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The debate is currently raging in the US Army and other services. I am making this thread not as a place to debate, but rather where I will post official and government-subsidized study information on various hemostatic agents.
Here is a very recent message; some names and proper nouns have been edited for privacy:
January 18, 2009
XXXXX, ScD
President and Chief Operating Officer
TraumaCure, Inc.
7735 Old Georgetown Road, Suite 1200
Bethesda, MD 20814
Dear Dr. XXXXXX,
I am writing this letter in response to your request for an unbiased opinion concerning the decision of the Army to temporarily remove WoundStat from clinical use until it could further evaluate the findings from an animal study that raised concerns about its safety. To clarify my position, I am the Chief of Trauma and Surgical Critical Care at Oregon Heath & Science University, which is a Level 1 Trauma Center and I have an active xxxxxxx research laboratory that studies hemostatic dressings. I am also a member of the US Army Reserves assigned to the Institute of Surgical Research (USAISR) and I have been deployed to Iraq where I utilized hemostatic dressings in the care of combat casualties. I have no pre-existing affiliation with WoundStat or TraumaCure and my primary interest as a trauma surgeon is to achieve the best possible outcomes for civilian and military casualties.
My opinion is based on a review of both published and unpublished studies comparing WoundStat to other dressings for safety and efficacy as well as discussions with experts in the field and personal experience with the dressing. The latest published guidelines of the Committee on Tactical Combat Casualty Care (TCCC) indicate that WoundStat should be used as a backup to Combat Gauze for compressible hemorrhage not amenable to tourniquet use or as an adjunct to tourniquet removal in the tactical field care environment. Studies comparing the efficacy of WoundStat to other dressings have been performed by the Virginia Commonwealth University (VCU), North America Science Associates (NAMSA), the US Air Force, the US Navy and the US Institute of Surgical Research. Ex vivo studies in normal blood, heparinized blood, blood with anti-platelet agents and diluted blood all reveal that WoundStat increases coagulability suggesting that at least part of the dressings’ effect is due to activation of the coagulation system. The dressing has also been noted to function by creating a sealant effect by its conversion to a clay form which has memory and confers compression even after manual pressure has been removed.
Pre-clinical trials have been performed in xxxxx models. These models have primarily involved femoral artery and/or vein punctures with uncontrolled hemorrhage followed by placement of study dressings with a variable compression period and resuscitation. These models are considered to be 100% lethal when treatment is with standard dressings.
Study endpoints have included short term survival, blood loss, resuscitation volumes and laboratory values. The numbers of xxxxx per group ranges from 5 to 10 and there are generally multiple dressings studied. These analyses are underpowered to show differences in survival or blood loss unless the differences are very large. Studies performed by VCU, NAMSA, Travis Air Force Base and the USAISR have revealed a 100% survival rate in xxxx treated with WoundStat. No other dressing achieved 100% survival rates in any of these studies. xxxx treated with WoundStat also had less than 10 ml/kg of post-treatment blood loss which was numerically less than any other dressing. The USAISR performed the only study that compared WoundStat to Combat Gauze. In this study, xxxxx treated with WoundStat had 100% survival compared to 80% for Combat Gauze. Blood loss was approximately 10 ml/kg in the WoundStat group versus approximately 40 ml/kg in the Combat Gauze group. These differences in survival and post-treatment blood loss did not achieve statistical significance. Histologic changes in tissues treated with various dressings were analyzed in the USAISR study and they were graded as mild to moderate tissue injury in both the combat gauze and WoundStat groups. Also of note, the USAISR has performed computed tomography angiograms to evaluate injured femoral vessels after they have been treated with various dressings and these studies have revealed that all agents have resulted in obstructed blood flow. These preliminary studies have uniformly shown excellent efficacy of WoundStat resulting in tremendous enthusiasm for its use and its addition to the TCCC guidelines as a secondary agent when Combat Gauze fails or the wound is more amenable to a granular agent.
Studies showing evidence of tissue injury and obstructed blood flow with hemostatic dressings induced the USAISR to produce a new model that was primarily designed to test safety in larger blood vessels. This model involves dissection of the carotid artery and external jugular vein followed by clamping and a 50% transection of both vessels made with scissors. Free bleeding is allowed for 30 seconds after which dressings are placed and compression is held sequentially until hemostasis is secured. xxxx are resuscitated with 500 ml of Hextend followed by LR to maintain a mean arterial pressure of 65 mmHg. Dressings are left in place for 2 hours and subsequently removed. The vessels are then primarily repaired and blood flow is restored. During the repair, xxxxx are given 1 liter of lactated Ringer’s. The wounds are subsequently closed. Heparin is not utilized either locally or systemically. Two hours after blood flow is restored, the wounds are reopened and blood flow is assessed with computed tomography angiography. The wounds are then reopened and blood flow is confirmed. Histology is obtained from the injured vessels as well as from lung and brain to look for evidence of material or clot embolization.
Combat Gauze, WoundStat and kerlix were compared utilizing this model. Post-treatment blood loss was significantly greater in the kerlix group but not significantly different between Combat Gauze and WoundStat. Combat Gauze and WoundStat xxxxxxx also required significantly less total compression time. In terms of safety, 7 out of 8 carotid arteries and 6 out of 8 jugular veins treated with WoundStat developed occlusive thrombi. All vessels that were treated with Combat Gauze and kerlix were patent but there was restricted flow in some of the vessels treated with these agents. There was also a large clot and WoundStat residues found in the lung of two xxxxxx that were treated with WoundStat. Histology revealed transmural injury in all vessels that were treated with WoundStat. Histologic changes associated with Combat Gauze and kerlix use were reported to be mild and equivalent.
It is important to note that QuikClot shares some common characteristics with WoundStat. QuikClot is a granular agent that has been shown to have pro-coagulant effects in vitro which are similar to WoundStat. QuikClot has the disadvantage of being an exothermic agent that induces thermal injury. QuikClot has been used extensively by military and civilian agencies. There is a published report of its use in 103 patients and neither pathologic vessel thrombosis nor embolization has been reported. QuikClot has not been studied in the USAISR safety model.
There have been scattered verbal reports of WoundStat use in human patients. However, to my knowledge, none of these reports have been published to date. Additional studies evaluating WoundStat for safety and efficacy are either planned or ongoing.
Based on the available data, I would make the following observations:
1. WoundStat is extremely effective in xxxx models of lethal hemorrhage. The trials that have been performed have been small and they do not have the power to distinguish the efficacy of WoundStat compared to Combat Gauze.
2. The findings by the USAISR of full thickness vessel injury and thrombosis associated with the use of WoundStat are of some concern. It is not clear if these finding are related to a mechanical effect of WoundStat related to the product’s intrinsic memory and its ability to maintain pressure when compression has been removed, an abrasive quality of the granules or a chemical reaction of the product. These findings should be interpreted within the scope of the xxxxx model. Similar to the femoral vessel injury model, the cervical model involves dissection of the vessels and partial transection with scissors exposing the vascular endothelium. The injuries were primarily repaired. This differs from injuries seen in combat in that those injuries generally involve high energy impact with significant damage to the vessels and surrounding tissues. The vast majority of these injuries require resection of injured vessels to healthy areas and interposition grafting. In addition, either systemic or local heparinization is used in clinical settings to help achieve prolonged patency. Finally, xxxxxx are a hypercoagulable xxxxx compared to humans. Further research studying the etiology of the thrombosis and endothelial injury seen with WoundStat as well as comparing WoundStat and Combat Gauze in injury models associated with high energy and the use of interposition grafting would help clarify the relative safety of these two products in realistic settings. It would also be interesting to test QuikClot in the USAISR cervical model to help determine if the findings seen with WoundStat are reproduced with another FDA approved agent that has similar characteristics.
3. It is not uncommon for potent hemostatic agents to cause thrombosis or systemic complications when they are exposed to the vascular endothelium. Topical thrombin which is used on a widespread basis by surgeons to control bleeding is contraindicated for intravascular use or for the treatment of brisk arterial bleeding. This has not prevented thrombin from being used widely for severe bleeding.
In conclusion, WoundStat is a granular hemostatic agent that differs mechanistically from tourniquets and Combat Gauze, expanding the medics’ ability to stop bleeding in extreme scenarios. In light of WoundStat’s intrinsic hemostatic capacity compared to preliminary data suggesting its potential for causing injury to blood vessels as well as thrombosis and embolization, it seems reasonable to continue using WoundStat when other measures have failed especially when the alternative is death. The safety of WoundStat has not been studied in realistic models that include modern vascular replacement techniques and heparinization. Furthermore, the use of WoundStat should be safe and potentially lifesaving in coagulopathic patients in whom large vessel bleeding has been controlled and exposure to vascular endothelium is limited. Both recombinant factor VIIa and tourniquets are commonly used to treat combat casualties. These agents have known complications that are limited by using them appropriately and the same concepts should be applied to WoundStat.
Sincerely,
XXXXXX, MD, FACS
Here is a very recent message; some names and proper nouns have been edited for privacy:
January 18, 2009
XXXXX, ScD
President and Chief Operating Officer
TraumaCure, Inc.
7735 Old Georgetown Road, Suite 1200
Bethesda, MD 20814
Dear Dr. XXXXXX,
I am writing this letter in response to your request for an unbiased opinion concerning the decision of the Army to temporarily remove WoundStat from clinical use until it could further evaluate the findings from an animal study that raised concerns about its safety. To clarify my position, I am the Chief of Trauma and Surgical Critical Care at Oregon Heath & Science University, which is a Level 1 Trauma Center and I have an active xxxxxxx research laboratory that studies hemostatic dressings. I am also a member of the US Army Reserves assigned to the Institute of Surgical Research (USAISR) and I have been deployed to Iraq where I utilized hemostatic dressings in the care of combat casualties. I have no pre-existing affiliation with WoundStat or TraumaCure and my primary interest as a trauma surgeon is to achieve the best possible outcomes for civilian and military casualties.
My opinion is based on a review of both published and unpublished studies comparing WoundStat to other dressings for safety and efficacy as well as discussions with experts in the field and personal experience with the dressing. The latest published guidelines of the Committee on Tactical Combat Casualty Care (TCCC) indicate that WoundStat should be used as a backup to Combat Gauze for compressible hemorrhage not amenable to tourniquet use or as an adjunct to tourniquet removal in the tactical field care environment. Studies comparing the efficacy of WoundStat to other dressings have been performed by the Virginia Commonwealth University (VCU), North America Science Associates (NAMSA), the US Air Force, the US Navy and the US Institute of Surgical Research. Ex vivo studies in normal blood, heparinized blood, blood with anti-platelet agents and diluted blood all reveal that WoundStat increases coagulability suggesting that at least part of the dressings’ effect is due to activation of the coagulation system. The dressing has also been noted to function by creating a sealant effect by its conversion to a clay form which has memory and confers compression even after manual pressure has been removed.
Pre-clinical trials have been performed in xxxxx models. These models have primarily involved femoral artery and/or vein punctures with uncontrolled hemorrhage followed by placement of study dressings with a variable compression period and resuscitation. These models are considered to be 100% lethal when treatment is with standard dressings.
Study endpoints have included short term survival, blood loss, resuscitation volumes and laboratory values. The numbers of xxxxx per group ranges from 5 to 10 and there are generally multiple dressings studied. These analyses are underpowered to show differences in survival or blood loss unless the differences are very large. Studies performed by VCU, NAMSA, Travis Air Force Base and the USAISR have revealed a 100% survival rate in xxxx treated with WoundStat. No other dressing achieved 100% survival rates in any of these studies. xxxx treated with WoundStat also had less than 10 ml/kg of post-treatment blood loss which was numerically less than any other dressing. The USAISR performed the only study that compared WoundStat to Combat Gauze. In this study, xxxxx treated with WoundStat had 100% survival compared to 80% for Combat Gauze. Blood loss was approximately 10 ml/kg in the WoundStat group versus approximately 40 ml/kg in the Combat Gauze group. These differences in survival and post-treatment blood loss did not achieve statistical significance. Histologic changes in tissues treated with various dressings were analyzed in the USAISR study and they were graded as mild to moderate tissue injury in both the combat gauze and WoundStat groups. Also of note, the USAISR has performed computed tomography angiograms to evaluate injured femoral vessels after they have been treated with various dressings and these studies have revealed that all agents have resulted in obstructed blood flow. These preliminary studies have uniformly shown excellent efficacy of WoundStat resulting in tremendous enthusiasm for its use and its addition to the TCCC guidelines as a secondary agent when Combat Gauze fails or the wound is more amenable to a granular agent.
Studies showing evidence of tissue injury and obstructed blood flow with hemostatic dressings induced the USAISR to produce a new model that was primarily designed to test safety in larger blood vessels. This model involves dissection of the carotid artery and external jugular vein followed by clamping and a 50% transection of both vessels made with scissors. Free bleeding is allowed for 30 seconds after which dressings are placed and compression is held sequentially until hemostasis is secured. xxxx are resuscitated with 500 ml of Hextend followed by LR to maintain a mean arterial pressure of 65 mmHg. Dressings are left in place for 2 hours and subsequently removed. The vessels are then primarily repaired and blood flow is restored. During the repair, xxxxx are given 1 liter of lactated Ringer’s. The wounds are subsequently closed. Heparin is not utilized either locally or systemically. Two hours after blood flow is restored, the wounds are reopened and blood flow is assessed with computed tomography angiography. The wounds are then reopened and blood flow is confirmed. Histology is obtained from the injured vessels as well as from lung and brain to look for evidence of material or clot embolization.
Combat Gauze, WoundStat and kerlix were compared utilizing this model. Post-treatment blood loss was significantly greater in the kerlix group but not significantly different between Combat Gauze and WoundStat. Combat Gauze and WoundStat xxxxxxx also required significantly less total compression time. In terms of safety, 7 out of 8 carotid arteries and 6 out of 8 jugular veins treated with WoundStat developed occlusive thrombi. All vessels that were treated with Combat Gauze and kerlix were patent but there was restricted flow in some of the vessels treated with these agents. There was also a large clot and WoundStat residues found in the lung of two xxxxxx that were treated with WoundStat. Histology revealed transmural injury in all vessels that were treated with WoundStat. Histologic changes associated with Combat Gauze and kerlix use were reported to be mild and equivalent.
It is important to note that QuikClot shares some common characteristics with WoundStat. QuikClot is a granular agent that has been shown to have pro-coagulant effects in vitro which are similar to WoundStat. QuikClot has the disadvantage of being an exothermic agent that induces thermal injury. QuikClot has been used extensively by military and civilian agencies. There is a published report of its use in 103 patients and neither pathologic vessel thrombosis nor embolization has been reported. QuikClot has not been studied in the USAISR safety model.
There have been scattered verbal reports of WoundStat use in human patients. However, to my knowledge, none of these reports have been published to date. Additional studies evaluating WoundStat for safety and efficacy are either planned or ongoing.
Based on the available data, I would make the following observations:
1. WoundStat is extremely effective in xxxx models of lethal hemorrhage. The trials that have been performed have been small and they do not have the power to distinguish the efficacy of WoundStat compared to Combat Gauze.
2. The findings by the USAISR of full thickness vessel injury and thrombosis associated with the use of WoundStat are of some concern. It is not clear if these finding are related to a mechanical effect of WoundStat related to the product’s intrinsic memory and its ability to maintain pressure when compression has been removed, an abrasive quality of the granules or a chemical reaction of the product. These findings should be interpreted within the scope of the xxxxx model. Similar to the femoral vessel injury model, the cervical model involves dissection of the vessels and partial transection with scissors exposing the vascular endothelium. The injuries were primarily repaired. This differs from injuries seen in combat in that those injuries generally involve high energy impact with significant damage to the vessels and surrounding tissues. The vast majority of these injuries require resection of injured vessels to healthy areas and interposition grafting. In addition, either systemic or local heparinization is used in clinical settings to help achieve prolonged patency. Finally, xxxxxx are a hypercoagulable xxxxx compared to humans. Further research studying the etiology of the thrombosis and endothelial injury seen with WoundStat as well as comparing WoundStat and Combat Gauze in injury models associated with high energy and the use of interposition grafting would help clarify the relative safety of these two products in realistic settings. It would also be interesting to test QuikClot in the USAISR cervical model to help determine if the findings seen with WoundStat are reproduced with another FDA approved agent that has similar characteristics.
3. It is not uncommon for potent hemostatic agents to cause thrombosis or systemic complications when they are exposed to the vascular endothelium. Topical thrombin which is used on a widespread basis by surgeons to control bleeding is contraindicated for intravascular use or for the treatment of brisk arterial bleeding. This has not prevented thrombin from being used widely for severe bleeding.
In conclusion, WoundStat is a granular hemostatic agent that differs mechanistically from tourniquets and Combat Gauze, expanding the medics’ ability to stop bleeding in extreme scenarios. In light of WoundStat’s intrinsic hemostatic capacity compared to preliminary data suggesting its potential for causing injury to blood vessels as well as thrombosis and embolization, it seems reasonable to continue using WoundStat when other measures have failed especially when the alternative is death. The safety of WoundStat has not been studied in realistic models that include modern vascular replacement techniques and heparinization. Furthermore, the use of WoundStat should be safe and potentially lifesaving in coagulopathic patients in whom large vessel bleeding has been controlled and exposure to vascular endothelium is limited. Both recombinant factor VIIa and tourniquets are commonly used to treat combat casualties. These agents have known complications that are limited by using them appropriately and the same concepts should be applied to WoundStat.
Sincerely,
XXXXXX, MD, FACS
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