CHAPTER 58 CURRENT CONCEPTS IN THE DIAGNOSIS AND MANAGEMENT OF HEMORRHAGIC SHOCK
The precipitating single common factor of hemorrhagic shock is severe acute blood loss, yet the clinical syndrome of hemorrhagic shock is heterogeneous. The diagnosis and management of this condition at first would appear to be simple. However, the very nature of how shock occurs and how the individual compensatory mechanisms respond to both the injury itself and the therapeutic interventions translate into a complex spectrum of diseases. This disease spectrum extends from immediate circulatory collapse to total body ischemia reperfusion injury with associated complex inflammatory and anti-inflammatory responses that in many instances evolve into multiple organ dysfunction. The purpose of this chapter is to provide a review of the current issues and a clinical perspective regarding the diagnosis and management of shock.
EPIDEMIOLOGY OF SEVERE HEMORRHAGIC SHOCK
Injury is the leading cause of death for individuals younger than age 44 years in the United States. Overall, trauma results in approximately 150,000 deaths per year, and severe hypovolemia caused by hemorrhage is a major factor in nearly half of those deaths. The leading causes of death remain head injury and hemorrhage. These findings have been reported both in the civilian literature1 and military experiences—the Vietnam conflict,2,3 and most recently in Baghdad.4 Approximately one-third of trauma deaths occur out of hospital; exsanguination is a major cause of deaths occurring within 4 hours of injury. The distribution of battlefield injuries in the Vietnam War showed that 25% of the deaths occurred as a result of massive exsanguination and were not salvageable. An additional 19% of deaths were deemed salvageable, and these were the result of torso exsanguination (10%) and peripheral exsanguination (19%).3
CLINICAL PERSPECTIVE: LENGTH AND DEPTH OF HYPOTENSION
Severe hemorrhagic shock is characterized by cool, moist, pallid, or cyanotic skin. The patient is tachycardic and hypotensive, and the severity of these clinical manifestations may vary from patient to patient depending on age, underlying cardiovascular disease, and the presence of medications or associated toxic compounds such as drugs or alcohol. Hypotension is the hallmark of shock, is easily measured, and its presence is always a predictor of poor outcome.5–7 The severity of shock, however, can only be partially quantified by the presence of hypotension. Obviously, patients with rapid and massive blood loss will manifest low blood pressure shortly after the injury. Sophisticated devices or monitoring techniques are not required to establish that such patients are close to dying. Prompt and efficient interventions must be instituted immediately, aimed at control of hemorrhage and replacement of the blood volume. Unfortunately, the absence of hypotension after injury does not rule out the presence of shock. In fact, it may mislead the inexperienced clinician to a false sense of security about the need for aggressive resuscitation.8
Injured patients arriving to the trauma center with hypotension or a history of transient hypotension comprise only 6%–9% of the total number of trauma patients.5,6 From a practical viewpoint, patients with hemorrhagic shock can be stratified into three groups. Group 1 comprises patients with exsanguinating hemorrhage. They generally have significant chest injuries to the heart or great vessels, and/or massively disrupted abdominal visceral or significant retroperitoneal bleeding such as pelvic fractures. This group represents one-third of the total number of hypotensive patients or 2% of the total trauma patient population. They arrive alive to our trauma centers only as a direct result of well-organized prehospital and trauma systems. The response to fluid administration in this group is minimal or completely absent, and these patients are termed nonresponders.
Some clinicians suggest that most shock states can be reversed with more volume resuscitation, with correction of hypothermia, and with inotropic agents. Yet, many patients die, if not acutely from irreversible shock, then later from events initiated by severe, prolonged, or unrecognized shock. Clinically, however, circulatory collapse associated with shock is the common pathway of early progressive deterioration precipitated by trauma and hemorrhage. Patients suffering from severe penetrating trauma to the chest or abdomen, with major injuries to the thoracic or intra-abdominal vessels, who do not die at the scene, may undergo aggressive interventions that may include an emergency thoracotomy and massive transfusion. These patients usually require damage control interventions, and manifest severe hypothermia, coagulopathy, and circulatory failure, even after their hemorrhage has been controlled.9 Much less common is the clinical scenario of combat casualty victims or civilian trauma patients from rural areas who may develop circulatory collapse and irreversible shock in a slow protracted fashion because of inadequate resuscitation as a result of lack of blood products, delayed evacuation, or prolonged hypotension before definitive care can be provided. Clearly these are two separate clinical scenarios that in the end may have similar outcomes. Because the spectrum of hypoperfusion, ischemia, and total body reperfusion may differ significantly from one clinical scenario to the next, future therapeutic interventions will need to be more sophisticated and targeted than what we offer today. Fluid resuscitation as currently prescribed represents a rather naive approach to therapy in a complicated pathophysiological process.10
The potential enhancement of early recognition of progressive or refractory shock and reducing the onset of circulatory collapse early in the management of the patient with hemorrhage offers the opportunity of redefining the “golden hour” (i.e., the window of opportunity for efficacious resuscitation).11,12
Discrepancies between Clinical Syndrome of Shock and Animal Models Used to Study Shock
When devising models of hemorrhagic shock, investigators in this field are challenged by two sometimes mutually incompatible goals. First, researchers desire to minimize animal-to-animal variability. Second, researchers seek to achieve a model with clinical relevance. Bleeding in the clinical environment is typically uncontrolled. As hemorrhage continues and arterial pressure decreases, the rate of bleeding tends to slow. Hemostatic mechanisms may come into play when blood pressure is low enough so that bleeding ceases entirely. Resuscitation can actually dislodge the nascent clot by raising blood pressure, and thereby precipitate recurrent hemorrhage.13 Numerous animal models of uncontrolled bleeding have been described.14 These models are generally useful for studying novel approaches to achieve hemostasis, for determining the optimal timing of resuscitation, or for determining the optimal parameters/endpoints for resuscitation.15–17 However, uncontrolled hemorrhage models, while attractive because of their clinical relevance, suffer from a high degree of animal-to-animal variability. Therefore, the use of these models for preclinical efficacy studies of new therapeutic agents requires relatively large sample sizes to obtain statistically meaningful data.
On the other hand, controlled hypotension, as originally described by Wiggers, allows a more standardized grading of injury. When hemorrhagic shock is induced using the Wiggers model, it is initially necessary to periodically withdraw additional aliquots of blood to maintain the target blood pressure because of the body’s normal compensatory responses to acute hypovolemia.18 However, after the shock state has persisted for a period of time, it is no longer possible to withdraw blood to maintain the target blood pressure. On the contrary, it now becomes necessary to reinfuse aliquots of the shed blood to maintain the target blood pressure. This phase has little resemblance to what happens in clinical practice, but in the laboratory it is used to delineate what is known as the “decompensation endpoint,” defined as the transition point from withdrawal to reinfusion of blood. This transition point typically occurs after 90–120 minutes of shock depending on the species. This model is imperfect as well, because variability occurs as to the time of the decompensation endpoint from one animal to the next one. Obviously the Wiggers model allows for a more reproducible injury, one that has little resemblance to the clinical scenario but one that facilitates mechanistic or cause/effect studies and that has been used extensively to delineate many of the cellular and molecular events described after hemorrhage.19,20
Diagnosis of Shock
The phenomenon of ischemia and reperfusion has been extensively studied. Shock and resuscitation are functionally a total body ischemia/reperfusion injury. SIRS (systemic inflammatory response syndrome) and MODS (multiple organ dysfunction syndrome) are the expressions of a conglomerate of events associated with ischemia and reperfusion. Unfortunately, we rely on nonspecific global methods to provide indirect information regarding tissue perfusion. The current challenge is to identify innovative methods for quantifying the magnitude of shock. Some of the questions that should guide future research in this field include: how the interaction among the patient’s physiological reserve, compensatory responses, and the individual organs endurance/response to ischemia may ultimately manifest, and identifying the best methods to accurately measure each of these components. Presently, we scarcely understand these issues and use rather crude methods to quantify the insult. The term tissue perfusion is used liberally to refer to an entity not readily quantifiable. In practical terms, we rely on base deficit and lactate as the global parameters used to gauge tissue perfusion. In the intensive care unit (ICU), we add to the interpretation of these values by hemodynamic parameters that are commonly obtained only after invasive monitoring techniques can be implemented, such as thermodilution cardiac output or continuous SVO2 from either the central or mixed venous circulation.21,22
Assessment of Tissue Perfusion
Base deficit (BD) and lactic acid provide information about the degree of anaerobic metabolism. Lactate is an indirect measure of oxygen debt. Base deficit is defined as the amount of buffer necessary to bring the pH back to 7.40 with pCO2 of 40 torr. Davis et al.23 stratified patients by BD as mild (2–5), moderate (6–14), and severe (>15). The magnitude of the initial BD was found to directly correlate with hypotension and further need for fluid resuscitation. In addition, 65% of patients who had a worsening BD despite resuscitation had ongoing hemorrhage. BD is considered a reliable marker for shock and the need for transfusion in multiple trauma patients.24 Davis et al.25 also demonstrated that BD could remain abnormal despite improvements in mean arterial pressure, cardiac output, mixed venous O2 saturation, and oxygen extraction in an animal model of hemorrhagic shock. Rutherford et al.26 found that BD, age, and head injury had an additive effect on the incidence of mortality. Base deficit is an expedient and sensitive measure of both the degree and the duration of inadequate perfusion. It is useful as a clinical tool and enhances the predictive ability of other trauma scores.
Lactate is the end product of anaerobic glycolysis. As a more direct measurement of tissue hypoxia induced acidosis, it has been shown to have strong prognostic value. Normalization of serum lactate below 2 mmol/l or less within the first 24 hours is associated with 100% survival. Only 78% of patients survived when lactate levels remained elevated during the period of 24–48 hours after shock. The mortality is greater than 85% if lactate remains elevated at 48 hours postshock.27 Sauaia et al. demonstrated an association between an early (12 hours) rise in serum lactate above 2.5 mmol/l and multiorgan failure.28 Manikis et al.29 further found that initial and peak lactate levels, as well as the duration of hyperlactatemia, correlated with the development of MODS after trauma. In summary, the initial lactate level and time to normalization of lactate correlate with risk of MODS and death. However, improved survival using lactate or BD as endpoints for resuscitation has not been shown.30
HEMORRHAGE CONTROL
Local Hemorrhage Control
QuikClot is a new agent designed to induce local hemostasis of large wounds associated with vascular lesions. It is a zeolite mineral granular powder that increases the concentration of clotting factors in the wound. It has been used in models of extremity arterial injury and hepatic laceration with good results. QuikClot has been deployed with the U.S. military forces. Other local hemostatic dressings are currently being tested, such as Chitosan dressings and compressive dressings with a layer of fibrinogen thrombin and calcium chloride embedded in a Dexon mesh.31,32
Systemic Hemorrhage Control
Failure of coagulation in trauma is multifactorial and has been characterized by the combined presence of coagulation abnormalities resembling disseminated intravascular coagulation (DIC), caused by systemic activation of coagulation and fibrinolysis.33 Fibrinolysis is probably caused by release of tissue plasminogen activator from injured tissues33–35 and dilutional coagulopathy caused by aggressive fluid resuscitation.36 This massive transfusion syndrome includes dilution of coagulation factors and impairment of platelet number and function.37 Hypothermia may contribute to the coagulopathy by slowing of enzymatic activities of the coagulation cascade38,39 and impeding platelet function.40
Ideally, the introduction of an effective hemostatic agent that would act only at the site of injury, without induction of systemic activation of coagulation, could improve hemorrhage control and reduce hemorrhage-related mortality and morbidity in both military and civilian trauma victims.41 Systemically administered hemostatic agents include coagulation factors in the form of cryoprecipitate and fresh frozen plasma. A general hemostatic agent may be one that enhances full thrombin generation, and thereby the formation of a stable, tight, fibrin hemostatic plug that is resistant to premature fibrinolysis.
Patients with profuse bleeding resulting from extensive surgery or trauma often develop a complex coagulation pattern that includes reduced plasma levels of fibrinogen, Factor VIII and Factor V, and decreased platelet counts. These patients may have an impaired capacity to generate thrombin. In addition, thrombocytopenia is common, as well as increased fibrinolysis as a result of massive tissue damage. Several of these factors are important for an adequate thrombin formation as well as for the formation of a tight fibrin plug. Thus, low levels of fibrinogen result in the formation of a loose fibrin structure and to decreased activation of Factor XIII, the fibrin-stabilizing factor.42
Factor VIIa
Trauma patients with massive bleeding thus may benefit from intravenous rFVIIa to help generate a thrombin peak, which may be enough to form a firm, stable fibrin hemostatic plug and thereby decrease the bleeding.43 Because thrombin has such a crucial role in providing hemostasis, any agent that enhances thrombin generation in situations with impaired thrombin formation may be characterized as a “general hemostatic agent.” Large animal studies with clinically relevant models have demonstrated the efficacy of rFactor VIIa in induction of clot and improved survival.44–47
An in vitro study reported by Meng et al.48 indicated that rFVIIa may not be efficient in acidosis, but hypothermia has little effect on rFVIIa efficacy. These authors recommended that clinicians who may contemplate using FVIIa in trauma patients take note of the level of acidosis present and consider biochemical correction of acidosis before administration of FVIIa. Because of the profound effect of pH on the prothrombinase (FXa/FVa) complex, correction of acidosis may by itself improve hemostasis.
A preliminary study of FVIIa use reported three patients with high-velocity penetrating trauma, and four suffered blunt trauma. They had all received multiple transfusions and conventional interventions without achieving hemostasis. In all cases, the administration of rFVIIa caused a cessation of the diffuse bleeding and their coagulation parameters normalized.44 Boffard and colleagues49 published a larger multicenter trial demonstrating benefit from the use of rFVIIa. Both animal and human data indicate that there is a need for more research in the field using greater numbers of individuals both in human and animal research, as well as long-term follow-up to understand the issues regarding possible complications related to increased thrombosis.
Fluids
Management priorities in the bleeding trauma patient begin with airway control, ventilation, and oxygenation.50 The goal of resuscitation is to stop the bleeding and replete intravascular blood volume to maximize tissue oxygen delivery. Cardiac output, blood pressure, and oxygenated blood flow to vital organs are important determinants of outcome. Measurement of blood pressure may not be feasible, and it is not a necessary requirement to initiate therapy during the primary survey. In fact, a quick global assessment of adequacy of perfusion can be obtained with examination of the characteristics of the pulse. Obvious signs of shock are sufficient to establish the diagnosis and determine the severity of blood volume deficit. Additional information such as blood pressure measurement, electrocardiographic monitoring, pulse oximetry, and capnography may be useful. Adequate intravenous (IV) access for infusion of normothermic fluids is the next priority while other causes of severe hypotension and shock are being sought, such as tension pneumothorax, pericardial tamponade, or neurogenic shock.
Vascular Access for Patients with Severe Hemorrhage
ATLS™ (Advanced Trauma Life Support) guidelines recommend rapid placement of two large-bore (16-gauge or larger) IV catheters in the patient with serious injuries and hemorrhagic shock.50 The first choice for IV insertion should be a peripheral extremity vein. The most suitable veins are at the wrist, the dorsum of the hand, the antecubital fossa in the arm, and the saphenous in the leg. These sites can be followed by the external jugular and femoral vein. The complication rate of properly placed intravenous catheters is low. Intravascular placement of a large-bore IV should be verified by checking for backflow of blood. An IV site should infuse easily without added pressure. Intravenous fluids can extravasate into soft tissues when pumped under pressure through an infiltrated IV line and may create a compartment syndrome. A patient in extremis who loses pulses in the trauma bay needs a cut-down in the femoral vein.
TIMING AND VOLUME OF RESUSCITATION FLUID THERAPY
The major controversy in intravenous fluid resuscitation relates to patients with uncontrolled hemorrhage. The optimal volume of intravenous fluid administered is a balance between improvement in tissue oxygen delivery against increase in the blood loss by raising blood pressure. Aggressive fluid resuscitation in an attempt to achieve normal systemic pressure before hemostasis and control of the bleeding may exacerbate blood loss and thereby potentially increase mortality. The knowledge regarding the best time to infuse fluids to patients with hemorrhagic shock dates from almost a century ago,51 yet studies addressing the effects of massive resuscitation and best fluid management strategies during the prehospital phase have created controversy.13,14 It is desirable that patients with penetrating injuries and without evidence of traumatic brain injury be resuscitated to a lower admissible blood pressure (hypotensive resuscitation) to prevent “popping the clot” until surgical or local control of the hemorrhage can be obtained. The effects of this strategy and the associated hypoperfusion on organs such an injured brain suggest that patients with central nervous system injuries should be managed with a higher blood pressure endpoint.
Type of Fluid
Crystalloids, the ATLS recommendation: Ringer’s Lactate Solution
Shires’ original studies of crystalloid volume replacement showed such an impressive improvement in survival compared with blood alone or plasma that these data were promptly translated into clinical practice. It is remarkable however that after having used Ringer’s lactate as a volume expander and resuscitation fluid for more than half a century, only recently have investigators described the immunological and proinflammatory effects of this solution on neutrophils and other cells involved in host defense mechanisms. Rhee et al.52 described neutrophil activation caused by hemorrhagic shock and resuscitation. Using a swine model of shock, they compared the effects of fluid resuscitation in three separate groups: group I received Ringer’s lactate solution; group II, shed blood; and group III, 7.5% hypertonic saline solution. Neutrophil activation was measured in whole blood using flow cytometry to detect intracellular superoxide burst activity. They found that neutrophil activation increased significantly immediately after hemorrhage, but it was greatest after resuscitation with Ringer’s lactate solution. Animals that received shed blood or hypertonic saline had neutrophil activity return to baseline state after resuscitation. Furthermore, the same group later described that different resuscitative fluids may immediately affect the degree of apoptosis after hemorrhagic shock. In a study in rats, they described that resuscitation with Ringer’s lactate solution resulted in a significant increase in small intestinal epithelial and smooth muscle cell and hepatocyte apoptosis.53 These effects can be ameliorated by use of only the L-isomer of lactate or substitution of ketone for lactate.54
Colloids
Albumin
The use of albumin in critically ill patients has been analyzed in a Cochrane report.55,56 The authors carried out a systematic review of randomized, controlled trials comparing administration of albumin or plasma protein fraction with no fluid or administration of crystalloid solution in critically ill patients with hypovolemia, burns, or hypoalbuminemia. A total of 1419 patients from 30 separate trials were studied. For each patient category, the risk of death in the albumin treated group was higher than in the comparison group. For hypovolemia, the relative risk of death after albumin administration was 1.46 (95% confidence interval 0.97–2.22), for burns the relative risk was 2.40 (1.11–5.19), and for hypoalbuminemia it was 1.69 (1.07–2.67). This review, however, was based on relatively small trials in which there were only a small number of deaths. Therefore, these results must be interpreted with caution. Interestingly, a recent abstract reported the results of a study comparing the safety and efficacy of 5% albumin solution and Ringer’s lactate solution for resuscitation of adult ICU patients with shock.57 This was an open-label randomized multicenter controlled trail. Nineteen patients were treated with albumin and 23 with Ringer’s lactate solution. There were no statistically significant differences between groups with respect to days on mechanical ventilation, oxygenation failure, length of ICU stay, or 28-day mortality. The incidence of bacteremia was significantly lower in the albumin group. The authors requested access to the Cochrane database and added the results of this trial to the meta-analyses for the burn patients’ subgroup. When the results from recent trials were added, the relative risk for death was no longer significant when comparing albumin versus crystalloids.57 Finally, recently published results of the SAFE trial carried out in Australia and New Zealand (the Saline versus Albumin Fluid Evaluation [SAFE] Study is a collaboration of the Australian and New Zealand Intensive Care Society Clinical Trials Group) indicated that there is no difference in mortality or incidence of organ failure between albumin and saline in a double-blind randomized population of 7000 patients.58 When treating patients with hypoalbuminemia, efforts must be centered on correction of the underlying disorder, rather than attempting to reverse primarily the hypoalbuminemia.59
Hextend
Hextend® (Abbott Laboratories, North Chicago, IL) is a modified, physiologically “balanced” first-generation, high-molecular-weight hydroxyethyl starch (HES) preparation (average molecular weight approximately 670 kDa; molecular weight 550 kDa). HES contains balanced electrolytes (Na, 143 mmol/l; Cl, 124 mmol/l; lactate, 28 mmol/l; Ca+2, 2.5 mmol/l; K, 3 mmol/l; Mg+2, 0.45 mmol/l; glucose, 5 mmol/l).60 Hextend is currently being used as the fluid of choice for resuscitation in battlefield casualties because of its greater effect on intravascular volume compared with Ringer’s lactate.4 Unlike previously used preparations of starch such as Dextran or Hespan, Hextend may have less effect on coagulation parameters, but even this observation is debatable.60–63 Animal studies have shown that Hextend is an efficient volume expander in models of hemorrhage and in models of combined hemorrhage and head injury. In addition, Hextend may be a more effective volume expander than smaller starches. A clinical study demonstrated that Hextend, with its novel buffered, balanced electrolyte formulation, is as effective as 6% hetastarch in saline for the treatment of hypovolemia.60 There are no studies of the effect of Hextend in acute hemorrhage in humans.
Hypertonic Saline
Hypertonic saline is characterized by its osmotic properties that attract fluid into the intravascular compartment, where the addition of a dextran, or hetastarch, helps to prolong its effects through binding of the recruited water. The concept of resuscitation using hypertonic solutions entails rapid infusion of a 4 ml/kg of body weight dose of 7.2%–7.5% NaCl, which corresponds to a 250-ml bolus in an adult patient. This is given in combination with a colloid solution. This mode of therapy has been shown to have a rapid effect in the circulation. Studies suggest that hypertonic saline seems to be superior to conventional volume therapy with faster normalization of microvascular perfusion during shock phases and early resumption of organ function. Patients with head trauma in association with systemic hypotension particularly appear to benefit.64,65
The available literature suggests that there is no clear benefit of hypertonic saline solutions in terms of survival or reduced morbidity. However, recent reanalysis of individual studies of hypertonic saline/dextran found an improved survival in hypotensive patients with head injury.65 A similar finding was reported in patients with penetrating injuries needing immediate surgery.66 The prehospital use of hypertonic saline/colloid solutions is limited to a few countries, most of them in Europe and South America.
Red Cell Transfusion
The decision to initiate blood transfusion during resuscitation is based on a clinical assessment which can be aided by estimating the mechanism of injury, the rate and magnitude of blood loss, the degree of cardiopulmonary reserve, and the overall oxygen consumption of the patient.67 Any storage of blood products outside a blood bank is difficult and may not be possible in many institutions. Thus, blood products are ordered at the physician’s discretion with the inherent risk of underestimating blood transfusion requirements. The options available are type O-negative, type-specific, typed and screened, or typed and cross-matched packed red blood cells (RBCs). (Fresh whole blood is generally not available, but has been used with success in wartime.) The initial choice will depend on the degree of hemodynamic instability. Type O-negative red cells have no major antigens and can be given reasonably safely to patients with any blood type. In patients with massive hemorrhage that require replacement of 50%–75% (e.g., ∼10 units of red cells in an adult patient), of the patient’s blood volume, it is recommended to continue to transfuse type O blood to avoid the risk of a major cross-match reaction. It is also advisable to have a massive transfusion protocol in place by which notification is given to the blood bank in anticipation for a major need for blood in the operating room. This will alert the blood bank personnel not only to have enough blood, but also to prepare the fresh frozen plasma and platelets that will be needed as a consequence of the ongoing massive hemorrhage.
The heart and brain are generally considered to be the organs most vulnerable to the effects of anemia. In normovolemic hemodilution, the heart begins to produce lactic acid at hematocrits between 15% and 20%,68 and heart failure generally occurs at hematocrit of 10%.69 One unit of packed RBCs will usually increase the hematocrit by ∼3% and the hemoglobin by 1 g/dl in a 70-kg nonbleeding adult. Obtaining type-specific red cells requires 5–10 minutes in most institutions, and temporizing measures can sometimes be used to gain the necessary time. The use of type-specific red cells is preferred over O-negative and the risk of a hemolytic transfusion reaction is very low.70 When blood is typed and screened, the patient’s blood group is identified and the serum is screened for major blood group antibodies. A full cross-match generally requires 45 minutes and involves mixing donor cells with recipient serum to evaluate for any antigen/antibody reactions. In a recent prospective study of the use of blood transfusion in 104 patients with severe injuries, Beale et al.71 found that 87% received a total of 324 transfusions; 6% were given in the emergency room, 60% after arrival to the ICU, and 30% in the operating room. The mean pretransfusion Hb level was 9.1 (±1.4) g/dl). This study showed that trauma patients received blood at a relatively high pretransfusion hemoglobin levels (mean of 9 g/dl). As shown previously, more than 4 units of blood was an independent risk factor for systemic inflammatory response.
Blood Substitutes
Attempts at developing artificial hemoglobin-based oxygen carriers (HBOCs) using hemoglobin derived from RBCs began in the 1930s. The greatest obstacle has been related to the toxic effect of stromal contamination. The hemoglobin molecule in HBOCs must be stabilized to prevent dissociation of the α2β2-hemoglobin tetramer. By doing so, intravascular retention is prolonged and nephrotoxicity is eliminated. Several products have been developed including diaspirin cross-linked hemoglobin (HemAssist), human recombinant hemoglobin (rHb1.1 and rHb2.0), polymerized bovine hemoglobin-based O2 carrier (HBOC-201), human polymerized hemoglobin (PolyHeme®), hemoglobin raffimer (Hemolink™), and maleimide-activated polyethylene glycol-modified hemoglobin (MP4). The most advanced products are in clinical phase III trials, but no product has achieved market approval yet in the United States, Europe, or Canada.72 Although the hemoglobin solutions may be considered as efficient resuscitative agents and good alternatives to RBC transfusion, their ability to improve microcirculation and to potentially restore metabolic parameters must be weighed against the excessive systemic vasoconstriction and oxidative damage described in some of these products. Diaspirin cross-linked hemoglobin looked promising in the laboratory, but the clinical trials were discontinued because of increased mortality.73 Its vasopressor effects cannot be attributed to all hemoglobin solutions. Newer products have been developed to minimize the vasomotor effects of hemoglobin. The blood substitute product most studied in trauma patients currently awaiting FDA approval is human polymerized hemoglobin (PolyHeme, Northfield Laboratories, Evanston, IL). This is a universally compatible, immediately available, disease-free, oxygen-carrying resuscitative fluid. The effect of treating patients with PolyHeme has been assessed in massively bleeding patients with lifethreatening hemorrhage.74 In a more recent study, 171 patients received rapid infusion of up to 20 units (1000 g, 10 liters) of PolyHeme in lieu of red cells as initial oxygen-carrying fluid replacement in trauma patients and patients undergoing urgent surgery. Thirty-day mortality was compared with a historical control group of 300 surgical patients who refused red cells on religious grounds. Forty patients had RBC hemoglobin as low as 3 g/dl. Total plasma hemoglobin added by PolyHeme was maintained at a mean of 6.8 (±1.2) g/dl. The 30-day mortality was 25.0% compared with 64.5% in historical control patients. In this study, PolyHeme increased survival from life-threatening acute anemia by maintaining an adequate level of total hemoglobin in the absence of red cell transfusion.75 A large multicenter trial is in progress. HBOC-201 has been studied for perioperative use, with a trial in trauma patients planned as well. Use of HBOC, when blood is unavailable or perhaps instead of blood, seems promising. It seems likely that at least one product will be available in the near future.
PHARMACOTHERAPY
Vasopressin
Vasopressin is emerging as a potentially major advance in the treatment of a variety of shock states. Increasing interest in the clinical use of vasopressin has resulted from the recognition of its importance in the endogenous response to shock and from advances in understanding of its mechanism of action. Vasopressin has been shown to produce greater blood flow diversion from nonvital to vital organ beds when compared with epinephrine during vasodilatory shock.76 Under normal conditions, the doses of vasopressin used have little or no pressor action, and significant elevation of plasma vasopressin resulting from the unregulated release of hormone (i.e., the syndrome of inappropriate secretion of antidiuretic hormone) does not cause hypertension.77,78
The likely effect of vasopressin in shock may be related to its effect on vascular smooth muscle. Vasopressin can inhibit both ATP-sensitive potassium (K+ATP) channels79 and nitric oxide (NO)–induced accumulation of cGMP.80 Landry and colleagues81 have shown that activation of the K+ATP channels contributes to the hypotension of several types of shock, including hemorrhagic shock.82 Furthermore, activation of NO synthesis also contributes to the hypotension of this condition.83 Thus, vasopressin inhibits vasodilator mechanisms that contribute to both hypotension and vascular hyporeactivity in the late phase of hemorrhagic shock.84–86 Arterial hypotension is the principal stimulus for vasopressin secretion via arterial baroreceptors located in the aortic arch and the carotid sinus. If central venous pressure diminishes, then these receptors first stimulate secretion of natriuretic factor, the sympathetic system, and renin secretion. Vasopressin is secreted when arterial pressure falls to the point that it can no longer be compensated for by the predominant action of the vascular baroreceptors.87,88 Vasopressin potentiates the vasopressor efficacy of catecholamines. However, it has the further advantage of eliciting less pronounced vasoconstriction in the coronary and cerebral vascular regions. It benefits renal function, although these data should be confirmed. The effects on other regional circulations remain to be determined in humans.
New Therapeutic Possibilities
Ethyl Pyruvate
Pyruvate has been identified as an effective scavenger of reactive oxygen species (ROS). For this reason, it has been proposed as therapeutic agent for various pathological conditions that are thought to be mediated by redox dependent phenomena, such as myocardial, intestinal, or hepatic ischemia/reperfusion–induced injury. Ethyl pyruvate (EP) has been shown to be more effective and safer than equimolar doses of sodium pyruvate with significant anti-inflammatory effects.89,90 The pharmacological basis for the anti-inflammatory effects of EP remains to be explained. It is plausible that EP mediates suppression of NF-KB activation and secretion of NO and of proinflammatory cytokines.91 Because organ system injury after hemorrhage and resuscitation could be considered a total body ischemia and reperfusion injury, it has been proposed that EP may have a protective role in the management of shock. In an animal study of bleeding and hypotension to a MAP of 40 mm Hg over a 60-minute period, Ringer’s lactate resuscitation was compared with EP. Survival at 4 hours after resuscitation was 100% in the EP group versus 50% in the RL group.92 In a similar study it was shown that EP had a protective effect on the shock associated permeability injury of the gut. Phase I and II studies on the effect of EP in humans are currently being undertaken in patients undergoing heart surgery and extracorporeal circulation.
HYPOTHERMIA AND HEMORRHAGIC SHOCK
Hypothermia during hemorrhagic shock appears to be a double-edged sword. Laboratory studies have consistently found that mild (33° C–36° C) to moderate (28° C–32° C) improves survival following hemorrhagic shock.10,93–96 In contrast, retrospective clinical trials have suggested that trauma patients who become hypothermic are generally more severely injured,97 with higher mortality than patients who remain normothermic.98–100 Laboratory studies have demonstrated beneficial effects of hypothermia during hemorrhagic shock on individual organs and the entire organism. As an example, Mizushima et al.93 found that mild hypothermia during hemorrhagic shock in rats with rewarming during resuscitation produced the best left ventricular performance and cardiac output, compared with normothermia throughout or prolonged hypothermia. Meyer and Horton94,95 similarly found better cardiac performance with hypothermia compared with normothermia during hemorrhagic shock in dogs. They also demonstrated improved survival. Studies by Wu and associates96,97 in rats have demonstrated benefit of continued hypothermia after cooling during hemorrhagic shock, mimicking exposure hypothermia as in patients, compared with active rewarming during resuscitation. Mild hypothermia is also beneficial during very prolonged hemorrhagic shock.
Clinically, retrospective studies by Luna et al.98 and Jurkovich et al.99 suggested that trauma patients who become hypothermic have increased mortality compared with those who remain normothermic. Because the more severely injured patients are more likely to become hypothermic, it has been difficult to separate the effects of hypothermia from those of confounding factors such as degree of shock, injury severity, volume of fluid and blood products infused, and need for operation. A more recent retrospective analysis from a large statewide database by Wang et al.100 demonstrated that body temperature of 35° C or lower upon admission was independently associated with an increased risk of death (odds ratio 3).
The only prospective trial of temperature management in trauma patients was that of Gentilello et al.101 Hypothermic trauma victims were randomized in the intensive care unit to standard rewarming versus more active rewarming via continuous arteriovenous rewarming (CAVR) using a countercurrent heat exchanger (Level I Technologies, Rockland, MA). The CAVR group rewarmed faster and required less fluids, but had similar hospital mortality compared with the standard treatment group.
To understand this dichotomy between the laboratory studies of hemorrhagic shock and the clinical findings with trauma victims, we must consider that uncontrolled, exposure hypothermia, which is common in trauma patients, is physiologically different from controlled, therapeutic hypothermia, during which shivering and the sympathetic response are blocked. Another issue is potential coagulopathy from hypothermia, although clinically significant changes do not seem to occur unless the temperature is less than 34° C.35,102
1 Sauaia A, Moore FA, Moore EE, et al. Epidemiology of trauma deaths: a reassessment. J Trauma. 1995;38(2):185-193.
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