- Email: [email protected]
Damage control resuscitation
Accepted Manuscript Damage Control Resuscitation Alexandra Briggs, MD, Reza Askari, MD PII:
S1743-9191(16)30024-3
DOI:
10.1016/j.ijsu.2016.03.064
Reference:
IJSU 2709
To appear in:
International Journal of Surgery
Received Date: 11 January 2016 Revised Date:
29 February 2016
Accepted Date: 3 March 2016
Please cite this article as: Briggs A, Askari R, Damage Control Resuscitation, International Journal of Surgery (2016), doi: 10.1016/j.ijsu.2016.03.064. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
SC
RI PT
ACCEPTED MANUSCRIPT
M AN U
Damage Control Resuscitation Authors: Alexandra Briggs, MD Reza Askari, MD*
AC C
EP
TE D
Brigham and Women’s Hospital, Boston, MA Harvard Medical School
*Corresponding Author
ACCEPTED MANUSCRIPT
Introduction to Damage Control Resuscitation
TE D
Resuscitation with Blood Products
M AN U
SC
RI PT
The pattern of deaths after traumatic injury has been extensively described, first with a classic description of a ‘trimodal’ distribution of deaths in a landmark 1983 study by Trunkey. However, there have been studies since that time that have noted a more bimodal distribution of deaths, with one in 2005 demonstrating that 50% occurred within the first hour of trauma, 18% between one and six hours 1 post-injury, and then only 7.6% after one week. Given these findings, the initial management of trauma patients has evolved in order to address this early peak in post-injury deaths. While the concept of 2 surgical ‘damage control’ has existed as a surgical approach to injury for the past two decades, this has now been expanded to the early medical management of traumatic patients. This approach to care has 3,4 been termed ‘damage control resuscitation’ (DCR) . The American College of Surgeons Trauma Quality Improvement Program (ACS-TQIP) describes DCR as the following : “(1) rapid recognition of traumainduced coagulopathy and shock; (2) permissive hypotension; (3) rapid surgical control of bleeding; (4) prevention/treatment of hypothermia, acidosis, and hypocalcemia; (5) avoidance of hemodilution by minimizing use of crystalloid intravenous fluid; (6) transfusion of red blood cells (RBC):plasma:platelets in a high unit ratio (>1:2) or reconstituted whole blood in a 1:1:1 unit ratio; (7) early and appropriate use of 4 coagulation factor concentrates; and (8) use of fresh RBCs and whole blood when available.” Early recognition of at-risk patients is key to the appropriate application of DCR principles, in order to avoid the onset of the ‘lethal triad’ of coagulopathy, hypothermia and acidosis. While hypothermia can be addressed through creating a warm environment and using methods of both passive and active rewarming, the prevention and treatment of acidosis and coagulopathy is more difficult and multifaceted. Fluid management and blood product transfusion strategies continue to be refined based upon evolving literature, but are focused on the minimization of crystalloid use and the balanced administration of all blood components. The final step of DCR is the definitive control of any ongoing bleeding, whether through angiography, operative procedures including damage control laparotomy, or other interventions. This chapter will focus on several key elements of DCR.
AC C
EP
The initial literature regarding the ratios of plasma and red blood cell (RBC) transfusion on trauma outcomes came from military reviews of massive transfusion. One such study of 246 patients in a US Army combat support hospital receiving 10 or more units of RBCs during massive transfusion demonstrated that high ratio (1:1.4) transfusion was associated with lower overall mortality and lower hemorrhage-related mortality rates, and that plasma to RBC ratio was independently associated with 5 survival. This led to the initial use of the term ‘damage control resuscitation’ in multiple manuscripts, adoption of the term by United States military investigators, and prompted further investigations into the 6,7 ratio of blood product transfusion in trauma patients. A subsequent analysis of 713 civilian patients in the German trauma registry also demonstrated lower 6 hour, 24 hour, and 30 day mortality rates in 8 patients with higher transfusion ratios. In addition, a 2008 study in the United States also demonstrated lower risk of mortality after massive transfusion with a ratio of FFP to RBC that was equal to or greater 9 than 1 to 1.5. Notably, the risk of Acute Respiratory Distress Syndrome (ARDS) was significantly higher in surviving patients undergoing high ratio transfusion, and further studies from this group in patients with hemorrhage undergoing transfusion again showed higher multiorgan failure (MOF) and ARDS rates with 10 FFP transfusion. This raises the concern that while hemorrhage related outcomes are improved, this may be achieved with subsequent development of significant complications requiring intensive management. The results of these studies have to be interpreted with the caveat that due to the time periods analyzed, survival bias could be influencing results. The concern is whether the results are due to the intervention or just that patients survived long enough to receive it. A study of 134 patients started to address this by factoring in the timing of transfusion into the analysis of blood product ratio, and found no statistical significance in survival between ratio groups, prompting a call for larger prospective trials to address the 11 question of transfusion ratio while accounting for the time of transfusion. Subsequently, several large prospective studies were completed. The Prospective, Observational, Multicenter, Major Trauma Transfusion (PROMMTT) study was a prospective cohort study analyzing the
ACCEPTED MANUSCRIPT
M AN U
SC
RI PT
relationship between the ratio and timing of transfusion and mortality in adult trauma patients who 12 required at least three units of blood during resuscitation. This study demonstrated that the time to transfusion of plasma and platelets was variable across the analysis cohort, and showed that higher ratios of both plasma and platelets to RBCs was associated with decreased 6 hour mortality, at which time the majority of hemorrhage related deaths have occurred. This was then followed by the Pragmatic, Randomized Optimal Platelet and Plasma Rations (PROPPR) trial which showed higher rates of hemostasis and lower bleeding related mortality by 24 hours in patients transfused with a 1:1:1 ratio of plasma, 13 platelets, and red blood cells, compared to a 1:1:2 ratio. These studies suggest that higher transfusion ratios, ideally 1:1:1 ratios, should be a goal in early resuscitation in order to decrease the mortality from hemorrhage during this time period. While there were no differences in rates of ARDS, MOF, or any of the analyzed complications at 30 days between the treatment groups in the PROPPR trial, the overall rates of MOF and ARDS were high in both groups. These trials did address the concern for survival bias from prior studies by discussing earlier timepoints during the resuscitation process and targeting early transfusion, though it should be noted that the Federal Drug Administration (FDA) only allowed primary end points of 24 hours and 30 days. The role of prehospital transfusion is currently an area of continued investigation. Most recently, a 2015 study of 1677 severely injured patients demonstrated decreased transfusion requirements at 6 and 24 hours, and a trend towards lower 6 hour mortality in all patients. The subset of patients deemed 14 most likely to benefit from early blood transfusion were shown to have lower 6 hour mortality. Of note, this study used the previously published Assessment of Blood Consumption (ABC) score to provide clear criteria for prehospital transfusion. This scoring system includes penetrating trauma to the trunk, hypotension, tachycardia, and positive Focused Assessment with Sonography in Trauma (FAST) exam as 15 predictors of need for transfusion. Multiple randomized trials have now been funded by the Department of Defense to investigate the use of prehospital plasma, in order to determine efficacy and to provide 16, 17, 18 additional guidelines as this practice becomes more widespread. Use of Tranexamic Acid and Recombinant Factors
AC C
EP
TE D
Tranexamic acid (TXA) is a synthetic derivative of the amino acid lysine, and acts as an antifibrinolytic by inhibiting the activation of plasminogen to plasmin. With prior evidence that use of TXA 19 reduced the need for transfusion in elective surgery both military and civilian groups have studied the utility of TXA in trauma patients. The Clinical Randomization of an Antifibrinolytic in Significant Hemorrhage (CRASH-2) study was a multinational randomized controlled trial of 20,211 adult trauma patients who were assigned to a loading dose followed by infusion of tranexamic acid versus placebo within 8 hours of the time of injury. All cause mortality was shown to be lower in those treated with tranexamic acid and also demonstrated lower risk of death due to bleeding, without any difference in the rates of any vascular occlusive event. Further analysis demonstrated that early treatment was particularly important in order to decrease the risk of bleeding-related death, with the most significant reduction seen in those treated within 1 hour of injury, though the effect also was seen in those treated between 1 and 3 hours after injury. The data also suggested that there may actually be increased risk of death if patients 20,21 were treated after 3 hours. The use of TXA in military trauma has also been investigated in the MATTERs studies from the United States military. These studies demonstrated that TXA was associated with a survival benefit in patients undergoing transfusion, though transfusion of other factors including 22,23 factor VII and cryoprecipitate does make interpretation of these studies more complex. While these studies suggest that TXA could be effective in trauma resuscitation, recent data does prompt questions regarding its utility. A 2014 retrospective review from Miami showed increased mortality in severely injured trauma patients receiving TXA compared to those who did not receive TXA, however there were multiple limitations to the study which limits the applicability to other patients and 24 trauma centers. A 2015 review publication analyzed the available data on TXA including both large and small scale trials and studies, with the authors concluding that the data does support the use of TXA, particularly in what they term ‘remote damage control resuscitation’ in the prehospital setting, without 25 significant risk of adverse side effects. However, another 2015 study looking at TXA use in 1032 patients with hyperfibrinolysis based upon thromboelastography showed that there was no benefit from TXA use,
ACCEPTED MANUSCRIPT
M AN U
SC
RI PT
first showing increased mortality at 24 hours, but then no difference in in-hospital mortality rates after 26 logistic regression analysis. Given the complexity of the data available on TXA and some of the limitations of existing studies, there is no consensus to this point on the utility of TXA in trauma resuscitation. However, in the deployed setting, the current United States Army Institute of Surgical Research (USAISR) Joint Theater Trauma System Clinical Practice Guideline on DCR from February 2013 states that early use of TXA should be “considered strongly for any patient requiring blood products in the treatment of combat-related hemorrhage and is most strongly advocated in patients judged likely to 27 require massive transfusion.” The use of other agents to reverse coagulopathy in trauma patients continues to be under investigation. The CONTROL trial was a phase three randomized clinical trial analyzing the use of recombinant Factor VIIa in trauma resuscitation. In this study, factor was used in 573 patients who continued to have bleeding despite damage control resuscitation and operative management. The trial was stopped due to low mortality and enrollment difficulties, though it did show decreased blood product 28 use in those patients who received Factor VIIa. The use of prothrombin complex concentrates (PCCs) has also been discussed in the treatment of trauma patients, however at this time studies are largely focused on experimental models or specifically investigate the reversal of anticoagulant therapy in trauma patients. Further investigation is required to determine the utility of any of these products in damage control resuscitation. Crystalloid Use in Damage Control Resuscitation
AC C
EP
TE D
Another element of damage control resuscitation is the judicious use of crystalloid resuscitation for trauma patients. To date, the evidence regarding crystalloid use has been variable depending on the setting and patient population. One important study regarding fluid resuscitation was published in 1994, and was a prospective trial of immediate versus delayed fluid resuscitation in 598 patients who were hypotensive after sustaining penetrating torso injuries. This study demonstrated increased survival in the 29 group receiving delayed fluid resuscitation, and also a trend towards fewer complications. An analysis of the National Trauma Data Bank in 2011 demonstrated that intravenous fluid (IVF) administration was associated with higher mortality in trauma patients, including a significant increase in mortality in patients with penetrating mechanism, which is consistent with prior evidence. While there can be limitations to large database studies such as this, the association demonstrated in this study is important to note within 30 the larger framework of literature on this topic. The interplay between transfusion and fluid resuscitation has also been studied in recent years. A 2011 study by Cotton et al analyzed 390 patients who underwent damage control laparotomy, comparing outcomes in the pre- and post-damage control resuscitation era. Those treated with damage control resuscitation received fewer blood products and less crystalloid, and had better 30 day survival. In addition, they demonstrated that these patients were less likely to exhibit the ‘lethal triad’ of 31 coagulopathy, hypothermia and acidosis upon arrival to the intensive care unit. A later multiinstitutional study analyzed the relationship between 24 hour crystalloid resuscitation volume and outcomes in patients receiving both high and low ratio plasma-red blood cell resuscitation. While this study again confirmed the benefit of high ratio resuscitation, it also demonstrated that crystalloid resuscitation was associated with higher complication rates. It is important to note that this study used 24 32 hour crystalloid volume as the point of study, not just pre-hospital volume. However, not all studies have shown consistent data regarding the effects of IVF resuscitation on trauma patients. A study from the PROMMTT investigators analyzed the differences between patients receiving pre-hospital IVF and those who did not. These patients received a median of 700mL of IVF and 33 this fluid resuscitation was associated with increased survival. Another retrospective study analyzed the volume of prehospital fluid given and correlated it with rates of shock and blood transfusion. They demonstrated that volumes from 0.5 to 2 liters of IVF were associated with lower rates of shock than lower volumes, and that volumes greater than 1 liters of fluid were associated with higher rates of blood 34 transfusion, particularly when over 2 liters of fluid were administered. A trauma registry study from Germany compared patients receiving low versus high volume pre-hospital IVF resuscitation. They
ACCEPTED MANUSCRIPT
RI PT
demonstrated that low volume resuscitation was associated with lower pRBC use, higher ICU-free days, 35 and lower rates of sepsis than high volume resuscitation. The literature regarding the use of intravenous fluid resuscitation in trauma patients continues to evolve at this time, and consensus guidelines have not been recently updated. The existing guidelines suggest that trauma patients who are alert and have a palpable radial pulse do not require prehospital fluid administration. Fluids should be given to patients with falling blood pressures to maintain mentation and regain a strong pulse. Goal blood pressures should be higher in patients with traumatic brain injury, 36, 37 however, in order to maintain cerebral perfusion with goal mean pressure greater than 60mmgHg. When these guidelines and the existing literature are taken together, they suggest that judicious use of pre-hospital crystalloids may be indicated in some trauma populations, as long as volumes are monitored carefully. The data do demonstrate that high volume crystalloid resuscitation is likely detrimental and may increase morbidity in trauma patients.
SC
Summary and Future Directions
AC C
EP
TE D
M AN U
The principles of damage control resuscitation include hemorrhage control, careful use of crystalloid intravenous fluids, and early delivery of high ratios of platelets and plasma to red blood cells. These have become more widely applied in trauma patients as both military and civilian experience continues to support this approach, and studies now are looking to expand DCR to the prehospital arena. Continued research is required to establish the ideal approach to blood product transfusion, to investigate the use of additional hemostatic agents, and to continue to optimize prehospital care of trauma patients.
ACCEPTED MANUSCRIPT
References: 1. Demetriades D, Kimbrell B, Salim A, et al. Trauma deaths in a mature urban trauma system: is ‘trimodal’ distribution a valid concept? J Am Coll Surg. 2005; 201: 343-348.
RI PT
2. Rotondo MF, Schwab CW, McGonigal MD, et al. ‘Damage Control’: An Approach for Improved Survival in Exsanguinating Penetrating Abdominal Injury. J Trauma. 1993; 35: 375-382. 3. Hess JR, Holcomb JB, Hoyt DB. Damage control resuscitation: the need for specific blood products to treat the coagulopathy of trauma. Transfusion. 2006; 46: 685-686.
SC
4. Camazine MN, Hemmila MR, Leonard JC, et al. Massive transfusion policies at trauma centers participating in the American College of Surgeons Trauma Quality Improvement Program. J Trauma Acute Care Surg. 2015; 78: S48-S53.
M AN U
5. Borgman MA, Spinella PC, Perkins JG, et al. The Ratio of Blood Products Transfused Affects Mortality in Patients Receiving Massive Transfusions at a Combat Support Hospital. J Trauma. 2007; 63: 805-813. 6. Hess JR, Holcomb JB, Hoyt DB. Damage control resuscitation: the need for specific blood products to treat the coagulopathy of trauma. Transfusion. 2006; 46: 685-686. 7. Holcomb JB, Jenkins D, Rhee P, et al. Damage control resuscitation: directly addressing the early coagulopathy of trauma. J Trauma. 2007; 62: 307-310.
TE D
8. Maegele M, Lefering R, Paffrath T, et al. Red-blood-cell to plasma ratios transfused during massive transfusion are associated with mortality in severe multiple injury: a retrospective analysis from the Trauma Registry of the Deutsche Gesellschaft für Unfallchirurgie. Vox Sang. 2008; 95: 112-119.
9. Sperry JL, Ochoa JB, Gunn SR, et al. An FFP:PRBC Transfusion Ratio ≥1:1.5 Is Associated With A Lower Risk of Mortality After Massive Transfusion. J Trauma. 2008; 65: 986-993.
EP
10. Watson GA, Sperry JL, Rosengart MR, et al. Fresh Frozen Plasma Is Independently Associated Wtih a Higher Risk of Multiple Organ Failure and Acute Respiratory Distress Syndrome. J Trauma. 2009; 67: 221230.
AC C
11. Snyder CW, Weinberg JA, McGwin G et al. The Relationship of Blood Product Ratio to Mortality : Survival Benefit or Survival Bias? J Trauma. 2009; 66:358-364. 12. Holcomb JB, del Junco DJ, Fox EF et al. The Prospective, Observational, Multicenter, Major Trauma Transfusion (PROMTT) Study. JAMA Surg. 2013;148:127-136. 13. Holcomb JB, Tilley BC, Baraniuk S, et al. Transfusion of Plasma, Platelets, and Red Blood Cells in a 1:1:1 vs a 1:1:2 Ratio and Mortality in Patients With Severe Trauma. The PROPPR Randomized Clinical Trial. JAMA. 2015; 313: 471-482. 14. Holcolmb JB, Donathan DP, Cotton BA. Prehospital Transfusion of Plasma and Red Blood Cells in Trauma Patients. Prehospital Emergency Care. 2015; 19: 1-9. 15. Nunez TC, Voskrensensky IV, Dossett LA. Early prediction of massive transfusion in trauma: simple as ABC (assessment of blood consumption)? J Trauma. 2009; 66: 346-352.
ACCEPTED MANUSCRIPT
16. Brown JB, Guyette FX, Neal MD. Taking the Blood Bank to the Field: The Design and Rationale of the Prehospital Air Medical Plasma (PAMPer) Trial. Prehosp Emerg Care. 2015; 19:343-350. 17. Prehospital Use of Plasma for Traumatic Hemorrhage (PUPTH) Study. Available at : https://clinicaltrials.gov/ct2/show/NCT02303964. Accessed : July 20th, 2015.
RI PT
18. Control of Major Bleeding After Trauma Study (COMBAT). Available at : https://clinicaltrials.gov/ct2/show/NCT01838863. Accessed : July 20th, 2015.
19. Ker K, Edwards P, Perel P et al. Effect of tranexamic acid on surgical bleeding: systematic review and cumulative meta-anaylsis. BMJ. 2012; 344: e3054.
SC
20. CRASH-2 Trial Collaborators. Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2) : a randomized, placebocontrolled trial. Lancet. 2010; 376: 23-32.
M AN U
21. CRASH-2 collaborators. The importance of early treatment with tranexamic acid in bleeding trauma patients: an exploratory analysis of the CRASH-2 randomised controlled trial. Lancet. 2011; 377: 10961101. 22. Morrison JJ, Dubose JJ, Rasmussen TE and Midwinter MJ. Military Application of Tranexamic Acid in Trauma Emergency Resuscitation (MATTERs) Study. Arch Surg. 2012; 147: 113-119. 23. Morrison JJ, Ross JD, Dubose JJ, et al. Association of Cryoprecipitate and Tranexamic Acid With Improved Survival Following Wartime Injury. JAMA Surg. 2013; 148: 218-225.
TE D
24. Valle EJ, Allen CJ, Van Haren RM, et al. Do all trauma patients benefit from tranexamic acid? J Trauma Acute Care Surg. 2014; 76: 1373-1378. 25. Ausset S, Glassberg E, Nadler R, et al. Tranexamic acid as part of remote damage-control resuscitation in the prehospital setting: A critical appraisal of the medical literature and available alternatives. J Trauma Acute Care Surg. 2015; 78: S70-S75.
EP
26. Harvin JA, Peirce CA, Mims MM. The impact of tranexamic acid on mortality in injured patients with hyperfibrinolysis. J Trauma Acute Care Surg. 2015; 78: 905-911.
AC C
27. US Army Institute of Surgical Research Joint Trauma System Clinical Practice Guidelines on Damage Control Resuscitation. Available at: http://www.usaisr.amedd.army.mil/cpgs/Damage%20Control%20Resuscitation%20th %201%20Feb%202013.pdf. Accessed : August 17 , 2015. 28. Hauser CJ, Boffard K, Dutton R, et al. Results of the CONTROL Trial: Efficacy and Safety of Recombinant Activated Factor VII in the Management of Refractory Traumatic Hemorrhage. J Trauma. 2010; 69: 489500. 29. Bickell WH, Wall MJ, Pepe PE, et al. Immediate versus delayed fluid resuscitation for hypotensive patients with penetrating torso injuries. NEJM. 1994; 331: 1105-1109. 30. Haut ER, Kalish BT, Cotton BA, et al. Prehospital Intravenous Fluid Administration is Associated With Higher Mortality in Trauma Patients : A National Trauma Data Bank Analysis. Ann Surg. 2011; 253: 371378.
ACCEPTED MANUSCRIPT
31. Cotton BA, Reddy N, Hatch QM, et al. Damage Control Resuscitation is Associated With a Reduction in Resuscitation Volumes and Improvement in Survival in 390 Damage Control Laparotomy Patients. Ann Surg. 2011; 254: 598-605. 32. Duchesne JC, Heaney K, Guidry C. Diluting the benefits of hemostatic resuscitation: A multiinstitutional analysis. J Trauma Acute Care Surg. 2013; 75: 76-82.
RI PT
33. Hampton DA, Fabricant LJ, Differding J, et al. Pre-Hospital Intravenous Fluid is Associated with Increased Survival in Trauma Patients. J Trauma Acute Care Surg. 2013; 75: S9-S15.
34. Geeraedts LMG, Pothof LAH, Caldwell E, et al. Prehospital fluid resuscitation in hypotensive trauma patients: Do we need a tailored approach? Injury. 2015; 46: 4-9.
SC
35. Humann B, Lefering R, Taeger G, et al. Influence of prehospital fluid resuscitation on patients with multiple injuries in hemorrhagic shock in patients from the DGU trauma registry. J Emerg Trauma Shock. 2011; 4: 465-471.
M AN U
36. Cotton BA, Jerome R, Collier BR, et al. Guidelines for Prehospital Fluid Resuscitation in the Injured Patient. Journal of Trauma-Injury Infection & Critical Care. 2009; 67: 389-402.
AC C
EP
TE D
37. McSwain NE, Champion HR, Fabian TC, et al. State of the Art of Fluid Resuscitation 2010 : Prehospital and Immediate Transition to the Hospital. Journal of Trauma-Injury Infection & Critical Care. 2011; 70: S2S10.
ACCEPTED MANUSCRIPT
Highlights:
• •
•
RI PT
SC
•
A balanced ratio of blood products, ideally 1:1:1 ratios, should be a goal in early resuscitation in order to decrease the mortality from hemorrhage during this time period. Tranexamic acid (TXA) is a synthetic derivative of the amino acid lysine, and acts as an antifibrinolytic by inhibiting the activation of plasminogen to plasmin.
M AN U
•
Fluid management and blood product transfusion strategies continue to be refined based upon evolving literature, but are focused on the minimization of crystalloid use and the balanced administration of all blood components.
Both military and civilian groups have studied the utility of TXA in trauma patients. The current United States Army Institute of Surgical Research (USAISR) Joint Theater Trauma System Clinical Practice Guideline on DCR from February 2013 states that early use of TXA should be “considered strongly for any patient requiring blood products in the treatment of combat-related hemorrhage and is most strongly advocated in patients judged likely to require massive transfusion.
TE D
•
Early recognition of at-risk patients is key to the appropriate application of DCR principles, in order to avoid the onset of the ‘lethal triad’ of coagulopathy, hypothermia and acidosis.
The literature regarding the use of intravenous fluid resuscitation in trauma patients continues to evolve at this time, and consensus guidelines have not been recently updated. The existing guidelines suggest that trauma patients who are alert and have a palpable radial pulse do not require prehospital fluid administration.
EP
•
The principles of damage control resuscitation (DCR) include hemorrhage control, careful use of crystalloid intravenous fluids, and early delivery of high ratios of platelets and plasma to red blood cells.
AC C
•
S1743-9191(16)30024-3
DOI:
10.1016/j.ijsu.2016.03.064
Reference:
IJSU 2709
To appear in:
International Journal of Surgery
Received Date: 11 January 2016 Revised Date:
29 February 2016
Accepted Date: 3 March 2016
Please cite this article as: Briggs A, Askari R, Damage Control Resuscitation, International Journal of Surgery (2016), doi: 10.1016/j.ijsu.2016.03.064. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
SC
RI PT
ACCEPTED MANUSCRIPT
M AN U
Damage Control Resuscitation Authors: Alexandra Briggs, MD Reza Askari, MD*
AC C
EP
TE D
Brigham and Women’s Hospital, Boston, MA Harvard Medical School
*Corresponding Author
ACCEPTED MANUSCRIPT
Introduction to Damage Control Resuscitation
TE D
Resuscitation with Blood Products
M AN U
SC
RI PT
The pattern of deaths after traumatic injury has been extensively described, first with a classic description of a ‘trimodal’ distribution of deaths in a landmark 1983 study by Trunkey. However, there have been studies since that time that have noted a more bimodal distribution of deaths, with one in 2005 demonstrating that 50% occurred within the first hour of trauma, 18% between one and six hours 1 post-injury, and then only 7.6% after one week. Given these findings, the initial management of trauma patients has evolved in order to address this early peak in post-injury deaths. While the concept of 2 surgical ‘damage control’ has existed as a surgical approach to injury for the past two decades, this has now been expanded to the early medical management of traumatic patients. This approach to care has 3,4 been termed ‘damage control resuscitation’ (DCR) . The American College of Surgeons Trauma Quality Improvement Program (ACS-TQIP) describes DCR as the following : “(1) rapid recognition of traumainduced coagulopathy and shock; (2) permissive hypotension; (3) rapid surgical control of bleeding; (4) prevention/treatment of hypothermia, acidosis, and hypocalcemia; (5) avoidance of hemodilution by minimizing use of crystalloid intravenous fluid; (6) transfusion of red blood cells (RBC):plasma:platelets in a high unit ratio (>1:2) or reconstituted whole blood in a 1:1:1 unit ratio; (7) early and appropriate use of 4 coagulation factor concentrates; and (8) use of fresh RBCs and whole blood when available.” Early recognition of at-risk patients is key to the appropriate application of DCR principles, in order to avoid the onset of the ‘lethal triad’ of coagulopathy, hypothermia and acidosis. While hypothermia can be addressed through creating a warm environment and using methods of both passive and active rewarming, the prevention and treatment of acidosis and coagulopathy is more difficult and multifaceted. Fluid management and blood product transfusion strategies continue to be refined based upon evolving literature, but are focused on the minimization of crystalloid use and the balanced administration of all blood components. The final step of DCR is the definitive control of any ongoing bleeding, whether through angiography, operative procedures including damage control laparotomy, or other interventions. This chapter will focus on several key elements of DCR.
AC C
EP
The initial literature regarding the ratios of plasma and red blood cell (RBC) transfusion on trauma outcomes came from military reviews of massive transfusion. One such study of 246 patients in a US Army combat support hospital receiving 10 or more units of RBCs during massive transfusion demonstrated that high ratio (1:1.4) transfusion was associated with lower overall mortality and lower hemorrhage-related mortality rates, and that plasma to RBC ratio was independently associated with 5 survival. This led to the initial use of the term ‘damage control resuscitation’ in multiple manuscripts, adoption of the term by United States military investigators, and prompted further investigations into the 6,7 ratio of blood product transfusion in trauma patients. A subsequent analysis of 713 civilian patients in the German trauma registry also demonstrated lower 6 hour, 24 hour, and 30 day mortality rates in 8 patients with higher transfusion ratios. In addition, a 2008 study in the United States also demonstrated lower risk of mortality after massive transfusion with a ratio of FFP to RBC that was equal to or greater 9 than 1 to 1.5. Notably, the risk of Acute Respiratory Distress Syndrome (ARDS) was significantly higher in surviving patients undergoing high ratio transfusion, and further studies from this group in patients with hemorrhage undergoing transfusion again showed higher multiorgan failure (MOF) and ARDS rates with 10 FFP transfusion. This raises the concern that while hemorrhage related outcomes are improved, this may be achieved with subsequent development of significant complications requiring intensive management. The results of these studies have to be interpreted with the caveat that due to the time periods analyzed, survival bias could be influencing results. The concern is whether the results are due to the intervention or just that patients survived long enough to receive it. A study of 134 patients started to address this by factoring in the timing of transfusion into the analysis of blood product ratio, and found no statistical significance in survival between ratio groups, prompting a call for larger prospective trials to address the 11 question of transfusion ratio while accounting for the time of transfusion. Subsequently, several large prospective studies were completed. The Prospective, Observational, Multicenter, Major Trauma Transfusion (PROMMTT) study was a prospective cohort study analyzing the
ACCEPTED MANUSCRIPT
M AN U
SC
RI PT
relationship between the ratio and timing of transfusion and mortality in adult trauma patients who 12 required at least three units of blood during resuscitation. This study demonstrated that the time to transfusion of plasma and platelets was variable across the analysis cohort, and showed that higher ratios of both plasma and platelets to RBCs was associated with decreased 6 hour mortality, at which time the majority of hemorrhage related deaths have occurred. This was then followed by the Pragmatic, Randomized Optimal Platelet and Plasma Rations (PROPPR) trial which showed higher rates of hemostasis and lower bleeding related mortality by 24 hours in patients transfused with a 1:1:1 ratio of plasma, 13 platelets, and red blood cells, compared to a 1:1:2 ratio. These studies suggest that higher transfusion ratios, ideally 1:1:1 ratios, should be a goal in early resuscitation in order to decrease the mortality from hemorrhage during this time period. While there were no differences in rates of ARDS, MOF, or any of the analyzed complications at 30 days between the treatment groups in the PROPPR trial, the overall rates of MOF and ARDS were high in both groups. These trials did address the concern for survival bias from prior studies by discussing earlier timepoints during the resuscitation process and targeting early transfusion, though it should be noted that the Federal Drug Administration (FDA) only allowed primary end points of 24 hours and 30 days. The role of prehospital transfusion is currently an area of continued investigation. Most recently, a 2015 study of 1677 severely injured patients demonstrated decreased transfusion requirements at 6 and 24 hours, and a trend towards lower 6 hour mortality in all patients. The subset of patients deemed 14 most likely to benefit from early blood transfusion were shown to have lower 6 hour mortality. Of note, this study used the previously published Assessment of Blood Consumption (ABC) score to provide clear criteria for prehospital transfusion. This scoring system includes penetrating trauma to the trunk, hypotension, tachycardia, and positive Focused Assessment with Sonography in Trauma (FAST) exam as 15 predictors of need for transfusion. Multiple randomized trials have now been funded by the Department of Defense to investigate the use of prehospital plasma, in order to determine efficacy and to provide 16, 17, 18 additional guidelines as this practice becomes more widespread. Use of Tranexamic Acid and Recombinant Factors
AC C
EP
TE D
Tranexamic acid (TXA) is a synthetic derivative of the amino acid lysine, and acts as an antifibrinolytic by inhibiting the activation of plasminogen to plasmin. With prior evidence that use of TXA 19 reduced the need for transfusion in elective surgery both military and civilian groups have studied the utility of TXA in trauma patients. The Clinical Randomization of an Antifibrinolytic in Significant Hemorrhage (CRASH-2) study was a multinational randomized controlled trial of 20,211 adult trauma patients who were assigned to a loading dose followed by infusion of tranexamic acid versus placebo within 8 hours of the time of injury. All cause mortality was shown to be lower in those treated with tranexamic acid and also demonstrated lower risk of death due to bleeding, without any difference in the rates of any vascular occlusive event. Further analysis demonstrated that early treatment was particularly important in order to decrease the risk of bleeding-related death, with the most significant reduction seen in those treated within 1 hour of injury, though the effect also was seen in those treated between 1 and 3 hours after injury. The data also suggested that there may actually be increased risk of death if patients 20,21 were treated after 3 hours. The use of TXA in military trauma has also been investigated in the MATTERs studies from the United States military. These studies demonstrated that TXA was associated with a survival benefit in patients undergoing transfusion, though transfusion of other factors including 22,23 factor VII and cryoprecipitate does make interpretation of these studies more complex. While these studies suggest that TXA could be effective in trauma resuscitation, recent data does prompt questions regarding its utility. A 2014 retrospective review from Miami showed increased mortality in severely injured trauma patients receiving TXA compared to those who did not receive TXA, however there were multiple limitations to the study which limits the applicability to other patients and 24 trauma centers. A 2015 review publication analyzed the available data on TXA including both large and small scale trials and studies, with the authors concluding that the data does support the use of TXA, particularly in what they term ‘remote damage control resuscitation’ in the prehospital setting, without 25 significant risk of adverse side effects. However, another 2015 study looking at TXA use in 1032 patients with hyperfibrinolysis based upon thromboelastography showed that there was no benefit from TXA use,
ACCEPTED MANUSCRIPT
M AN U
SC
RI PT
first showing increased mortality at 24 hours, but then no difference in in-hospital mortality rates after 26 logistic regression analysis. Given the complexity of the data available on TXA and some of the limitations of existing studies, there is no consensus to this point on the utility of TXA in trauma resuscitation. However, in the deployed setting, the current United States Army Institute of Surgical Research (USAISR) Joint Theater Trauma System Clinical Practice Guideline on DCR from February 2013 states that early use of TXA should be “considered strongly for any patient requiring blood products in the treatment of combat-related hemorrhage and is most strongly advocated in patients judged likely to 27 require massive transfusion.” The use of other agents to reverse coagulopathy in trauma patients continues to be under investigation. The CONTROL trial was a phase three randomized clinical trial analyzing the use of recombinant Factor VIIa in trauma resuscitation. In this study, factor was used in 573 patients who continued to have bleeding despite damage control resuscitation and operative management. The trial was stopped due to low mortality and enrollment difficulties, though it did show decreased blood product 28 use in those patients who received Factor VIIa. The use of prothrombin complex concentrates (PCCs) has also been discussed in the treatment of trauma patients, however at this time studies are largely focused on experimental models or specifically investigate the reversal of anticoagulant therapy in trauma patients. Further investigation is required to determine the utility of any of these products in damage control resuscitation. Crystalloid Use in Damage Control Resuscitation
AC C
EP
TE D
Another element of damage control resuscitation is the judicious use of crystalloid resuscitation for trauma patients. To date, the evidence regarding crystalloid use has been variable depending on the setting and patient population. One important study regarding fluid resuscitation was published in 1994, and was a prospective trial of immediate versus delayed fluid resuscitation in 598 patients who were hypotensive after sustaining penetrating torso injuries. This study demonstrated increased survival in the 29 group receiving delayed fluid resuscitation, and also a trend towards fewer complications. An analysis of the National Trauma Data Bank in 2011 demonstrated that intravenous fluid (IVF) administration was associated with higher mortality in trauma patients, including a significant increase in mortality in patients with penetrating mechanism, which is consistent with prior evidence. While there can be limitations to large database studies such as this, the association demonstrated in this study is important to note within 30 the larger framework of literature on this topic. The interplay between transfusion and fluid resuscitation has also been studied in recent years. A 2011 study by Cotton et al analyzed 390 patients who underwent damage control laparotomy, comparing outcomes in the pre- and post-damage control resuscitation era. Those treated with damage control resuscitation received fewer blood products and less crystalloid, and had better 30 day survival. In addition, they demonstrated that these patients were less likely to exhibit the ‘lethal triad’ of 31 coagulopathy, hypothermia and acidosis upon arrival to the intensive care unit. A later multiinstitutional study analyzed the relationship between 24 hour crystalloid resuscitation volume and outcomes in patients receiving both high and low ratio plasma-red blood cell resuscitation. While this study again confirmed the benefit of high ratio resuscitation, it also demonstrated that crystalloid resuscitation was associated with higher complication rates. It is important to note that this study used 24 32 hour crystalloid volume as the point of study, not just pre-hospital volume. However, not all studies have shown consistent data regarding the effects of IVF resuscitation on trauma patients. A study from the PROMMTT investigators analyzed the differences between patients receiving pre-hospital IVF and those who did not. These patients received a median of 700mL of IVF and 33 this fluid resuscitation was associated with increased survival. Another retrospective study analyzed the volume of prehospital fluid given and correlated it with rates of shock and blood transfusion. They demonstrated that volumes from 0.5 to 2 liters of IVF were associated with lower rates of shock than lower volumes, and that volumes greater than 1 liters of fluid were associated with higher rates of blood 34 transfusion, particularly when over 2 liters of fluid were administered. A trauma registry study from Germany compared patients receiving low versus high volume pre-hospital IVF resuscitation. They
ACCEPTED MANUSCRIPT
RI PT
demonstrated that low volume resuscitation was associated with lower pRBC use, higher ICU-free days, 35 and lower rates of sepsis than high volume resuscitation. The literature regarding the use of intravenous fluid resuscitation in trauma patients continues to evolve at this time, and consensus guidelines have not been recently updated. The existing guidelines suggest that trauma patients who are alert and have a palpable radial pulse do not require prehospital fluid administration. Fluids should be given to patients with falling blood pressures to maintain mentation and regain a strong pulse. Goal blood pressures should be higher in patients with traumatic brain injury, 36, 37 however, in order to maintain cerebral perfusion with goal mean pressure greater than 60mmgHg. When these guidelines and the existing literature are taken together, they suggest that judicious use of pre-hospital crystalloids may be indicated in some trauma populations, as long as volumes are monitored carefully. The data do demonstrate that high volume crystalloid resuscitation is likely detrimental and may increase morbidity in trauma patients.
SC
Summary and Future Directions
AC C
EP
TE D
M AN U
The principles of damage control resuscitation include hemorrhage control, careful use of crystalloid intravenous fluids, and early delivery of high ratios of platelets and plasma to red blood cells. These have become more widely applied in trauma patients as both military and civilian experience continues to support this approach, and studies now are looking to expand DCR to the prehospital arena. Continued research is required to establish the ideal approach to blood product transfusion, to investigate the use of additional hemostatic agents, and to continue to optimize prehospital care of trauma patients.
ACCEPTED MANUSCRIPT
References: 1. Demetriades D, Kimbrell B, Salim A, et al. Trauma deaths in a mature urban trauma system: is ‘trimodal’ distribution a valid concept? J Am Coll Surg. 2005; 201: 343-348.
RI PT
2. Rotondo MF, Schwab CW, McGonigal MD, et al. ‘Damage Control’: An Approach for Improved Survival in Exsanguinating Penetrating Abdominal Injury. J Trauma. 1993; 35: 375-382. 3. Hess JR, Holcomb JB, Hoyt DB. Damage control resuscitation: the need for specific blood products to treat the coagulopathy of trauma. Transfusion. 2006; 46: 685-686.
SC
4. Camazine MN, Hemmila MR, Leonard JC, et al. Massive transfusion policies at trauma centers participating in the American College of Surgeons Trauma Quality Improvement Program. J Trauma Acute Care Surg. 2015; 78: S48-S53.
M AN U
5. Borgman MA, Spinella PC, Perkins JG, et al. The Ratio of Blood Products Transfused Affects Mortality in Patients Receiving Massive Transfusions at a Combat Support Hospital. J Trauma. 2007; 63: 805-813. 6. Hess JR, Holcomb JB, Hoyt DB. Damage control resuscitation: the need for specific blood products to treat the coagulopathy of trauma. Transfusion. 2006; 46: 685-686. 7. Holcomb JB, Jenkins D, Rhee P, et al. Damage control resuscitation: directly addressing the early coagulopathy of trauma. J Trauma. 2007; 62: 307-310.
TE D
8. Maegele M, Lefering R, Paffrath T, et al. Red-blood-cell to plasma ratios transfused during massive transfusion are associated with mortality in severe multiple injury: a retrospective analysis from the Trauma Registry of the Deutsche Gesellschaft für Unfallchirurgie. Vox Sang. 2008; 95: 112-119.
9. Sperry JL, Ochoa JB, Gunn SR, et al. An FFP:PRBC Transfusion Ratio ≥1:1.5 Is Associated With A Lower Risk of Mortality After Massive Transfusion. J Trauma. 2008; 65: 986-993.
EP
10. Watson GA, Sperry JL, Rosengart MR, et al. Fresh Frozen Plasma Is Independently Associated Wtih a Higher Risk of Multiple Organ Failure and Acute Respiratory Distress Syndrome. J Trauma. 2009; 67: 221230.
AC C
11. Snyder CW, Weinberg JA, McGwin G et al. The Relationship of Blood Product Ratio to Mortality : Survival Benefit or Survival Bias? J Trauma. 2009; 66:358-364. 12. Holcomb JB, del Junco DJ, Fox EF et al. The Prospective, Observational, Multicenter, Major Trauma Transfusion (PROMTT) Study. JAMA Surg. 2013;148:127-136. 13. Holcomb JB, Tilley BC, Baraniuk S, et al. Transfusion of Plasma, Platelets, and Red Blood Cells in a 1:1:1 vs a 1:1:2 Ratio and Mortality in Patients With Severe Trauma. The PROPPR Randomized Clinical Trial. JAMA. 2015; 313: 471-482. 14. Holcolmb JB, Donathan DP, Cotton BA. Prehospital Transfusion of Plasma and Red Blood Cells in Trauma Patients. Prehospital Emergency Care. 2015; 19: 1-9. 15. Nunez TC, Voskrensensky IV, Dossett LA. Early prediction of massive transfusion in trauma: simple as ABC (assessment of blood consumption)? J Trauma. 2009; 66: 346-352.
ACCEPTED MANUSCRIPT
16. Brown JB, Guyette FX, Neal MD. Taking the Blood Bank to the Field: The Design and Rationale of the Prehospital Air Medical Plasma (PAMPer) Trial. Prehosp Emerg Care. 2015; 19:343-350. 17. Prehospital Use of Plasma for Traumatic Hemorrhage (PUPTH) Study. Available at : https://clinicaltrials.gov/ct2/show/NCT02303964. Accessed : July 20th, 2015.
RI PT
18. Control of Major Bleeding After Trauma Study (COMBAT). Available at : https://clinicaltrials.gov/ct2/show/NCT01838863. Accessed : July 20th, 2015.
19. Ker K, Edwards P, Perel P et al. Effect of tranexamic acid on surgical bleeding: systematic review and cumulative meta-anaylsis. BMJ. 2012; 344: e3054.
SC
20. CRASH-2 Trial Collaborators. Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2) : a randomized, placebocontrolled trial. Lancet. 2010; 376: 23-32.
M AN U
21. CRASH-2 collaborators. The importance of early treatment with tranexamic acid in bleeding trauma patients: an exploratory analysis of the CRASH-2 randomised controlled trial. Lancet. 2011; 377: 10961101. 22. Morrison JJ, Dubose JJ, Rasmussen TE and Midwinter MJ. Military Application of Tranexamic Acid in Trauma Emergency Resuscitation (MATTERs) Study. Arch Surg. 2012; 147: 113-119. 23. Morrison JJ, Ross JD, Dubose JJ, et al. Association of Cryoprecipitate and Tranexamic Acid With Improved Survival Following Wartime Injury. JAMA Surg. 2013; 148: 218-225.
TE D
24. Valle EJ, Allen CJ, Van Haren RM, et al. Do all trauma patients benefit from tranexamic acid? J Trauma Acute Care Surg. 2014; 76: 1373-1378. 25. Ausset S, Glassberg E, Nadler R, et al. Tranexamic acid as part of remote damage-control resuscitation in the prehospital setting: A critical appraisal of the medical literature and available alternatives. J Trauma Acute Care Surg. 2015; 78: S70-S75.
EP
26. Harvin JA, Peirce CA, Mims MM. The impact of tranexamic acid on mortality in injured patients with hyperfibrinolysis. J Trauma Acute Care Surg. 2015; 78: 905-911.
AC C
27. US Army Institute of Surgical Research Joint Trauma System Clinical Practice Guidelines on Damage Control Resuscitation. Available at: http://www.usaisr.amedd.army.mil/cpgs/Damage%20Control%20Resuscitation%20th %201%20Feb%202013.pdf. Accessed : August 17 , 2015. 28. Hauser CJ, Boffard K, Dutton R, et al. Results of the CONTROL Trial: Efficacy and Safety of Recombinant Activated Factor VII in the Management of Refractory Traumatic Hemorrhage. J Trauma. 2010; 69: 489500. 29. Bickell WH, Wall MJ, Pepe PE, et al. Immediate versus delayed fluid resuscitation for hypotensive patients with penetrating torso injuries. NEJM. 1994; 331: 1105-1109. 30. Haut ER, Kalish BT, Cotton BA, et al. Prehospital Intravenous Fluid Administration is Associated With Higher Mortality in Trauma Patients : A National Trauma Data Bank Analysis. Ann Surg. 2011; 253: 371378.
ACCEPTED MANUSCRIPT
31. Cotton BA, Reddy N, Hatch QM, et al. Damage Control Resuscitation is Associated With a Reduction in Resuscitation Volumes and Improvement in Survival in 390 Damage Control Laparotomy Patients. Ann Surg. 2011; 254: 598-605. 32. Duchesne JC, Heaney K, Guidry C. Diluting the benefits of hemostatic resuscitation: A multiinstitutional analysis. J Trauma Acute Care Surg. 2013; 75: 76-82.
RI PT
33. Hampton DA, Fabricant LJ, Differding J, et al. Pre-Hospital Intravenous Fluid is Associated with Increased Survival in Trauma Patients. J Trauma Acute Care Surg. 2013; 75: S9-S15.
34. Geeraedts LMG, Pothof LAH, Caldwell E, et al. Prehospital fluid resuscitation in hypotensive trauma patients: Do we need a tailored approach? Injury. 2015; 46: 4-9.
SC
35. Humann B, Lefering R, Taeger G, et al. Influence of prehospital fluid resuscitation on patients with multiple injuries in hemorrhagic shock in patients from the DGU trauma registry. J Emerg Trauma Shock. 2011; 4: 465-471.
M AN U
36. Cotton BA, Jerome R, Collier BR, et al. Guidelines for Prehospital Fluid Resuscitation in the Injured Patient. Journal of Trauma-Injury Infection & Critical Care. 2009; 67: 389-402.
AC C
EP
TE D
37. McSwain NE, Champion HR, Fabian TC, et al. State of the Art of Fluid Resuscitation 2010 : Prehospital and Immediate Transition to the Hospital. Journal of Trauma-Injury Infection & Critical Care. 2011; 70: S2S10.
ACCEPTED MANUSCRIPT
Highlights:
• •
•
RI PT
SC
•
A balanced ratio of blood products, ideally 1:1:1 ratios, should be a goal in early resuscitation in order to decrease the mortality from hemorrhage during this time period. Tranexamic acid (TXA) is a synthetic derivative of the amino acid lysine, and acts as an antifibrinolytic by inhibiting the activation of plasminogen to plasmin.
M AN U
•
Fluid management and blood product transfusion strategies continue to be refined based upon evolving literature, but are focused on the minimization of crystalloid use and the balanced administration of all blood components.
Both military and civilian groups have studied the utility of TXA in trauma patients. The current United States Army Institute of Surgical Research (USAISR) Joint Theater Trauma System Clinical Practice Guideline on DCR from February 2013 states that early use of TXA should be “considered strongly for any patient requiring blood products in the treatment of combat-related hemorrhage and is most strongly advocated in patients judged likely to require massive transfusion.
TE D
•
Early recognition of at-risk patients is key to the appropriate application of DCR principles, in order to avoid the onset of the ‘lethal triad’ of coagulopathy, hypothermia and acidosis.
The literature regarding the use of intravenous fluid resuscitation in trauma patients continues to evolve at this time, and consensus guidelines have not been recently updated. The existing guidelines suggest that trauma patients who are alert and have a palpable radial pulse do not require prehospital fluid administration.
EP
•
The principles of damage control resuscitation (DCR) include hemorrhage control, careful use of crystalloid intravenous fluids, and early delivery of high ratios of platelets and plasma to red blood cells.
AC C
•