Importantly, the benefit of SIAC to arterial repair patency did not appear to come at the expense of increased bleeding complications. There was no increase in the return to operative suite rate for bleeding (SIAC, 3.9% vs. no SIAC, 6.5%, p = 0.29) or overall bleeding complications (SIAC, 3.9% vs. no SIAC, 10.1%, p = 0.03) in those administered SIAC. Patients with torso injuries (OR 3.5, 95% CI 1.5–8.3, p = 0.005) or those treated with postoperative anticoagulation (OR 3.4, 95% CI 1.5–7.6; p = 0.003) were more likely to have bleeding complications when controlling for age, ISS, admission hemodynamics, anatomic location of arterial injury, postoperative anticoagulation, and SIAC (Table 5). However, SIAC was not independently associated with bleeding complications when controlling for these factors (p = 0.31).
The most important finding of this multi-institution study is that the use of systemic heparin during the operative repair of arterial injuries leads to improved short-term arterial patency without an associated increase in bleeding complications. We believe that these findings should embolden surgeons tasked with repairing arterial injuries to consider more liberal use of SIAC.
The discovery, purification, and application of heparin in peripheral vascular surgery revolutionized the field.1,2,13,14 Thrombus formation along suture lines and areas of stasis because of large amounts of tissue thromboplastin and other procoagulant factors could now be countered, allowing bypass grafts to remain patent.4,15 Subsequently, intraoperative systemic heparinization during arterial reconstruction was nearly universally accepted without challenge, as evidenced by the lack of prospective, randomized, controlled trials evaluating its use in this context to date.6,15–17
Many developments in the field of vascular surgery have been driven by elective peripheral vascular surgery and subsequently evaluated in the setting of vascular trauma. Literature focused on factors influencing vascular bypass patency infrequently consider the impact of SIAC and instead have focused largely on the use of antiplatelet agents,18–25 as systemic heparinization is nearly universally accepted in peripheral vascular surgery. However, the frequency of SIAC application in vascular trauma is unclear. In the current series, only 47.7% of patients with operative arterial injuries received SIAC, including the cohort of patients with isolated lower extremity arterial injury in which a mere 62.9% received SIAC. However, those patients seemed to clearly benefit from the anticoagulation, as our multivariate logistic regression model demonstrated patients repaired with SIAC were 2.6 times more likely to maintain arterial patency when other potential risk factors were controlled.
Although SIAC is not uniformly evaluated as a factor contributing to patency rates, several publications have supported its use. Melton et al. found that intraoperative use of systemic heparin or local urokinase was the only directly controllable factor associated with limb salvage in a study of 102 patients with popliteal artery injuries.26 Guerrero et al. also evaluated the factors associated with limb salvage in patients with lower extremity arterial injuries. The investigators found an increase in limb salvage without a concomitant increase in bleeding complications associated with the use of intraoperative anticoagulation.7 These authors therefore advocated for the use of systemic anticoagulation to maximize limb salvage during the repair of popliteal artery injuries.
Although arterial patency was improved with the use of SIAC in the current series, we were unable to demonstrate an improvement in limb salvage rates with the use of SIAC. Our study sample though was composed of arterial injuries of varied anatomic locations, not entirely the high-risk popliteal area. Unlike the isolated popliteal artery literature, our cohort was mixed, including patients with amputations following injuries to the iliac, femoral, popliteal, and axillary arteries, in which arterial patency was likely not the only factor influencing limb salvage. Other factors, such as degree of soft tissue injury, delayed compartment syndrome, infection, and the effects of concomitant injury are often difficult to capture in a retrospective analysis. Importantly, although we demonstrated only a possible “trend” toward improved limb salvage rates in patients who underwent arterial repair with SIAC (p = 0.16), we did demonstrate an improvement in arterial patency and, in turn, patients with patent repairs less often returned to the operative suite and had shorter ICU and hospital LOS.
Although we have demonstrated that arterial repair with SIAC is associated with improved arterial patency, associated bleeding risks may limit its applicability in the trauma population. The bleeding risk attributable to full-dose anticoagulation has been most fully evaluated in the medical population and is estimated between 0 and 44%.27–31 These rates reflect patients who are primarily on long-term anticoagulation for indications including venous thromboembolic disease, atrial fibrillation, valvular pathology, ischemic stroke, and acute coronary syndrome. The patient population represented in these medical reports is older and more often with significant comorbidities than the young trauma population.27 According to the CHEST guidelines, the risk of bleeding associated with intravenous unfractionated heparin in patients with acute venous thromboembolism is <3% in recent trials, but the risk is increased in patients >70 years of age and in those with baseline renal insufficiency.32 The mean age of our study sample patients was 30.8, and rates of preexisting renal insufficiency are presumably quite low.
Unlike the anticoagulated medical patient population, the elective vascular surgery population has the added risk factor for bleeding from an operative field. Although this would suggest that there should be higher rates of bleeding, several studies on the topic have failed to substantiate this risk.17 The traumatic arterial injury cohort has an additional risk factor for bleeding in the presence of associated injuries, at times spanning multiple body cavities. In our study population, each of the 323 patient study sample had associated injuries. Despite this, we did not detect any increase in the rate of postoperative bleeding complications requiring intervention, including blood transfusion or return to the operating room for patients with associated injuries.
Although SIAC was not related to any measured bleeding complication in our analysis, multivariate logistic regression modeling did determine that patients with arterial injuries of the torso were more likely to have bleeding complications than those of other injured anatomic areas. Caution and careful intraoperative surgical decision-making before utilizing SIAC in this setting seems prudent. It is likely that the good judgment of the operating surgeon contributed to the decision not to use SIAC in this cohort of patients.
In addition, it is likely that this very same good judgment led to the observed differences between the cohort of patients receiving SIAC and those not receiving SIAC. On the basis of the increased ISS, ICU, and hospital LOS in the no SIAC cohort, it is possible that those patients not given SIAC were at higher baseline risk of bleeding complications.
Conversely, patients with isolated lower extremity arterial injuries often have minimal risk for bleeding after SIAC. In the current series, only 62.9% of patients in this particular low-risk subset were given SIAC. These and other injured patients with limited bleeding risk then offer a potential opportunity to improve clinical care and outcomes in patients with operative vascular injuries. Sound surgical judgment and proper patient selection is critical to the appropriate application of SIAC.
We acknowledge our study limitations. Limitations to this study include the retrospective nature of this report and potential limitations inherent to this study design. The decision to utilize SIAC was left to the discretion of the operating surgeon, not a study-defined protocol. As such, an unmeasured study bias may exist. Our analysis was also restricted to the use of SIAC defined as systemic heparinization. As such, we did not evaluate the potential impact that regional heparin administration had on the outcomes of interest. Finally, we did not evaluate the intraoperative anticoagulant effect of SIAC with either thromboelastography or laboratory values. Trauma patients may present with trauma-induced coagulopathy, which manifests in hypocoaguable or hypercoagulable states.33 A future prospective study that includes functional coagulation assays upon both presentation and operative repair would further the evidentiary basis for patient selection for SIAC administration during arterial repairs.
Patients who underwent operative repair of arterial injuries utilizing SIAC appear to have better arterial patency without additional bleeding complications as compared to those repaired without SIAC. Our data suggest that (1) SIAC may improve arterial patency rates after operative vascular injury and (2) the attributable bleeding risk of SIAC may be overstated. Despite these suggestions, the safe application of SIAC relies on sound clinical judgment and the utilization in the right clinical scenario. Further investigation to clarify the patient population in whom these findings apply.
Z.M., N.S., J.W.C., and M.J.S. designed this study. Z.M. and N.S. conducted the literature search. Z.M., B.F., N.S., A.G., E.D., J.P.H., and A.L. contributed to data collection. All authors participated in data analysis. Z.M., B.F., A.G., E.D., J.P.H., A.L., H.Z., J.W.C., and M.J.S. performed data interpretation. Z.M. and M.J.S. wrote the manuscript, which all authors critically revised.
The authors declare no conflicts of interest.
1. Howell WH. Two new factors in blood coagulation—heparin and proantithrombin. Am J Physiol
2. Murray DWG. Heparin in surgical treatment of blood vessels. Arch Surg
3. Assadian A, Senekowitsch C, Assadian O, Eidher U, Hagmüller GW, Knöbl P. Antithrombotic strategies in vascular surgery: evidence and practice. Eur J Vasc Endovasc Surg
4. Clagett GP. Vascular Surgery: Theory and practice. Callow AD, Ernst CB, eds. 1995. Stamford, CT: Appleton and Lange. Chapter 59. Thrombosis and Antithrombotic Therapy; pp. 817–845.
5. Goodman MC. Vascular trauma. Rich NM, Spencer FC, eds. 1978. Philadelphia: Holt–Saunders. Chapter 5. Management of Acute Arterial Injuries; pp. 75–105.
6. Wiersema A, Jongkind V, Bruijninckx C, Reijnen M, Vos J, Van Delden O, Zeebregts C, Moll F. Prophylactic intraoperative antithrombotics in open infrainguinal arterial bypass surgery: a systematic review. J Cardiovasc Surg (Torino)
7. Guerrero A, Gibson K, Kralovich KA, Pipinos I, Agnostopolous P, Carter Y, Bulger E, Meissner M, Karmy-Jones R. Limb loss following lower extremity arterial trauma: what can be done proactively? Injury
8. Fox N, Rajani RR, Bokhari F, Chiu WC, Kerwin A, Seamon MJ, Skarupa D, Frykberg E. Eastern Association for the Surgery of Trauma. Evaluation and management of penetrating lower extremity arterial trauma: an eastern association for the surgery of trauma practice management guideline. J Trauma Acute Care Surg
9. DuBose JJ, Savage SA, Fabian TC, Menaker J, Scalea T, Holcomb JB, Skarupa D, Poulin N, Chourliaras K, Inaba K, et al. The american association for the surgery of trauma PROspective observational vascular injury treatment (PROOVIT) registry: multicenter data on modern vascular injury diagnosis, management, and outcomes. J Trauma Acute Care Surg
. 2015;78:215–222; discussion 222–3.
10. Shireman PK, Rasmussen TE, Jaramillo CA, Pugh MJ. VA Vascular Injury Study (VAVIS): VA-DoD extremity injury outcomes collaboration. BMC Surg
11. Klocker J, Bertoldi A, Benda B, Pellegrini L, Gorny O, Fraedrich G. Outcome after interposition of vein grafts for arterial repair of extremity injuries in civilians. J Vasc Surg
12. Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture (REDCap)—a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform
13. Murray G, Janes JM. Prevention of acute failure of circulation following injuries to large arteries. Experiments with glass cannulae kept patent by administration of heparin. Br Med J
14. Charles AF, Scott DA. Studies on heparin: observations on the chemistry of heparin. Biochem J
15. Collins GJ Jr, Kimball DB, Rich NM, Andersen CA, McDonald PT. Heparin utilization during arterial revascularization. Am J Surg
16. Effeney DJ, Goldstone J, Chin D, Krupski WC, Ellis RJ. Intraoperative anticoagulation in cardiovascular surgery. Surgery
17. Quigley FG, Jamieson GG, Lloyd JV, Faris IB. Monitoring of heparin in vascular surgery. J Vasc Surg
18. Bedenis R, Lethaby A, Maxwell H, Acosta S, Prins MH. Antiplatelet agents for preventing thrombosis after peripheral arterial bypass surgery. Cochrane Database Syst Rev
19. Belch JJ, Dormandy J, Biasi GM, Cairols M, Diehm C, Eikelboom B, Golledge J, Jawien A, Lepäntalo M, et alCASPAR Writing Committee. Results of the randomized, placebo-controlled clopidogrel and acetylsalicylic acid in bypass surgery for peripheral arterial disease (CASPAR) trial. J Vasc Surg
. 2010;52:825–833, 833.e1-2.
20. Gassman AA, Degner BC, Al-Nouri O, Philippi L, Hershberger R, Halandras P, Aulivola B, Milner R. Aspirin usage is associated with improved prosthetic infrainguinal bypass graft patency. Vascular
21. Geraghty AJ, Welch K. Antithrombotic agents for preventing thrombosis after infrainguinal arterial bypass surgery. Cochrane Database Syst Rev
22. Hafez HM, Woolgar J, Robbs JV. Lower extremity arterial injury: results of 550 cases and review of risk factors associated with limb loss. J Vasc Surg
23. Harris DG, Drucker CB, Brenner ML, Narayan M, Sarkar R, Scalea TM, Crawford RS. Management and outcomes of blunt common and external iliac arterial injuries. J Vasc Surg
24. Clagett GP, Sobel M, Jackson MR, Lip GY, Tangelder M, Verhaeghe R. Antithrombotic therapy in peripheral arterial occlusive disease: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest
. 2004;126(Supp. 3):609S–626S.
25. Watson HR, Belcher G, Horrocks M. Adjuvant medical therapy in peripheral bypass surgery. Br J Surg
26. Melton SM, Croce MA, Patton JH, Pritchard FE, Minard G, Kudsk KA, Fabian TC. Popliteal artery trauma. systemic anticoagulation and intraoperative thrombolysis improves limb salvage. Ann Surg
. 1997;225:518–527; discussion 527–9.
27. Cossette B, Pelletier ME, Carrier N, Turgeon M, Leclair C, Charron P, Echenberg D, Fayad T, Farand P. Evaluation of bleeding risk in patients exposed to therapeutic unfractionated or low-molecular-weight heparin: a cohort study in the context of a quality improvement initiative. Ann Pharmacother
28. Hylek EM, Regan S, Henault LE, Gardner M, Chan AT, Singer DE, Barry MJ. Challenges to the effective use of unfractionated heparin in the hospitalized management of acute thrombosis. Arch Intern Med
29. Levine MN, Raskob G, Landefeld S, Kearon C. Hemorrhagic complications of anticoagulant treatment. Chest
30. Niccolai CS, Hicks RW, Oertel L, Francis JL. Heparin Consensus Group. Unfractionated heparin: focus on a high-alert drug. Pharmacotherapy
. 2004;24(8 Pt 2):146S–155S.
31. Zidane M, Schram MT, Planken EW, Molendijk WH, Rosendaal FR, van der Meer FJ, Huisman MV. Frequency of major hemorrhage in patients treated with unfractionated intravenous heparin for deep venous thrombosis or pulmonary embolism: a study in routine clinical practice. Arch Intern Med
32. Schulman S, Beyth RJ, Kearon C, Levine MN. American College of Chest Physicians. Hemorrhagic complications of anticoagulant and thrombolytic treatment: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest
33. Park MS, Xue A, Spears GM, Halling TM, Ferrara MJ, Kuntz MM, Dhillon SK, Jenkins DH, Harmsen WS, Ballman KV, et al. Thrombin generation and procoagulant microparticle profiles after acute trauma: a prospective cohort study. J Trauma Acute Care Surg
Dr. Ian Civil (Auckland, New Zealand): I appreciate the opportunity to discuss this paper which is the second on this program at this meeting addressing heparin and vascular trauma. And for those of you who heard the earlier paper, the results seem in contradistinction to that.
Despite the scientific basis of modern medicine there are still many aspects where practice is based on tradition. And the use of heparin in acute vascular trauma is one of these.
All trauma and vascular surgeons are caught by the conundrum that while it is likely that heparin will be helpful in preventing thrombosis in the vascular system, the risks of bleeding in other injured areas, particular the brain and solid organs, may make its use counterproductive.
Vascular trauma is relatively uncommon and this retrospective cohort study only managed to amass 323 patients over nine years in three Level I trauma centers, which speaks to the difficulty in addressing the underlying question.
In addition, the difference between a severe blunt injury with a popliteal artery disruption, a gunshot wound to the abdomen with multiple visceral and solid organ injuries, as well as an iliac artery injury, and a patient who simply puts their arm through a plate glass window and lacerates the brachial artery are so great that it’s hard to see how these can be studied collectively.
Nevertheless, the authors combined these groups and had equal numbers in those receiving heparin and those not. There was a small but statistically significant improvement in patency rates in those receiving heparin and no increase in return to the operating room for bleeding.
So does this mean it’s safe and beneficial for everyone to receive heparin? I suspect not. It may well be, given the small numbers, that despite the apparent statistical similarity between the groups given heparin and those not, the heparin group were, in fact, in some way less injured and the heparin did help patency without the penalty of increased bleeding.
The result probably means the clinicians finely judged the safety of giving heparin and managed to give it in situations where it did not actually result in the return to the operating room at a small patency advantage.
The statistics in small patient numbers like this are always going to be complex and I suspect that maybe some of the non-significant results are so just because of small numbers.
I have three questions.
Firstly, was there any difference in outcome between those who were repaired or reconstructed with vein versus prosthetic?
Secondly, what dose of heparin was given on average? Was it likely to be that necessary to therapeutically anticoagulate the patient or was it less than that given in the elective setting, recognizing the potential for bleeding at other sites?
And, thirdly, this study focused on patients getting operative intervention but we know nowadays with our common investigations we find a lot of patients who have vascular injury that don’t need operative intervention but, nonetheless, may need or may benefit from anticoagulation. Do you have plans to study that group or can you make any comments on that group from the work that you’ve done?
Thank you for a nice presentation of a challenging clinical issue and I thank the Association for the privilege of being able to discuss this paper.
Dr. Anthony A. Meyer (Chapel Hill, North Carolina): I enjoyed the paper. I think the comment or evidence that you can’t fear giving systemic heparin in a significant arterial injury— but I think, as was pointed out by Dr. Civil, the frequency of these injuries is not so great that you can rely on a series of 500 to tell you what to do.
This is really where judgment and experience comes in to know which patient might not get systemic heparin but, again, not to fear giving it when it seems to be appropriate with an isolated or largely isolated vascular injury.
Dr. Ronald I. Simon (Brooklyn, New York): I enjoyed the paper. I’m just wondering if there isn’t a real selection bias in how you are looking at things.
In my experience with vascular surgeons and vascular repairs, the vascular repairs that look really good after they’re done don’t get anticoagulation. The ones where they say, “I don’t know whether this is going to stay open,” those are the ones that get post-operative anticoagulation. How did you control for that?
Dr. Scott d’Amours (Sydney, Australia): Thank you, I enjoyed your presentation. I’m just wondering if any of the patients in either group received other forms of perioperative (pre- or post-operative) anticoagulation, fractionated or unfractionated heparin, or antiplatelet therapy. These other forms could impact your results significantly.
Dr. Zoe Maher (Philadelphia, Pennsylvania): Thank you for your insightful comments and, Dr. Civil, I appreciate the review.
Regarding the first question on the outcomes between vein and prosthetic graft, we did look at that. Again, many of you have touched on the issue of when the N is so low it’s very difficult to make conclusions that are valid in these kind of analyses.
Looking at those two groups there was no difference in patency rate. There was no difference in the utilization of systemic intraoperative anticoagulation between those two groups. But, again, the numbers in each group are fairly small and I would be hesitant to make any strong suggestions based on that data.
Regarding the dosing of heparin, unfortunately, this is the problem with a retrospective cohort review. We build a dataset, we collect a ton of variables and then you get to the end and you wish you had more. And that is one of the variables that I wish we had collected. We did not.
I will say based on the experience at our institution our vascular surgeons when they are involved in repairs tend to give the standard dosing that they give during elective vascular surgery; but there were several patients in the cohort who actually received infusions.
It was a very small number of patients who did not actually get bolus. So there is some variability in the application certainly in the trauma patient population.
And then regarding the need to investigate the non-operatively managed vascular injured patient, we did not collect any data on that, though we have a consortium now in Philadelphia and I think that would be an excellent next project for us. Thank you for the suggestion.
Regarding the issue of judgment and experience, I couldn’t agree more. As someone with a fairly small number of years of experience and lots of people around me with great judgment, certainly we rely on that to figure out which patients should be heparinized and which should no.
What I found really fascinating was that when we looked at the population of patients who had isolated lower extremity injuries with or without fracture, with or without associated significant injuries, the rates of utilization of heparin is still extremely low. In fact, only 70% of patients with isolated lower extremity injury who underwent bypass were heparinized.
So I would say that there is actually a real opportunity, at least amongst our institutions, to sort of more liberally utilize heparin in the patient population that’s fairly low-risk for bleeding, which I would consider the isolated, lower-extremity injured patient to be.
Regarding the issue of selection bias and the use of postoperative anticoagulation, surely this is true. This is a very, very complex issue. And there are lots of things that can induce a selection bias in patients like this.
We did, during our multivariate logistic regression, including postoperative anticoagulation as a factor that was controlled for and, therefore, I feel confident that systemic anticoagulation use was, in fact, a significant difference.
And, then, finally, regarding the use of perioperative anticoagulants, including therapeutic and a prophylactic dose as well as aspirin, we did look at that. Actually, 50% of patients in the patent group received postoperative aspirin and 35% in the failure of patency received postoperative aspirin.
I have to go back to the data to really elucidate the timing of that because presumably in a patient who has arterial thrombosis early-on and has either a revision or a ligation as their ultimate outcome, there may be no need for postoperative aspirin. So I will have to look at that for the manuscript.
I thank you very much.