Historical Perspective

Hemorrhagic shock accounts for a significant number of deaths in patients arriving at hospital with acute injury. Patients with uncontrolled hemorrhage continue to die despite adoption of new surgical techniques with improved transport and emergency care.46,47 Coagulopathy, occurring even before resuscitation, contributes significantly to the morbidity associated with bleeding.^48,49 Recognition of the morbidity associated with bleeding and coagulation abnormality dates to the Vietnam conflict. At that time, standard tests including prothrombin time (PT) and partial thromboplastin time (PTT) correlated poorly with effectiveness of acute resuscitation efforts. Similar work in the late 1970s was performed in civilian patients receiving massive transfusion. Again, PT, PTT, and bleeding time were only helpful if markedly prolonged.^50,51

Studies in the 1970s and 1980s provided additional detail regarding the limitation of simple laboratory parameters and factor levels.51,52 In a study of multiple patients requiring massive transfusion, platelet counts fell in proportion to the size of transfusion although factors V and VIII correlated poorly with the volume of blood transfused. Where coagulopathy appeared, patients seemed to respond to platelet administration. In subsequent studies, patients receiving a large number of blood products were followed for microvascular bleeding. Moderate deficiencies in clotting factors were common, but they were not associated with microvascular bleeding. Microvascular bleeding was associated with severe coagulation abnormalities such as clotting factor levels less than 20% of control values. In statistical analysis, clotting factor activities less than 20% of control levels were predicted by significant prolongation of PT and PTT. These earlier investigators also suggested that empiric blood replacement formulas available at the time were not likely to prevent microvascular bleeding because consumption of platelets or clotting factors did not consistently appear and simple dilution caused by resuscitation fluids frequently did not correspond to microvascular bleeding.⁵²

The attention of the American trauma community was drawn to coagulopathy after trauma with the description of the “bloody vicious cycle” by the Denver health team over 20 years ago.⁴⁸ These investigators noted the contribution of hypothermia, acidosis, and hemodilution associated with inadequate resuscitation and excessive use of crystalloids. Subsequent work extended these observations describing early coagulopathy that could be independent of clotting factor deficiency.⁵³ In a more recent trial, early coagulopathy was noted in the setting of severe injury, which was present in the field, prior to emergency department arrival and initiation of fluid resuscitation. Coagulopathic patients were at increased risk for organ failure and death.

In a study questioning historical transfusion practice emphasizing administration of packed red blood cells (PRBCs) in the setting of massive trauma, Hirshberg and coworkers, using clinical data, developed a computer model designed to capture interactions between bleeding, hemodynamics, hemodilution, and blood component replacement during severe hemorrhage. Resuscitation options were offered in this model and their effectiveness evaluated.⁵⁴ After setting thresholds for acceptable loss of clotting factors, platelets, and fibrinogen, the authors modeled behavior of coagulation during rapid exsanguation without clotting factor or platelet replacement. The PT reached a critical level first followed by fibrinogen and platelets. If patients were resuscitated with small amounts of crystalloid, leaving overall blood volume reduced, the effective life of components in the coagulation cascade was increased. More aggressive fresh frozen plasma (FFP) replacement in the patient with significant bleeding was supported by this model. The optimal ratio for administration of FFP to PRBCs in this analysis was 2 : 3. Delayed administration of FFP led to critical clotting factor deficiency regardless of subsequent administration of FFP. Fibrinogen depletion was easier to correct. After administration of 5 units of PRBCs, the hemostatic threshold for fibrinogen was not exceeded if a FFP-to-PRBC ratio of 4 : 5 was employed. Analysis of platelet dilution demonstrated that even if platelet replacement was delayed until 10 units of PRBCs were infused, critical platelet dilution was prevented with a subsequent platelet-to-PRBC ratio of 8 : 10.⁵⁴

The essential message of this work is that massive transfusion protocols, emphasizing PRBCs, in existence when this study was performed provide inadequate clotting factor replacement during major hemorrhage and neither prevent nor correct dilutional coagulopathy.

Recent Studies

Brohi and coworkers from the United Kingdom helped to reinvigorate discussion of coagulopathy after injury by adding new coagulation laboratory techniques to previous clinical observations.⁵⁵ After reviewing over 1000 cases, patients with acute coagulopathy after injury had higher mortality rates throughout the spectrum of Injury Severity Scores (ISS). Contrary to historical teaching that coagulopathy was a function of hemodilution with massive crystalloid resuscitation, these authors noted that the incidence of coagulopathy increased with severity of injury but not necessarily in relationship to the volume of intravenous fluid administered to patients. Brohi and others helped to reemphasize the observation that acute coagulopathy could occur before significant fluid administration, which was attributable to the injury itself and proportional to the volume of injured tissue. Development of coagulopathy was an independent predictor of poor outcome. Mediators associated with tissue trauma including humoral and cellular immune system activation with coagulation, fibrinolysis, complement, and kallikrein cascades have been associated with changes in hemostatic mechanisms similar to those identified in the setting of sepsis.^55–57

Factors contributing to coagulopathy in the setting of injury have been further reviewed.⁵⁸ Hypothermia relates to development of coagulopathy by reduction in platelet aggregation and decreased function of coagulation factors in nondiluted blood. Patients with temperature reduction below 34° C had elevated PT and PTT. Coagulation, like most biologic enzyme systems, works best at normal temperature. Similarly, acidosis occurring in the setting of trauma as a result of bleeding and hypotension also contributes to clotting failure. Animal work shows that a pH less than 7.20 is associated with hemostatic impairment. Platelet dysfunction and coagulation enzyme system changes are noted when blood from healthy volunteers is subjected to an acidic environment.^59,60

We are now seeing that with or without hypothermia and acidosis, posttraumatic coagulopathy may develop in a significant number of patients. Although dilution-driven coagulopathy must be considered, loss of clotting factors has been associated with exaggerated inflammation in association with injury.

Hess and coworkers, as part of an international medical collaboration, developed a literature review to increase awareness of coagulopathy independent of crystalloid administration following trauma.⁵⁷ The key initiating factor is volume of tissue injury. Patients with severe tissue injury but no physiologic derangement, however, rarely present with coagulopathy and have a lower mortality rate.^61,62 Tissue damage initiates coagulation as endothelial injury at the site of trauma leads to exposure of subendothelial collagen and activation of the coagulation cascade.

Hyperfibrinolysis is seen as a direct consequence of the combination of tissue injury and shock. Endothelial injury accelerates fibrinolysis because of direct release of tissue plasminogen activator.57,63 Tissue plasminogen activator expression by endothelium is increased in the presence of thrombin. Fibrinolysis is accelerated because of the combined effects of endothelial tissue plasminogen activator release with ischemia and inhibition of plasminogen activator inhibitor in shock. Although hyperfibrinolysis may focus clot propagation on sites of actual vascular injury, with widespread insults, this localization may be lost.

A number of important cofactors must be present to stimulate coagulopathy in the setting of injury.⁵⁷ Shock is a dose-dependent cause of tissue hypoperfusion. Elevated base deficit has been associated with coagulopathy in as many as 25% of patients in one large study. Progression of shock appears to result in hyperfibrinolysis. One mediator implicated in coagulopathy after injury is activated protein C. Immediate postinjury coagulopathy is likely a combination of effects caused by large volume tissue trauma and hypoperfusion (Fig. 27.2).⁵⁷

As will be discussed later, equivalent ratios of FFP, PRBCs, and platelets are now considered for management of significant hemorrhage with coagulopathy after injury. Hypothermia and acidemia must be controlled to reduce their impact on enzyme systems.⁶⁴ Similar to sepsis, cross-talk has been noted between coagulation and inflammation systems with injury. Activation of coagulation proteases may induce inappropriate inflammation with activation of cascades such as complement and platelet degranulation.^65,66 Trauma patients are initially coagulopathic with increased bleeding. This condition may progress to a hypercoagulable state, putting them at risk for thrombotic events. This late thrombotic state bears similarities with coagulopathy of severe sepsis and depletion of protein C. Injured and septic patients share a propensity toward multiple organ failure and prothrombotic states.^67,68

Isotonic Crystalloids

Of isotonic crystalloids, lactated Ringer’s solution has been most extensively studied to determine its role in hemorrhage-induced immune dysfunction, inflammation, and management of ischemia and reperfusion injury. Lactated Ringer’s solution has been shown to upgrade vascular endothelial adhesion molecules and to increase expression of CD11b and CD18 binding sites on neutrophils. Neutrophil oxidative burst is also stimulated by lactated Ringer’s solution. In other organs, Ringer’s lactate has been found to increase apoptosis in the bowel, the liver, and the lung with multiple cell types affected including macrophages, endothelial cells, epithelial cells, and smooth muscle cells.70,77

Despite laboratory findings about the dangers of lactated Ringer’s solution, it remains the fluid of choice in many centers and the recommended fluid of the Advanced Trauma Life Support (ATLS) protocol. Efforts have been made to examine why lactated Ringer’s solution is cytotoxic and identify ways to improve it. Traditionally, lactated Ringer’s solution came in racemic form; laboratory work implicates the D-isomer of lactate as its primary toxic component.⁷⁸ The D-isomer was found to increase neutrophil oxidative burst, enhance apoptosis, and drive inflammation. The L-isomer of lactate may confer immune protection through attenuation of neutrophil activation, alteration of leukocyte gene expression, and reduction in apoptosis.^79,80

Colloids

Hyperoncotic colloid solutions have also been studied in resuscitation roles for traumatic hemorrhage. The natural colloid albumin does not induce neutrophil oxidative burst and may confer a protective immunologic effect by decreasing neutrophil expression of adhesion molecules.⁸¹ At present, albumin sees little application in resuscitation at the scene of injury but has been investigated in critical care practice.

An artificial colloid, 6% hetastarch, has been found to have a number of deleterious resuscitation effects in animal models including increased neutrophil oxidative burst and pulmonary apoptosis. Beneficial effects include decreased neutrophil migration. At present, natural and artificial colloids have failed to show clinical benefits in comparison with crystalloid solutions.82,83 Laboratory concerns and lack of a positive clinical outcomes mandate argue against the use of colloids in early resuscitation of hemorrhagic shock.

Recent reviews suggest important differences in safety among colloids. Examination of data comparing colloids with crystalloids must take into account materials employed. When albumin was used as a reference, the incidence ratio for anaphylactoid reactions was 4.51 after administration of hydroxyethyl starch, 2.32 after dextran, and 12.4 after gelatin. Artificial colloid administration was consistently associated with coagulopathy and clinical bleeding, most frequently in cardiac surgery patients receiving starches. Albumin had the lowest rate of total adverse events and serious adverse events.⁸⁴ Although albumin is isolated from human plasma, no evidence of viral disease transmission has been consistently identified. Life-threatening anaphylactoid reactions were infrequent for all colloids. Hydroxyethyl starch, as compared with albumin, more than quadrupled the incidence of anaphylactic reactions, whereas dextran more than doubled them. The incidence of these reactions in recipients of gelatin was greater by an order of magnitude than after albumin infusion. Because artificial colloids are derived from nonhuman source materials, they may be recognized as foreign and are more likely to provoke this immune-mediated response. The foreign nature of artificial colloids also may hinder metabolic clearance and promote tissue deposition. On the basis of extensive evidence, albumin is the safest colloid for consideration in resuscitation of traumatic shock.⁸⁴ Although factors such as desirability of anticoagulant activity may favor other artificial colloids, this is not true in the setting of injury.^85–87

Multicenter data comparing albumin and saline for fluid resuscitation were obtained in Australia and published in 2004.⁸⁸ Nearly 7000 patients were randomly assigned to administration of 4% albumin or normal saline for intravascular fluid resuscitation procedures. Mortality rate and the incidence of single and multiple organ dysfunction were comparable in the two groups. Subset analysis suggests, however, poorer outcomes in the setting of injury. In the subgroup of 140 patients included with principal diagnoses of trauma, a treatment effect seemed to favor administration of saline. In this trial, the increased relative risk of death among patients with trauma compared with patients without trauma resulted from an excess number of deaths among patients who had trauma with brain injury. The difference in mortality rates between albumin and saline groups among patients with trauma involving brain injury must be viewed cautiously because the number of involved subjects is small. In the Australian trial, patients with traumatic brain injury constituted only 7% of the study population, and the excess number of deaths in the albumin group was 21. Other parameters that could be helpful in evaluation of the impact of albumin in the setting of brain injury, such as functional neurologic status, were not provided. In contrast with the experience in trauma, the Australian trial suggests some evidence of treatment benefit favoring administration of albumin in patients with severe sepsis. Given contemporary resuscitation technology, factors influencing the choice of resuscitation for critically ill patients include specific clinician concerns, treatment tolerance, safety, and cost.

Hypertonic Saline

Increased transmembrane sodium gradient caused by hypertonic saline generates intravascular volume expansion similar to hyperoncotic colloids and superior to conventional isotonic crystalloids such as lactated Ringer’s solution and normal saline. Animal models suggest that hypertonic saline solutions dilate precapillary arterioles and shunt oxygen to vital organs.89,90 Hypertonic saline solutions also have fewer proinflammatory properties than other clinical crystalloids and colloids. Hypertonic saline does not induce expression of inflammatory cytokine receptor genes in multiple studies and blunts hemorrhage-induced increase in plasma levels of proinflammatory cytokines, IL-10, and granulocyte-macrophage colony-stimulating factor. Hypertonic saline also does not increase apoptotic cell death in liver, lung, or bowel.⁷⁰

What about the impact of hypertonic saline and associated hypernatremia on head injury?⁹¹ Studies in experimental animals and humans suggest that hypertonic saline may be highly effective in treating head injury, either alone or associated with hemorrhagic hypotension. Tissue swelling in a closed cranium threatens to cause major pressure-induced brain damage or death, and concomitant hemorrhage hypotension reduces cerebral oxygen delivery, resulting in a secondary ischemic insult. Historical data suggest a twofold higher incidence of adverse outcomes in patients with brain injury combined with hypotension. Early data suggest that patients treated with hypertonic saline with dextran are more likely to survive to discharge than individuals treated with standard resuscitation care.^92,93

Despite laboratory data suggesting that hypertonic saline may be an effective tool in resuscitation-induced injury, mixed clinical data have not led to widespread utilization of this material.

Hypertonic-Hyperoncotic Fluids

Mixture of hypertonic saline with dextran has been the most extensively tested hypertonic-hyperoncotic fluid.⁷⁰ Use of combinations of hypertonic saline and dextran suggests that this material is effective in expanding plasma volume, restoring hemodynamics, and improving microcirculatory perfusion. In the laboratory, hypertonic saline and dextran solutions blunt hemorrhage-induced inflammatory response by neutrophils and, in clinical trials, decreased adhesion molecule expression.⁹⁴ As with hypertonic saline solutions, there has been concern that hypertonic saline mixed with dextran could accelerate hemorrhage, increase mortality rate, and cause hypernatremia and hyperchloremia.⁹⁵ Despite multiple clinical trials comparing hypertonic saline and dextran solutions to more traditional resuscitation products, no improvement in mortality rate or change in the pattern of organ failure is seen.⁹⁶

Mechanisms by which hypertonic/hyperoncotic resuscitation may be effective in models of head injury and hemorrhage show reduction in water content in noninjured portions of the brain with reduction in intracranial pressure and cerebral edema. In a large animal model, when hypertonic saline was compared with a synthetic colloid, colloid alone had no effect on brain water content.97,98

The optimal crystalloid/nonblood colloid resuscitation fluid or regimen has yet to be defined. Hypertonic solutions remain on the horizon of opportunity owing to rapid expansion of plasma volume and improvement of hemodynamics, expanding the therapeutic window until patients may be transported to definitive treatment. Optimally, resuscitation as applied clinically and studied in the preclinical setting must be titrated to desired physiologic and metabolic performance objectives.

Crystalloids Versus Colloids

Plasma and blood were the fluid replacements of choice in traumatic shock until the early 1960s, when a variety of investigators showed the need to replace the extracellular fluid deficit with crystalloid solutions. These observations were followed by a variety of clinical studies comparing colloid, typically albumin, solutions with crystalloids, typically lactated Ringer’s solution. Consistent with early studies, colloids, when given on an equal volume basis, more effectively increase cardiac output and oxygen transport. Another finding of this early work was the need to give crystalloids in far greater quantities than colloids to achieve consistent hemodynamic objectives.99,100

Later studies from the Vietnam era compared resuscitation of patients who were given whole blood and crystalloids with patients given whole blood plus 5% albumin. Fluid infusion volumes were far higher in the patients given crystalloid solutions. There was no evidence of pulmonary edema, and patients treated with crystalloids seemed to fare better than patients treated with resuscitation containing albumin. Albumin seemed to have less effect on restoration of renal function with suggestion of detrimental effects in pulmonary response, myocardial contractility, and coagulation. Large animal models suggested that pulmonary compromise could relate to increased capillary permeability to albumin. Increased losses of albumin to the heart, kidneys, liver, and brain also were reported.99,101 More extensive studies in injured patients supported reservations regarding the use of albumin. Evaluation of patients randomly selected to receive 150 g of albumin per day intraoperatively and postoperatively noted poorer outcomes than in patients receiving lactated Ringer’s solution. Both groups received whole blood and FFP. Patients treated with albumin required greater ventilator support and had poorer oxygenation.^99,102,103 In another carefully conducted trial of patients with multiple trauma, no differences in cardiopulmonary function between patients resuscitated with lactated Ringer’s solution and patients given 5% albumin and lactated Ringer’s solution were identified.¹⁰⁴ Normal cardiac index was used as a therapeutic end point. To maintain adequate cardiac output, patients who received crystalloids required far more resuscitation volume than patients treated with albumin. These authors concluded that cardiac output was an appropriate end point for resuscitation, and that no advantage was accrued based on the type of fluid employed. A clear cost advantage of crystalloids was identified.⁹⁹

Guyton and Lindsey¹⁰⁵ examined the effect of colloid oncotic pressure on pulmonary edema. They observed that reducing the serum protein level lowered the threshold of left atrial pressure at which pulmonary edema could occur. Zarins and colleagues¹⁰⁶ subsequently showed that a low colloid oncotic pressure alone did not cause an elevation in extravascular lung water. Because of the remarkable efficiency of pulmonary lymphatics, arterial blood gases, shunt fraction, and lung compliance were unchanged despite a 14% increase in body weight caused by infusion of lactated Ringer’s solution to keep high pulmonary artery occlusion pressures. No pulmonary edema was created despite the presence of ascites and marked peripheral edema. Demling and coworkers¹⁰⁷ confirmed these findings with a chronic lung lymph fistula in sheep. Holcroft and coworkers¹⁰⁸ produced pulmonary edema in baboons during resuscitation from hemorrhage by continuously administering large volumes of lactated Ringer’s solution sufficient to elevate pulmonary artery occlusion pressures 15 mm Hg above baseline levels. With cessation of infusion, filling pressure rapidly returned to normal.

The Problem

Severely injured trauma patients are at high risk of developing multiple organ failure or death. Initial treatment priorities include appropriate fluid administration and rapid hemostasis.114,115 Inadequate tissue oxygenation leads to anaerobic metabolism and tissue acidosis. Depth and duration of shock are associated with cumulative oxygen and metabolic debt. Resuscitation is incomplete until the metabolic debt is paid, and tissue acidosis is eliminated with restoration of aerobic metabolism. Many patients seem to be adequately resuscitated based on normalization of vital signs but have occult hypoperfusion and ongoing tissue acidosis (compensated shock). These individuals are at risk for later organ dysfunction and death.⁶⁹

As stated in the Advanced Trauma Life Support protocol, the standard of care remains restoration of normal blood pressure, heart rate, and urine output.⁶⁹ When these parameters remain abnormal (uncompensated shock), the need for additional resuscitation is obvious. After normalization of these parameters, however, many trauma patients still have evidence of inadequate tissue oxygenation or gastric mucosal ischemia. Recognition of this state and its reversal are crucial to reduce the risk of organ dysfunction or death. The optimal marker of adequate resuscitation in injury remains unclear.¹¹⁶

Not all patients can be managed in the same way. More recent literature describing management of neurologic trauma suggests poor outcome with any degree of hypotension during prehospital care, resuscitation, or subsequent in-hospital course. Episodes of hypotension and hypoxia were associated with poor neurologic outcome in a review of more than 700 patients from the Traumatic Coma Data Bank with a Glasgow Coma Scale score less than 9. In this large study, patients without hypotension or hypoxia had a 27% risk of death and a 51% chance of favorable recovery. In the presence of hypotension, with or without hypoxia, the risk of death increased to 65% to 75%. Contrary to the needs of patients with penetrating trauma in whom early aggressive resuscitation may lead to increased bleeding, hypotension should be avoided in head-injured patients. Resuscitation parameters specific to various types of injury have not been reported.117–119

Oxygen Delivery Parameters

Shoemaker and various coworkers provided early stimulus to optimization of hemodynamic management in high-risk surgical patients by examining hemodynamic profiles of survivors of surgical shock states versus patients who died.¹²⁰ Survivors had significantly higher oxygen delivery and cardiac index values than nonsurvivors. Values correlating with survival included cardiac index greater than 4.5 L/minute/m², oxygen delivery greater than 600 mL/minute/m², and oxygen consumption equal to or greater than 170 mL/minute/m². These initial observations led to a series of articles from this group suggesting reduction in resource consumption and improvement in morbidity and mortality rates with resuscitation to supranormal oxygen delivery parameters. Initial augmentation of oxygen delivery came with volume loading followed by dobutamine and blood transfusions as needed to a hemoglobin level of 14 g/dL.^121–124

Attempts by other investigators to replicate these findings met limited success. Moore and coworkers used a resuscitation protocol aimed at maximizing oxygen delivery and found no benefit with resuscitation to achieve supranormal oxygen delivery.116,125 A variety of studies suggested that patients failing to reach resuscitation goals were at increased risk for multiple organ failure. Other workers noted that patients who did not obtain supranormal oxygen delivery values were at high risk of developing organ failure regardless of treatment strategy.^126,127 Obtaining hemodynamic and oxygen transport parameters seems to be more predictive of survival than useful as a goal for resuscitation, particularly if fluid administration is adequate.

In addition to conflicting outcomes in oxygen transport trials, technical concerns have been raised.¹¹⁶ These studies cannot be totally blinded. Patients in control groups often obtain similar physiologic end points to those in treatment groups. Other aspects of care were sometimes inconsistent, and entrance criteria varied among investigators. There also is potential mathematical coupling of oxygen delivery and consumption because both are calculated values that share many of the same measured variables.¹¹⁷ Some clinicians argue that the pathologic relationship between oxygen delivery and consumption trials cannot be accepted with confidence, unless oxygen consumption is measured directly. Finally, use of traditional oxygen delivery and consumption as resuscitative end points requires a pulmonary artery catheter and special expertise for operation and insertion. Routine use of pulmonary artery catheterization or central venous catheters has not been a part of acute trauma resuscitation or emergency medical management.^69,116,117

Lactate

As an indicator of shock, blood lactate has proved accurate at assessing severity, predicting mortality risk, and assessing response to resuscitation in the hands of various workers.116,117 At the cellular level, the explanation is based on oxygen transport principles. With shock and inadequate oxygen delivery, mitochondrial respiration is impaired. The primary cellular fuel, pyruvate, is shunted from its normal aerobic path (conversion by pyruvate dehydrogenase to acetyl coenzyme A and subsequent entry into the tricarboxylic acid cycle) to the anaerobic pathway (conversion to lactate by lactate dehydrogenase). Anaerobic metabolism makes inefficient use of cellular substrate, and high-energy phosphate stores are rapidly depleted. During cellular ischemia, lactate is released into the bloodstream and ultimately converted to glucose in the liver and kidney via the Cori cycle. Because it directly reflects anaerobic metabolism, lactate is thought to serve as a mirror of global hyperperfusion because increasing lactate levels indicate increasing oxygen debt.^117,128

Initial and peak lactate levels and duration of increased lactate concentration correlate with development of multiorgan dysfunction after trauma.¹¹⁶ In a study of trauma patient resuscitation, patients normalizing lactate levels at 24 hours survived, whereas patients who normalized lactate levels between 24 and 48 hours had a 25% mortality rate; patients who did not normalize by 48 hours had an 86% mortality rate.¹²⁹ Theoretically, severity of metabolic acidosis secondary to tissue hyperperfusion should be reflected in lactate levels, anion gap, and base deficit. This is not a consistent finding among investigators studying trauma resuscitation.^130,131 In addition, although lactate levels are rapidly available, conclusive data tying specific lactate levels and targets to improved resuscitation outcomes are unavailable.

Base Deficit

Inadequate oxygen delivery to tissues leads to anaerobic metabolism. The degree of anaerobiosis is proportional to the depth and severity of hemorrhagic shock, which should be reflected in lactate and base deficit. Arterial pH is not as useful because compensatory mechanisms attempt to normalize this parameter. Serum bicarbonate levels offer better correlation with base deficit (removal or addition of base in the blood).116,132,133

Similar to lactate, base deficit has been carefully studied.¹¹⁶ A greater base deficit has been associated with blood pressure reduction, increased blood loss, and transfusion requirements. A series of studies by Davis and coworkers link base deficit to resuscitation requirements and end-organ dysfunction, such as acute respiratory distress syndrome, renal failure, and coagulopathy. Cytokine and adhesion molecule changes also have been found to parallel changes in base deficit.^134–140

Base deficit may vary with patient populations. Concern remains in older patients that base deficit is nonspecific and may reflect metabolic acidosis due to a variety of causes, including renal dysfunction and diabetes.116,117 Similar to temporal changes in lactate, base deficit variation over time may add to the value of this parameter.¹³² Patients with elevated base deficit also showed impaired oxygen use reflected in lower oxygen consumption. The timing of base deficit measurement also is important. One study suggested that the worst base deficit in the initial 24 hours was predictive of mortality rate along with blood pressure and estimated blood loss.¹³⁸ Some workers debate whether alcohol intoxication may worsen base deficit for similar levels of injury severity and hemodynamics after trauma. In a large database survey, use of alcohol did not change significant predictive value of admission lactate and base deficit.^141,142 Resuscitation with normal saline (hyperchloremic metabolic acidosis) or lactated Ringer’s solution (accumulation of D-lactate) may increase base deficit independent of injury severity. Acidosis associated with hyperchloremia is associated with lower mortality rate than that from other causes, particularly anaerobic metabolism.^116,143 Base deficit levels and time to normalization of base deficit are similar to data for lactate in that correlation has been established with the need for resuscitation and risk of organ dysfunction and death after injury. Specific thresholds for outcome have not been determined, however, and there are no multicenter data that conclusively show that using base deficit as an end point for resuscitation improves survival.¹¹⁶

Gastric Mucosal pH

As systemic perfusion decreases, blood flow to vulnerable organs (brain and heart) is maintained at the expense of other organs (skin, muscle, kidneys, and intestines). Detection of subclinical ischemia to these organs may allow identification of patients requiring additional resuscitation despite normalized vital signs.116,144 Gastric tonometry is based on the finding that tissue ischemia leads to an increase in tissue partial pressure of carbon dioxide (PCO₂) and subsequent decrease in tissue pH. Because CO₂ diffuses readily across tissues and fluids, the PCO₂ of gastric secretions rapidly equilibrates with that in gastric mucosa. For elevation in gastric pH values to be accurate, it is important to withhold gastric feedings and suppress gastric acid secretion. To perform gastric tonometry, a semipermeable balloon is attached to a special nasogastric tube and placed in the stomach. The balloon is filled with saline, and CO₂ is allowed to diffuse into the balloon for a specific time. PCO₂ in the saline is then measured. Continuous CO₂ measuring electrodes are sometimes employed. Intramucosal pH is calculated from the Henderson-Hasselbalch equation. The difference between intragastric PCO₂ and arterial PCO₂, or the intramucosal pH, correlates with the degree of gastric ischemia.¹⁴⁵

In studies of a small number of trauma patients, patients with low intramucosal pH (≤7.32) were more likely to develop complications or die.146–148 Patients with normal intramucosal pH fared well. Correlation to other parameters has not been rigorously studied. A larger trial examined the value of intramucosal pH and the gastric mucosal-arterial CO₂ gap (difference between intragastric PCO₂ and arterial PCO₂). Ability to predict multiple organ dysfunction and death was maximized with intramucosal pH less than 7.25 and CO₂ gap greater than 18 mm Hg. Similar to studies using blood lactate and base deficit, time course for changes in CO₂ gap or intramucosal pH may be important. Ivatury and associates^149,150 compared changes in intramucosal pH with oxygen transport values. Although intramucosal pH changes paralleled improvement in oxygen transport, delay in achieving intramucosal pH was more predictive of organ system failure than oxygen transport parameters. The gap between gastric mucosal and arterial PCO₂ was similarly predictive. After resuscitation, changes in mucosal pH were an early predictor of complications.

Newer fiber-optic technologies increase the ease of gastric mucosal pH assessment.¹⁵¹ Although this parameter may be predictive of early resuscitation failure, accepted thresholds for failure and outcome data do not support widespread use to guide initial resuscitation after injury (Fig. 27.3).

Near-Infrared Spectroscopy

Measurement of skeletal muscle oxyhemoglobin levels by near-infrared spectroscopy offers a noninvasive measurement for evaluating adequacy of resuscitation from normalization of tissue oxygenation.116,117,145,152 This technology allows simultaneous measurement of tissue partial pressure of oxygen (PO₂), PCO₂, and pH. In human volunteers, cerebral cortex and calf oxygen saturation as measured by near-infrared spectroscopy decreased in proportion to blood loss. Oxygenation index (oxygenated hemoglobin—deoxygenated hemoglobin) also decreased. Studies in injury suggest correlation of tissue oxygen saturation with systemic oxygen delivery, base deficit, lactate, and gastric mucosal PCO₂.¹⁵³

This technology provides information regarding mitochondrial function. Normally, tissue oxyhemoglobin levels reflecting local oxygenation are tightly coupled to cytochrome function, reflecting mitochondrial oxygen consumption. In preliminary studies, when patients showed change in mitochondrial function, even in the absence of abnormality in systemic oxygen transport, multiple organ failure was more likely.¹⁵⁴ Nonetheless, at this time, work in this area is preliminary, and a role for this technology in management of traumatic shock has not been defined.

Adrenal Insufficiency

Adrenal insufficiency is reviewed in Box 27.2.

Early Limited Resuscitation

Clinical Pathway—Early Resuscitation

In all of the preclinical and clinical work described, the mechanism of injury and survival remains unclear. Among considerations are the impact of fluid resuscitation on early clot formation in the setting of uncontrolled hemorrhage.115,169 Other workers suggest that rapidity in resuscitation of pulse pressure may relate to mechanical disruption of initial thrombus.¹⁶⁹ Fluid resuscitation may contribute to dilution of clotting factors in the setting of exaggerated bleeding in uncontrolled hemorrhage.^115,160 The data to support these observations are limited. Coagulopathy proportional to volume of injured tissue and severity of shock may be seen even before resuscitation fluids are provided.¹¹

Despite provocative preclinical and clinical data, there is insufficient evidence to propose practice guidelines or make recommendations. “Uncontrolled” hemorrhage itself remains undefined. This problem is best seen as injury with blood loss occurring in the absence of surgical or mechanical hemostasis or the “control” provided by regulated blood removal through a vascular cannula. It is unclear whether a vascular injury after a torso gunshot wound and a shattered spleen after an automobile crash are different in this regard. The bottom-line message from all of the studies is that elevation of the blood pressure to normal or supranormal levels results in resumption of bleeding from the uncontrolled site, and rebleeding leads to recurrent shock and death of the experimental animal. Other work shows that animals subjected to shock could be successfully resuscitated at lower than “normal” mean arterial pressures if the bleeding site was controlled as part of the resuscitation program. Shock victims resuscitated with electrolyte solutions are subject to progressive hemodilution, and this may lead to death. The lessons that clinicians should learn from this body of data are as follows.69,115,145,11

The clinical trials that have sought to extend the previously described experimental concepts into the realm of patient care have dealt primarily with blood loss secondary to penetrating injury because this clinical condition is as close a simulation to a pure hemorrhage model as is available in clinical medicine. It is useful to emphasize that multiple blunt injury, multiple wounds, and extensive soft tissue trauma are not similar to pure hemorrhage models in that occult blood and fluid losses and other inflammatory factors exist that make the quantitation of injury severity difficult.

Massive Transfusion

Independent of mechanism of injury, hemorrhagic shock consistently is the second leading cause of early death among injured patients, with only CNS injury consistently more lethal.¹⁸⁶ Primary CNS injury is devastating and has a high rate of prehospital mortality; prevention is the best strategy.¹⁸⁷ Hemorrhagic shock accounts for 30% to 40% of trauma deaths and is more amenable to interventions to reduce mortality and morbidity rates.¹⁸⁶ In addition, approximately 25% of CNS injuries are complicated by hemorrhagic shock.^188,189 Hemorrhage contributes to death during the prehospital period in 33% to 56% of cases, and exsanguination is the most common cause of death among individuals found dead on arrival of emergency medical services personnel.⁴⁷ Hemorrhage accounts for the largest proportion of mortality rates occurring within the first hour of trauma center care and greater than 80% of operating room deaths after major trauma.^186,190 Although the need for massive transfusion (defined as administration of ≥10 units of PRBC in <24 hours) is probably necessary in only 3% of patients in busy trauma centers, this intervention can be lifesaving, and preliminary data suggest that early aggressive administration of blood products reduces morbidity and mortality rate and decreases overall product use.¹⁹¹

Numerous general observations can be made.191–193 Most patients receiving massive transfusion are treated initially with crystalloid fluids followed by non-cross-matched type O red blood cells. Plasma therapy is typically delayed while waiting for blood typing and plasma to thaw. Platelets frequently are not given until patients have multiple units of PRBCs. Coagulopathy is common and difficult to correct. Plasma and platelets are inadequately used and greater emphasis is needed on plasma and platelet administration.

A typical massive transfusion protocol begins in the emergency department when the senior trauma practitioner orders transfusion of O-negative PRBC and invokes an organization-specific massive transfusion protocol.193,194 This is followed by administration of 4 to 6 additional typed or O-negative units of PRBC and a similar number of units of FFP and platelets. Therapy continues with containers sent from the blood bank, each containing red blood cells, plasma, and platelets. Goals are normalization of the PT and elevation of the platelet count to 50 to 100 × 10⁹/L. The fibrinogen level is checked after 6 to 12 units of PRBC, and cryoprecipitate is given if the fibrinogen level is less than 1 g/L. This triggers administration of 10 units of cryoprecipitate. Once a common component of massive transfusion strategies, recombinant activated factor VII has been deemphasized in both military and civilian practice.^195–198

Major trauma centers have developed transfusion protocols to address rapid blood loss and trauma-associated coagulopathy. This strategy has demonstrated improved survival in severely injured trauma patients. Although many centers have implemented massive transfusion protocols, a standardized initiation policy has not been defined. Frequently, activation of massive transfusion protocols is provider dependent and variability exists among high-volume centers.

A number of scoring systems have been developed to rapidly predict the patient requiring massive transfusion.199–201 Of these scores, the ABC (assessment of blood consumption) score, which incorporates penetrating mechanism of injury, positive ultrasound examination of the abdomen in the emergency department, arrival systolic blood pressure of 90 mm Hg or less, and arrival heart rate of 120 beats/minute or more, has been reported and validated in large patient sets. Although multiple more sophisticated criteria have been proposed, having an ABC score of two criteria or greater correctly classified the patient requiring massive transfusion in up to 85% of cases. Other investigators point out that hypotension and evidence of coagulopathy are the strongest predictors of massive transfusion. Additional data from military and civilian practice is awaited to bring further clarity to appropriate transfusion triggers.

Tranexamic Acid

Tranexamic acid is a derivative of amino acid lysine that inhibits fibrinolysis by blocking binding sites on plasminogen. This agent has been used in a variety of surgical trials and has been demonstrated to reduce blood transfusion requirement. The massive CRASH-2 study, incorporating over 20,000 patients, evaluates tranexamic acid as a means to address fibrinolysis occurring as a component of coagulopathy after trauma.202,203 CRASH-2 was conducted in over 250 hospitals and 40 countries. Over 20,000 patients with significant bleeding or at risk for significant bleeding were assigned within 8 hours of injury to either tranexamic acid or matching placebo. All-cause mortality rate was significantly reduced with tranexamic acid. Specific risk of death due to bleeding was also significantly reduced. This remarkable outcome was accomplished without a significant increase in thrombotic events. Subsequent analysis of the CRASH-2 data, however, reveals that greatest efficacy came when treatment was initiated within 3 hours after injury. In fact, treatment after 3 hours seemed to increase the risk of death due to bleeding. A recent review of military experience with tranexamic acid, the MATTERs trial, also demonstrates improved outcomes with early administration of this inexpensive drug shortly after injury. This military experience with tranexamic acid suggests improvement in outcome in patients receiving as little as 1 unit of PRBCs. Incremental risk with administratin of tranexamic acid was not demonstrated.²⁰⁴

The role for tranexamic acid in trauma systems where massive transfusion protocols incorporate FFP containing all indigenous antifibrinolytic elements in plasma remains unclear. In developed trauma systems, the best place for tranexamic acid may actually be in the prehospital environment as this material can readily be maintained in helicopter and road transport programs. Prehospital administration of blood products, especially plasma, is uncommon in civilian settings; thus, tranexamic acid offers an early opportunity to manage coagulopathy.²⁰⁵ Opportunities for use of this promising material in the critical care setting are being defined.

Risks of Early Red Blood Cell Transfusion

Blood transfusion in trauma has been identified as an independent predictor of multiple organ failure, systemic inflammatory response syndrome, increased postinjury infection, and increased mortality rate in multiple studies.²⁰⁶ Cumulative risks have been related to the number of units of PRBC transfused, increased storage time of transfused blood, and possibly the presence of leukocytes in donor blood. Many authors have concluded that blood transfusion in an injured patient should be minimized whenever possible.²⁰⁷

Large single-institution data sets examined the impact of blood transfusion in postinjury multiple organ failure.136,208,209 Variables identified as early independent predictors of multiple organ failure included age older than 55 years, ISS equal to or greater than 25, and greater than 6 units of PRBC in the first 12 hours after admission. Base deficit greater than 8 mEq/L in the first 12 hours and lactate greater than 2.5 mol/L also were independent predictors of multiple organ failure. Subsequent prospective work confirmed the importance of blood transfusion as an independent risk factor for postinjury multiple organ failure after controlling for other indices of shock, including base deficit and lactate. Additional studies of blood product use after injury associate blood transfusion with increased mortality rate. Potential confounding shock variables, including base deficit, serum lactate, age, gender, race, Glasgow Coma Scale score, and ISS, were controlled in this analysis.

Factors contributing to complications associated with red blood cell transfusion include storage time, increased endothelial adherence of stored red blood cells, nitric oxide binding by free hemoglobin in stored blood, donor leukocytes, host inflammatory response, and reduced red blood cell deformability.205,210 Nonetheless, transfusion of an injured patient with balanced blood component therapy is the only option for treatment of severe hemorrhagic shock. Although other hemoglobin-based oxygen carriers hold great promise and ultimately may provide better outcomes for injured patients, these materials have not come to be used. In an effort to minimize adverse events, attempts to minimize the use of blood transfusion in injury are appropriate outside major hemorrhage.

Abdominal Compartment Syndrome

A compartment syndrome is a condition in which increased pressure within a confined anatomic space adversely affects function and viability of tissues contained within. Confined anatomic spaces associated with compartment syndromes are fascial spaces of the extremities, the globe as in glaucoma, and the cranial cavity as in epidural or subdural hematoma. Abdominal compartment syndrome is a condition in which sustained pressure within the abdominal wall, pelvis, diaphragm, and retroperitoneum adversely affects the function of the gastrointestinal tract and related extraperitoneal organs. Abdominal compartment syndrome is receiving increasing recognition as a complication of massive resuscitation after trauma, burns, or other surgical procedures (Box 27.3). Operative decompression is frequently required. Pressures around 5 to 7 mm Hg in the peritoneal cavity are normal. Short-duration pressure increases frequently occur with coughing, Valsalva maneuvers, defecation, and weightlifting. Intra-abdominal pressure can be nonpathologically increased in obese individuals. Elevated intra-abdominal pressure is a common finding among critically ill medical and surgical patients.^211–213

A more recent consensus conference on abdominal compartment syndrome has created improved definitions in relation to abdominal compartment syndrome (Table 27.4). For standardization, intra-abdominal pressure should be expressed in mm Hg and measured at end expiration with the patient supine after ensuring that abdominal muscle contractions are absent. The transducer is zeroed at the midaxillary line. The current reference standard for intra-abdominal pressure measurement is pressure measured via an indwelling urinary drainage catheter within the bladder. The recommended technique for measuring intra-abdominal pressure is to clamp the urinary catheter and instill a maximal volume of 25 mL of sterile, room-temperature saline into the bladder with the patient in the supine position. After zeroing a transducer and a stabilization period of at least 30 to 60 seconds, the mean intra-abdominal pressure can be read on a bedside monitor or as the height of the fluid column in urinary drainage tubing.

Intra-abdominal hypertension is defined by a sustained or repeated intra-abdominal pressure greater than 12 mm Hg or an abdominal perfusion pressure less than 60 mm Hg, where abdominal perfusion pressure = mean arterial pressure − intra-abdominal pressure. Abdominal compartment syndrome is present when organ dysfunction occurs as a result of intra-abdominal hypertension. Abdominal compartment syndrome is further defined by sustained or repeated intra-abdominal pressure greater than 20 mm Hg or abdominal perfusion pressure less than 60 mm Hg in association with new-onset single or multiple organ system failure. In contrast to intra-abdominal hypertension, abdominal compartment syndrome is not graded but rather considered as an “all or none” phenomenon.213,214

Intra-abdominal hypertension has a variety of physiologic effects. In experimental preparations, animals die as a result of congestive heart failure as abdominal pressure passes a critical threshold. Increased intra-abdominal pressure decreases cardiac output and left and right ventricular stroke work, while increasing central venous pressure, pulmonary artery wedge pressure, and systemic and pulmonary vascular resistance. Abdominal decompression reverses these changes. As both hemidiaphragms are displaced upward with increased intra-abdominal pressure, decreased thoracic volume and compliance are seen. Decreased volume within the pleural cavity causes atelectasis and decreases alveolar clearance. Pulmonary infections also may result. Ventilated patients with abdominal hypertension require increased airway pressure to deliver a fixed tidal volume. As the diaphragm protrudes into the pleural cavity, intrathoracic pressure increases with reduction in cardiac output and increased pulmonary vascular resistance. Ventilation and perfusion abnormalities result, and blood gas measurements show hypoxemia, hypercarbia, and acidosis.²¹⁵

Elevation in intra-abdominal pressure also causes renal dysfunction. Inadequate renal perfusion pressure and renal filtration gradient have been proposed as critical factors in the development of renal insufficiency associated with elevated intra-abdominal pressure. The filtration gradient is the mechanical force across the glomerulus and equals the difference between glomerular filtration pressure and proximal tubular pressure. In the presence of intra-abdominal hypertension, proximal tubular pressure may be assumed to equal intra-abdominal pressure. Glomerular filtration pressure may be estimated as mean arterial pressure minus intra-abdominal pressure. Changes in intra-abdominal pressure may have a greater impact on renal function and urine production than changes in mean arterial pressure. Oliguria is thought to be one of the first signs of intra-abdominal hypertension. Control of intra-abdominal pressure leads to reversal of renal impairment. Oliguria may be seen with intra-abdominal pressure of 15 to 20 mm Hg. Deterioration in cardiac output plays a role in diminished renal perfusion, but even with maintenance of cardiac output, impairment of renal function persists in intra-abdominal hypertension.211,216–218

Other organs affected by increased intra-abdominal pressure include the liver, where hepatic blood flow has been shown to decrease with abdominal hypertension.219,220 It may be assumed that hepatic synthesis of acute-phase proteins, immunoglobulins, and other factors of host defense may be impaired by reduced hepatic blood flow. Other gastrointestinal functions may be compromised by increased intra-abdominal pressure. Splanchnic hypoperfusion may begin with an intra-abdominal pressure of 15 mm Hg. Reduced perfusion may create changes in mucosal pH, translocation, bowel motility, and production of gastrointestinal hormones. Finally, intracranial hypertension is seen with chronically increased intra-abdominal pressure. Intracranial hypertension has been shown to decrease when intra-abdominal pressure is reduced in morbidly obese patients and in intracranial injury.

Operative decompression is the method of choice for treatment of patients with intra-abdominal hypertension and associated evidence of organ dysfunction. After decompression, improvements in hemodynamics, pulmonary function, tissue perfusion, and renal function have been shown in a variety of clinical settings. To prevent hemodynamic decompensation during decompression, intravascular volume should be restored, oxygen delivery should be normalized, and hypothermia and coagulation defects should be corrected. The abdomen should be opened in patients with adequate venous access and controlled ventilation. Adjunctive measures to combat reperfusion washout from by-products of anaerobic metabolism include acute use of vasoconstrictor agents to avoid sudden changes in blood pressure. After decompression of the abdomen, the fascial gap is left open using one of a variety of temporary abdominal closure methods.

In a recent report, Cheatham and Safcsak review their experience with percutaneous, ultrasound-guided drainage of ascitic fluid contributing to abdominal hypertension and abdominal compartment syndrome.221,222 These investigators suggest that in patients with significant fluid accumulation creating abdominal hypertension, percutaneous drainage can avoid the need for decompressive laparotomy with its associated morbidity and occasional complications. Additional reports from other centers are required. To date, apart from the large experience described previously, percutaneous control of fluid accumulation to manage abdominal hypertension and compartment syndrome is limited to case reports.

Extremity Compartment Syndrome

The numerous causes of extremity compartment syndrome include complications of open and closed fractures, arterial injury, temporary vascular occlusion, snakebite, drug abuse, burns, physical exertion, and gunshot wounds. The most common cause of compartment syndrome is muscle injury leading to edema, which is correlated to the amount of tissue damage. Pressure is increased within the closed fascial space first by intracellular swelling followed by hematoma formation if a fracture is present. Because extremities, particularly at the calf, are composed of relatively unyielding fascial compartments, circulatory compromise occurs as tissue pressure increases with resulting ischemia and tissue damage. Leakage of intracellular fluid follows, and a further increase in intracompartmental pressure is seen.²²³

When extremity injuries produce complete ischemia, skeletal muscle that is deprived of oxygen may survive for 4 hours without irreversible damage. Total ischemia of 8 hours’ duration produces irreversible change. Peripheral nerves conduct for 1 hour after onset of total ischemia and can survive for 4 hours with only neurapraxic damage. After 8 hours, axonotmesis and irreversible damage occur. Ischemia caused by reduction or cessation of blood flow occurs when the perfusion gradient to a muscle compartment falls below a critical level. Perfusion is related to the compartment pressure. When intracompartmental blood pressure is 25 mm Hg, tissue perfusion in injured tissues is substantially decreased.223–225

Fasciotomy should be performed when intracompartmental pressure approaches 25 mm Hg, or if an extremity has been completely ischemic for 6 hours, the patient’s clinical condition is worsening, substantial tissue injury is present, or tissue pressure is increasing.²²⁵ Prophylactic treatment is valuable because fasciotomy does not reverse changes caused by initial extremity injury but can prevent changes resulting from secondary ischemic insults.

Pain, pallor, paralysis, paresthesias, and pulselessness are the classic hallmarks of extremity compartment syndrome. If treatment is not initiated until all of these signs are present, poor results are obtained. Pain and aggravation of pain by passive stretching of the muscles in the involved compartment is the most sensitive clinical finding. Assessment of pain is useful when patients are conscious and can respond cognitively to examination. In unconscious patients at risk for compartment syndrome, tissue pressure measurements may be the only objective criteria for diagnosis. Measurement of compartment pressures is obtained in all extremity compartments at risk and proximal and distal to any fractures. The highest pressure noted should serve as the basis for determining the need for fasciotomy.

Pelvic Fractures

Substantial blunt force is required to disrupt the pelvic ring. The extent of injury is related to the direction and magnitude of force applied. Associated abdominal, thoracic, and head injuries are common. Force applied to the pelvis can cause rotational displacement with opening or compression of the pelvic ring. Other types of displacement seen with pelvic fractures are vertical with complete disruption of the ring and the posterior sacroiliac complex.²²⁶

Patients with pelvic ring injuries are easily divided into two groups on the basis of clinical presentation—patients who are hemodynamically stable and patients who are hemodynamically unstable.²²⁶ There is a dramatic difference in mortality rates between pelvic fracture patients who are hypotensive and patients who are hemodynamically stable. Hemodynamic stability and biomechanical pelvic instability are separate though related issues, which tends to confuse the clinical picture. The source of bleeding may be multifactorial and not directly related to the pelvic fracture itself. Blood loss secondary to pelvic fracture that contributes to hemodynamic instability is a significant risk factor, however. Early fracture diagnosis and stabilization using external skeletal fixation are crucial in the acute phase of patient management.²²⁷ Treatment of the patient also is directed by response to initial fluid resuscitation. Retroperitoneal bleeding in a pelvic fracture usually arises from a low-pressure source—the cancellous bone at the fracture site or adjacent venous injury. Significant retroperitoneal arterial bleeding occurs in approximately 10% of patients. Clinical evidence has suggested that provisional fracture stabilization using external fixation devices or even wrapping the fractured pelvis in a bed sheet can control low-pressure venous bleeding. Continued, unexplained bleeding after provisional fracture stabilization suggests an arterial source. Angiography with embolization of the involved vessel is indicated. Therapeutic angiography also may be required after abdominal exploration if a rapidly expanding or pulsatile retroperitoneal hematoma is encountered.²²⁸

1. Blalock, A. Principles of Surgical Care, Shock, and Other Problems. St. Louis: Mosby; 1940.

2. Peitzman, AB, Billiar, TR, Harbrecht, BG, et al. Hemorrhagic shock. Curr Probl Surg. 1995; 32:925–1002.

3. Spodick, DH. Acute cardiac tamponade. N Engl J Med. 2003; 349:684–690.

4. Moore, FA, Moore, EE. Initial management of life-threatening trauma. In: Souba WW, Fink MP, Jurkovich GJ, et al, eds. ACS Surgery: Principles and Practices 2006. New York: WebMD Professional Publishing; 2006:1125–1144.

5. Goris, RJ. Pathophysiology of shock in trauma. Eur J Surg. 2000; 166:100–111.

6. Horovitz, JH, Carrico, CJ, Shires, GT. Pulmonary response to major injury. Arch Surg. 1974; 108:349–355.

7. Ayala, A, Wang, P, Ba, ZF, et al. Differential alterations in plasma IL-6 and TNF levels after trauma and hemorrhage. Am J Physiol. 1991; 260:R167–R171.

8. Bitterman, H, Kinarty, A, Lazarovich, H, et al. Acute release of cytokines is proportional to tissue injury induced by surgical trauma and shock in rats. J Clin Immunol. 1991; 11:184–192.

9. Huynh, T, Currin, RT, Tanaka, Y, et al. Activation of Kupffer cells in vivo following femur fracture. Arch Surg. 1994; 129:1324–1329.

10. Rady, MY, Kirkman, E, Cranley, J, et al. A comparison of the effects of skeletal muscle injury and somatic afferent nerve stimulation on the response to hemorrhage in anesthetized pigs. J Trauma. 1993; 35:756–761.

11. Dries, DJ. The contemporary role of blood products and components used in trauma resuscitation. Scand J Trauma Resuscitation Emerg Med. 2010; 18:63.

12. Gann, DS, Cross, JS. The neuroendocrine response to critical illness. In: Barrie PS, Shires GT, eds. Surgical Intensive Care. Boston: Little Brown; 1993:93–134.

13. Jones, MT, Gillman, B. Factors involved in the regulation of adrenocorticotropic hormone/betalipotropic hormone. Physiol Rev. 1988; 68:743–818.

14. Bereiter, DA, Zaid, AM, Gann, DS. Effect of rate of hemorrhage on sympathoadrenal catecholamine release in cats. Am J Physiol. 1986; 250:E69–E75.

15. Bereiter, DA, Zaid, AM, Gann, DS. Effect of rate of hemorrhage on release of ACTH in cats. Am J Physiol. 1986; 250:E76–E81.

16. Hume, DM, Bell, CC, Bartter, F. Direct measurement of adrenal secretion during operative trauma and convalescence. Surgery. 1962; 52:174–187.

17. Chernow, B, Lake, CR, Barton, M, et al. Sympathetic nervous system sensitivity to hemorrhagic hypotension in the subhuman primate. J Trauma. 1984; 24:229–232.

18. Berne, RM, Levy, MN, Koeppen, BM, et al. Physiology, 5th ed. St. Louis: Mosby; 2004.

19. O’Regan, RG, Majcherczyk, S. Role of peripheral chemoreceptors and central chemosensitivity in the regulation of respiration and circulation. J Exp Biol. 1982; 100:23–40.

20. Holmes, CL, Patel, BM, Russell, JA, et al. Physiology of vasopressin relevant to management of septic shock. Chest. 2001; 120:989–1002.

21. Cryer, PE. Physiology and pathophysiology of the human sympathoadrenal neuroendocrine system. N Engl J Med. 1980; 303:436–444.

22. Jeremitsky, E, Omert, LA, Dunham, M, et al. The impact of hyperglycemia on patients with severe brain injury. J Trauma. 2005; 58:47–50.

23. Wiggers, CJ. Experimental hemorrhagic shock. In: Wiggers C, ed. Physiology of Shock. New York: Commonwealth Publications; 1950:121–146.

24. Bone, RC. Toward a theory regarding the pathogenesis of the systemic inflammatory response syndrome: What we do and do not know about cytokine regulation. Crit Care Med. 1996; 24:163–172.

25. Rivkind, AI, Siegel, JH, Guadalupi, P, et al. Sequential patterns of eicosanoid, platelet and neutrophil interactions in the evolution of the fulminant post-traumatic adult respiratory distress syndrome. Ann Surg. 1989; 210:355–373.

26. Waydhas, C, Nast-Kolb, D, Jochum, M, et al. Inflammatory mediators, infection, sepsis, and multiple organ failure after severe trauma. Arch Surg. 1992; 127:460–467.

27. Deitch, EA. Multiple organ failure: Pathophysiology and potential future therapy. Ann Surg. 1992; 216:117–134.

28. Nast-Kolb, D, Waydhas, C, Gippner-Steppert, C, et al. Indicators of the posttraumatic inflammatory response correlate with organ failure in patients with multiple injuries. J Trauma. 1997; 42:446–455.

29. Roumen, RM, Hendriks, T, van der Ven-Jongekrijg, J, et al. Cytokine patterns in patients after major vascular surgery, hemorrhagic shock, and severe blunt trauma: Relation with subsequent adult respiratory distress syndrome and multiple organ failure. Ann Surg. 1993; 218:769–776.

30. van der Kleij, AJ, de Koning, J, Beerthuizen, G, et al. Early detection of hemorrhagic hypovolemia by muscle oxygen pressure assessment: Preliminary report. Surgery. 1983; 93:518–524.

31. Redl, H, Dinges, HP, Buurman, WA, et al. Expression of endothelial leukocyte adhesion molecule-1 in septic but not traumatic hypovolemic shock in the baboon. Am J Pathol. 1991; 139:461–466.

32. Anderson, BO, Brown, JM, Harken, AH. Mechanisms of neutrophil-mediated tissue injury. J Surg Res. 1991; 51:170–179.

33. Henson, PM, Johnston, RB, Jr. Tissue injury in inflammation: Oxidants, proteinases, and cationic proteins. J Clin Invest. 1987; 79:669–674.

34. Smedly, LA, Tonnesen, MG, Sandhaus, RA, et al. Neutrophil-mediated injury to endothelial cells: Enhancement by endotoxin and essential role of neutrophil elastase. J Clin Invest. 1986; 77:1233–1243.

35. Nathan, CF. Secretory products of macrophages. J Clin Invest. 1987; 79:319–326.

36. Gordon, S. Alternative activation of macrophages. Nat Rev Immunol. 2003; 3:23–35.

37. Molina, PE. Neurobiology of the stress response: Contribution of the sympathetic nervous system to the neuroimmune axis in traumatic injury. Shock. 2005; 24:3–10.

38. Selye, H. A syndrome produced by diverse nocuous agents—1936. J Neuropsychiatry Clin Neurosci. 1998; 10:230–231.

39. Chrousos, GP. The role of stress and the hypothalamic-pituitary-adrenal axis in the pathogenesis of the metabolic syndrome: Neuroendocrine and target tissue-related causes. Int J Obes Relat Metab Disord. 2000; 24(Suppl 2):S50–S55.

40. Rozlog, LA, Kiecolt-Glaser, JK, Marucha, PT, et al. Stress and immunity: Implications for viral disease and wound healing. J Periodontol. 1999; 70:786–792.

41. Bjontorp, P. Stress and cardiovascular disease. Acta Physiol Scand Suppl. 1997; 640:144–148.

42. Felten, DL, Felten, SY, Carlson, SL, et al. Noradrenergic and peptidergic innervation of lymphoid tissue. J Immunol. 1985; 135(Suppl 2):755S–765S.

43. Rivest, S. How circulating cytokines trigger the neural circuits that control the hypothalamic-pituitary-adrenal axis. Psychoneurology. 2001; 26:761–788.

44. Banks, WA, Kastin, AJ, Broadwell, RD. Passage of cytokines across the blood-brain barrier. Neuroimmunology. 1995; 2:241–248.

45. Goehler, LE, Gaykema, RP, Hansen, MK, et al. Vagal immune-to-brain communication: A visceral chemosensory pathway. Auton Neurosci. 2000; 85:49–59.

46. Kashuk, JL, Moore, EE, Sawyer, M, et al. Postinjury coagulopathy management: Goal directed resuscitation via POC thrombelastography. Ann Surg. 2010; 251:604–614.

47. Sauaia, A, Moore, FA, Moore, EE, et al. Epidemiology of trauma deaths: A reassessment. J Trauma. 1995; 38:185–193.

48. Kashuk, JL, Moore, EE, Millikan, JS, et al. Major abdominal vascular trauma—A unified approach. J Trauma. 1982; 22:672–679.

49. Cosgriff, N, Moore, EE, Sauaia, A, et al. Predicting life-threatening coagulopathy in the massively transfused trauma patient: Hypothermia and acidoses revisited. J Trauma. 1997; 42:857–862.

50. Simmons, RL, Collins, JA, Heisterkamp, CA, et al. Coagulation disorders in combat casualties. I. Acute changes after wounding. II. Effects of massive transfusion. III. Post-resuscitative changes. Ann Surg. 1969; 169:455–482.

51. Counts, RB, Haisch, C, Simon, TL, et al. Hemostasis in massively transfuse trauma patients. Ann Surg. 1979; 190:91–99.

52. Ciavarella, D, Reed, RL, Counts, RB, et al. Clotting factor levels and the risk of diffuse microvascular bleeding in the massively transfused patient. Br J Haematol. 1987; 67:365–368.

53. MacLeod, JB, Lynn, M, McKenney, MG, et al. Early coagulopathy predicts mortality in trauma. J Trauma. 2003; 55:39–44.

54. Hirshberg, A, Dugas, M, Banez, EI, et al. Minimizing dilutional coagulopathy in exsanguinating hemorrhage: A computer simulation. J Trauma. 2003; 54:454–463.

55. Brohi, K, Singh, J, Heron, M, et al. Acute traumatic coagulopathy. J Trauma. 2003; 54:1127–1130.

56. Holcomb, JB, Jenkins, D, Rhee, P, et al. Damage control resuscitation: Directly addressing the early coagulopathy of trauma. J Trauma. 2007; 62:307–310.

57. Hess, JR, Brohi, K, Dutton, RP, et al. The coagulopathy of trauma: A review of mechanisms. J Trauma. 2008; 65:748–754.

58. MacLeod, JB. Trauma and coagulopathy. A new paradigm to consider. Arch Surg. 2008; 143:797–801.

59. Martini, WZ. Coagulopathy by hypothermia and acidosis: Mechanisms of thrombin generation and fibrinogen availability. J Trauma. 2009; 67:202–209.

60. Duchesne, JC, Islam, TM, Stuke, L, et al. Hemostatic resuscitation during surgery improves survival in patients with traumatic-induced coagulopathy. J Trauma. 2009; 67:33–39.

61. Brohi, K, Cohen, MJ, Ganter, MT, et al. Acute traumatic coagulopathy: Initiated by hypoperfusion: Modulated through the protein C pathway? Ann Surg. 2007; 245:812–818.

62. Niles, SE, McLaughlin, DF, Perkins, JG, et al. Increased mortality associated with the early coagulopathy of trauma in combat casualties. J Trauma. 2008; 64:1459–1465.

63. Brohi, K, Cohen, MJ, Ganter, MT, et al. Acute coagulopathy of trauma: Hypoperfusion induces systemic anticoagulation and hyperfibrinolysis. J Trauma. 2008; 64:1211–1217.

64. Reed, RL, Bracey, AW, Jr., Hudson, JD, et al. Hypothermia and blood coagulation: Dissociation between enzyme activity and clotting factor levels. Circ Shock. 1990; 32:141–152.

65. Landis, RC. Protease activated receptors: Clinical relevance to hemostasis and inflammation. Hematol Oncol Clin North Am. 2007; 21:103–113.

66. Ganter, MT, Brohi, K, Cohen, MJ, et al. Role of the alternative pathway in the early complement activation following major trauma. Shock. 2007; 28:29–34.

67. Bernard, GR, Vincent, JL, Laterre, PF, et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med. 2001; 344:699–709.

68. Cohen, MJ, Call, M, Nelson, M, et al. Critical role of activated protein C in early coagulopathy and later organ failure, infection and death in trauma patients. Ann Surg. 2012; 255:379–385.

69. American College of Surgeons Committee on Trauma. Advanced Trauma Life Support for Doctors, 8th ed. Chicago: American College of Surgeons; 2008.

70. Santry, HP, Alam, HB. Fluid resuscitation: Past, present, and the future. Shock. 2010; 33:229–241.

71. Demling, RH. The pathogenesis of respiratory failure after trauma and sepsis. Surg Clin North Am. 1980; 60:1373–1390.

72. Moon, PF, Hollyfield-Gilbert, MA, Myers, TL, et al. Effects of isotonic crystalloid resuscitation on fluid compartments in hemorrhaged rats. Shock. 1994; 2:355–361.

73. Madigan, MC, Kemp, CD, Johnson, JC, et al. Secondary abdominal compartment syndrome after severe extremity injury: Are early, aggressive fluid resuscitation strategies to blame? J Trauma. 2008; 64:280–285.

74. Lee, CC, Chang, IJ, Yen, ZS, et al. Effect of different resuscitation fluids on cytokine response in a rat model of hemorrhagic shock. Shock. 2005; 24:177–181.

75. Chen, H, Koustova, E, Shults, C, et al. Differential effect of resuscitation on toll-like receptors in a model of hemorrhagic shock without a septic challenge. Resuscitation. 2007; 74:526–537.

76. Chen, H, Inocencio, R, Alam, HB, et al. Differential expression of extracellular matrix remodeling genes in rat model of hemorrhagic shock and resuscitation. J Surg Res. 2005; 123:235–244.

77. Alam, HB, Sun, L, Ruff, P, et al. E- and P-selectin expression depends on the resuscitation fluid used in hemorrhaged rats. J Surg Res. 2000; 94:145–152.

78. Fluid Resuscitation. State of the Science for Treating Combat Casualties and Civilian Injuries. Washington, DC: Institute of Medicine; 1999.

79. Ayuste, EC, Chen, H, Koustova, E, et al. Hepatic and pulmonary apoptosis after hemorrhagic shock in swine can be reduced through modifications of conventional Ringer’s solution. J Trauma. 2006; 60:52–63.

80. Koustova, E, Stanton, K, Gushchin, V, et al. Effects of lactated Ringer’s solutions on human leukocytoses. J Trauma. 2002; 52:872–878.

81. Chen, H, Alam, HB, Querol, RI, et al. Identification of expression patterns associated with hemorrhage and resuscitation: Integrated approach to data analysis. J Trauma. 2006; 60:701–724.

82. Alam, HB, Stanton, K, Koustova, E, et al. Effect of different resuscitation strategies on neutrophil activation in a swine model of hemorrhagic shock. Resuscitation. 2004; 60:91–99.

83. Deb, S, Sun, L, Martin, B, et al. Lactated Ringer’s solution and hetastarch but not plasma resuscitation after rat hemorrhagic shock is associated with immediate lung apoptosis by the up-regulation of the Bax protein. J Trauma. 2000; 49:47–55.

84. Barron, ME, Wilkes, MM, Navickis, RJ. A systemic review of the comparative safety of colloids. Arch Surg. 2004; 139:552–563.

85. Vincent, JL, Navickis, RJ, Wilkes, MM. Morbidity in hospitalized patients receiving human albumin: A meta-analysis of randomized, controlled trials. Crit Care Med. 2004; 32:2029–2038.

86. Wilkes, MM, Navickis, RJ. Does albumin infusion affect survival? Review of meta-analytic findings. In: Vincent JL, ed. 2002 Yearbook of Intensive Care and Emergency Medicine. Berlin: Springer-Verlag; 2002:454–464.

87. Blunt, MC, Nicholson, JP, Park, GR. Serum albumin and colloid osmotic pressure in survivors and nonsurvivors of prolonged critical illness. Anaesthesia. 1998; 53:755–761.

88. Finfer, S, Bellomo, R, Boyce, N, et al. A comparison of albumin and saline for fluid resuscitation in the intensive care unit. SAFE Study Investigators. N Engl J Med. 2004; 350:2247–2256.

89. Rocha-e-Silva, M, Negraes, GA, Soares, AM, et al. Hypertonic resuscitation from severe hemorrhagic shock: Patterns of regional circulation. Circ Shock. 1986; 19:165–175.

90. Chiara, O, Pelosi, P, Brazzi, L, et al. Resuscitation from hemorrhagic shock: Experimental model comparing normal saline, dextran, and hypertonic saline solutions. Crit Care Med. 2003; 31:1915–1922.

91. Dubick, MA, Bruttig, SP, Wade, CE. Issues of concern regarding the use of hypertonic/hyperoncotic fluid resuscitation of hemorrhagic hypotension. Shock. 2006; 25:321–328.

92. Shackford, SR, Schmoker, JD, Zhuang, J. The effect of hypertonic resuscitation on pial arteriolar tone after brain injury and shock. J Trauma. 1994; 37:899–908.

93. Wade, CE, Grady, JJ, Kramer, GC, et al. Individual patient cohort analysis of the efficacy of hypertonic saline/dextran in patients with traumatic brain injury and hypotension. J Trauma. 1997; 42(Suppl):S61–S65.

94. Rizoli, SB, Rhind, SG, Shek, PN, et al. The immunomodulatory effects of hypertonic saline resuscitation in patients sustaining traumatic hemorrhagic shock: A randomized, controlled, double-blinded trial. Ann Surg. 2006; 243:47–57.

95. Riddez, L, Drobin, D, Sjöstrand, F, et al. Lower dose of hypertonic saline dextran reduces the risk of lethal rebleeding in uncontrolled hemorrhage. Shock. 2002; 17:377–382.

96. Wade, CE, Kramer, GC, Grady, JJ, et al. Efficacy of hypertonic 7. 5% saline and 6% dextran-70 in treating trauma: A meta-analysis of controlled clinical studies. Surgery. 1997; 122:609–616.

97. Kempski, O, Obert, C, Mainka, T, et al. “Small volume resuscitation” as treatment of cerebral blood flow disturbances and increased ICP in trauma and ischemia. Acta Neurochir Suppl. 1996; 66:114–117.

98. Goulin, GD, Duthie, SE, Zornow, MH, et al. Global cerebral ischemia: Effects of pentastarch after reperfusion. Anesth Analg. 1994; 79:1036–1042.

99. Poole, GV, Meredith, JW, Pennell, T, et al. Comparison of colloids and crystalloids in resuscitation from hemorrhagic shock. Surg Gynecol Obstet. 1982; 154:577–586.

100. Hauser, CJ, Shoemaker, WC, Turpin, I, et al. Oxygen transport responses to colloids and crystalloids in critically ill surgical patients. Surg Gynecol Obstet. 1980; 150:811–816.

101. Carey, LC, Lowery, BD, Cloutier, CT. Hemorrhagic shock. Curr Probl Surg. 1971; 8:1–48.

102. Weaver, DW, Ledgerwood, AM, Lucas, CE, et al. Pulmonary effects of albumin resuscitation for severe hypovolemic shock. Arch Surg. 1978; 113:387–392.

103. Lowe, RJ, Moss, GS, Jilek, J, et al. Crystalloid vs. colloid in the etiology of pulmonary failure after trauma: A randomized trial in man. Surgery. 1977; 81:676–683.

104. Shah, DM, Browner, BD, Dutton, RE, et al. Cardiac output and pulmonary wedge pressure: Use for evaluation of fluid replacement in trauma patients. Arch Surg. 1977; 112:1161–1168.

105. Guyton, AC, Lindsey, AW. Effect of elevated left atrial pressure and decreased plasma protein concentration on the development of pulmonary edema. Circ Res. 1959; 7:649–657.

106. Zarins, CK, Rice, CL, Smith, DE, et al. Role of lymphatics in preventing hypooncotic pulmonary edema. Surg Forum. 1976; 27:257–259.

107. Demling, RH, Manohar, M, Will, JA, et al. The effect of plasma oncotic pressure on the pulmonary microcirculation after hemorrhagic shock. Surgery. 1979; 86:323–328.

108. Holcroft, JW, Trunkey, DD, Carpenter, MA. Excessive fluid administration in resuscitating baboons from hemorrhagic shock, and an assessment of the thermodye technic for measuring extravascular lung water. Am J Surg. 1978; 135:412–416.

109. Ledgerwood, AM, Lucas, CE. A review of studies on the effects of hemorrhagic shock and resuscitation on the coagulation profile. J Trauma. 2003; 54(Suppl):S68–S74.

110. Teixeira, PG, Inaba, K, Shulman, I, et al. Impact of plasma transfusion in massively transfused trauma patients. J Trauma. 2009; 66:693–697.

111. Kashuk, JL, Moore, EE, Johnson, JL, et al. Postinjury life threatening coagulopathy: Is 1:1 fresh frozen plasma:packed red blood cells the answer? J Trauma. 2008; 65:261–271.

112. Cotton, BA, Gunter, OL, Isbell, J, et al. Damage control hematology: The impact of a trauma exsanguination protocol on survival and blood product utilization. J Trauma. 2008; 64:1177–1183.

113. Holcomb, JB, Wade, CD, Michalek, JE, et al. Increased plasma and platelets to red blood cell ratios improves outcome in 466 massively transfused civilian trauma patients. Ann Surg. 2008; 248:447–458.

114. Hirshberg, A, Hoyt, DB, Mattox, KL. Timing of fluid resuscitation shapes the hemodynamic response to uncontrolled hemorrhage: Analysis using dynamic modeling. J Trauma. 2006; 60:1221–1227.

115. Dries, DJ. Hypotensive resuscitation. Shock. 1996; 6:311–316.

116. Tisherman, SA, Barie, P, Bokhari, F, et al. Clinical practice guideline: End points of resuscitation. J Trauma. 2004; 57:898–912.

117. Elliott, DC. An evaluation of the end points of resuscitation. J Am Coll Surg. 1998; 187:536–547.

118. Brain Trauma Foundation. Management and prognosis of severe traumatic brain injury. J Neurotrauma. 2000; 17:449–627.

119. Chesnut, RM, Marshall, LF, Klauber, MR, et al. The role of secondary brain injury in determining outcome from severe head injury. J Trauma. 1993; 34:216–222.

120. Shoemaker, WC, Appel, P, Bland, R. Use of physiologic monitoring to predict outcome and to assist in clinical decisions in critically ill postoperative patients. Am J Surg. 1983; 146:43–50.

121. Shoemaker, WC, Appel, PL, Kram, HB, et al. Prospective trial of supranormal values of survivors as therapeutic goals in high-risk surgical patients. Chest. 1988; 94:1176–1186.

122. Bishop, MH, Shoemaker, WC, Appel, PL, et al. Relationship between supranormal circulatory values, time delays, and outcome in severely traumatized patients. Crit Care Med. 1993; 21:56–63.

123. Fleming, A, Bishop, M, Shoemaker, W, et al. Prospective trial of supranormal values as goals of resuscitation in severe trauma. Arch Surg. 1992; 127:1175–1181.

124. Bishop, MH, Shoemaker, WC, Appel, PL, et al. Prospective, randomized trial of survivor values of cardiac index, oxygen delivery, and oxygen consumption as resuscitation end points in severe trauma. J Trauma. 1995; 38:780–787.

125. Moore, FA, Haenel, JB, Moore, EE, et al. Incommensurate oxygen consumption in response to maximal oxygen availability predicts postinjury multisystem organ failure. J Trauma. 1992; 33:58–67.

126. Durham, RM, Neunaber, K, Mazuski, JE, et al. The use of oxygen consumption and delivery as end points for resuscitation in critically ill patients. J Trauma. 1996; 41:32–40.

127. Velmahos, GC, Demetriades, D, Shoemaker, WC, et al. End points of resuscitation of critically injured patients: Normal or supranormal? A prospective randomized trial. Ann Surg. 2000; 232:409–418.

128. Mizock, BA, Falk, JL. Lactic acidosis in critical illness. Crit Care Med. 1992; 20:80–93.

129. Abramson, D, Scalea, TM, Hitchcock, R, et al. Lactate clearance and survival following injury. J Trauma. 1993; 35:584–589.

130. McNelis, J, Marini, CP, Jurkiewicz, A, et al. Prolonged lactate clearance is associated with increased mortality in the surgical intensive care unit. Am J Surg. 2001; 182:481–485.

131. Mikulaschek, A, Henry, SM, Donovan, R, et al. Serum lactate is not predicted by anion gap or base excess after trauma resuscitation. J Trauma. 1996; 40:218–224.

132. Davis, JW, Kaups, KL, Parks, SN. Base deficit is superior to pH in evaluating clearance of acidosis after traumatic shock. J Trauma. 1998; 44:114–118.

133. Eachempati, SR, Reed, RL, 2nd., Barie, PS. Serum bicarbonate as an endpoint of resuscitation in critically ill patients. Surg Infect (Larchmt). 2003; 4:193–197.

134. Davis, JW, Shackford, SR, Mackersie, RC, et al. Base deficit as a guide to volume resuscitation. J Trauma. 1988; 28:1464–1467.

135. Falcone, RE, Santanello, SA, Schulz, MA, et al. Correlation of metabolic acidosis with outcome following injury and its value as a scoring tool. World J Surg. 1993; 17:575–579.

136. Sauaia, A, Moore, FA, Moore, EE, et al. Early predictors of postinjury multiple organ failure. Arch Surg. 1994; 129:39–45.

137. Kincaid, EH, Miller, PR, Meredith, JW, et al. Elevated arterial base deficit in trauma patients: A marker of impaired oxygen utilization. J Am Coll Surg. 1998; 187:384–392.

138. Rixen, D, Raum, M, Bouillon, B, et al. Base deficit development and its prognostic significance in posttrauma critical illness: An analysis by the trauma registry of the Deutsche Gesellschaft für Unfallchirurgie. Shock. 2001; 15:83–89.

139. Davis, JW, Parks, SN, Kaups, KL, et al. Admission base deficit predicts transfusion requirements and risk of complications. J Trauma. 1996; 41:769–774.

140. Rixen, D, Siegel, JH. Metabolic correlates of oxygen debt predict posttrauma early acute respiratory distress syndrome and the related cytokine response. J Trauma. 2000; 49:392–403.

141. Dunham, CM, Watson, LA, Cooper, C. Base deficit level indicating major injury is increased with ethanol. J Emerg Med. 2000; 18:165–171.

142. Davis, JW, Kaups, KL, Parks, SN. Effect of alcohol on the utility of base deficit in trauma. J Trauma. 1997; 43:507–510.

143. Brill, SA, Stewart, TR, Brundage, SI, et al. Base deficit does not predict mortality when secondary to hyperchloremic acidosis. Shock. 2002; 17:459–462.

144. Dantzker, DR. The gastrointestinal tract: The canary of the body? JAMA. 1993; 270:1247–1248.

145. Harbrecht, BG, Alarcon, LH, Peitzman, AB. Management of shock. In: Moore EE, Feliciano DV, Mattox KL, eds. Trauma. 5th ed. New York: McGraw-Hill; 2004:201–226.

146. Roumen, RM, Vreugde, JP, Goris, RJ. Gastric tonometry in multiple trauma patients. J Trauma. 1994; 36:313–316.

147. Chang, MC, Cheatham, ML, Nelson, LD, et al. Gastric tonometry supplements information provided by systemic indicators of oxygen transport. J Trauma. 1994; 37:488–494.

148. Miller, PR, Kincaid, EH, Meredith, JW, et al. Threshold values of intramucosal pH and mucosal-arterial CO₂ gap during shock resuscitation. J Trauma. 1998; 45:868–872.

149. Ivatury, RR, Simon, RJ, Havriliak, D, et al. Gastric mucosal pH and oxygen delivery and oxygen consumption indices in the assessment of adequacy of resuscitation after trauma: A prospective, randomized study. J Trauma. 1995; 39:128–136.

150. Ivatury, RR, Simon, RJ, Islam, S, et al. A prospective randomized study of end points of resuscitation after major trauma: Global oxygen transport indices versus organ-specific gastric mucosal pH. J Am Coll Surg. 1996; 183:145–154.

151. Wall, P, Henderson, L, Buising, C, et al. Monitoring gastrointestinal intraluminal PCO₂: Problems with airflow methods. Shock. 2001; 15:360–365.

152. Soller, BR, Cingo, N, Puyana, JC, et al. Simultaneous measurement of hepatic tissue pH, venous oxygen saturation and hemoglobin by near infrared spectroscopy. Shock. 2001; 15:106–111.

153. McKinley, BA, Marvin, RG, Cocanour, CS, et al. Tissue hemoglobin O₂ saturation during resuscitation of traumatic shock monitored using near infrared spectrometry. J Trauma. 2000; 48:637–642.

154. Cairns, CB, Moore, FA, Haenel, JB, et al. Evidence for early supply independent mitochondrial dysfunction in patients developing multiple organ failure after trauma. J Trauma. 1997; 42:532–536.

155. Keynes, G. The Apology and Treatise of Ambroise Paré Containing the Voyages Made Into Divers Places With Many of His Writings Upon Surgery. Chicago: University of Chicago Press; 1952.

156. Simeone, FA. Shock, trauma and the surgeon. Ann Surg. 1963; 158:759–774.

157. Cannon, WB. Traumatic Shock. New York: Appleton; 1923.

158. Mapstone, J, Roberts, I, Evans, P. Fluid resuscitation strategies: A systemic review of animal trials. J Trauma. 2003; 55:571–589.

159. Cannon, WB, Fraser, J, Cowell, EM. The preventive treatment of wound shock. JAMA. 1918; 70:618–621.

160. Capone, AC, Safar, P, Stezoski, W, et al. Improved outcome with fluid restriction in treatment of uncontrolled hemorrhagic shock. J Am Coll Surg. 1995; 180:49–56.

161. Shaftan, GW, Chiu, CJ, Dennis, C, et al. Fundamentals of physiologic control of arterial hemorrhage. Surgery. 1965; 58:851–856.

162. Milles, G, Koucky, CJ, Zacheis, HG. Experimental uncontrolled arterial hemorrhage. Surgery. 1966; 60:434–442.

163. Shires, T, Coln, D, Carrico, J, et al. Fluid therapy in hemorrhagic shock. Arch Surg. 1964; 88:688–693.

164. Traverso, LW, Lee, WP, Langford, MJ. Fluid resuscitation after an otherwise fatal hemorrhage, I: Crystalloid solutions. J Trauma. 1986; 26:168–175.

165. Baue, AE, Tragus, ET, Wolfson, SK, Jr., et al. Hemodynamic and metabolic effects of Ringer’s lactate solution in hemorrhagic shock. Ann Surg. 1967; 166:29–38.

166. Wiggers, CJ. Physiology of Shock. New York: Commonwealth Publications; 1950.

167. Gann, DS, Wright, PA, Shock—the final common pathway?. Advances in Trauma Critical Care. Maull, KI, eds. Advances in Trauma Critical Care; Vol. 10. Mosby-Year Book, St. Louis, 1995:43–59.

168. Bickell, WH, Bruttig, SP, Millnamow, GA, et al. The detrimental effects of intravenous crystalloid after aortotomy in swine. Surgery. 1991; 110:529–536.

169. Stern, SA, Dronen, SC, Birrer, P, et al. Effect of blood pressure on hemorrhage volume and survival in a near-fatal hemorrhage model incorporating a vascular injury. Ann Emerg Med. 1993; 22:155–163.

170. Kowalenko, T, Stern, S, Dronen, S, et al. Improved outcome with hypotensive resuscitation of uncontrolled hemorrhagic shock in a swine model. J Trauma. 1992; 33:349–353.

171. Novak, L, Shackford, SR, Bourguignon, P, et al. Comparison of standard and alternative prehospital resuscitation in uncontrolled hemorrhagic shock and head injury. J Trauma. 1999; 47:834–844.

172. Martin, RR, Bickell, WH, Pepe, PE, et al. Prospective evaluation of preoperative fluid resuscitation in hypotensive patients with penetrating truncal injury: A preliminary report. J Trauma. 1992; 33:354–362.

173. Bickell, WH, Wall, MJ, Jr., Pepe, PE, et al. Immediate versus delayed fluid resuscitation for hypotensive patients with penetrating torso injuries. N Engl J Med. 1994; 331:1105–1109.

174. Champion, HR, Sacco, WJ, Copes, WS, et al. A revision of the trauma score. J Trauma. 1989; 29:623–629.

175. The Abbreviated Injury Scale, 1990. Des Plaines, IL: Association for the Advancement of Automotive Medicine, 1990.

176. Wall, MJ, Jr., Granchi, T, Liscum, K, et al. Delayed versus immediate resuscitation in patients with penetrating trauma: Subgroup analysis. J Trauma. 1995; 39:173.

177. McSwain, NE, Champion, HR, Fabian, TC, et al. State of the art of fluid resuscitation 2010: Prehospital and immediate transition to the hospital. J Trauma. 2011; 70(Suppl):S2–S10.

178. Marr, AB, Moore, FA, Sailors, RM, et al. Preload optimization using “Starling curve” generation during shock resuscitation: Can it be done? Shock. 2004; 21:300–305.

179. McKinley, BA, Kozar, RA, Cocanour, CS, et al. Normal versus supranormal oxygen delivery goals in shock resuscitation: The response is the same. J Trauma. 2002; 53:825–832.

180. McKinley, BA, Marvin, RG, Cocanour, CS, et al. Blunt trauma resuscitation: The old can respond. Arch Surg. 2000; 135:688–695.

181. McKinley, BA, Kozar, RA, Cocanour, CS, et al. Standardized trauma resuscitation: Female hearts respond better. Arch Surg. 2002; 137:578–584.

182. McKinley, BA, Valdivia, A, Moore, FA. Goal-oriented shock resuscitation for major torso trauma: What are we learning? Curr Opin Crit Care. 2003; 9:292–299.

183. Scalea, TM, Simon, HM, Duncan, AO, et al. Geriatric blunt multiple trauma: Improved survival with early invasive monitoring. J Trauma. 1990; 30:129–136.

184. Balogh, Z, McKinley, BA, Cocanour, CS, et al. Supranormal trauma resuscitation causes more cases of abdominal compartment syndrome. Arch Surg. 2003; 138:637–643.

185. Friese, RS, Shafi, S, Gentilello, LM. Pulmonary artery catheter use is associated with reduced mortality in severely injured patients: A National Trauma Data Bank analysis of 53,312 patients. Crit Care Med. 2006; 34:1597–1601.

186. Kauvar, DS, Lefering, R, Wade, CE. Impact of hemorrhage on trauma outcome: An overview of epidemiology, clinical presentations, and therapeutic considerations. J Trauma. 2006; 60:S3–S11.

187. Bouillon, B, Raum, M, Fach, H, et al. The incidence and outcome of severe brain trauma—Design and first results of an epidemiological study in an urban area. Restor Neurol Neurosci. 1999; 14:85–92.

188. Manley, G, Knudson, MM, Morabito, D, et al. Hypotension, hypoxia, and head injury: Frequency, duration, and consequences. Arch Surg. 2001; 136:1118–1123.

189. Chesnut, RM, Marshall, SB, Piek, J, et al. Early and late systemic hypotension as a frequent and fundamental source of cerebral ischemia following severe brain injury in the Traumatic Coma Data Bank. Acta Neurochir Suppl (Wien). 1993; 59:121–125.

190. Hoyt, DB, Bulger, EM, Knudson, MM, et al. Death in the operating room: An analysis of a multi-center experience. J Trauma. 1994; 37:426–432.

191. Como, JJ, Dutton, RP, Scalea, TM, et al. Blood transfusion rates in the care of acute trauma. Transfusion. 2004; 44:809–813.

192. Ketchum, L, Hess, JR, Hiippala, S. Indications for early fresh frozen plasma, cryoprecipitate, and platelet transfusion in trauma. J Trauma. 2006; 60:S51–S58.

193. Malone, DL, Hess, JR, Fingerhut, A. Massive transfusion practices around the globe and a suggestion for a common massive transfusion protocol. J Trauma. 2006; 60:S91–S96.

194. Vaslef, SN, Knudsen, NW, Neligan, PJ, et al. Massive transfusion exceeding 50 units of blood products in trauma patients. J Trauma. 2002; 53:291–296.

195. 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; 69:489–500.

196. Nishijima, DK, Zehtabchi, S. The efficacy of recombinant activated factor VII in severe trauma. Ann Emerg Med. 2009; 54:737–744.

197. Al-Ruzzeh, S, Navia, JL. The “off-label” role of recombinant factor VII in surgery: Is the problem deficient evidence or defective concept? J Am Coll Surg. 2009; 209:659–667.

198. Levi, M, Levy, JH, Andersen, HF, et al. Safety of recombinant activated factor VII in randomized clinical trials. N Engl J Med. 2010; 363:1791–1800.

199. Nunez, TC, Voskresensky, IV, Dossett, LA, et al. Early prediction of massive transfusion in trauma: Simple as ABC (assessment of blood consumption)? J Trauma. 2009; 66:346–352.

200. Cotton, BA, Dossett, LA, Haut, ER, et al. Multicenter validation of a simplified score to predict massive transfusion in trauma. J Trauma. 2010; 69(suppl):S33–S39.

201. Callcut, RA, Johannigman, JA, Kadon, KS, et al. All massive transfusion criteria are not created equal: Defining the predictive value of individual transfusion triggers to better determine who benefits from blood. J Trauma. 2011; 70:794–801.

202. The CRASH-2 CollaboratorsRoberts, I, Shakur, H, et al. The importance of early treatment with tranexamic acid in bleeding trauma patients: An exploratory analysis of the CRASH-2 randomised controlled trial. Lancet. 2011; 377:1096–1101.

203. CRASH-2 Collaborators. Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): A randomized, placebo-controlled trial. Lancet. 2010; 376:23–32.

204. Morrison, JJ, Dubose, JJ, Rasmussen, TE, et al. Military application of tranexamic acid in trauma emergency resuscitation (MATTERs) study. Arch Surg. 2012; 147:113–119.

205. Gruen, RL, Mitra, B. Tranexamic acid for trauma. Lancet. 2011; 377:1052–1054.

206. Napolitano, L. Cumulative risks of early red blood cell transfusion. J Trauma. 2006; 60:S26–S34.

207. Silliman, CC, Moore, EE, Johnson, JL, et al. Transfusion of the injured patient: Proceed with caution. Shock. 2004; 21:291–299.

208. Moore, FA, Moore, EE, Sauaia, A. Blood transfusion: An independent risk factor for postinjury multiple organ failure. Arch Surg. 1997; 132:620–625.

209. Dunne, JR, Malone, DL, Tracy, JK, et al. Allogenic blood transfusion in the first 24 hours after trauma is associated with increased systemic inflammatory response syndrome (SIRS) and death. Surg Infect. 2004; 5:395–404.

210. Blajchman, MA. The clinical benefits of the leukoreduction of blood products. J Trauma. 2006; 60:S83–S90.

211. Schein, M, Wittmann, DH, Aprahamian, CC, et al. The abdominal compartment syndrome: The physiological and clinical consequences of elevated intra-abdominal pressure. J Am Coll Surg. 1995; 180:745–753.

212. Chang, MC, Miller, PR, D’Agostino, R, Jr., et al. Effects of abdominal decompression on cardiopulmonary function and visceral perfusion in patients with intra-abdominal hypertension. J Trauma. 1998; 44:440–445.

213. Cheatham, ML, White, MW, Sagraves, SG, et al. Abdominal perfusion pressure: A superior parameter in the assessment of intra-abdominal hypertension. J Trauma. 2000; 49:621–627.

214. Malbrain, ML, Cheatham, ML, Kirkpatrick, A, et al. Results from the International Conference of Experts on Intra-abdominal Hypertension and Abdominal Compartment Syndrome, I: Definitions. Intensive Care Med. 2006; 32:1722–1732.

215. Ivatury, RR, Diebel, L, Porter, JM, et al. Intra-abdominal hypertension and the abdominal compartment syndrome. Surg Clin North Am. 1997; 77:783–800.

216. Sugrue, M, Buist, MD, Hourihan, F, et al. Prospective study of intra-abdominal hypertension and renal function after laparotomy. Br J Surg. 1995; 82:235–238.

217. Sugrue, M, Jones, F, Janjua, KJ, et al. Temporary abdominal closure: A prospective evaluation of its effects on renal and respiratory physiology. J Trauma. 1998; 45:914–921.

218. Sugrue, M, Jones, F, Deane, SA, et al. Intra-abdominal hypertension is an independent cause of postoperative renal impairment. Arch Surg. 1999; 134:1082–1085.

219. Diebel, LN, Dulchavsky, SA, Wilson, RF. Effect of increased intra-abdominal pressure on mesenteric arterial and intestinal mucosal blood flow. J Trauma. 1992; 33:45–49.

220. Diebel, LN, Wilson, RF, Dulchavsky, SA, et al. Effect of increased intra-abdominal pressure on hepatic arterial, portal venous, and hepatic microcirculatory blood flow. J Trauma. 1992; 33:279–283.

221. Cheatham, ML, Safcsak, K. Percutaneous catheter decompression in the treatment of elevated intra-abdominal pressure. Chest. 2011; 140:1428–1435.

222. Dries, DJ. Abdominal compartment syndrome: Toward less-invasive management (editorial). Chest. 2011; 140:1396–1398.

223. Mubarak, SJ, Hargens, AR. Acute compartment syndromes. Surg Clin North Am. 1983; 63:539–565.

224. Duis, HJ, Nijsten, MW, Klasen, HJ, et al. Fat embolism in patients with an isolated fracture of the femoral shaft. J Trauma. 1988; 28:383–390.

225. Feliciano, DV, Cruse, PA, Spjut-Patrinely, V, et al. Fasciotomy after trauma to the extremities. Am J Surg. 1988; 156:533–536.

226. Scalea, TM, Burgess, AR. Pelvic fractures. In: Moore EE, Feliciano DV, Mattox KL, eds. Trauma. 5th ed. New York: McGraw-Hill; 2004:779–807.

227. Gylling, SF, Ward, RE, Holcroft, JW, et al. Immediate external fixation of unstable pelvic fractures. Am J Surg. 1985; 150:721–724.

228. Ben-Menachem, Y, Coldwell, DM, Young, JW, et al. Hemorrhage associated with pelvic fractures: Causes, diagnosis, and emergent management. Am J Roentgenol. 1991; 157:1005–1014.