Keywords
Protamine sulphate is widely used to reverse anticoagulation with heparin after various surgical and interventional procedures, and is currently the only drug licensed for this indication. Reversal of intra-operative heparin after carotid endarterectomy (CEA) to reduce the incidence of post-operative bleeding complications, particularly re-exploration for neck haematoma (NH) with airway compromise, has received renewed attention in recent years. Two meta-analyses have shown that intra-operative heparin reversal can be done without increasing the risk of post-operative stroke, myocardial infarction (MI), or death.
1
,2
These results are supported by two database analyses including over 80 000 patients.3
,- Stone D.H.
- Giles K.A.
- Kubilis P.
- Suckow B.D.
- Goodney P.P.
- Huber T.S.
- et al.
Editor's Choice – Protamine reduces serious bleeding complications associated with carotid endarterectomy in asymptomatic patients without increasing the risk of stroke, myocardial infarction, or death in a large national analysis.
Eur J Vasc Endovasc Surg. 2020; 60: 800-807
4
However, return to theatre after CEA is associated with significant consequences, including a sevenfold increase in MI, an eightfold increase in stroke, and a 13 fold increase in death.3
Patients with NH not needing to return to theatre still have an increased length of hospital stay. Both meta-analyses showed significantly reduced incidence of wound haematoma requiring return to theatre without increasing procedural stroke risk, but both were limited by a lack of randomised prospective data. Despite the European of Society of Vascular Surgery Carotid Guidelines- Stone D.H.
- Giles K.A.
- Kubilis P.
- Suckow B.D.
- Goodney P.P.
- Huber T.S.
- et al.
Editor's Choice – Protamine reduces serious bleeding complications associated with carotid endarterectomy in asymptomatic patients without increasing the risk of stroke, myocardial infarction, or death in a large national analysis.
Eur J Vasc Endovasc Surg. 2020; 60: 800-807
5
recommendation that protamine “should be considered” to reduce NH requiring re-exploration, its use has not been adopted widely. This is, in part, due to historical data from underpowered studies implying an increased risk of thrombotic complications and protamine’s undesirable haemodynamic side effects.A prospective online survey was undertaken to capture current UK practice of protamine use in theatre for patients undergoing CEA. It was distributed to consultant surgeons via email through the Vascular Society of Great Britain and Ireland and to trainees through the Rouleaux Club via social media. Data were collected over a four week period in July 2021.
There were 205 responses: 84% from consultant surgeons, 12% from surgical trainees, and 4% from other grades and consultant anaesthetists. For consultant surgeons there was a 38% response rate. Overall, 51% stated they never used protamine, 39% use it occasionally, and 10% use routinely. When looking at responses by grade, more consultants never used protamine (53% vs. 42%) than trainees, but trainees were more likely to use it occasionally (54% vs. 34%).
Of those who do not use it routinely, 35% were concerned about the risk of stroke, 12% about the risk of MI, and 10% about other side effects, including anaphylaxis and haemodynamic instability. When stratified by grade, consultants were less worried about stroke (34% vs. 43%) but more concerned about MI (12% vs. 9%) than trainees. Thirty-one per cent of respondents stated that there was no indication for its use. Fifty-two per cent of respondents stated that they would use protamine in CEA if there was strong evidence regarding its safety, with 46% supporting a randomised trial to investigate.
Contemporary data from the USA suggests that 50% of surgeons there use protamine routinely.
3
This contrasts with the finding that only 10% of UK surgeons use it. Historical reports of increased rates of post-operative stroke, MI, and death with protamine use have since been partially alleviated with large registry analyses, demonstrating that protamine reduces bleeding complications without increasing morbidity or mortality.- Stone D.H.
- Giles K.A.
- Kubilis P.
- Suckow B.D.
- Goodney P.P.
- Huber T.S.
- et al.
Editor's Choice – Protamine reduces serious bleeding complications associated with carotid endarterectomy in asymptomatic patients without increasing the risk of stroke, myocardial infarction, or death in a large national analysis.
Eur J Vasc Endovasc Surg. 2020; 60: 800-807
3
,- Stone D.H.
- Giles K.A.
- Kubilis P.
- Suckow B.D.
- Goodney P.P.
- Huber T.S.
- et al.
Editor's Choice – Protamine reduces serious bleeding complications associated with carotid endarterectomy in asymptomatic patients without increasing the risk of stroke, myocardial infarction, or death in a large national analysis.
Eur J Vasc Endovasc Surg. 2020; 60: 800-807
4
However, this survey suggests that a perceived increased risk of stroke remains prevalent among UK vascular surgeons. Despite literature demonstrating that NH occurs at a rate of 8% – 15%, 30% of respondents stated there was no indication for protamine use in CEA, citing personal rates of post-operative bleeding.Protamine is often given matching the initial heparin dose 1:1, not considering drug half life or individual variations in its metabolism. Some institutions use intra-operative coagulation assessment with activated clotting time, or similar, alongside clinical judgement and patients’ pre-operative antiplatelet regimen. Besides emphasising undesirable effects, such as haemodynamic instability, overdosing protamine is known to lead to impaired coagulation, potentially compounding any existing bleeding.
6
Heparin reversal adjusted to the amount remaining in circulation at the time of application can help to overcome this undesirable effect. A large, randomised trial in cardiac surgery suggests that using a specific algorithm to determine optimal protamine dosing is a safe intervention that leads to superior coagulation compared with standard 1:1 dosing.7
Applying this algorithm to CEA patients may reduce bleeding complications and mitigate protamine side effects.There is recent observational, retrospective evidence that heparin reversal with protamine after CEA reduces the incidence of NH without increasing the risk of complications.
3
Despite this, the present survey of UK vascular surgeons highlights large variation in practice. It is proposed that the lack of randomised studies in this field is likely to halt routine adoption of protamine use in CEA and that a large pragmatic randomised controlled trial is the only reliable way to assess its clinical effectiveness.- Stone D.H.
- Giles K.A.
- Kubilis P.
- Suckow B.D.
- Goodney P.P.
- Huber T.S.
- et al.
Editor's Choice – Protamine reduces serious bleeding complications associated with carotid endarterectomy in asymptomatic patients without increasing the risk of stroke, myocardial infarction, or death in a large national analysis.
Eur J Vasc Endovasc Surg. 2020; 60: 800-807
References
- Use of Protamine for anticoagulation during carotid endarterectomy: a meta-analysis.JAMA Surg. 2016; 151: 247-255
- Protamine reduces bleeding complications without increasing the risk of stroke after carotid endarterectomy: a meta-analysis.Eur J Vasc Endovasc Surg. 2016; 52: 296-307
- Editor's Choice – Protamine reduces serious bleeding complications associated with carotid endarterectomy in asymptomatic patients without increasing the risk of stroke, myocardial infarction, or death in a large national analysis.Eur J Vasc Endovasc Surg. 2020; 60: 800-807
- Shared quality data are associated with increased protamine use and reduced bleeding complications after carotid endarterectomy in the Vascular Study Group of New England.J Vasc Surg. 2013; 58: 1518-1524
- Editor's Choice – Management of atherosclerotic carotid and vertebral artery disease: 2017 Clinical Practice Guidelines of the European Society for Vascular Surgery (ESVS).Eur J Vasc Endovasc Surg. 2018; 55: 3-81
- Anticoagulant and side-effects of protamine in cardiac surgery: a narrative review.Br J Anaesth. 2018; 120: 914-927
- Optimal protamine dosing after cardiopulmonary bypass: the PRODOSE adaptive randomised controlled trial.PLoS Med. 2021; 18e1003658
Article info
Publication history
Published online: February 17, 2022
Accepted:
January 9,
2022
Received:
October 11,
2021
Identification
Copyright
© 2022 European Society for Vascular Surgery. Published by Elsevier B.V. All rights reserved.
User license
Elsevier user license | How you can reuse 
Elsevier's open access license policy
Elsevier user license
Permitted
For non-commercial purposes:
- Read, print & download
- Text & data mine
- Translate the article
Not Permitted
- Reuse portions or extracts from the article in other works
- Redistribute or republish the final article
- Sell or re-use for commercial purposes
Elsevier's open access license policy
ScienceDirect
Access this article on ScienceDirectLinked Article
- Protamine In Carotid Surgery: the Advantages Outweigh the DisadvantagesEuropean Journal of Vascular and Endovascular SurgeryVol. 64Issue 1
- PreviewThis study by Singh et al.1 indicates that I am one of only 10% who employ routine heparin reversal with protamine. Despite high level evidence supporting its use,2,3 and vascular surgery being a highly evidence based specialty,4 many seemingly ignore the evidence, letting possibly unfounded concerns override an analytical approach. These also arise from anaesthetists (the survey could have included them too), and despite concerns regarding anaphylaxis (more appropriately massive histamine release, minimised by avoiding injections via central lines),5 the risks are miniscule.
- Full-Text
- Preview
Related Articles
Comments
Commenting Guidelines
To submit a comment for a journal article, please use the space above and note the following:
- We will review submitted comments as soon as possible, striving for within two business days.
- This forum is intended for constructive dialogue. Comments that are commercial or promotional in nature, pertain to specific medical cases, are not relevant to the article for which they have been submitted, or are otherwise inappropriate will not be posted.
- We require that commenters identify themselves with names and affiliations.
- Comments must be in compliance with our Terms & Conditions.
- Comments are not peer-reviewed.
