Adult pleural infection (alternative terms include pleural empyema and complicated parapneumonic effusion) is associated with a high mortality and morbidity: approximately 20% of patients die and 20% require surgery within 12 months of their infection. Combination intra-pleural fibrinolytic therapy with Alteplase (rt-PA) and Dornase alfa (rhDNase) should be used in the following situations:

1. standard medical treatment (intercostal drainage and antibiotics) has failed to achieve satisfactory clearance of the pleural space after 12-24 hours, and

2. surgical intervention is considered clinically inappropriate or will be significantly delayed potentially leading to a negative impact on patient outcome.

The diagnosis of pleural infection must have been confirmed either biochemically and/or microbiologically in line with the British Thoracic Society guidelines:

• pus seen on pleural aspiration,

• pleural fluid pH <7.20,

• positive microbiology on culture or gram stain.

Pleural fluid lactate dehydrogenase (LDH) and glucose levels are also useful in supporting the diagnosis of pleural infection.

In case of clinical doubt then the case should be discussed with a Respiratory Consultant.

The responsible clinician may consider that standard medical treatment has failed in the following circumstances:

• persistent adverse clinical features (raised temperature, tachycardia, hypotension)

• non-responsive biochemical markers (WBC, Neutrophils, CRP)

• non-draining residual pleural collection (defined on imaging by one or more of chest radiograph, thoracic CT scan or thoracic ultrasound)

The use of Alteplase and Dornase alfa for intra-pleural fibrinolysis is off-licence. For this reason, a Respiratory Consultant must be involved in the patient’s care prior to administration, and it should occur in an appropriate specialist environment (respiratory ward, MADU or the intensive care unit). Combination intra-pleural fibrinolytics should only be administered by doctors or nurses trained in their administration.

2.1 Absolute

• Less than 18 years of age

• Known sensitivity or allergy to intra-pleural fibrinolytic agents

• Coincidental stroke

• Coincidental major hemorrhage or trauma (including thoracic hemorrhage or trauma)

• Major surgery in the previous week

• Irreversible bleeding diathesis or platelet count <50 x10⁹/L

• Previous pneumonectomy on the affected side

• Pregnant or breastfeeding

2.2 Relative

• Concurrent anticoagulation with Warfarin, treatment dose LMWH or Direct Oral Anticoagulant (DOAC) or concurrent use of Clopidogrel.

• Severe hepatic and renal failure – these patients are often at higher risk of bleeding and careful consideration of risk: benefit ratio will need to be made. It may be appropriate to use a lower dose of Alteplase and/or frequency of administration.

The competing risks and benefits of stopping anticoagulation/anti-platelets Vs avoiding intra-pleural fibrinolytics must be assessed. They would ideally have been held prior to chest drain insertion. If it is deemed appropriate to stop them then:

• Warfarin – stop as soon as possible and wait for INR to be <1.5. If reversal of Warfarin is required, then this should be done.

• DOAC – stop as soon as possible. If it is clinically possible then hold for 48 hours prior to administering intra-pleural fibrinolytics.

• Clopidogrel – should be held for 7 days prior to administration of intra-pleural fibrinolytics for greatest bleeding risk reduction. However, in most cases this will not be possible due to the urgency of treatment and therefore is should be held as soon as possible. This is likely to have occurred at the time of chest drain insertion.

• Prophylactic LMWH can be administered as per the trust guideline.

Written consent should be taken prior to the administration of intra-pleural fibrinolytics in all cases. If the individual patient lacks capacity regarding this decision, then consent should be taken in their best interests and should include discussion where possible with their next of kin or legally appointed representative.

The consent form should include the following potential complications:

• Intrapleural hemorrhage

• Hemoptysis

• Gastrointestinal (or other systemic) bleeding

• Hypersensitivity reaction (including anaphylaxis, widespread rash or erythema)

• Chest pain

• Nausea

• Fever

• Transient confusion

The following routine blood tests must have been performed in the 24 hours preceding administration of intra-pleural fibrinolysis:

FBC, clotting (APTT, PT), U&E, LFT, CRP

Position of the intercostal drain must be confirmed. The drain should be inspected to ensure it has not migrated. Pleural fluid should be aspirated if possible. The drain should then be flushed with 20ml normal saline to confirm patency and that there is no leakage of fluid externally indicating inappropriate drain position.

The drugs should be administered concurrently via the chest drain, immediately followed by closing of the drain for 1 hour and then free drainage until the next dose is due. Both medications must be available and administered in combination. Either medication in isolation is ineffective.

These drugs are not kept as stock item on the respiratory ward. Prescribe them on the drug chart and contact the ward pharmacist for supply.

1. Alteplase:

   a. Add the contents of the provided solvent (water for injections) to the Alteplase powder making up a volume of 1mg/ml.

   b. Draw up 5-10mg (depending on prescribed dose) into a 30ml syringe

   c. Draw up normal saline to a total volume of 30ml.

   d. Once prepared, use immediately.

2. Dornase alfa

   a. This medication should be stored in the refrigerator.

   b. Draw up 5mg (usually 2 x 2.5mg/2.5ml vials) into a 30ml syringe

   c. Draw up normal saline to a total volume of 30ml.

   d. Once prepared, use immediately

1. Isolate the chest drain:

   a. Seldinger drain with 3 way-tap: by turning off the 3-way tap thereby isolating the drain from the distal tubing and underwater seal bottle

   b. Wide-bore blunt dissected drain: by clamping the drain and disconnecting the distal tubing.

2. Inject the alteplase or urokinase intra-pleurally followed by a 10ml flush of normal saline. Alteplase or urokinase should always be given first.

3. Inject the Dornase alfa intra-pleurally and a further 10ml flush of normal saline.

Note: if injecting into a wide bore drains then intra-pleural fibrinolytics and normal saline flushes may need to be transferred into a bladder syringe prior to injection to ensure an appropriate seal between syringe and drain.

4. The drain should then be closed for 1 hour before re-opening and leaving on free drainage.

5. Drug administration should be recorded and signed for on the patient’s drug chart.

All patients receiving intra-pleural fibrinolysis should have regular physical observations recorded (heart rate, blood pressure, respiratory rate, oxygen saturations, temperature and conscious level). These should be recorded immediately prior to administration and then at 30 minutes, 1 hour, 2 hours, 3 hours and 4 hours post administration.

Chest-drain output should be recorded 2 hours following administration (1 hour post re-opening of the chest drain) including volume of fluid drained and a description of fluid appearance (e.g. straw-coloured, blood stained, haemorrhagic).

The chest drain site should be monitored for erythema or rash. If a suspected hypersensitivity reaction occurs, then the administration should be stopped, and appropriate treatment administered.

The most-common side effect of intra-pleural fibrinolytics is intra-pleural haemorrhage. Some blood-stained pleural fluid is to be expected but if large volumes of heavily haemorrhagic fluid drains or if there is new haemodynamic instability (tachycardia, hypotension, drop in haemoglobin) then the senior respiratory team (SpR or Consultant) should be involved.

Items needed:

3x 10ml Syringes 2x 20ml Syringe 1x 2% Chlorhexidine wipes 2x Filtered needles Alteplase & Dornase alfa as prescribed 1x 100ml bag of 0.9% Sodium Chloride 1 pair of gloves

Procedure:

1. Check prescription of Alteplase and Dornase alfa on drug chart as per trust guideline.
2. Ensure written consent taken as per trust guideline.
3. Prepare Alteplase and Dornase alfa as per section 8 of trust guideline. Also prepare 3 x 10ml normal saline flushes.
4. Once satisfied with the drain position (section 6 of trust guideline), clamp the drain as shown in the picture below.

Remove the cap from the side port of the 3-way tap and clean the side port with the chlorhexidine wipe. Attach the first normal saline flush to the side port and open the 3-way tap to the side port (as in the picture below). Inject the flush.

5. Clamp the drain then remove the flush and keep and the drain clamped.

6. Attach the 30ml syringe containing Alteplase to the side port and open the 3-way tap to the side port. Inject the Alteplase.

7. Re-clamp the drain and then remove the syringe containing Alteplase.

8. Administer the second flush of normal saline as described in Steps 4 to 5.
9. Attach the 30ml syringe containing Dornase alfa to the side port and open the 3-way tap to the side port. Inject the Dornase alfa.

10. Re-clamp the drain and then remove the syringe containing Dornase alfa.

11. Administer the third flush of normal saline as shown in Steps 4 to 5.
12. Leave the drain clamped for 1 hour. Inform the ward nurses/doctors that the drain has been clamped and the plan to unclamp it in 1 hour.
13. Ensure the Alteplase and Dornase alfa prescriptions on the drug chart have been signed for.

3 Way Tip! The section with no spike/knob (labelled in the picture) is the section that is clamped/locked

Roberts ME, Rahman NM, Maskell NA On behalf of the BTS Pleural Guideline Development Group, et alBritish Thoracic Society Guideline for pleural disease. Thorax 2023;78:s1-s42.

Asciak R, Bedawi EO, Bhatnagar R, et al British Thoracic Society Clinical Statement on pleural procedures Thorax 2023;78:s43-s68.

Piccolo F, Pitman N, Bhatnagar R, et al. Intrapleural tissue plasminogen activator and deoxyribonuclease for pleural infection. An effective and safe alternative to surgery. Ann Am Thorac Soc 2014; 11(9):1419-25 (PMID 25296241) https://www.atsjournals.org/doi/full/10.1513/AnnalsATS.201407-329OC

Majid A, Kheir F, Folch A, et al. Concurrent intrapleural instillation of tissue plasminogen activator and DNase for pleural infection. A single-centre experience. Ann Am Thorac Soc 2016; 13(9):1512-8 (PMID 27333122) https://www.atsjournals.org/doi/10.1513/AnnalsATS.201602-127OC

Popowicz N, Bintcliffe O, De Fonseka D, et al. Dose de-escalation of intrapleural tissue plasminogen activator therapy for pleural infection. The Alteplase Dose Assessment for Pleural Infection Therapy Project. Ann Am Thorac Soc 2017; 14(6):929-36 (PMID 28324671) https://www.atsjournals.org/doi/10.1513/AnnalsATS.201609-673OC

BTS response to the national shortage of alteplase in relation to pleural infection management. August 2022. Website: brit-thoracic.org.uk

This guideline has been registered with the trust. However, clinical guidelines are guidelines only. The interpretation and application of clinical guidelines will remain the responsibility of the individual clinician. If in doubt, contact a senior colleague or expert. Caution is advised when using guidelines after the review date. This guideline is for use in Frimley Health Trust hospitals only. Any use outside this location will not be supported by the Trust and will be at the risk of the individual using it.

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