Critical Care Update
David J. Dries, MSE, MD
Resuscitation: Part 1 Brohi K, Singh J, Heron M, Coats T. Acute traumatic coagulopathy. J Trauma. 2003;54:1127-1120. Hess JR, Brohi K, Dutton RP, et al. The coagulopathy of trauma: a review of mechanisms. J Trauma. 2008;65:748-754. Khan S, Brohi K, Chana M, et al. Hemostatic resuscitation is neither hemostatic nor resuscitative in trauma hemorrhage. J Trauma Acute Care Surg. 2014;76:561-568. Coagulopathy after severe injury probably affects 25% of patients in civilian practice. Historically, this phenomenon was attributed to the dilution of clotting factors from intravenous fluid therapy; massive blood transfusion, particularly with packed red blood cells; progressive hypothermia; and acidosis. More recent studies show that a variety of insults contribute to coagulation changes in up to 25% of severely injured patients and that these changes can be identified before injured individuals reach the emergency department. The release of mediators after tissue trauma clearly activates humoral cascades including coagulation, fibrinolysis, complement, and kallikrein. There are many secondary effects on neutrophils, macrophages, platelets, and other cellular elements that provoke changes in the hemostatic response. Notably, these mechanisms are similar to those contributing to the development of systemic inflammatory response and multiple organ failure. There are a number of injuries that are known to interfere with coagulation, thus complicating resuscitation. Brain injuries have been shown to lead to coagulopathy caused in part by the release of brain tissue thromboplastins after neuronal injury. Long-bone fractures have also been associated with disorders of hemostasis. Works in recent years identifying coagulopathy after trauma initiated by Brohi and others identify a severe metabolic response to major injury, which, if present, has dramatic adverse outcome consequences. Coagulopathy after trauma is multifactorial and involves all components of hemostasis. The inappropriate activation or dysfunction of fibrin generation, platelets, and endothelium plays a role together with the relative inhibition of stable clot formation by anticoagulant and fibrinolytic pathways. Which of these parallel mechanisms predominates may depend on the nature and severity of tissue injuries, the degree of circulatory derangement with associated perfusion compromise, and any deleterious side effects of medical therapies (Fig. 1).
Initiators of Coagulopathy in Trauma Tissue injury is universal in trauma, but traumatic injuries vary widely in the amount of associated tissue damage. For 190
example, crush or explosion injuries carry an enormous tissue injury burden, whereas lethal penetrating trauma may have very little associated tissue damage, yet coagulopathy may be a feature in both clinical situations. There is no doubt that injury severity is closely associated with the degree of coagulopathy after trauma. However, patients with severe tissue injury but no physiologic derangement rarely present with coagulopathy and have a relatively low mortality rate. Among coagulation changes associated with tissue trauma are excessive breakdown of fibrin, inappropriate clotting cascade activation because of endothelial injury, and exhaustion of platelet and clotting factor stores. As a result, tissue trauma leads to a disorganized and ineffective pattern of clot formation and lysis. Shock is another essential driver of early coagulopathy. There appears to be a dose-dependent association between the severity of tissue hypoperfusion and the degree of admission coagulopathy. Base deficit ⬎ 6 mmol/L has been associated with coagulopathy in a quarter of patients in 1 large review. Remarkably, patients whose trauma does not include a component of shock generally have normal coagulation parameters at admission despite major mechanical insults as indicated by high Injury Severity Scores. As noted previously, clotting derangements have been identified before dilutional effects of fluid administration in the field or in the hospital. Mechanisms underlying shock-induced coagulopathy remain unclear. The shock state appears to result in the hemostatic system becoming globally anticoagulant and hyperfibrinolytic. The dilution of coagulation factors must still be considered as a cause of clinical coagulopathy in trauma. During shock, reduced intravascular hydrostatic pressure results in shifts of fluid deficient in coagulation factors from the cellular and interstitial spaces into the plasma. Attendant dilution of coagulation factors is compounded by resuscitation using standard crystalloid solutions. Adverse effects of crystalloid administration on coagulation have been shown in a variety of experimental settings. Simple administration of packed red cell therapy also results in the dilution of clotting factors and a reduction in clotting ability. Therefore, mathematical models suggest that blood component therapy must be administered in a ratio of 1:1:1 (red cell:plasma:platelets) to avoid the effects of dilution and administer a mixture of available components that is as physiologically close to whole blood as possible (Table 1). Hypothermia inhibits coagulation protease activity and platelet function. Low temperatures decrease platelet activation. Mild hypothermia is common in trauma patients. In addition to environmental exposure, injured patients have reduced heat production by underperfused muscles and increased heat loss because of evaporation from exposed body cavities during operative procedures. Historic data show Air Medical Journal 33:5
Figure 1. ACoTS ⫽ Acute Coagulopathy of Trauma Shock (Reprinted with permission from Hess et al., The coagulopathy of trauma: A review of mechanisms. J Trauma 2008;65:748-754.)
increased mortality from traumatic hemorrhage when core temperatures fall below 32°C. Within the temperature range commonly seen in trauma patients (33°C-36°C), isolated hypothermia probably has limited clinical impact on clotting. Acidemia is another common event in trauma typically produced by low-flow states and excess chloride administered during resuscitation. Acidemia impairs the function of coagulation factors with associated prolongation of clotting times and reduction in clot strength. Although acidemia can be corrected by the administration of buffer solutions, this does not eliminate coagulopathy. This implies that the acid effect on clotting is more than a simple physical reduction in protein activity. Again, an overlap in underlying mechanisms contributing to coagulopathy is suggested. Inflammation is a byproduct of trauma and systemic inflammatory response syndrome and another common consequence in severe injury. Endothelial activation and injury leads to the activation of cellular and humoral elements of the immune system with significant cross talk between the coagulation and inflammation cascades. The activation of inflammation may also lead to derangements in coagulation. Over their clinical course, trauma patients are initially coagulopathic with increased bleeding but then switch to a hypercoagulable state, putting them at increased risk of thrombotic events. This late prothrombotic state resembles the coagulopathy of severe sepsis. Trauma patients have a higher incidence of sepsis than average critical care populations, and in both trauma and sepsis patients, an episode of coagulopathy may include a later prothrombotic state and multiple organ failure. In response to the coagulation changes associated with severe injury, the concept of hemostatic or damage control resuscitation has evolved. Frequently, this strategy involves titration of blood products in a 1:1:1 ratio including red blood cells, plasma, and platelets for empiric therapy or specific addition of plasma and platelets to red blood cell infuSeptember-October 2014
sions based on bedside guidance with thromboelastography. Although this approach to the injured patient with major bleeding has been associated with improved clinical outcomes, the efficacy of damage control resuscitation to restore tissue perfusion and correct coagulopathy during acute hemorrhage has not been critically evaluated. Coagulopathy and hypoperfusion have been shown to correct with damage control resuscitation but only at the end of damage control surgery or after admission to the critical care setting when hemorrhage control has been achieved. In the most recent work by Brohi and an international group of investigators, the effectiveness of damage control resuscitation in the improvement of coagulopathy or hypoperfusion during acute bleeding remains in question. Using thromboelastography and serial lactate determination as a measure of perfusion, severely injured trauma patients requiring blood transfusions were studied if the patient presented with a systolic blood pressure ⬍ 90 mm Hg, demonstrated a poor response to initial crystalloid resuscitation, and/or had suspected active hemorrhage. On admission, this patient group was hypoperfused with an admission lactate of 6.2 mEq/L, and 43% of patients were coagulopathic on thromboelastography at the time of presentation. If patients continued to require blood product administration, the percent of coagulopathic patients increased to 69% after the administration of the 12th unit of packed red blood cells. Again, a consistent observation was failure of resolution of coagulopathy and acidemia until hemorrhage control was achieved. This latest work questions the fundamental therapeutic mechanism of damage control resuscitation in the acute phase of trauma hemorrhage. Aggressive high-volume replacement using a combination of blood products did not restore deranged thromboelastographic parameters in hypoperfusion until bleeding had ceased. It appears that better design and titration of damage control resuscitation with refinement of target values for coagulation parameters in the bleeding trauma patient is neces191
Table 1. Whole Blood Composition Compared With Component Therapy Whole Blood (500 mL) Component Therapy (660 mL) Hematocrit 38%-50% 1 unit PRBCs ⫽ 335 mL with hematocrit 55% Platelets 150-400 K/L 1 unit platelets ⫽ 50 mL with 5.5 × 1010 platelets Plasma coagulation factors ⫽ 100% 1 unit plasma ⫽ 275 mL with 80% of the coagulation activity compared with whole blood PRBC ⫽ packed red blood cells. One unit PRBCs ⫹ 1 unit platelets ⫹ 1 unit fresh frozen plasma ⫽ 660 mL with hematocrit 29%, platelets 88 K/L, and coagulation activity 65% compared with whole blood. Reprinted with permission from Sihler KC and Napolitano LM, Complications of massive transfusion. Chest. 2010;137:209-220.
sary. As we better understand these metabolic changes, opportunities exist to improve management and further support outcomes for major bleeding in the setting of injury.
Neal MD, Hoffman MK, Cuschieri J, et al. Crystalloid to packed red blood cell transfusion ratio in the massively transfused patient: when a little goes a long way. J Trauma. 2012;72:892-898. Duke MD, Guidry C, Guice J, et al. Restrictive fluid resuscitation in combination with damage control resuscitation: time for adaptation. J Trauma Acute Care Surg. 2012;73:674-678. Hemostatic resuscitation with damage control administration of blood products has been advanced to avoid coagulopathy and associated morbidities seen with large-volume blood transfusions. In addition to the use of blood products, however, the use of crystalloid solutions remains common in patients experiencing significant hemorrhage. Large-volume crystalloid resuscitation has been shown to be associated with cardiac, pulmonary, and coagulopathic complications occurring secondary to the cellular and metabolic disturbances associated with the administration of large volumes of these salt solutions after hemorrhage. The 2 studies included here highlight the incremental risk of large-volume crystalloid administration in the setting of significant bleeding. The first study included data from the multicenter National Institutes of Health study known as The Inflammation and The Host Response Injury Large Scale Collaborative Program (Glue Grant) supported by the National Institute of General Medical Sciences. This is an excellent data set to examine because standardized protocols were used for early resuscitation, glycemic control, thromboembolism prophylaxis, mechanical ventilation, and blood product use. A review of resuscitation practice in these Glue Grant patients identified incremental risk of multiple organ failure, acute respiratory distress syndrome, and abdominal compartment syndrome because patients received administration of 1 L crystalloid for each unit of packed red blood cells infused during the first 24 hours after injury. In fact, during the early years of patient accrual, if the ratio of crystalloid liters to packed red blood cell units was ⬎ 1.5:1, there was a 5-fold increased risk of acute respiratory distress syndrome and a 6-fold independent risk increase of abdominal compartment syndrome. Interestingly, early central venous pressure, shock parameters 192
including pH and base deficit, and requirement for early vasopressor administration was similar across the entire study cohort, suggesting that end points for resuscitation across patients receiving different ratios of crystalloid to packed red blood cells were similar. A second similar study comes from Tulane University and the Louisiana State University Health Science Center. This was single-center retrospective data examining patients with penetrating torso injuries and a presenting systolic blood pressure ⬍ 90 mm Hg. All patients received damage control resuscitation followed by resuscitative surgery. Groups were stratified according to the quantity of crystalloid obtained before surgical intervention. Patients with restricted fluid resuscitation received ⬍ 150 mL fluid, whereas standard resuscitation patients received approximately 3 L crystalloid before the operating room. Intraoperative mortality was significantly lower (3-fold) in patients receiving restrictive crystalloid administration, hospital stay was significantly less, and patients with restrictive fluid administration had an overall odds ratio for mortality of 0.69 relative to patients receiving standard fluid administration. These authors had a target systolic blood pressure of 90 mm Hg with minimal use of crystalloid solutions before administration of blood products and rapid transition to surgery. Again, in the setting of severe injury associated with active blood loss, the need to avoid crystalloid administration and, if necessary, accept relative hypotension is supported.
McDaniel LM, Neal MD, Sperry JL, et al. Use of a massive transfusion protocol in nontrauma patients: activate away. J Am Coll Surg. 2013;26:1103-1109. Baumann Kreuziger LM, Morton CT, Subramanian AT, et al. Not only in trauma patients: hospital-wide implementation of a massive transfusion protocol. Transfus Med. 2014;24:162-168. Although data supporting the use of massive transfusion or damage control resuscitation grew from the practice of trauma surgeons and trauma programs, many institutions use blood product transfusion protocols in nontrauma patients with major bleeding. Common nontrauma patients receiving transfusion protocols have gastrointestinal bleeding, postsurgical bleeding complications, vascular catastrophes such as aortic aneurysm rupture, and operative management of complicated cerebral hemorrhage. Data from Air Medical Journal 33:5
McDaniel et al at the University of Pittsburgh suggest that damage control resuscitation was activated more frequently when not needed in nontrauma patients but that a standardized administration of products in patients without trauma but significant bleeding from other sources created benefit from more rapid administration of multicomponent therapy in a standardized fashion. The rate of “overactivation” in nontrauma patients was much higher (53.8%) than that for trauma patients (19.2%). In part, this may be because of the availability of standard algorithms to predict the need for massive transfusion in the setting of trauma, whereas similar criteria have not been developed for damage control resuscitation in the nontrauma setting. Baumann Kreuziger et al from the University of Minnesota examined the hospital impact of activation of a standard blood product resuscitation protocol for trauma and nontrauma patients. One hundred twenty-five patients received activation of the protocol over a 2-year period. Only 8 patients in this institution had massive transfusion off protocol during this time. As noted by the Pittsburgh group, the Minnesota investigators also noted a consistent pattern of blood product administration to both medical, nontrauma surgical, and trauma patients. Nontrauma vascular emergencies accounted for 83% of the nontrauma problems requiring high-volume blood product use. Transfusion reactions and other complications were infrequent in the Minnesota cohort (2.4%). The Minnesota investigators evaluated the impact of massive transfusion protocols on overall blood product use in the hospital. Doing “before/after” analysis, the use of high-volume blood product resuscitation for both trauma and nontrauma patients did not impact hospital-wide blood product use nor was a significant hospital-wide change in plasma or platelet use noted despite the tendency to use components in a 1:1:1 ratio. In fact, a trend toward decreased red blood cell infusion per patient was noted but was not statistically significant after the implementation of a massive transfusion protocol. Aggressive product use in bleeding patients did not conflict with a hospital initiative toward blood product conservation. In summary, protocols for multicomponent blood product administration may be used with both trauma and nontrauma patients without affecting transfusion-related complication rates or overall blood product use in the hospital.
improved outcomes in the setting of massive bleeding after injury, but coagulation and metabolic parameters do not improve until bleeding is controlled. • When the use of a massive transfusion protocol or damage control resuscitation is anticipated, crystalloid administration should be reduced in favor of blood product administration because of the increased risk of multiple organ failure and mortality with high-volume crystalloid administration. • Damage control resuscitation (or massive transfusion protocols) may be used in both trauma and nontrauma patients. The overall hospital use of products is not affected by the use of a blood product administration protocol for emergent bleeding, and a consistent approach to emergent transfusion is achieved throughout the institution. David J. Dries, MSE, MD, is assistant medical director for surgical services at HealthPartners Medical Group and professor of surgery and anesthesiology at the University of Minnesota in Minneapolis, MN, and can be reached at [email protected].
Acknowledgment The author acknowledges the assistance of Ms. Sherry Willett in preparation of this series for Air Medical Journal. 1067-991X/$36.00 Copyright 2014 by Air Medical Journal Associates http://dx.doi.org/10.1016/j.amj.2014.06.003
Summary Points • Coagulopathy has been shown in the setting of injury even before the administration of crystalloid solutions. This observation contradicts the historic view that dilution of clotting factors by crystalloid solutions was the major source of coagulation abnormality early after injury. • Coagulopathy complicating trauma resuscitation occurs in up to 25% of severely injured patients. Factors contributing in parallel to this process include shock, tissue injury, hypothermia, inflammation, hemodilution, and acidemia. • Damage control resuscitation with the aggressive use of red blood cells, plasma, and platelets in a 1:1:1 ratio have September-October 2014
193
David J. Dries, MSE, MD
Resuscitation: Part 1 Brohi K, Singh J, Heron M, Coats T. Acute traumatic coagulopathy. J Trauma. 2003;54:1127-1120. Hess JR, Brohi K, Dutton RP, et al. The coagulopathy of trauma: a review of mechanisms. J Trauma. 2008;65:748-754. Khan S, Brohi K, Chana M, et al. Hemostatic resuscitation is neither hemostatic nor resuscitative in trauma hemorrhage. J Trauma Acute Care Surg. 2014;76:561-568. Coagulopathy after severe injury probably affects 25% of patients in civilian practice. Historically, this phenomenon was attributed to the dilution of clotting factors from intravenous fluid therapy; massive blood transfusion, particularly with packed red blood cells; progressive hypothermia; and acidosis. More recent studies show that a variety of insults contribute to coagulation changes in up to 25% of severely injured patients and that these changes can be identified before injured individuals reach the emergency department. The release of mediators after tissue trauma clearly activates humoral cascades including coagulation, fibrinolysis, complement, and kallikrein. There are many secondary effects on neutrophils, macrophages, platelets, and other cellular elements that provoke changes in the hemostatic response. Notably, these mechanisms are similar to those contributing to the development of systemic inflammatory response and multiple organ failure. There are a number of injuries that are known to interfere with coagulation, thus complicating resuscitation. Brain injuries have been shown to lead to coagulopathy caused in part by the release of brain tissue thromboplastins after neuronal injury. Long-bone fractures have also been associated with disorders of hemostasis. Works in recent years identifying coagulopathy after trauma initiated by Brohi and others identify a severe metabolic response to major injury, which, if present, has dramatic adverse outcome consequences. Coagulopathy after trauma is multifactorial and involves all components of hemostasis. The inappropriate activation or dysfunction of fibrin generation, platelets, and endothelium plays a role together with the relative inhibition of stable clot formation by anticoagulant and fibrinolytic pathways. Which of these parallel mechanisms predominates may depend on the nature and severity of tissue injuries, the degree of circulatory derangement with associated perfusion compromise, and any deleterious side effects of medical therapies (Fig. 1).
Initiators of Coagulopathy in Trauma Tissue injury is universal in trauma, but traumatic injuries vary widely in the amount of associated tissue damage. For 190
example, crush or explosion injuries carry an enormous tissue injury burden, whereas lethal penetrating trauma may have very little associated tissue damage, yet coagulopathy may be a feature in both clinical situations. There is no doubt that injury severity is closely associated with the degree of coagulopathy after trauma. However, patients with severe tissue injury but no physiologic derangement rarely present with coagulopathy and have a relatively low mortality rate. Among coagulation changes associated with tissue trauma are excessive breakdown of fibrin, inappropriate clotting cascade activation because of endothelial injury, and exhaustion of platelet and clotting factor stores. As a result, tissue trauma leads to a disorganized and ineffective pattern of clot formation and lysis. Shock is another essential driver of early coagulopathy. There appears to be a dose-dependent association between the severity of tissue hypoperfusion and the degree of admission coagulopathy. Base deficit ⬎ 6 mmol/L has been associated with coagulopathy in a quarter of patients in 1 large review. Remarkably, patients whose trauma does not include a component of shock generally have normal coagulation parameters at admission despite major mechanical insults as indicated by high Injury Severity Scores. As noted previously, clotting derangements have been identified before dilutional effects of fluid administration in the field or in the hospital. Mechanisms underlying shock-induced coagulopathy remain unclear. The shock state appears to result in the hemostatic system becoming globally anticoagulant and hyperfibrinolytic. The dilution of coagulation factors must still be considered as a cause of clinical coagulopathy in trauma. During shock, reduced intravascular hydrostatic pressure results in shifts of fluid deficient in coagulation factors from the cellular and interstitial spaces into the plasma. Attendant dilution of coagulation factors is compounded by resuscitation using standard crystalloid solutions. Adverse effects of crystalloid administration on coagulation have been shown in a variety of experimental settings. Simple administration of packed red cell therapy also results in the dilution of clotting factors and a reduction in clotting ability. Therefore, mathematical models suggest that blood component therapy must be administered in a ratio of 1:1:1 (red cell:plasma:platelets) to avoid the effects of dilution and administer a mixture of available components that is as physiologically close to whole blood as possible (Table 1). Hypothermia inhibits coagulation protease activity and platelet function. Low temperatures decrease platelet activation. Mild hypothermia is common in trauma patients. In addition to environmental exposure, injured patients have reduced heat production by underperfused muscles and increased heat loss because of evaporation from exposed body cavities during operative procedures. Historic data show Air Medical Journal 33:5
Figure 1. ACoTS ⫽ Acute Coagulopathy of Trauma Shock (Reprinted with permission from Hess et al., The coagulopathy of trauma: A review of mechanisms. J Trauma 2008;65:748-754.)
increased mortality from traumatic hemorrhage when core temperatures fall below 32°C. Within the temperature range commonly seen in trauma patients (33°C-36°C), isolated hypothermia probably has limited clinical impact on clotting. Acidemia is another common event in trauma typically produced by low-flow states and excess chloride administered during resuscitation. Acidemia impairs the function of coagulation factors with associated prolongation of clotting times and reduction in clot strength. Although acidemia can be corrected by the administration of buffer solutions, this does not eliminate coagulopathy. This implies that the acid effect on clotting is more than a simple physical reduction in protein activity. Again, an overlap in underlying mechanisms contributing to coagulopathy is suggested. Inflammation is a byproduct of trauma and systemic inflammatory response syndrome and another common consequence in severe injury. Endothelial activation and injury leads to the activation of cellular and humoral elements of the immune system with significant cross talk between the coagulation and inflammation cascades. The activation of inflammation may also lead to derangements in coagulation. Over their clinical course, trauma patients are initially coagulopathic with increased bleeding but then switch to a hypercoagulable state, putting them at increased risk of thrombotic events. This late prothrombotic state resembles the coagulopathy of severe sepsis. Trauma patients have a higher incidence of sepsis than average critical care populations, and in both trauma and sepsis patients, an episode of coagulopathy may include a later prothrombotic state and multiple organ failure. In response to the coagulation changes associated with severe injury, the concept of hemostatic or damage control resuscitation has evolved. Frequently, this strategy involves titration of blood products in a 1:1:1 ratio including red blood cells, plasma, and platelets for empiric therapy or specific addition of plasma and platelets to red blood cell infuSeptember-October 2014
sions based on bedside guidance with thromboelastography. Although this approach to the injured patient with major bleeding has been associated with improved clinical outcomes, the efficacy of damage control resuscitation to restore tissue perfusion and correct coagulopathy during acute hemorrhage has not been critically evaluated. Coagulopathy and hypoperfusion have been shown to correct with damage control resuscitation but only at the end of damage control surgery or after admission to the critical care setting when hemorrhage control has been achieved. In the most recent work by Brohi and an international group of investigators, the effectiveness of damage control resuscitation in the improvement of coagulopathy or hypoperfusion during acute bleeding remains in question. Using thromboelastography and serial lactate determination as a measure of perfusion, severely injured trauma patients requiring blood transfusions were studied if the patient presented with a systolic blood pressure ⬍ 90 mm Hg, demonstrated a poor response to initial crystalloid resuscitation, and/or had suspected active hemorrhage. On admission, this patient group was hypoperfused with an admission lactate of 6.2 mEq/L, and 43% of patients were coagulopathic on thromboelastography at the time of presentation. If patients continued to require blood product administration, the percent of coagulopathic patients increased to 69% after the administration of the 12th unit of packed red blood cells. Again, a consistent observation was failure of resolution of coagulopathy and acidemia until hemorrhage control was achieved. This latest work questions the fundamental therapeutic mechanism of damage control resuscitation in the acute phase of trauma hemorrhage. Aggressive high-volume replacement using a combination of blood products did not restore deranged thromboelastographic parameters in hypoperfusion until bleeding had ceased. It appears that better design and titration of damage control resuscitation with refinement of target values for coagulation parameters in the bleeding trauma patient is neces191
Table 1. Whole Blood Composition Compared With Component Therapy Whole Blood (500 mL) Component Therapy (660 mL) Hematocrit 38%-50% 1 unit PRBCs ⫽ 335 mL with hematocrit 55% Platelets 150-400 K/L 1 unit platelets ⫽ 50 mL with 5.5 × 1010 platelets Plasma coagulation factors ⫽ 100% 1 unit plasma ⫽ 275 mL with 80% of the coagulation activity compared with whole blood PRBC ⫽ packed red blood cells. One unit PRBCs ⫹ 1 unit platelets ⫹ 1 unit fresh frozen plasma ⫽ 660 mL with hematocrit 29%, platelets 88 K/L, and coagulation activity 65% compared with whole blood. Reprinted with permission from Sihler KC and Napolitano LM, Complications of massive transfusion. Chest. 2010;137:209-220.
sary. As we better understand these metabolic changes, opportunities exist to improve management and further support outcomes for major bleeding in the setting of injury.
Neal MD, Hoffman MK, Cuschieri J, et al. Crystalloid to packed red blood cell transfusion ratio in the massively transfused patient: when a little goes a long way. J Trauma. 2012;72:892-898. Duke MD, Guidry C, Guice J, et al. Restrictive fluid resuscitation in combination with damage control resuscitation: time for adaptation. J Trauma Acute Care Surg. 2012;73:674-678. Hemostatic resuscitation with damage control administration of blood products has been advanced to avoid coagulopathy and associated morbidities seen with large-volume blood transfusions. In addition to the use of blood products, however, the use of crystalloid solutions remains common in patients experiencing significant hemorrhage. Large-volume crystalloid resuscitation has been shown to be associated with cardiac, pulmonary, and coagulopathic complications occurring secondary to the cellular and metabolic disturbances associated with the administration of large volumes of these salt solutions after hemorrhage. The 2 studies included here highlight the incremental risk of large-volume crystalloid administration in the setting of significant bleeding. The first study included data from the multicenter National Institutes of Health study known as The Inflammation and The Host Response Injury Large Scale Collaborative Program (Glue Grant) supported by the National Institute of General Medical Sciences. This is an excellent data set to examine because standardized protocols were used for early resuscitation, glycemic control, thromboembolism prophylaxis, mechanical ventilation, and blood product use. A review of resuscitation practice in these Glue Grant patients identified incremental risk of multiple organ failure, acute respiratory distress syndrome, and abdominal compartment syndrome because patients received administration of 1 L crystalloid for each unit of packed red blood cells infused during the first 24 hours after injury. In fact, during the early years of patient accrual, if the ratio of crystalloid liters to packed red blood cell units was ⬎ 1.5:1, there was a 5-fold increased risk of acute respiratory distress syndrome and a 6-fold independent risk increase of abdominal compartment syndrome. Interestingly, early central venous pressure, shock parameters 192
including pH and base deficit, and requirement for early vasopressor administration was similar across the entire study cohort, suggesting that end points for resuscitation across patients receiving different ratios of crystalloid to packed red blood cells were similar. A second similar study comes from Tulane University and the Louisiana State University Health Science Center. This was single-center retrospective data examining patients with penetrating torso injuries and a presenting systolic blood pressure ⬍ 90 mm Hg. All patients received damage control resuscitation followed by resuscitative surgery. Groups were stratified according to the quantity of crystalloid obtained before surgical intervention. Patients with restricted fluid resuscitation received ⬍ 150 mL fluid, whereas standard resuscitation patients received approximately 3 L crystalloid before the operating room. Intraoperative mortality was significantly lower (3-fold) in patients receiving restrictive crystalloid administration, hospital stay was significantly less, and patients with restrictive fluid administration had an overall odds ratio for mortality of 0.69 relative to patients receiving standard fluid administration. These authors had a target systolic blood pressure of 90 mm Hg with minimal use of crystalloid solutions before administration of blood products and rapid transition to surgery. Again, in the setting of severe injury associated with active blood loss, the need to avoid crystalloid administration and, if necessary, accept relative hypotension is supported.
McDaniel LM, Neal MD, Sperry JL, et al. Use of a massive transfusion protocol in nontrauma patients: activate away. J Am Coll Surg. 2013;26:1103-1109. Baumann Kreuziger LM, Morton CT, Subramanian AT, et al. Not only in trauma patients: hospital-wide implementation of a massive transfusion protocol. Transfus Med. 2014;24:162-168. Although data supporting the use of massive transfusion or damage control resuscitation grew from the practice of trauma surgeons and trauma programs, many institutions use blood product transfusion protocols in nontrauma patients with major bleeding. Common nontrauma patients receiving transfusion protocols have gastrointestinal bleeding, postsurgical bleeding complications, vascular catastrophes such as aortic aneurysm rupture, and operative management of complicated cerebral hemorrhage. Data from Air Medical Journal 33:5
McDaniel et al at the University of Pittsburgh suggest that damage control resuscitation was activated more frequently when not needed in nontrauma patients but that a standardized administration of products in patients without trauma but significant bleeding from other sources created benefit from more rapid administration of multicomponent therapy in a standardized fashion. The rate of “overactivation” in nontrauma patients was much higher (53.8%) than that for trauma patients (19.2%). In part, this may be because of the availability of standard algorithms to predict the need for massive transfusion in the setting of trauma, whereas similar criteria have not been developed for damage control resuscitation in the nontrauma setting. Baumann Kreuziger et al from the University of Minnesota examined the hospital impact of activation of a standard blood product resuscitation protocol for trauma and nontrauma patients. One hundred twenty-five patients received activation of the protocol over a 2-year period. Only 8 patients in this institution had massive transfusion off protocol during this time. As noted by the Pittsburgh group, the Minnesota investigators also noted a consistent pattern of blood product administration to both medical, nontrauma surgical, and trauma patients. Nontrauma vascular emergencies accounted for 83% of the nontrauma problems requiring high-volume blood product use. Transfusion reactions and other complications were infrequent in the Minnesota cohort (2.4%). The Minnesota investigators evaluated the impact of massive transfusion protocols on overall blood product use in the hospital. Doing “before/after” analysis, the use of high-volume blood product resuscitation for both trauma and nontrauma patients did not impact hospital-wide blood product use nor was a significant hospital-wide change in plasma or platelet use noted despite the tendency to use components in a 1:1:1 ratio. In fact, a trend toward decreased red blood cell infusion per patient was noted but was not statistically significant after the implementation of a massive transfusion protocol. Aggressive product use in bleeding patients did not conflict with a hospital initiative toward blood product conservation. In summary, protocols for multicomponent blood product administration may be used with both trauma and nontrauma patients without affecting transfusion-related complication rates or overall blood product use in the hospital.
improved outcomes in the setting of massive bleeding after injury, but coagulation and metabolic parameters do not improve until bleeding is controlled. • When the use of a massive transfusion protocol or damage control resuscitation is anticipated, crystalloid administration should be reduced in favor of blood product administration because of the increased risk of multiple organ failure and mortality with high-volume crystalloid administration. • Damage control resuscitation (or massive transfusion protocols) may be used in both trauma and nontrauma patients. The overall hospital use of products is not affected by the use of a blood product administration protocol for emergent bleeding, and a consistent approach to emergent transfusion is achieved throughout the institution. David J. Dries, MSE, MD, is assistant medical director for surgical services at HealthPartners Medical Group and professor of surgery and anesthesiology at the University of Minnesota in Minneapolis, MN, and can be reached at [email protected].
Acknowledgment The author acknowledges the assistance of Ms. Sherry Willett in preparation of this series for Air Medical Journal. 1067-991X/$36.00 Copyright 2014 by Air Medical Journal Associates http://dx.doi.org/10.1016/j.amj.2014.06.003
Summary Points • Coagulopathy has been shown in the setting of injury even before the administration of crystalloid solutions. This observation contradicts the historic view that dilution of clotting factors by crystalloid solutions was the major source of coagulation abnormality early after injury. • Coagulopathy complicating trauma resuscitation occurs in up to 25% of severely injured patients. Factors contributing in parallel to this process include shock, tissue injury, hypothermia, inflammation, hemodilution, and acidemia. • Damage control resuscitation with the aggressive use of red blood cells, plasma, and platelets in a 1:1:1 ratio have September-October 2014
193
