Medicines Q&As
Q&A 117.3
What is the evidence for the use of nebulised heparin in cystic
fibrosis?
Prepared by UK Medicines Information (UKMi) pharmacists for NHS healthcare professionals
Before using this Q&A, read the disclaimer at www.ukmi.nhs.uk/activities/medicinesQAs/default.asp
Date prepared: 11th June 2013
Background
Cystic fibrosis (CF) is a hereditary disease of the exocrine glands, which mainly affects the
gastrointestinal and respiratory systems. It results in exocrine pancreatic insufficiency, hepatobiliary
disease, chronic lung disease and abnormally high sweat electrolytes (1).
Progressive lung damage in CF results from the bacterial colonisation of thickened respiratory
secretions and subsequent airways inflammation (2,3). Agents with mucolytic or anti-inflammatory
effects may therefore be beneficial in the treatment of lung disease in these patients. It has been
suggested that heparin may have both of these properties (2). An in vitro study demonstrated that
unfractionated heparin reduced the elasticity, but not the viscosity of the sputum of adult CF patients
(4).
Answer
One study, which investigated the safety of increasing doses of nebulised heparin in 10 healthy
volunteers, showed that single high doses of inhaled unfractionated heparin had no adverse effect on
lung function. Four single doses ranging from 100,000 units to 400,000 units of heparin were
administered on 4 different days via a jet nebuliser. A dose dependent increase in anti-Xa, activated
partial thromboplastin time (APTT) and release of tissue factor pathway inhibitor (TFPI) was seen, but
this anticoagulant effect was not considered to be clinically relevant. The study concluded that
inhalation of heparin at these doses was safe with respect to pulmonary function and systemic
coagulation (5).
In another small pilot study, six stable adult CF patients colonised with Burkholderia cepacia received
25,000 units of nebulised heparin sulfate daily for 7 days. This was administered after their usual
bronchodilator therapy and chest physiotherapy. Levels of lung inflammation in such patients can be
up to ten times that seen in CF patients colonised with Pseudomonas aeruginosa. The findings of this
study suggest that nebulised heparin has an anti-inflammatory action since a reduction in sputum and
serum interleukin-6 and interleukin-8 (inflammatory cytokines) was seen. According to visual
analogue scores, patients found sputum easier to expectorate (p<0.04) with a trend towards thinner
sputum (p=0.07) but with no change in sputum volume (p=0.12). Nebulised heparin was well tolerated
with no bleeding, thrombocytopenia or change in coagulation parameters observed. Spirometry was
also unchanged (2).
A randomised, double-blind, placebo-controlled crossover study in 18 adult CF patients investigated
the safety and tolerability of 50,000 units of nebulised unfractionated heparin sodium. This was
administered twice daily for 2 weeks via a jet nebuliser, after a short-acting β2-agonist and usual chest
physiotherapy. There was a one-week washout before the crossover. Subsequently 4 patients were
withdrawn, so 14 patients completed the study. Whilst CF patients are potentially at risk of pulmonary
bleeding, no bleeding complications were observed. Treatment was well tolerated and no effect on
coagulation markers was seen. However, nebulised heparin had no significant effect on the primary
outcome measure, forced expiratory volume in one second (FEV1) or on sputum symptom scores or
sputum inflammatory markers. The authors suggest that this could be a result of insufficient dosing or
inadequate duration, so further dose-ranging studies are needed (3).
Available through NICE Evidence Search at www.evidence.nhs.uk
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Medicines Q&As
Whilst there is a lack of published evidence supporting the efficacy of nebulised heparin in adult CF
patients, it has been used anecdotally, on a short-term basis, prior to chest physiotherapy to aid
expectoration of mucus. A trial dose of nebulised heparin is given initially, with lung function
measured prior to heparin administration and again 15-30 minutes post dose. Provided that there is
no more than a 15% reduction in lung function then nebulised heparin may be prescribed routinely. In
practice, the usual dose is 50,000 units twice a day, but in patients who require chest physiotherapy
more frequently than twice a day, doses of up to 50,000 units four times a day have been used. As
bronchospasm may occur, salbutamol should be prescribed as required (6).
Experimentally, in two patients who were not expectorating sufficiently with 50,000 units, a dose of
100,000 units twice daily has been used, with good response and no adverse effects (6).
Clearly, further larger long-term studies are needed to determine the clinical effects and safety of this
treatment (2).
There have been no published studies using inhaled low molecular weight heparins in cystic fibrosis.
Heparin is not licensed to treat cystic fibrosis or to be administered via the nebulised route, and use in
this way is therefore the responsibility of the prescriber.
Summary

There is very little published information available on the use of nebulised heparin in cystic
fibrosis.

Two small short-term studies have shown that nebulised heparin sulfate 25,000 units daily for
7 days (2) and heparin sodium 50,000 units twice daily for 14 days (3) is safe in patients with
cystic fibrosis, but clinical efficacy was not demonstrated.

Further larger long-term studies are needed to determine the clinical effects and safety of this
treatment (2).

Anecdotally in one UK Trust, nebulised heparin doses of up to 50,000 units four times daily
(or 100,000 units twice daily in two patients) have been used in adults on a short-term basis
(6).

Heparin is not licensed to treat cystic fibrosis or to be administered via the nebulised route,
and use in this way is therefore the responsibility of the prescriber.

There have been no published studies using nebulised low molecular weight heparins in
cystic fibrosis.
Limitations
This Q&A relies upon anecdotal evidence from one UK Foundation Trust and limited published
evidence on the use of nebulised heparin in adult CF patients. No published studies evaluating the
use of nebulised heparin in paediatric CF patients are available.
Different nebuliser devices may deliver different doses of heparin to the lower respiratory tract (5).
The use of nebulised heparin for the management of other respiratory conditions has not been
considered in this Medicines Q&A.
Available through NICE Evidence Search at www.evidence.nhs.uk
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Medicines Q&As
References
1. Porter RS, Kaplan JL, editors. The Merck Manual of Diagnosis and Therapy. Whitehouse
Station, New Jersey; Merck Sharp and Dohme Corp. Cystic fibrosis monograph. Last full
review/revision September 2012. Pediatrics section. Available at:
http://www.merck.com/mmpe/sec19/ch278/ch278a.html?qt=cystic%20fibrosis&alt=sh.
Date accessed June 20th 2013.
2. Ledson M, Gallagher M, Hart CA et al. Nebulized heparin in Burkholderia cepacia colonized
adult cystic fibrosis patients. Eur Respir J 2001;17:36-8.
3. Serisier DJ, Shute JK, Hockey PM et al. Inhaled heparin in cystic fibrosis. Eur Respir J
2006;27:354-358.
4. Broughton-Head VJ, Shur J, Carroll MP et al. Unfractionated heparin reduces the elasticity of
sputum from patients with cystic fibrosis. Am J Physiol Lung Cell Mol Physiol
2007;293:L1240-L1249.
5. Bendstrup KE, Gram J, Jensen JI. Effect of inhaled heparin on lung function and coagulation
in healthy volunteers. Eur Respir J 2002;19:606-610.
6. Personal communication. Adult cystic fibrosis specialist pharmacist, University Hospital
Southampton NHS Foundation Trust. July 2013.
Quality Assurance
Prepared by
Kate Pickett (based on earlier work by Nicola Watts), Medicines Q&A Pharmacist, Wessex Drug and
Medicines Information Centre, University Hospital Southampton NHS Foundation Trust
Date Prepared
11th June 2013
Checked by
Dr Simon Wills (based on the Q&A checked by Sandra Hicks and Sue Gough), Head of Wessex Drug
and Medicines Information Centre, University Hospital Southampton NHS Foundation Trust
Date of check
12th September 2013
Search strategy
Medline (NICE Evidence Search):
: exp heparin/ AND exp administration, inhalation/ AND exp cystic fibrosis/
: exp heparin, low-molecular-weight/ AND exp administration, inhalation/ AND
exp cystic fibrosis/
Embase (NICE Evidence Search):
: exp heparin/ih AND exp cystic fibrosis/
: exp heparin/ AND exp inhalational drug administration/ AND exp cystic
fibrosis/
: exp low molecular weight heparin/ih AND exp cystic fibrosis/
: exp low molecular weight heparin AND exp inhalational drug administration/
AND exp cystic fibrosis
Micromedex
British National Formulary (Accessed via http://www.bnf.org)
Martindale: The Complete Drug Reference (Accessed via http://www.medicinescomplete.com)
AHFS Drug Information (Accessed via http://www.medicinescomplete.com)
NICE Evidence Search (Accessed via https://www.evidence.nhs.uk/)
Cystic Fibrosis Medicine website. Accessed via http://www.cysticfibrosismedicine.com/
CF Trust website. Accessed via https://www.cysticfibrosis.org.uk/
British Thoracic Society website. Accessed via http://www.brit-thoracic.org.uk/
Clinical expert – Dr Mary Carroll, Director of the Regional adult CF service based at Southampton
General Hospital (2009).
Available through NICE Evidence Search at www.evidence.nhs.uk
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