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The incidence of thromboembolism formation following the use of recombinant factor VIIa in patients suffering blunt force compared to penetrating trauma: a systematic review protocol

Source:

JBI Evidence Synthesis

February 2015, Volume :13 Number 2 , page 125 - 135 [Free]

Authors

  1. Bonanno, Laura DNP, CRNA
  2. Badeaux, Jennifer DNP, CRNA
  3. Devlin, Raymond MSN, CRNA

Abstract

Review question/objective: This review aims to identify the incidence of thromboembolism formation in patients suffering traumatic injuries after receiving recombinant factor VIIa (rFVIIa).

 

To achieve this objective, the following question will be addressed.

 

In both civilian and combat trauma patients 15 years or older that have received intravenous recombinant factor VIIa (rFVIIa), is there a difference in the incidence of thromboembolism formation between injuries sustained from blunt force trauma compared to injuries sustained from penetrating trauma?

 

Background: During the first hours of trauma resuscitation and surgery, early control of hemorrhage is critical for patient survival. In a retrospective study by Hoyt et al.1 involving eight academic trauma centers, uncontrolled hemorrhage accounted for death in 82% of those patients studied.1 Rapid replacement of blood loss can be challenging during times when the demand for blood products exceeds the supply. This situation often occurs during mass casualty scenarios as a result of civilian disaster situations and military combat operations. As available blood supplies are overwhelmed, other interventions have shown promise.

 

Factor VII plays an important role in activating the extrinsic clotting cascade, in turn promoting hemostasis. When Factor VII combines with tissue factor it becomes activated. The resulting combination enhances the formation of thrombin on the surface of platelets thus forming an effective hemostatic bond.2 The recombinant form of FVII has been considered a treatment for hemophilia for over 30 years when it first demonstrated promise for its hemostatic effects.2 Today, recombinant factor VIIa (rFVIIa) is used under certain conditions as a treatment for uncontrolled hemorrhage in surgical trauma patients. It must be noted that the use of rFVIIa is only approved by the United States Food and Drug Administration (FDA) for use in certain patients suffering from hemophilia A and B. Any other use of rFVIIa would be considered an off-label use. The demonstrated safety of rFVIIa for off-label use in traumatic hemorrhage is most likely due to the localization of its effects at specific sites of vascular injury, in turn avoiding a systemic activation of the clotting cascade.3 This belief is not shared by all. When rFVIIa is activated it initiates the clotting cascade and at pharmacological doses, circulates at levels 1000 times greater than normal endogenous levels and a half-life that is considerably longer in duration.3

 

rFVIIa has recently been administered to injured military members in both Operation Iraqi Freedom and Operation Enduring Freedom. rFVIIa has also been used as an adjunct for hemorrhage control in civilian hospitals for patients suffering similar injuries. In both civilian and combat situations common injuries seen are blunt force trauma and penetrating wounds. During combat operations and mass casualty and stateside disasters, available blood supplies have often been depleted due to overwhelming numbers of casualties. This situation created the need for an effective hemostatic agent to assist in limiting the amount of blood products patients would require. Due to a constant threat of low supplies of banked blood products, many efforts have been made to develop blood substitutes. A blood substitute should be one that can be used safely especially during times of hemorrhage when banked blood products are not always immediately available.4 Although the use of rFVIIa has gained popularity, it is not without controversy as to the efficacy or potential side effects of its use.5 One such side effect to consider with regards to administering rFVIIa to surgical trauma patients is the risk of thromboembolism formation.

 

This use of rFVIIa in surgical trauma patients has shown promise in reducing the requirements of blood products needed but questions remain as to whether the risk of thromboembolism outweighs these benefits.6 This systematic review will review current research to determine if there is an increased risk of thromboembolism between two types of traumatic injuries: blunt force trauma and penetrating wounds. The target population consists of trauma patients ages 15 years and older, suffering blunt force trauma or penetrating wounds. Traumatic injuries most commonly affect patients bet ween the ages of 15 to 40 years.6 In this age group, uncontrolled bleeding is a leading cause of death due to those injuries.6

 

Interventions for this study include those patients suffering blunt force trauma and penetrating wounds that received rFVIIa as an adjunct to hemorrhage control measures. Both groups would have received standard resuscitation efforts consisting of varying amounts of packed red blood cells, fresh frozen plasma and platelets. The outcome of thromboembolism formation will be evaluated for both injury types, blunt force trauma and penetrating wounds.

 

In recent years rFVIIa has been the subject of scrutiny for its off-label use as an adjunct for uncontrolled hemorrhage. Although the use of rFVIIa has shown to be relatively safe, controversy and differing opinions exist over the concerns of thromboembolism formation.3 Although rFVIIa has a tendency to remain localized to areas of vascular insult, there may be an increase in thromboembolism formation when a patient suffers multiple sites of injury as seen in blunt force trauma. This systematic review will determine if there is a difference between the type of traumatic injury and the incidence of inadvertent thromboembolism formation. It is possible that rFVIIa may be best avoided in certain types of injuries.

 

Databases were searched to identify if any systematic reviews existed on the study of recombinant factor VIIa. Searches included both the Cochrane and JBI database. Search terms including recombinant factor VIIa (rFVIIa) revealed no published systematic reviews in both databases. An internet search did reveal a systematic review by Yank et al.7 Yank et al.7 performed a systematic review to evaluate the benefits and harms of off-label use of rFVIIa. In this study, the use of rFVIIa increased the incidence of thromboembolism for intracranial hemorrhage and cardiac surgery but not for body trauma.7 This study did not address whether there was a difference in the incidence of thromboembolism formation between the two types of injuries: blunt force trauma versus penetrating wounds.

 

Article Content

Inclusion criteria

Types of participants

This review will consider studies of participants who are:

 

1. 15 years and older

 

2. suffering blunt force trauma and penetrating trauma injuries, and

 

3. civilian and combat trauma injuries.

 

 

Patients suffering burn injuries, a combination of blunt force and penetrating trauma and those patients with a combination of blunt force trauma and penetrating trauma and those on pharmacological anticoagulation will be excluded from this review.

 

Types of intervention(s)/phenomena of interest

The incidence of thromboembolism formation associated with rFVIIa administration including:

 

1. control (non-rFVIIa) and rFVIIa in blunt force trauma populations

 

2. control (non-rFVIIa) and rFVIIa in penetrating trauma populations

 

3. in both control and rFVIIa, usual care will be administered to include packed red blood cells, fresh frozen plasma, platelets and crystalloid solutions.

 

 

Types of outcomes

Criteria used to determine a diagnosis of thromboembolism may differ based on varying guidelines. Criteria used in each study reviewed will be considered in an assessment of heterogeneity between studies.

 

Diagnosis of thromboembolism formation will be confirmed by the following:

 

Deep venous thrombosis (DVT)

 

1. high-sensitivity D-dimer assay

 

2. ultrasound.

 

 

Pulmonary embolism (PE)

 

1. ventilation-perfusion (V/Q) scan

 

2. computerized tomography (CT)

 

3. pulmonary angiography.

 

 

Types of studies

This review will consider both experimental and epidemiological study designs including randomized controlled trials, non-randomized controlled trials, quasi-experimental, before and after studies, prospective and retrospective cohort studies, case control studies and analytical cross sectional studies.

 

Search strategy

The search strategy aims to find both published and unpublished studies. A three-step search strategy will be utilized in this review. An initial limited search of Ovid MEDLINE and CINAHL will be undertaken followed by analysis of the text words contained in the title and abstract, and of the index terms used to describe article. A second search using all identified keywords and index terms will then be undertaken across all included databases. Thirdly, the reference list of all identified reports and articles will be searched for additional studies. Only studies published in English or available in English translation will be considered for inclusion in this review. If appropriate articles are located in other languages, authors will be contacted to identify if they are published in English. If unsuccessful, JBI resources will be contacted for assistance in translation. Studies published after June 1986 (the date of initial development of recombinant factor VIIa) will be considered for inclusion in this review.

 

The databases to be searched include:

 

CINAHL

 

PubMed

 

Web of Science

 

Embase

 

Cochrane Control Register of Clinical Trials

 

The search for unpublished studies will include:

 

Theses and dissertations; reports; non-independent research, or other documents produced and published by government agencies, academic institutions and other groups that are not distributed or indexed by commercial publishers; and unpublished scholarly papers. This search will include ProQuest Dissertations and Theses and http://www.clinicaltrials.gov.

 

Initial keywords to be used to develop full search strategies will be:

 

Assessment of methodological quality

Quantitative papers selected for retrieval will be assessed by two independent reviewers for methodological validity prior to inclusion in the review using standardized critical appraisal instruments from the Joanna Briggs Institute Meta-Analysis of Statistics Assessment and Review Instrument (JBI-MAStARI) (Appendix I). Any disagreements that arise between the reviewers will be resolved through discussion, or with a third reviewer.

 

Data collection

Quantitative data will be extracted from papers included in the review using the standardized data extraction tool from JBI-MAStARI (Appendix II). The data extracted will include specific details about the interventions, populations, study methods and outcomes of significance to the review question and specific objectives. Data will be extracted independently by primary (LB) and secondary (JB) reviewer independently before discussing or exchanging any opinions in order to facilitate accurate and reliable data entry. The authors of primary studies will be contacted for missing or unclear data.

 

Data synthesis

Experimental quantitative papers will be pooled in statistical meta-analysis using JBI-MAStARI. All results will be subject to double data entry. Effect sizes expressed as odds ratio and weighted mean differences and their 95% confidence intervals will be calculated for analysis. Heterogeneity will be assessed statistically using the standard Chi-square and also examined via subgroup analysis, for blunt force trauma and penetrating trauma populations, isolating the different degrees of traumatic injury sustained and the amount of blood products administered per patient, where possible. When statistical pooling is not possible, the findings will be presented in narrative form including tables and figures to aid in data presentation when appropriate.

 

Observational quantitative papers will be pooled in statistical meta-analysis using JBI-MAStARI. All results will be subject to double data entry. Effect sizes expressed as relative risk for cohort studies, odds ratios for case control studies, weighted mean differences for continuous data and their 95% confidence intervals will be calculated for analysis. A random effects model will be used and heterogeneity will be assessed statistically using the standard Chi-square. When statistical pooling is not possible the findings will be presented in narrative form including tables and figures to aid in data presentation when appropriate.

 

In the absence of any experimental or observational studies, descriptive findings will be considered. If needed, descriptive studies will be synthesized and presented in a tabular summary with the aid of narrative and figures when appropriate. If more than one study design was selected, the set text will change appropriately to reflect this broader inclusion.

 

When possible, study results will be pooled in statistical meta-analysis using either MAStARI or another method (such as RevMan) when MAStARI is inappropriate for the type of data being examined. All numeric outcome data will be double entered to prevent data entry errors. When statistical pooling is not possible the findings will be presented in a narrative summary.

 

Conflicts of interest

There are no conflicts of interest.

 

Acknowledgements

This review contributes to the Doctor of Nursing Practice degree award for Raymond Devlin.

 

References

 

1. Hoyt DB, Bulger EM, Knudson MM, Morris J, Ierardi R, Sugerman HJ, et al. Death in the operating room: An analysis of a multi-center experience. J Trauma. 1994 Sep;37(3):426-32. [Context Link]

 

2. Hedner U. Mechanism of action of factor VIIa in the treatment of coagulopathies. Semin Thromb Hemost. 2006 Apr;32 Suppl 1:77-85. [Context Link]

 

3. Roberts HR, Monroe DM,3rd, Hoffman M. Safety profile of recombinant factor VIIa. Semin Hematol. 2004 Jan;41(1 Suppl 1):101-8. [Context Link]

 

4. Nouwairi NS. The risks of blood transfusions and the shortage of supply leads to the quest for blood substitutes. AANA J. 2004 Oct;72(5):359-64. [Context Link]

 

5. Smith JE. The use of recombinant activated factor VII (rFVIIa) in the management of patients with major haemorrhage in military hospitals over the last 5 years. Emerg Med J. 2013 Apr;30(4):316-9. [Context Link]

 

6. Boffard KD, Riou B, Warren B, Choong PI, Rizoli S, Rossaint R, et al. Recombinant factor VIIa as adjunctive therapy for bleeding control in severely injured trauma patients: Two parallel randomized, placebo-controlled, double-blind clinical trials. J Trauma. 2005 Jul;59(1):8,15; discussion 15-8. [Context Link]

 

7. Yank V, Tuohy CV, Logan AC, Bravata DM, Staudenmayer K, Eisenhut R, et al. Systematic review: Benefits and harms of in-hospital use of recombinant factor VIIa for off-label indications. Ann Intern Med. 2011 Apr 19;154(8):529-40. [Context Link]

Appendix I: Appraisal instruments

MAStARI appraisal instrument[Context Link]

Appendix II: Data extraction instruments

MAStARI data extraction instrument[Context Link]

 

Keywords: Recombinant Factor VIIa; rVIIa; Factor VII; Factor VIIa; Thromboembolism; Trauma; Penetrating trauma; Blunt force trauma; Combat; Hemorrhage control

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