+/-0.40 & Acet 2.83+/-0.40 (p=0.027) (Scoring system used ranged from 0=normal to 4=complete obliteration of pleural space)	Small animal study with short term outcome Relies on extrapolation to humans
			Scored for microscopic pleurodesis (microscopic evidence of fibrosis, inflammation |& collagenization)	Mean microscopic score Dic 2.3+/-1.03 & Acet 3.5+/-0.54 (p=0.045) (Scoring system used ranged from 0=absent to 4=severe)

Comment(s)

The use of non-steroidal anti-inflammatory agents (NSAIDS) such as diclofenac following interventional procedures is widespread as they provide effective analgesia with few central nervous system effects. It works by blocking cyclo-oxygenase and the production of prostaglandins, which are produced in response to injury or certain diseases and would otherwise go on to cause pain, swelling and inflammation. Lardinosis notes that in animal models the breaking strength and collegen concentration at wound sites was less after use of NSAIDS. Whether mechanical abrasion or a chemical sclerosing agents such as talc is used, pleurodesis relies on the generation of inflammation and consequent adhesion between the two layers of pleura to prevent the build of fluid in the pleural cavity. The studies reviewed address whether the use of NSAIDS inhibits pleurodesis. All studies were in animals. In two studies rabbits were used and in one study pigs. Kaya used intrapleural tetracycline and compared macroscopic and microscopic evidence of pleurodesis after 3 weeks in animals on diclofenac or acetaminophen (paracematol). Following IM adminstration of diclofenac for 10 days tetracycline pleurodesis was reduced both macroscopically and microscopically, though not significantly. Teixeira using the same animal model, albeit a larger number of animal concluded that systemic administration of both steroidal and non-steroidal anti-inflammatory agents reduces the degree of pleurodesis with talc but not silver nitrate. The final animal study involved thorascopic abrasion pleurodesis of pigs and evaluated gross and microscopic evidence of pleurodesis after 21 days in pigs given oral diclofenac or controls (Lardinosis). Macroscopically pleurodesis appeared to be reduced in animals taking NSAIDS but microscopically no statically significant difference between the two groups was found. However, a trend toward a higher amount of organised collagen fibres suggestive of dense adhesions was observed in the control group. The authors concluded that peri-operative use of NSAIDS affects quality of pleural adhesions obtained after mechanical abrasion in pig models. In the available animal studies the histopathological influence of NSAIDS on pleurodesis was assessed. The authors suggest that there is a reduction in the quality of pleurodesis achieved at a macroscopic and or microscopic level. There are no studies which assesses clinical outcomes such as recurrence of pneumothorax or pleural effusion. Clinical studies would be very hard to perform because the only realistic means of assessing outcome is to await recurrence; a substantial proportion do not recur in the natural history of the condition and the stapling of the apex may on its own be sufficient to prevent some of the recurrences.

Editor Comment

(IM = Intramuscular; Dic = Diclofenac; Acet = Acetaminophen; NZ = New Zealand; Pred = methylprednisolone; VATS = Video Assisted Thoracoscopic Surgery; NSAIDS = Non-Steroidal Anti-inflammatory Drugs; VLS = Schweizerisches Veredeltes Landschwein; GI = Gastrointestinal; D&V = Diarrhoea & Vomiting)

Clinical Bottom Line

Best Evidence suggests that there is some histopathological evidence dervide from animal experiments that the use of NSAIDS may decrease the effect of pleurodesis. Until clinical evidence becomes available, the routine use of NSAIDS following pleurodesis should probably be avoided.

References

1. Lardinois D, Vogt P, Yang L, Hegyi I, Baslam M, Weder W. Non-steroidal anti-inflammatory drugs decrease the quality of pleurodesis after mechanical pleural abrasion. European Journal of Cardio-Thoracic Surgery 25(5):865-71, 2004.
2. Teixeira LR, Vargas FS, Acencio MM et al. Influence of antiinflammatory drugs (methylprednisolone and diclofenac sodium) on experimental pleurodesis induced by silver nitrate or talc. Chest 128(6):4041-5, 2005.
3. Ors KS, Bir F, Atalay H, Onem G, Aytekin FO, Sacar M. Effect of diclofenac on experimental pleurodesis induced by tetracycline in rabbits. Journal of Investigative Medicine 53(5):267-70, 2005.