Journal of Clinical & Experimental Orthopaedics

Introduction

Cancellous bone bleeding (CBB) is a significant source of blood loss in orthopedic and other surgery involving bone. Large blood loss in orthopedic surgery has been associated with transfusion risk, sequelae of shock, coagulopathy, electrolyte abnormalities, disseminated intravascular coagulation, infection, hematoma and neurologic injury [1-8]. Current hemostatic methods either are ineffective or interfere with bone healing [9-14]. Commonly used xenograft gelatin-based hemostatic agents swell, which can cause neurologic injury, anaphylaxis or intravascular thrombosis [15-17]. Other agents utilizing gelatin or cellulose have been useful in vascular surgery [18].

A novel fibrin dressing (trade name SurgiClot) controls bleeding in a variety of tissues in preclinical animal studies, including arterial and bone bleeding [19-21]. We conducted a single-arm clinical study to determine its safety and efficacy on CBB in humans as a Phase I prelude to a Phase III controlled trial. This is a report of our findings.

Materials and Methods

This was a Level IV single-arm study of patients who met the inclusion eligibility criteria. Enrollment was consecutive and was conducted in 9 centers in the UK, Norway and India. The followup period was 6 weeks. Forty patients were enrolled in this study.

When confronted intraoperatively with significant cancellous bone bleeding, the surgeon identified the site as appropriate for testing the NFD. Severity of CBB was graded according to a standardized system developed by Renkens. Bleeding was graded as either pulsatile, flowing, oozing or none. The surgeon then applied the dressing directly to the bleeding site and applied slight manual pressure using a standard gauze sponge. After 3 min the gauze sponge was removed and the bleeding site was assessed for the presence of residual bleeding which was assessed using the same criteria. If bleeding persisted, a second dressing was applied for another 3 min and then the site was reassessed. If significant bleeding persisted the surgeon then used other means to control the bleeding and the dressing was considered a failure.

The primary endpoint was control of bleeding at 3 min. Secondary endpoints included control of bleeding at 6 min, as well as clinical and laboratory criteria. Treatment sites included posterior spinal fusion (PSF), iliac crest graft (ICG), and pelvic osteotomy (PO).

Patients were assessed clinically at 24 h and 6 weeks (for hematoma, allergic reaction, etc.) and with lab analysis, including complete blood count (CBC), pro-time (PT), activated partial thromboplastin time (aPTT) and international normalized ratio (INR). Surgeons completed a questionnaire regarding handling properties of the dressing.

Results

Thirty-eight of 40 patients completed the 6 week follow-up. Thirty-two PSF treatment sites were tested in 23 patients. Sixteen ICG treatment sites were tested in 14 patients. Three PO treatment sites were tested in 3 patients. The dressing was used at 2 anatomic sites in 11 of the 40 patients for a total of 51 treatment sites.

Of the 51 treatment sites, bleeding was controlled at 3 min in 41 (80.4%) and 6 min in 48 (94.1%). Nine of the 51 treatment sites required a second dressing application (17.6%) and a surgeon deviated from protocol on one patient who required a third application (2.0%) which controlled the bleeding. The second dressing application achieved hemostasis in 7 of the 9 sites (77.8%). Two sites required alternative treatment, but in total 49 of 51 (96%) bleeding sites were controlled with one or two dressing applications.

Interestingly, 100% of the secondary treatments sites (11/11) achieved hemostasis with a single dressing application at 3 min. Bleeding in all 3 of the PO patients, the most vigorous bleeding, was controlled with the dressing.

We saw no difference between pre-op and post-op protime (PT), activated partial thromboplastin time (aPTT) or international normalized ratio (INR) (Table 1).

Table 1: Analysis of pre-op and post-op PT, aPT and INR.

Adverse events (AE) considered by the Clinical Review Committee (CEC) to be “possibly device-related” occurred in 2 patients (10%). These included elevated ESR and eosinophilia in 1 patient, monocytosis in 1 patient, neutrophilia and monocytosis in 1 patient, and wound infection in 1 patient.

A further secondary endpoint was handling characteristics determined by the surgeons (Table 2).

Table 2: Characteristics determined by the surgeons.

Discussion

This feasibility study successfully demonstrated the efficacy and safety of this novel fibrin dressing.

We have shown it to be superior to a standard U.S. Army dressing in achieving hemostasis in arterial injuries in hypothermic, coagulopathic swine and it easily controlled bleeding cancellous bone in goats [19,20].

The surgeons participating in the present study were naive to the dressing yet were able to achieve 3 min hemostasis with one dressing application 80.4% of the time. They were able to achieve 3 min hemostasis 100% of the time upon treatment of subsequent different anatomic sites. Therefore, the learning curve is very short. Surgeons universally graded the dressing as either "as easy to use" or "easier to use" than currently available hemostatic products.

We believe it will have wide application in all surgical procedures involving bone and will help mitigate some of the complications and costs associated with blood loss in surgery where bone is cut, such as orthopedic surgery, spine surgery, cardiovascular surgery and head/neck surgery.

Since the dextran component quickly dissolves this dressing has the added advantage of leaving no residual foreign material. Pre-clinical safety studies have demonstrated inflammatory response comparable to controls with minimal foreign body reaction.

Conclusions

SurgiClot^® is efficacious and safe at controlling CBB in spine and pelvis procedures (PSF, ICG, PO). A global randomized, controlled FDA trial of the dressing on bleeding cancellous bone currently is underway.

Ethics Committee Approvals

1. Norway: REK (Regionale Komiteer for Medicinisk of Helsefaglig Forskningsetikk) 2015-1382-16.

2. United Kingdom: WoSRES (West of Scotland Research Ethics Service) 14/WS/1153.

3. India: STAR Hospitals Institutional Ethics Committee SH/EC/AX2/SOP02/V1.

References

1. Irita K (2011) Risk and crisis management in intraoperative hemorrhage: Human factors in hemorrhagic critical events. Korean J Anesthesiol 60: 151–160.
2. Browne JA, Adib F, Brown TE, Novicoff WM (2013) Transfusion rates are increasing following total hip arthroplasty: risk factors and outcomes. J Arthroplasty 28: 34–37.
3. Hu SS (2004) Blood loss in adult spinal surgery. Eur Spine J 13: S3–S5. 
4. Cha CW, Deible C, Muzzonigro T, Lopez-Plaza I, Vogt M, et al. (2002) Allogeneic transfusion requirements after autologous donations in posterior lumbar surgeries. Spine 27: 99–104.
5. Möller H, Hedlund R (2000) Instrumented and noninstrumented posterolateral fusion in adult spondylolisthesis--a prospective randomized study: part 2. Spine 25: 1716–1721.
6. Atwal NS, Bedi G, Lankester BJ, Campbell D, Gargan MF (2008) Management of blood loss in periacetabular osteotomy. Hip Int 18: 95–100.
7. Pulido LF, Babis GC, Trousdale RT (2008) Rate and risk factors for blood transfusion in patients undergoing periacetabular osteotomy. J Surg Orthop Adv 17: 185–187.
8. Dimitriou R, Mataliotakis GI, Angoules AG, Kanakaris NK, Giannoudis PV (2011) Complications following autologous bone graft harvesting from the iliac crest and using the RIA: a systematic review. Injury 42: S3–S15.
9. Lavigne M, Boddu Siva Rama KR, Doyon J, Vendittoli PA (2008) Bone wax granuloma after femoral neck osteoplasty. Can J Surg 51: 58–60.
10. Schonauer C, Tessitore E, Barbagallo G, Albanese V, Moraci A (2004) The use of local agents: bone wax, gelatin, collagen, oxidized cellulose. Eur Spine J 13: S89–S96.
11. Nelson DR, Buxton TB, Luu QN, Rissing JP (1990) The promotional effect of bone wax on experimental Staphylococcus aureus osteomyelitis. J Thorac Cardiovasc Surg 99: 977–980.
12. Nooh N, Abdullah WA, Grawish Mel-A, Ramalingam S, Javed F, et al. (2014) The effects of surgicel and bone wax hemostatic agents on bone healing: An experimental study. Indian J Orthop 48: 319–325.
13. Brodbelt AR, Miles JB, Foy PM, Broome JC (2002) Intraspinal oxidised cellulose (Surgicel) causing delayed paraplegia after thoracotomy--a report of three cases. Ann R Coll Surg Engl 84: 97–99.
14. Ibarrola JL, Bjorenson JE, Austin BP, Gerstein H (1985) Osseous reactions to three hemostatic agents. J Endod 11: 75–83.
15. Buchowski JM, Bridwell KH, Lenke LG, Good CR (2009) Epidural spinal cord compression with neurologic deficit associated with intrapedicular application of hemostatic gelatin matrix during pedicle screw insertion. Spine 34: 473–477.
16. Spencer HT, Hsu JT, McDonald DR, Karlin LI (2012) Intraoperative anaphylaxis to gelatin in topical hemostatic agents during anterior spinal fusion: a case report. Spine J 12: e1–e6.
17. Steinestel K, Geiger A, Naraghi R, Kunz U, Danz B, et al. (2013) Fatal thromboembolism to the left pulmonary artery by locally applied hemostatic matrix after surgical removal of spinal schwannoma: a case report. Hum Pathol 44: 294–298.
18. Janczak D, Rucinski A, Rucinska Z, Janczak D, Dorobisz K, et al. (2013) Modern topical hemostatic agents–a breakthrough in vascular surgery. Polim Med 43: 141-146.
19. Floyd CT, Rothwell SW, Martin R, Risdahl J, Olson CE (2012) A salmon thrombin-fibrinogen dressing controls hemorrhage in a swine model compared to standard koalin-coated gauze. J Spec Oper Med 12: 49–55.
20. Floyd CT, Rothwell SW, Risdahl J, Martin R, Olson C, et al. (2012) Salmon thrombin-fibrinogen dressing allows greater survival and preserves distal blood flow compared to standard kaolin gauze in coagulopathic swine with a standardized lethal femoral artery injury. J Spec Oper Med 12: 16–26.
21. Floyd CT, Padua RA, Olson CE (2017) Hemostasis and safety of a novel fibrin dressing versus standard gauze in bleeding cancellous bone in a caprine spine surgery model. Spine Deform 5: 310–313.