A multicentre, prospective, randomized, controlled study to evaluate the use of a fibrin sealant as an adjunct to sutured dural repair

Abstract

Background. Obtaining intra-operative watertight closure of the dura is considered important in reducing post-operative cerebrospinal fluid (CSF) leak. The purpose of this study was to evaluate a fibrin sealant as an adjunct to sutured dural repair to obtain intra-operative watertight closure in cranial neurosurgery. Methods. This randomized, controlled multicenter study compared a fibrin sealant (EVICEL^® Fibrin Sealant [Human]) to sutured dural closure (Control). Subjects underwent supratentorial or posterior fossa procedures. Following primary dural repair by sutures, the closure was evaluated for intra-operative CSF leak by moderately increasing the intracranial pressure. If present, subjects were randomized to EVICEL^® or additional sutures (2:1 ratio), stratified by surgical approach. Following treatment, subjects were successful if no CSF leaks were present during provocative challenge. Safety was assessed to 30 days post-surgery, including incidence of CSF leakage. Results. One hundred and thirty-nine subjects were randomized: 89 to EVICEL^® and 50 to Control. Intra-operative watertight closure was achieved in 92.1% EVICEL^®-treated subjects versus 38.0% controls; a treatment difference of 54.1% (p < 0.001). The treatment differences in the supratentorial and posterior fossa strata were 49.1% and 75.7%, respectively (p < 0.001). The incidence of adverse events was similar between treatment groups. No deaths or unexpected serious adverse drug reactions were reported. CSF leakage within 30 days post-operatively was 2.2% and 2.0% in EVICEL^® and control groups, respectively. In addition, 2 cases of CSF rhinorrhoea were observed in the EVICEL^® group. Although not associated with the suture line where EVICEL^® was applied, when combined with the other CSF leaks, the observed leak rate in the EVICEL^® group was 4.5%. Conclusions. These results indicate that EVICEL^® is effective as an adjunct to dural sutures to provide watertight closure of the dura mater in cranial surgery. The study confirmed the safety profile of EVICEL^®.

Keywords::

• cerebrospinal fluid leak
• dural repair
• fibrin sealant
• watertight dural closure

Acknowledgments

This clinical trial was conducted under the guidance of the following principal investigators, who participated in data collection for this study at 14 sites; A.L. Green (John Radcliffe Hospital, Oxford, UK), I. Whittle (Western General Hospital, Edinburgh, UK), S. Eljamel (Ninewells Hospital & Medical School, Dundee, UK), M. Mehdorn (University Clinics of Schleswig-Holstein, Kiel, Germany), U. Sure (Universitatsklinikum Essen, Essen, Germany), V. Sklencar (Klinikum Ingolstadt GmbH, Ingolstadt, Germany), S. Peerdeman (VU Medical Centre, Amsterdam, The Netherlands), F. Weyns (Ziekenhuis Oost Limburg, Genk, Belgium), D. Martin (CHU de Sart Tilman, Liege, Belgium), J. Ohman (Tampere University Hospital, Tampere, Finland), B. Vallee (CHU Lyon, Lyon France), H. Dufour (La Timone Adulte, Marseille, France), R. Assaker (CHU Lille, Lille France), and M. Murphy (St Vincent's Hospital, Victoria, Australia).

The authors acknowledge the contributions of Jessica Shen and Bob Patel (ETHICON, Somerville, USA), Ailie Smith and Christopher McEleney (Johnson & Johnson Medical, Livingston, UK). Support for the writing of the manuscript was provided by Gemma Brindley (Johnson & Johnson Medical, Livingston, UK).

Declaration of interest: The Sponsor company was ETHICON Inc (Somerville, New Jersey, USA), and was responsible for the initiation, management and financing the clinical trial. As employees of the Sponsor, Axel Arnaud, Jonathan Batiller and Judi Gauld were involved in the study design, study conduct, data analysis and reporting of the results as co-authors of the manuscript. As a consultant statistician paid by the company, Peter Jones conducted the statistical analyses and contributed as a co-author.

Alexander L. Green was the lead Investigator, involved in the protocol development, data interpretation and lead author. The following were all Investigators, who participated as authors in the review and approval of the manuscript: Sam Eljamel, Didier Martin, Maximilian Mehdorn, Juha Ohman and Frank Weyns. These authors were not compensated for their contributions to the writing of the manuscript. The authors declare no other conflict of interest.

Financial support

This study was sponsored by ETHICON.

Notice of correction

Following the initial online publication of the article (12th August 2014), the authors have requested some corrections, which have been incorporated into this final version of the article (30 September 2014).

1).	In Figure 1, the value for the ‘Per protocol control’ group has been corrected to n = 47 (was previously n = 50).
2).	The additional sentences “In addition, 2 cases of CSF rhinorrhoea were observed in the EVICEL® group. Although not associated with the suture line where EVICEL® was applied, when combined with the other CSF leaks, the observed leak rate in the EVICEL® group was 4.5%” have been added to the end of the Abstract-Results section.
3).	In the Abstract-Conclusions section, the following sentence has been corrected to read: “These results indicate that EVICEL® is effective as an adjunct to dural sutures to provide watertight closure of the dura mater in cranial surgery. The study confirmed the safety profile of EVICEL®.”
4).	In the Conclusion section, the following sentence has been corrected to read: “This study demonstrates that EVICEL® is highly effective as an adjunct to primary dural sutures to provide watertight closure of the dura mater. The study confirmed the safety profile of EVICEL®.”