Control of severe, life-threatening external bleeding in the out-of-hospital setting: Hemostatic dressings (FA 696): Systematic Review

Conflict of Interest Declaration

The ILCOR Continuous Evidence Evaluation process is guided by a rigorous ILCOR Conflict of Interest policy. The following Task Force members and other authors were recused from the discussion as they declared a conflict of interest: none applicable

The following Task Force members and other authors declared an intellectual conflict of interest and this was acknowledged and managed by the Task Force Chairs and Conflict of Interest committees: none applicable

CoSTR Citation

Charlton NP, Swain JM, Nieuwlaat R, Singletary EM, Zideman DA, Epstein JL, Bendall JC, Berry DC, Borra V, Carlson JN, Cassan P, Chang WT, Hood N, Markenson DS, Meyran D, Woodin JA, Sakamoto T, Lang E: Control of severe external bleeding in the out-of-hospital setting: Hemostatic dressings Consensus on Science with Treatment Recommendations [Internet] Brussels, Belgium: International Liaison Committee on Resuscitation (ILCOR) First Aid Task Force, 2019 December 20. Available from: http://ilcor.org

Methodological Preamble and Link to Published Systematic Review

The continuous evidence evaluation process for the production of the Consensus on Science with Treatment Recommendations (CoSTR) started with a systematic review of control of severe external bleeding in the out-of-hospital setting (22 March 2018, PROSPERO CRD42018091326) conducted by Evidence Prime, a Knowledge Synthesis Unit from Ontario, Canada with involvement of ILCOR First Aid Task Force clinical content experts. Evidence from adult and pediatric literature was sought and considered by the First Aid Task Force. Additional scientific literature published after the completion of the systematic review was identified by the content experts and incorporated into the CoSTR. These data were taken into account when formulating the Treatment Recommendations.

We included all studies from the out-of-hospital setting (direct evidence), as well as studies providing indirect evidence about the effects of interventions collected in combat (military) settings, simulations (i.e. human volunteers, human cadaver or other models excluding animal models), and studies performed in the hospital setting, that clinical content experts judged as were performed in sufficiently similar conditions to still be both relevant and informative. Bleeding from compressible and non-compressible external sites were included, except for epistaxis.

This CoSTR is one of four CoSTRs related to the systematic review completed by Evidence Prime on Control of Severe, Life-threatening Bleeding in the Out-of-Hospital Setting. This CoSTR specifically addresses use of hemostatic dressings compared with direct pressure or another type of hemostatic dressing. The other CoSTRs will be published separately on ILCOR.org/costr.

Systematic Review

PICOST

The PICOST (Population, Intervention, Comparator, Outcome, Study Designs and Timeframe)

Population: Adults and children with severe, life-threatening external bleeding in out-of-hospital settings. Bleeding from both compressible and non-compressible external sites were included.

Intervention: All bleeding control methods applicable for use by trained or untrained first aid providers including manufactured or improvised tourniquets, hemostatic dressings or agents, cryotherapy, direct (manual) pressure, pressure points, pressure dressings or bandages or elevation of the injured area. Manufactured tourniquets included windlass-style or elastic, with single or double application.

Comparators: Studies with comparators of bleeding control methods are included, as well as observational cohorts with a single bleeding control technique which in an observational meta-analysis may allow comparison of one technique against another.

Outcomes:

• Mortality due to bleeding (Critical)
• Cessation of bleeding / achieving hemostasis (Critical)
• Time to achieving hemostasis (Critical)
• Mortality from any cause (Important)
• Decrease in bleeding (Important)
• Complications/adverse effects (e.g. wound infection, limb loss, re-bleeding, pain related to an intervention) (Important)

Study Designs: Randomized controlled trials (RCTs) and non-randomized studies (non-randomized controlled trials, interrupted time series, controlled before-and-after studies, cohort studies) were eligible for inclusion.

Timeframe: All years and all languages were included as long as there was an English abstract; unpublished studies (e.g., conference abstracts, trial protocols) were excluded. Literature search updated to November 22, 2019.

PROSPERO Registration: CRD42018091326

Consensus on Science

Hemostatic dressings compared with direct pressure

For the critical outcome of cessation of bleeding, we identified very low certainty evidence (downgraded for serious risk of bias, indirectness, and imprecision) from one RCT{Hatamabadi 2015 e23862} that compared chitosan-coated gauze dressings with simple pressure dressing in 160 civilian casualties in the in-hospital setting. Hemostatic dressings showed no difference in outcome when compared with direct pressure alone as complete cessation of bleeding was achieved in all patients in both groups (80/80 compared with 80/80; RR not estimable).

We identified very low certainty evidence (downgraded for serious risk of bias, very serious indirectness, and serious imprecision) from two RCTs{Balzer 2007 693; Waragai 2011 262} in the in-hospital setting with a total of 141 participants who received treatment with a hemostatic dressing following an endovascular procedure. Due to heterogeneity these studies could not be combined for meta-analysis. The first RCT{Balzer 2007 693} found that 57/60 (95%) had cessation of bleeding with the use of a hemostatic dressing compared with 60/60 (100%) (RR, 0.95; 95% CI, 0.90-1.01; p = 0.24) with the use of manual compression. In the second RCT{Waragai 2011 262} the use of hemostatic dressings showed no difference in outcome when compared with the use of direct pressure alone as cessation of bleeding was achieved in all participants (8/8 compared with 13/13).

We identified very low certainty evidence (downgraded for serious risk of bias, very serious indirectness, and serious imprecision) from one cohort study{Tjiong 2012 88} in the in-hospital setting with a total of 88 participants who received treatment with a hemostatic dressing following an endovascular procedure. In this study the use of a hemostatic dressing showed no difference in outcome when compared with the use of direct pressure alone as cessation of bleeding was achieved in all participants.

For the critical outcome of time to hemostasis, we identified low certainty evidence (downgraded for serious risk of bias and indirectness) from one RCT{Hatamabadi 2015 e23862} with 160 civilian casualties in the in-hospital setting. This study showed a benefit with the use of hemostatic dressings as cessation of bleeding was achieved within 5 minutes in 41/80 (51.2%) participants receiving chitosan-coated gauze compared with 26/80 (32.5%) in participants receiving pressure dressings (RR, 1.58; 95% CI, 1.08-2.31).

We identified low certainty evidence (downgraded for very serious indirectness) from fourteen RCTs {Arbel 2011 1104; Balzer 2007 693; Behler 2009 159; Kang 2017 e0181099; Kordestani 2012 501; McConnell 2012 E1; Mlekusch 2006 23; Narins 2008 579; Nguyen 2007 801; Sairaku 2011 157; Schwarz 2009 53; Trabattoni 2012 53; Waragai 2011 262; Zhu 2010 582} in the in-hospital setting with a total of 2,419 participants undergoing endovascular procedures. These studies could not be combined due to heterogeneity but showed that the use of hemostatic dressings compared with direct pressure alone resulted in hemostasis in a range of 4.6-17.8 minutes with hemostatic dressings compared with 12.4-43.5 minutes with direct manual pressure. The range of mean differences among these studies ranged from 2.00 minutes (95% CI, 0.46 to 3.54) to 32.00 minutes (95% CI, 28.03 to 35.97).

For the important outcome of all-cause mortality, we identified very low certainty evidence (downgraded for serious risk of bias and imprecision) from one cohort study{Schauer 2017 101} in the prehospital military setting with 190 participants. This study did not show an apparent benefit from the use of hemostatic dressings compared with direct pressure, reporting an 11% (3/28) mortality in those receiving hemostatic gauze and 6% (9/162) in those who did not (unadjusted RR, 1.93; 95% CI, 0.56-6.69; p = 0.39). However, these results were not adjusted for selection bias and potential confounding variables.

We identified very low certainty evidence (downgraded for very serious indirectness and serious imprecision) from two RCTs{Politi 2011 65; Schwarz 2009 53} in the in-hospital setting with a total of 1,028 participants undergoing endovascular procedures. These studies showed no difference in all-cause mortality for participants treated with hemostatic dressings compared with direct pressure alone. One RCT{Politi 2011 65} reported no deaths in either the hemostatic dressing or direct pressure alone groups [0/50 compared with 0/50 (RR=1.00, 95% CI: 0.02-49.44; p=1.00).], however, in this study the duration of compression was much longer in the manual compression group compared with the use of a hemostatic dressing (15 minutes compared with 2 hours). A second RCT{Schwarz 2009 53} compared participants treated with either one of two hemostatic dressings compared with a pneumatic compression device and also reported no deaths in any of the groups (0/303 compared with 0/303 and 0/302).

For the important outcome of decrease in bleeding,

We identified low certainty evidence (downgraded for serious risk of bias and indirectness) from one RCT{Hatamabadi 2015 e23862} with 160 civilian participants in the in-hospital setting. This study showed benefit with the use of hemostatic dressings (chitosan-coated gauze) compared with use of direct pressure alone for the outcome of decreased bleeding, as measured by the mean number of blood-soaked gauzes [mean difference 0.43 gauzes fewer (95% CI, 0.85 to 0.01 fewer)].

For the important outcome of complications/adverse effects,

We identified very low certainty evidence (downgraded for very serious indirectness and serious imprecision) from four RCTs{Balzer 2007 693; Dai 2015 192; Politi 2011 65; Trabattoni 2012 53} in the in-hospital setting with a total of 1,040 participants undergoing endovascular procedures. Due to heterogeneity these studies could not be combined for meta-analysis, however none of the studies demonstrated a benefit with the use of hemostatic dressings compared with the use of direct pressure alone for the outcome of complications. Three RCT{(Balzer 2007 693; Dai 2015 192; Politi 2011 65} reported no complications including major bleeding in either group. One RCT{Trabattoni 2012 53} reported major bleeding complications in the hemostatic dressings group (2/100 [2.0%] compared with 4/100 (4.0%) (RR, 0.50; 95% CI, 0.09-2.67; p = 0.68) in the direct pressure group.

For the outcome of adverse effects (as reported by pain scores), we identified very low certainty evidence (downgraded for serious risk of bias, indirectness, and imprecision) from two cohort studies{Arbel 2011 1104; Tjiong 2012 88} in the in-hospital setting with a total of 224 participants undergoing endovascular procedures. These studies showed no difference in outcome for participants treated with hemostatic dressings compared with direct pressure alone. One study{Tjiong 2012 88} reported no significant differences in pain scores between the use of hemostatic dressing and the use of direct pressure.

We did not find evidence for the critical outcome of death due to bleeding.

One Hemostatic Dressing type compared with another Hemostatic Dressing type

For the critical outcome of time to hemostasis, we identified moderate certainty evidence (downgraded for serious indirectness) from three RCTs{McConnell 2012 E1; Nguyen 2007 801; Schwarz 2009 53} in the in-hospital setting with a total of 750 participants undergoing endovascular procedures. Due to heterogeneity meta-analysis could not be performed, however all three studies found no difference in time to hemostasis for the use of one type of hemostatic dressing compared with another. One RCT{Schwarz 2009 53} with 606 participants reported comparable times to hemostasis with the use of a calcium ion releasing wound dressing pad (Neptune-PAD®) compared with the use of a hemostatic thrombin covered bandage (D-Stat® Dry), 11.5 minutes (SD ±8.0) and 12.4 minutes (SD ±6.7) respectively. The second RCT{Nguyen 2007 801} with 90 participants reported a comparable time to hemostasis with the use of a chitosan-based hemostasis pad (Chito-Seal™) and the use of a biopolymer-based hemostatic pad (Clo-Sur P.A.D.®), 16.2 minutes (SD ±4.9) and 16.0 minutes (SD ±5.3) respectively. The third RCT{McConnell 2012 E1} with 54 participants reported a comparable time to hemostasis between the use of a poly-N-acetyl glucosamine hemostatic pad (SyvekPatch®) and the use of a thrombin covered bandage (D-Stat® Dry), 17.8 minutes (SD ±1.3) and 17.5 minutes (SD ±1.4), respectively.

For the important outcome of all-cause mortality, we identified very low certainty evidence (downgraded for serious indirectness and imprecision) from one RCT{Nguyen 2007 801} in the in-hospital setting enrolling 90 participants undergoing endovascular procedures. This study showed no difference in all-cause mortality for one type of hemostatic dressing (chitosan-based Chito-Seal™) compared with another (biopolymer-based Clo-Sur P.A.D.®), as no deaths were reported in either of the two study arms [0/47 compared with 0/43 (RR, 0.92; 95% CI, 0.02-45.22; p = 1.0).

For the important outcome of adverse effects, we identified very low certainty evidence (downgraded for serious risk of bias, indirectness, and imprecision) from two RCTs{Nguyen 2007 801; Schwarz 2009 53} in the in-hospital setting with a total of 696 participants undergoing endovascular procedures that reported rebleeding. These studies showed variable results regarding the comparison of different types of hemostatic dressings. One RCT{Schwarz 2009 53} with 606 participants showed a lower rate of minor bleeding following use of a calcium ion releasing wound dressing pad [Neptune-PAD®; 6.6% (20/303)] compared with using a hemostatic thrombin covered bandage [D-Stat® Dry; 12.2% (37/303)] (RR, 0.54; 95% CI, 0.32-0.91; p = 0.02). The second RCT{Nguyen 2007 801} with 90 participants showed a similar rate of re-bleeding following use of a chitosan-based hemostasis pad [Chito-Seal™; 21.2% (10/47)] compared with using a biopolymer-based hemostatic pad [Clo-Sur P.A.D.®; 23.2% (10/43)] (RR, 1.09; 95% CI, 0.50-2.37; p = 0.82).

We did not find evidence for the critical outcomes of death due to bleeding and cessation of bleeding, or the important outcomes of any complication/adverse events

Treatment Recommendations

We suggest that first aid providers use a hemostatic dressing with direct pressure as opposed to direct pressure alone for severe, life-threatening external bleeding (weak recommendation, very low certainty of evidence).

For the treatment of severe, life-threatening external bleeding by first aid providers, due to very limited data and very low confidence in effect estimates, we are unable to recommend the use of any one specific type of hemostatic dressing compared with another.

Justification and Evidence to Decision Framework Highlights

• In making this recommendation the Task Force was strongly influenced by one RCT{Hatamabadi 2011 e23862} from the civilian in-hospital setting in which a larger percentage of participants (51.2% compared with 32.5%) achieved cessation of bleeding within 5 minutes when a hemostatic dressing was used with direct pressure compared with direct pressure alone.

• In Task Force discussion we recognized that it is pressure that stops bleeding and, when used appropriately, hemostatic dressings can be used as an adjunctive therapy to direct pressure to help stop life-threatening external bleeding.

• Some studies included pediatric participants; however, these numbers were limited and data specifically pertaining to the pediatric population was sparse, therefore no subgroup analysis could be performed. However, in task force discussions it was felt that in the absence of specific evidence for the Pediatric population that it would be reasonable for guideline groups to apply recommendations for control of life-threatening bleeding to children.

• The Task Force recognizes that the use of hemostatic dressings requires additional equipment and training expense that may increase healthcare disparity in some cases. In addition, implementation of the use hemostatic dressings in some areas may not be feasible due to restrictions in availability for lay providers. Therefore, we feel that local conditions may dictate the availability and type of hemostatic dressing.
  
  

• The Task Force recognizes the lack of pre-hospital data. We discussed how the use of in-hospital data derived from endovascular puncture and arterio-venous puncture may not be applicable to pre-hospital life threatening bleeding. We acknowledge that in many of these in-hospital environments the subjects were given anticoagulants that may or may not have been reversed, thereby further complicating the assessment of cessation of bleeding.

Knowledge Gaps

Current knowledge gaps include but are not limited to:

• Are first aid providers able to use typical hemostatic dressings?
• Is one type of hemostatic dressing superior to another type of hemostatic dressing?
• Is one clotting agent superior to another clotting agent when used on a hemostatic dressing?
• Are hemostatic dressings useful in the pediatric population

Attachments

ETD summary table: A-14-Et D-Hemostatic-dressings-vs.-direct-pressure-01-04-2020; A-15-Et D-Comparison-across-hemostatic-dressing-types

References

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