Early studies, such as that of G. Thomas Shires, seemed to point to a need for aggressive resuscitation in patients with hemorrhagic shock. Early on, the American College of Surgeons Advanced Trauma Life Support program advocated for a protocol of aggressive resuscitation for all trauma patients regardless of the mechanism of injury, with the end goal being the administration of crystalloid in a 3:1 ratio to the estimated amount of blood lost.

With the Vietnam War, the negative outcomes after over-resuscitation became more recognized. Patients who received significant resuscitation developed “DaNang Lung,” which later became known as acute respiratory distress syndrome (ARDS). They also had increased incidences of abdominal compartment syndrome. In fact, it is now clear that aggressive crystalloid infusion, targeting endpoints aimed at restoring blood volume and central venous pressure, may have the untoward effect of worsening the lethal triad of acidosis, coagulopathy, and hypothermia.

The three components of the lethal triad have been found to be predictors of poor outcomes. The body has an outstanding capacity to compensate for physiologic derangements following penetrating trauma, but the lethal triad is the beginning of a whirlwind cascade of physiologic events that become very difficult, if not impossible, to overcome. Components of the triad have been targets of intense research aimed at looking for ways to prevent negative side effects of physiologic abnormalities.

The first arm, hypothermia, is an independent risk factor for mortality after injury. Hypothermia occurs often in the initial assessment and can be exacerbated by cold crystalloid infusions. Hypothermia is graded slightly differently in injured patients due to the association with mortality at higher temperatures compared to patients with environmental exposure. Severe hypothermia, defined as a temperature less than 32 °C, has been shown to correlate with 100 % mortality. Moderate hypothermia, defined as a temperature between 32 °C and 34 °C, has been associated with a mortality rate of about 14 %. Mild hypothermia is from 34 °C to 36 °C. Hypothermia impairs platelet function and coagulation cascade enzyme activities. With prolonged extrication times, heat loss, intoxication, and potentially open body cavities, trauma patients with hemorrhagic shock have an uncoupling of metabolic pathways resulting in the loss of normal thermoregulatory mechanisms. Therapeutic hypothermia has not yet demonstrated improved outcomes in trauma patients. All trauma patients should receive warmed fluids, and both passive adjuncts and active adjuncts for warming should be applied to achieve normothermia (36–37 °C, 96.8–98.6 °F).

Acidosis, the second arm of the lethal triad, generally results from lactic acid production from anaerobic metabolism in the setting of insufficient oxygen delivery to peripheral tissues. Oxygen delivery is reduced by decreased oxygen-carrying capacity (decreased hemoglobin), poor oxygen diffusion, and decreased cardiac output (pump capacity or intravascular volume). A pH less than 7.2 affects cellular functions such as ATP generation, fatty acid biosynthesis, and enzymatic reactions. Injured patients with a pH of less than 7.0 have an approximately 70 % mortality rate. Oxygen delivery is vital to maintain proper tissue perfusion and organ function. Insufficient oxygenation eventually leads to multisystem organ failure, which is difficult to reverse. It is for this reason that acidosis has been linked with poorer outcomes in trauma patients and why lactate, base deficit, and mixed venous saturation are included as endpoints of resuscitation.

The hypothermia and acidosis both contribute to and are exacerbated by the final arm of the triad, coagulopathy. Coagulopathy in trauma also occurs as a result of a consumption of clotting factors and the dilution of these factors and platelets due to aggressive crystalloid resuscitation. In addition, there is growing evidence that suggests that the trauma patient may arrive to the trauma bay with existing trauma-specific endogenous mechanisms of coagulopathy which may be worsened by the rapid administration of crystalloid fluids. These include activation of the thrombomodulin-protein C system, platelet dysfunction, endothelial dysfunction, oxidative modification, and hyperfibrinolysis.

Correction of the lethal triad should guide clinical judgment when it comes to the care of the trauma patient. Unfortunately, hypothermia, coagulopathy, and acidosis potentiate one another, precipitating a cycle pattern that is difficult to break. Both clinically and experimentally, attempts to block these three facets have been targets of intense interest.

There are three phases in the development of hemorrhagic shock. The first is a nonprogressive phase in which the patient’s intrinsic mechanisms maintain mean arterial pressure, the second is a progressive phase in which patients transition to a subacute lethal phase of shock, and the third is an irreversible phase in which the patient becomes unresponsive to resuscitative efforts. The period of time in which recovery is possible varies with respect to the innate response of individuals and the interactions of the systems involved, including cardiovascular, neuroendocrine, and immunologic.

The effect of fluid resuscitation on the risk of death in models of uncontrolled hemorrhage is related to the severity of hemorrhage. A combination of the patient’s coagulation system, hypotension, and vessel spasm temporarily arrests traumatic hemorrhage. Early surgical pioneers, first Cannon and later Wangensteen, noted that intravenous fluids before surgical control were detrimental to the injured patient. These astute discoveries were supported by animal models of hemorrhagic shock that aggressive fluid resuscitation increased mortality. These findings lead to the concept of “popping the clot.” Injuries with faster rates of bleeding achieve a faster intrinsic hemostatic plug at a lower mean arterial pressure. Therefore, giving too much fluid to these patients delays innate hemostatic mechanisms. Injuries with slower rates of bleeding will achieve a slower innate hemostatic plug and therefore may appear as transient responders to a fluid bolus, as the patient will not become hypotensive within 15 or 30 min from injury.

These findings and the concern for “popping the clot” led to a large trial examining different resuscitation strategies. In 1994, Bickell et al. published their landmark study, a prospective trial examining resuscitation strategies in patients with penetrating torso trauma. They were able to demonstrate that patients who received immediate, preoperative resuscitation experienced a statistically significant increase in mortality and a strong trend toward increased morbidity and hospital length of stay, when compared with patients who received delayed, posthemorrhage cessation resuscitation. Furthermore, Bickell was able to show that there was a significant increase in bleeding time, with respect to prothrombin and partial thromboplastin times, in the early resuscitation groups when compared to those patients who received fluid in a delayed manner.

A subsequent study by Dutton et al. attempted to randomize between two systolic blood pressure targets 100 mmHg and 70 mmHg. However, the achieved blood pressure in both groups was 114 mmHg and 100 mmHg, respectively. This study demonstrated no difference in mortality between the two arms. A true systolic blood pressure goal of 70–100 mmHg may be an appropriate acceptable target range for patients presenting with hemorrhagic shock who have had hemorrhage control. Other studies have demonstrated that greater than 1.5 L crystalloid associated with increased risk of death and that prehospital fluid resuscitation are associated with increased mortality, especially in those patients with penetrating injuries or hypotension. This suggests that it is the timing and volume of fluid administration, with respect to intrinsic hemostasis, that shape the hemorrhaging of patient’s hemodynamic response. Early boluses delay intrinsic hemostasis and, therefore, increase blood loss, while late boluses trigger rebleeding. Therefore, fluid administration before and after intrinsic hemostasis may have entirely different hemodynamic consequences. Mild to moderate hypotension initially allows for clot formation and slows bleeding from injured blood vessels until surgical hemostasis can be achieved. Penetrating trauma patients should not be aggressively resuscitated for blood pressure targets in the trauma bay. Rather they should be expeditiously transferred to a setting where definitive control of bleeding can be accomplished.

As discussed above, there is concern that crystalloid administration has the potential to worsen the lethal triad through worsening dilutional coagulopathy. Crystalloids do not carry oxygen nor do they clot. Instead, it has become clear that significant blood loss must be replaced with blood. It is widely acknowledged that in patients with massive hemorrhage and transfusion requirements, initial resuscitation with red blood cells (RBC), fresh frozen plasma (FFP), and platelets may improve survival when compared to a crystalloid first approach. The goal has now become to provide the blood components that approximate the whole blood that a hemorrhaging patient has lost. As whole blood has not demonstrated significant benefit over component therapy and as the blood bank system in the United States is largely adapted for component therapy, there has been much interest in identifying the optimal ratio of blood products in component therapy. A number of clinical trials have concluded that the initial approach to patients who are likely to receive massive transfusions, such as a hypotensive patient with a penetrating injury, be performed in a 1 unit of platelets to 1 unit FFP to 1 RBC or a 1:1:1 ratio. Holcomb et al. studied the benefit of a 1:1:1 ratio compared to the 1:1:2 ratio in the PROPPR trial, a large, multicenter, randomized clinical trial. This trial found that patients transfused with a 1:1:1 ratio had fewer deaths due to exsanguination at 24 h and achieved hemostasis more often. Patients with severe trauma requiring massive blood transfusion should be treated with a 1:1:1 transfusion ratio of blood products. Labs are often unreliable and too slow to use properly in the setting of hemorrhagic shock. Rapid point-of-care thromboelastrography can be used to guide resuscitation in this setting but is not universally available. Instead the 1:1:1 ratio should be used as a guide until bleeding has subsided.

The temporal distribution of trauma deaths has shifted since first described by Trunkey in 1983. Today, the proportion of late-phase deaths has decreased significantly, while the early phase deaths have not changed. Instead, the proportion of immediate phase deaths has increased even more.