Department of Surgery A and the Laboratory for Shock and Trauma Research, Rambam Medical Center, and The Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
Clinical as well as laboratory studies on hemorrhagic shock have questioned the initial therapeutic goal of normalizing systemic blood pressure by isotonic or hypertonic crystalloid solutions.
The current regimen of prehospital fluid administration consists of using massive volumes of isotonic crystalloid solutions such as Ringer's lactate administered as rapidly as possible. These recommendations for the management of trauma victims who are hypotensive from acute hemorrhage are based on the interpretation of data from studies conducted beginning in the 1940s. These classic studies utilized a Wiggers model of hemorrhage in which animals were bled from an intravascular catheter into a reservoir and maintained at a prescribed level of hypotension prolonged periods of time prior to initiating resuscitation. When the animals were subjected to several hours of hypotension that included a short period of severe hypotension (mean arterial pressure of 30 to 40mmHg) they developed microvascular damage, termed "irreversible shock," which ultimately led to death of the animals despite what was considered appropriate resuscitation. This prolonged period of hemorrhagic hypotension was associated with the development of microvascular injury with marked extracellular fluid deficit that could be corrected only by the administration of isotonic crystalloids in volumes 2 to 3 times the estimated blood loss to achieve survival. This was the basis of the current well known dogma "3 to 1 rule" for the treatment of hemorrhagic hypotension, which was adopted by the ATLS for the treatment of trauma casualties.
Based on these data, advocates of early aggressive resuscitation argued that the need for increasing cardiac output and oxygen delivery, to maintain microvascular perfusion and oxygenation, exceeds any risk of accentuating hemorrhage, and therefore trauma victims in hypotensive hemorrhage should receive large volumes of fluids as early as possible.
Data published by Stern et al. support Wiggers's observations that severe hemorrhagic hypotension left untreated for several hours will progress to end-organ dysfunction and ultimately death. However, substantial periods of moderate hypotension (MAP 50 to 60mmHg), such as the interval from time of injury to the time of operative intervention, can be tolerated effectively without resulting in significant permanent microvascular damage and end-organ failure.
These fixed-pressure (Wiggers) and fixed-volume models of hemorrhagic shock were developed and refined over the past century and have served as a basis for developing the standard therapeutic approaches of aggressive fluid therapy, whereas studies using uncontrolled hemorrhage models that have emerged more recently have been used increasingly over the past decade.
The model of uncontrolled continuing hemorrhage was assumed to be more relevant to the clinical scenario of trauma casualties with internal bleeding that cannot be effectively controlled in the prehospital environment.
The fundamental problem in patients with exsanguinating hemorrhage is a bleeding source that cannot be readily controlled. In this situation the common practice of "raising blood pressure" makes no clinical sense because this action is likely to increase blood pressure, reduce vasoconstriction, and accelerate the rate of bleeding.
The goal of therapy in traumatic internal hemorrhage leading to severe hemorrhagic shock was therefore altered to rapid evacuation to a trauma center, termed "scoop and run," and development of therapies aimed at buying time until surgical control of bleeding is possible.
The goal of deliberate underresuscitation was recognized as early as World War I by Cannon, who wrote in 1918:
Injection of fluid that will increase blood pressure has dangers in itself. Hemorrhage in a case of shock may not have occurred to a marked degree because blood pressure has been too low and the flow too scant to overcome the obstacle offered by the clot. If the pressure is raised before the surgeon is ready to check the bleeding that may take place, blood that is sorely needed, will be lost.
More than 30 years ago, Milles et al. and Shaftan et al observed that spontaneous control of arterial hemorrhage depends on clot formation and a fall in blood pressure. Animals subjected to arterial injury and subsequently made normotensive with either fluid resuscitation or vasopressor infusion experienced larger hemorrhage volumes, longer hemorrhage durations, and a higher incidence of rebleeding compared to animals subjected to a similar injury but left untreated and hypotensive.
In 1988 two types of experimental hemorrhagic shock were defined: controlled hemorrhagic shock, in which bleeding was induced through an arterial catheter that was occluded immediately after hemorrhage (as in Wiggerstype models); and uncontrolled hemorrhagic shock, in which internal abdominal blood loss was induced by injury to major intra-abdominal blood vessels (ileocolic artery). In this model blood loss stopped only after blood pressure was markedly reduced with vasoconstriction and temporary clot formation. Bolus small-volume hypertonic saline infusion in this rat model of uncontrolled hemorrhagic shock or in uncontrolled hemorrhage induced by rat tail resection led to resumed blood loss from the injured blood vessels, hemody-namic deterioration, and increased mortality compared to no resuscitation.
These results were later confirmed by Bickell et al. in 1992 in other animal models such as a pig model with an acute aortotomy.
The mechanisms suggested for increased bleeding following bolus fluid resuscitation in uncontrolled hemorrhagic shock include increased blood pressure, vasodilatation, and disruption of an early unstable thrombus followed by a fatal secondary hemorrhage. In addition, rapid intravenous infusion of crystalloid may promote hemorrhage by diluting coagulating factors and by lowering blood viscosity in the microvasculature, thereby decreasing the resistance to flow around an incomplete thrombus. Shaftan et al. described direct observations regarding the effect of blood pressure elevation on clot formation. They noted that following blood vessel injury and hypotension a large but "soft and jelly like" extramural clot was formed that surrounded the vascular defect. As time elapsed the clot was observed to become more palpably firm. With fluid resuscitation and blood pressure elevation, the margins of the clot began to leak, and rebleeding subsequently occurred. This gross and visual description is consistent with light and electron microscopic observations that transformation of an initially friable unstable clot to a more rigid hemostatic plug requires the formation and deposition of a significant amount of fibrin, which occurs in an intact coagulation system after at least 20-30 minutes. Therefore, it is not surprising that resuscitation strategies that result in early increase in blood flow and blood pressure would present a higher risk of accentuating ongoing or initiating new hemorrhage.
Following these animal studies of uncontrolled hemorrhage, Bickell et al. published in 1994 a clinical study in patients with penetrating torso injury, comparing those who received delayed fluid resuscitation only after the source of hemorrhage was controlled to patients receiving immediate fluid resuscitation according to the ATLS guidelines. It was found that delayed resuscitation was followed by improved survival of 70 percent compared to 62 percent in the early treatment group.
These results went against the conventional dogma that early prompt administration of large volumes of intravenous crystalloids improves outcome in trauma patients.
Subsequently more sophisticated animal studies in models of uncontrolled hemorrhage by Kowalenko et al. in 1992 suggested that fluid resuscitation to a mean arterial pressure of 40 to 60 mmHg improved microvascular perfusion optimally to a sufficient level to improve survival compared to over- or underresuscitation and gained sufficient time until the bleeding can be surgically controlled. This was termed hypotensive resuscitation.
Most laboratory models and clinical observations of uncontrolled hemorrhagic shock in trauma casualties were studied in large-vessel injury models and did not incorporate solid-organ tissue injury that may be a critical variable in blood loss and survival.
In an effort to more accurately simulate the tissue damage and the rapid blood loss clinically seen in severe blunt abdominal trauma, animal models of solid organ injury, with a standardized liver injury in rats, lethal hemorrhagic shock in a swine liver injury model, and massive splenic injury in rats have been developed. In these models, animal survival was critically determined by the severity of injury, rate of blood loss, and the type of fluid that was used for resuscitation.
Matsuoka et al., using a standardized model of liver injury of uncontrolled hemorrhagic shock, claimed that large-vessel-injury animal models are relevant only to a small segment of penetrating injuries but not to most patients with blunt abdominal trauma with solid organ injury. In this liver-injury model the infusion of hypertonic saline or large volumes of isotonic solutions maintained circulatory stability in spite of increased bleeding with no increased mortality.
Further studies in uncontrolled hemorrhage following solid-organ injury were performed in a rat model of massive or moderate splenic injury. In this model bolus infusion of large volumes of normal saline, Ringer's lactate, or hydrox-yethyl starch was followed by increased bleeding and increased mortality similar to large-vessel injury, whereas hypertonic saline (HS) infusion in this model of solid organ injury did not increase blood loss or mortality.
The clinical use of HS solutions for the resuscitation of trauma patients has been debated for many years. Although HS has been approved for use throughout Europe, North America, and South America, a clear endorsement for its use has not emerged. The few large studies on prehospital administration of HS and dextran (HSD) have not demonstrated a significant survival advantage. Proponents of using these solutions cite beneficial physiologic responses seen with HSD. Those opposed to using HSD express concern over its application in settings of uncontrolled hemorrhage because of a propensity to increase bleeding.
HS rapidly improves blood pressure and cardiac output in the severely injured patient. This is generally attributed to its ability to draw water into the vascular space, leading to increase in plasma volume. The beneficial effects of HS are, however, transitory because it increases microvascular permeability by shrinkage of endothelial cells leading to opening gap junctions. Dextran was therefore added to prolong its ability to hold water in the vascular space. The reflection coefficient of dextran (0.8), which is similar to that of albumin (0.9), provides the oncotic driving force for water flow through the newly expanded gap junctions into the vascular space.
The difference in the response to hypertonic saline in uncontrolled hemorrhagic shock, between large-vessel injury and solid-organ injury, is not readily explained. HS infusion in large-vessel injury leads to increased blood loss, probably by dislodgement of the temporary clot formed in the injured large vessel induced by the temporary increase in blood pressure. It is hypothesized that in solid organ (hepatic or splenic) injury the multiple small clots that were formed in the small-caliber vessels throughout the parenchyma of the injured organ cannot presumably be dislodged by the increase in blood pressure, and thus rebleeding is not initiated, and the net effect of the increase in plasma volume by the fluid shift into the circulation caused by HS is manifested.
In a further study aimed at simulating more closely the clinical scenario of uncontrolled hemorrhagic shock following solid-organ injury treated by isotonic solutions, slow continuous volume infusion of Ringer's lactate combined with splenectomy was used to treat massive splenic injury. In this model of uncontrolled hemorrhagic shock, continuous infusion of moderate volumes of crystalloid or colloid solutions resulted in less blood loss and improved hemody-namics and survival when compared to no fluid infusion.
These results were later confirmed by direct comparison of rapid bolus infusion of large volumes of Ringer's lactate (RL) with splenectomy to slow continuous infusion and splenectomy in the rat model of uncontrolled hemorrhagic shock after massive splenic injury. It was found that continuous infusion of RL combined with splenectomy resulted in significantly less blood loss and improved survival compared to bolus infusion of RL or untreated animals. Another significant finding of this study was that bolus as well as continuous infusion of small-volume hypertonic saline (5mL/kg NaCl 7.5%) did not increase blood loss in this model of solid-organ injury and resulted in improved survival compared to untreated animals.
Similar results were also observed by Stern et al. in a swine model of uncontrolled hemorrhagic shock induced by large-vessel injury (4-mm aortic tear). In this model of near-lethal uncontrolled hemorrhage slow infusion of HSD (7.5% NaCl/6% dextran-70) restored cardiodynamics while minimizing hemorrhage volume and mortality. Rapid infusion of HSD in this model led to an immediate rise in aortic pressure and flow within 1 minute leading immediately to rebleeding from the aortic tear.
Resuscitation strategies of bolus large-volume resuscitation with isotonic solutions in uncontrolled hemorrhagic shock induced by large-vessel injury, as well as solid-organ injury, result in early abrupt increase in blood pressure and microvascular blood flow, which lead to clot dislodgement and increased rebleeding from large and small injured blood vessels, hemodynamic deterioration, and increased mortality. Limited continuous volume resuscitation titrated to achieve optimal microvascular perfusion and pressure that is sufficient to maintain organ viability until the bleeding source can be surgically controlled (termed hypotensive resuscitation) results in less blood loss and improved survival.
Bolus hypertonic saline resuscitation in uncontrolled hemorrhagic shock following large-vessel injury also results in increased blood loss, hemodynamic instability, and increased mortality. Bolus infusion of HS in this setting of acute hemorrhagic shock should therefore be avoided. Bolus as well as continuous HS resuscitation following solidorgan injury does not increase blood loss from the injured organ and leads to improves hemodynamics and survival.
Controlled hemorrhage: hemorrhage that was topped
Fluid resuscitation: infusion of fluids to improve hemodynamics
Hypertonic saline: NaCl—7.5%
Large-vessel injury: damage to blood vessels larger than 3mm Solid-organ injury: injury to intra-abdominal organs Uncontrolled hemorrhage: hemorrhage that was not occluded
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Dr. Krausz has headed the Department of Surgery A at the Rambam Medical center in Haifa, Israel, since 1996. His main research interests are fluid treatment of trauma casualties in civilian as well as military scenarios; lately his research has also focused on gender differences in hemorrhagic as well as septic shock, and the role of leukocytes in pathophysiology of these phenomena. He has received grants from the Israel Academy of Sciences and the Israeli Ministry of Health.
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