Resuscitation of Hypovolemic Shock

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191 Resuscitation of Hypovolemic Shock

Fluids have been given intravenously (IV) for the management of fluid deficits for more than 100 years. In 1883, the English physiologist Sidney Ringer discovered that calcium-containing tap water was better than distilled water for maintaining the viability of tissues from animals in vitro. The understanding of the circulatory system and the importance of maintaining adequate circulatory volume were realized long ago. Furthermore, the desired elements and their approximate concentrations in IV fluids for plasma substitution have been known for many years.

The first reported IV transfusion occurred in 1492. In a desperate attempt to save a dying pope, blood was transfused from three youngsters, using a vein-to-vein anastomosis. The pope and all three youngsters died. The first known successful animal-to-animal transfusion was carried out in 1667. In 1818, Dr. James Blundell performed the first successful transfusion on a patient suffering from hemorrhage during childbirth. In 1830, the gold-plated steel needle for IV use was invented. In 1831, a paper published by O’Shaughnessy described the need for administering salts and water to cholera victims, an idea that was put into practice by Thomas Latta soon thereafter. During the 1930s, Baxter and Abbott produced the first commercial saline solutions. In the 1950s, plastic IV tubing replaced rubber tubing, and soon thereafter, the central venous approach for venous access was described by a French military surgeon. This approach represented a breakthrough for estimations of the state of hydration (central venous pressure [CVP] measurements) and the need for volume support.

Blalock’s fundamental work on shock showed that injury precipitated obligatory local and regional fluid losses, the effects of which could be ameliorated by vigorous restoration of intravascular volume. This concept became a cornerstone to the understanding of the pathophysiology of shock and provided the fundamental rationale for IV therapy for hemorrhage and hypovolemia.

The introduction of blood transfusions as the result of contributions by surgeons during World War I and World War II dramatically changed outcomes in cases of severe hemorrhage. During the Korean War, fluid overload became a common and lethal side effect of resuscitation, owing to a lack of knowledge about how infusates disperse and are eliminated during trauma. Between the Korean War and the Vietnam War, Shires and colleagues described the shifts of fluid and electrolytes into cells after severe hemorrhagic shock. As a consequence, treatment of patients with shock was altered during the Vietnam War, leading to better outcomes and a lower incidence of acute renal failure.

Epidemiology of Severe Hemorrhagic Shock

Traumatic injury is the leading cause of death for individuals younger than 44 years of age in the United States. Overall, trauma results in approximately 150,000 deaths per year, and severe hypovolemia due to hemorrhage is a major factor in nearly half of those deaths. Approximately one-third of trauma deaths occur out of hospital, and exsanguination is a major cause of death occurring within 4 hours of injury. The distribution of battlefield injuries in the Vietnam War showed that 25% of deaths occurred as a result of massive exsanguinations and that the victims were not salvageable. An additional 19% of deaths occurred in cases that were deemed salvageable, and these were the result of torso exsanguinations (10%) and peripheral exsanguinations (19%). As evidenced recently in the Iraq campaign, the fighting of the future is likely to involve terrorists and guerrilla interdictions and will be fought by small groups of combatants over shorter time periods with smaller numbers of casualties at any point in time. However, because of the likely locations of these conflicts, evacuation by air may be difficult or impossible, as was the case in Somalia in 1993. As a result, immediate and even ongoing treatment of casualties may be significantly extended. Shock and ensuing circulatory failure, therefore, may result from a variety of different trauma scenarios. Therapies used in the field may vary depending on the time frame from injury to medical evacuation, the skills and resources of first responders, and the field site of combatant injury.

Mechanisms of injury and severity of blood loss as well as prehospital interventions vary widely among trauma centers. Preferred fluid resuscitation strategies and optimal blood pressures are still being studied.^1,² The number of preventable deaths due to hemorrhage are still significant. Definitive control of hemorrhage and resuscitative strategies are the cornerstone of treatment.³

Current State of Knowledge About Inadequate or Incomplete Resuscitation in Hemorrhagic and Hypovolemic Shock

Early studies by Wiggers showed that bleeding animals to a shock state followed by reinfusion of blood would not save the animal’s life. This phenomenon was termed irreversible shock. Clinically, circulatory collapse is the common endpoint of irreversible shock whether it is precipitated by trauma, hemorrhage, or severe hypovolemia.

Hemodynamic Phases of Irreversible Shock

There are four distinct phases of irreversible shock. Phase I is a nonhypotensive period of hemorrhage persisting through a 20% blood volume loss. It is associated with a reduction in cardiac output in the resting individual. In phase II at roughly 20% of blood volume loss, mean arterial pressure decreases due to an inappropriate reduction in sympathetic tone known as Bezold-Jarisch or empty ventricle reflex. There are variations in the blood volume loss required for this reflex, and in animal models it is modulated by the degree of external stress or pain. Arterial blood pressure stabilizes in phase III as the brain triggers an intense vasoconstriction of all nonessential organs. Blood is diverted to the heart and brain. If hypovolemia is not corrected, an irreversible state of shock in phase IV is entered. During hemorrhage there is also increased adhesion of polymorphonuclear neutrophils leading to leukosequestration in the microcirculation. These processes (decreased cardiac output, vasoconstriction, and leukosequestration) lead to impaired tissue perfusion and eventual death.

Cardiovascular and Hemodynamic Response

Shock is defined as inadequate delivery of O₂ to metabolically active tissues. Failure of O₂ delivery can lead to eventual organ dysfunction and ultimate complete circulatory collapse. Guyton described three major stages describing the mechanisms.⁴ First is compensated shock, in which the individual will achieve full recovery with minimal interventions. Regional tissues and organs have different mechanisms to prevent damage. The next stage is decompensated shock. Aggressive resuscitation is required in this stage, or a substantial fraction of individuals will die. There is a poor correlation between changes in cardiac output and systemic blood pressure. Irreversible shock is the last stage. Shock has progressed to the point that all known therapies are inadequate.

Neuroendocrine Response

Pressure and stretch receptors in the carotid body and aortic arch play a key role in maintaining perfusion to the heart and brain. The nervous system responds immediately to loss of circulating blood volume with sympathetically mediated arteriolar and venous vasoconstriction. Baroreceptors in the carotid bulb and aortic arch sense decreased stretch in the arterial wall. Afferent vagal fibers carry signals that tonically inhibit central processors. A decrease in the effective circulating blood volume or blood pressure causes release of the chronic inhibition imposed by baroreceptors. This message ascends to the nucleus tractus solitarius in the medulla oblongata, resulting in tonic inhibition of heart rate and up-regulation of the sympathetic system.

Acute hypovolemia initiates multiple endocrine responses. The nucleus tractus solitarius signals the hypothalamus to release corticotropin releasing factor and vasopressin. Consequently, corticotropin (ACTH), cortisol, vasopressin, and glucagon levels increase. Glucagon and cortisol are crucial in providing substrate for energy production. Circulating catecholamines inhibit insulin release to increase glucose level. The renin-aldosterone system is stimulated to minimize loss of fluid or salt. Angiotensin II also promotes vasoconstriction. The summation of the neuroendocrine response is to maximize cardiac function, conserve salt and water for the maintenance of circulating blood volume, and provide nutrients and oxygen to the heart and brain.

Metabolic Response

If hemorrhage is massive, the compensatory mechanisms designed to spare blood flow to the brain and heart may be overwhelmed, as occurs in cases of irreversible shock. However, if the hemorrhage is controlled or fluid replacement therapy is initiated promptly, the patient may enter a phase described as compensatory shock. Recent observations in severely injured patients suggest that continuous monitoring of oxidative metabolism and tissue pH in peripheral organs may be used as indicators of cellular stress and impaired tissue perfusion. Minimally invasive assessment of cellular stress—using interstitial pH, tissue PCO₂, and nicotinamide adenine dinucleotide (NADH) autofluorescence (marker of cellular redox state) as read outs—may reflect anaerobic metabolism and dysoxia. These measurements have been obtained from the gut mucosa, skeletal muscle, subcutaneous tissue, and several other organs. Measurements such as tissue PCO₂, PO₂, and pH in these organs have been correlated with specific measurements of cellular dysfunction specific to those organs.

As a consequence of the stoichiometry of the reactions responsible for the substrate level phosphorylation of adenosine diphosphate (ADP) to form adenosine triphosphate (ATP), anaerobic metabolism is inevitably associated with the net accumulation of protons. Accordingly, determination that tissue pH is not in the acid range should be sufficient to conclude that perfusion (and therefore arterial oxygen content) are sufficient to meet the metabolic demands of the cells, even without knowledge of the actual values for tissue blood flow or oxygen delivery. By the same token, the detection of tissue acidosis should alert the clinician to the possibility that perfusion is inadequate. It seems likely that monitoring tissue PCO₂ (tissue capnometry) will play a role in establishing thresholds for and transition points into the metabolic failure associated with circulatory collapse. By eliminating the potentially confounding effects of systemic hypocarbia or hypercarbia, calculating and monitoring the gap between tissue PCO₂ and arterial PCO₂ may prove to be even more valuable than simply following changes in tissue PCO₂.

Weil et al. described a sublingual PCO₂ sensor and demonstrated that changes in sublingual PCO₂ are more sensitive to changes in cardiac output and blood pressure than any other parameter currently used to quantify hypoperfusion. Shoemaker et al. described the use of transcutaneous oxygen tension (PtcCO₂) as an early warning signal of tissue hypoxia and transcutaneous carbon dioxide tension (PtcCO₂) as an early signal of tissue hypoperfusion. These authors proposed the use of transcutaneous sensors for the assessment of PtcO₂ and PtcCO₂ that have been used for years in neonatal medicine as a surrogate measure of arterial blood gases. They showed that compared with survivors, patients who died had significantly lower PtcO₂ and higher PtcCO₂ values, beginning with the early stage of resuscitation. Periods of PtcCO₂ at less than 50 mm Hg for more than 60 minutes or PtcCO₂ at greater than 60 mm Hg for more than 30 minutes were associated with 90% mortality and 100% morbidity.

McKinley and colleagues have demonstrated a correlation between skeletal muscle PCO₂, PO₂, and pH with hemorrhagic shock using fiberoptic sensor technology that allows for continuous monitoring. Both skeletal muscle and gastric mucosa respond similarly to hypotension, and the magnitude of this response is similar for gastric intramucosal pH (pHi) and muscle pH. Skeletal muscle parameters (PO₂, PCO₂, and pH), however, appear to indicate a greater severity of shock and more prolonged recovery than mixed venous measurements or gastric mucosal parameters. Muscle PO₂ may also provide information that is comparable to other more elaborate calculations of O₂ delivery and utilization. In one case report, continuous monitoring of skeletal muscle pH, PCO₂, and PO₂ was able to detect ongoing hemorrhage of a severely injured trauma patient in the setting of “normal” systemic variables. Although preliminary, these findings suggest that continuous monitoring of skeletal muscle pH and related parameters may provide a minimally invasive and more sensitive way of following the resuscitative effort.

Acute Inflammatory Response

The innate and adaptive immune system is triggered in hypovolemia, hemorrhage, and trauma. When appropriately contained, the immune system can restore the body to healthy function following clearance of the offending agents and appropriate tissue repair. In more severe settings, inflammation is persistent and leads to the detrimental consequences described earlier.

Neutrophils and macrophages react to damaged tissue. Macrophages are present in almost all tissues and can directly detect bacterial lipopolysaccharide through genetically encoded pattern recognition receptors. Adhesion of neutrophils to damaged or dysfunctional endothelium leads to microvascular “plugs” that contribute to progressive hypoperfusion. Additionally, neutrophils reach other capillary beds by detecting specific signals on vascular endothelium and navigate to their target by following chemoattractants. The complement pathway is also activated, triggering further activation of neutrophils and macrophages.

Once activated, neutrophils and macrophages produce and secrete cytokines. Cytokines regulate the activation of neutrophils, macrophages, lymphocytes and other cytokines. Proinflammatory cytokines such as tumor necrosis factor (TNF) and interleukins (IL-1 and IL-6) are produced at various stages of the inflammatory response and promote immune cell activation. Production of these proinflammatory cytokines is counterbalanced by production of antiinflammatory cytokines such as IL-10 and transforming growth factor beta (TGF-β₁) that serve to restore homeostasis and promote tissue repair.

Proinflammatory cytokines also induce macrophages and neutrophils to produce reactive oxygen and nitrogen species such as nitric oxide (NO), superoxide, hydroxyl radical, and hydrogen peroxide, which are directly toxic to tissue. The reactive oxygen species can incite more inflammation and are implicated in the pathology of reperfusion injury. Nitric oxide seems to be especially relevant in irreversible shock. Inducible nitric oxide synthase (iNOS) and its products were found only during the irreversible phase of hemorrhagic shock in rats.

Resuscitative Strategies in Hemorrhagic Shock

The mainstays of therapy in hemorrhagic shock are bleeding control, tissue oxygenation, coagulation support, and maintenance of normothermia.³ Fluid resuscitation strategies in the prehospital and hospital setting are important.

Vascular Access for Patients with Severe Hemorrhage

In the trauma patient presenting with multiple serious injuries and hemorrhagic shock, vascular access is necessary. Venous access should never be initiated on an injured limb. When thoracoabdominal injury is suspected, it is prudent to obtain infra-diaphragmatic and supradiaphragmatic access.

Advanced Trauma Life Support (ATLS) guidelines recommend rapid placement of two large-bore (16 gauge or larger) IV catheters. The most suitable veins are at the wrist, on the dorsum of the hand, at the antecubital fossa in the arm, and on the saphenous in the leg. If peripheral IV catheters are unable to be placed, catheters can be placed in the central veins. The femoral vein is the most frequent central vein cannulated. The subclavian vein is another alternative and can be placed safely in experienced hands. The internal jugular vein is rarely used in trauma patients because of the possibility of cervical spine injuries and the need for cervical immobilization with a collar. Patients with absent pulses may need to undergo cutdown to cannulate the femoral vein under direct vision to obtain IV access.

Resuscitative Fluids

Colloids Versus Crystalloids

In the prehospital setting, blood and blood products may not be available, but colloids and isotonic crystalloids are readily available. Randomized controlled trials comparing resuscitation with crystalloids versus colloids showed no survival benefit.⁵ A Cochrane Database review concluded that there is no evidence that one colloid solution is more effective or safe than any other.⁴ Crystalloids are less expensive than colloids and are recommended as the initial resuscitative fluid.

Hypertonic Saline

Hypertonic saline (7.5% [HS]) resuscitation has been thought of as an attractive option because it rapidly pulls water into the intravascular space owing to its osmotic pressure. A 250-mL bolus of HS has been shown to increase systolic arterial pressure (SAP) in hemorrhagic shock patients.⁶ In addition, it is associated with immunomodulatory effects. In a rat model, HS downregulated neutrophil activation, oxidative stress, and proinflammatory mediator production when compared to lactated Ringer’s solution.⁷ Interestingly, there does not seem to be a difference in bacterial clearance in the peritoneum when comparing the two solutions, suggesting that HS can be safely used in the setting of peritoneal contamination.⁸ Given these possible beneficial effects, it has been proposed as a prehospital resuscitative strategy. In fact, it has been used as a prehospital resuscitative fluid, especially in European countries.

However, on March 26, 2009, the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health (NIH) halted the study by the Resuscitation Outcomes Consortium (ROC) comparing 250 mL of HS, 250 mL of normal saline, and 250 mL of HS with dextran in patients with hemorrhagic shock. There was no significant cumulative difference in 28-day survival in the HS groups versus the normal saline group. In fact, there was a trend toward earlier death in the HS groups. In the United States, normal saline is the recommended prehospital fluid for patients with hemorrhagic shock.

Red Cells

Early identification of severe injuries with the likelihood of hemorrhage should suffice for the trauma team leader to alert the blood bank. Hematocrit levels should not guide the decision for transfusion in acute hemorrhage. Protocols for massive transfusion should be established, and the blood bank should automatically begin preparation of fresh frozen plasma and platelet packs if massive bleeding is anticipated.

Available options are type O-negative, type-specific, typed and screened, or typed and cross-matched packed red blood cells. The initial choice depends on the degree of hemodynamic instability. Type O-negative red cells have no major antigens and can be used safely for patients with any blood type. Unfortunately, only 8% of the population has O-negative blood, and blood bank reserves for O-negative blood are low. O-positive blood can be used in male patients but may be a problem in female Rh-negative patients.

If 50% to 75% of the patient’s blood volume has been replaced with type O blood, one should continue to administer type O red cells. Otherwise, the risk of a major cross-match reaction increases, since the patient may have received enough anti-A or anti-B antibodies to precipitate hemolysis if A, B, or AB units are subsequently given. Obtaining type-specific red cells requires 5 to 10 minutes in most institutions.

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 about 45 minutes and involves mixing donor cells with recipient serum to rule out antigen/antibody reactions.

Coagulation Factors, Platelets, and Coagulopathy

Severe bleeding, surgery, and massive transfusion interact synergistically to lead to the lethal triad: hypothermia, acidosis, and coagulopathy. Coagulopathy promotes bleeding and hypotension, which leads to hypothermia and acidosis. Hypothermia and acidosis impair thrombin generation and decrease fibrinogen levels.⁹

Failure of coagulation in trauma is multifactorial and is characterized by the combined presence of coagulation abnormalities resembling disseminated intravascular coagulation (DIC), excessive fibrinolysis (likely caused by to release of tissue plasminogen activator [TPA] from damaged tissues), dilutional coagulopathy due to excessive fluid treatment, and massive transfusion syndrome resulting in dilution of coagulation factors and platelets.¹⁰

Massive transfusion protocols have been developed and utilized in major trauma centers. Activating the massive transfusion protocol gives a fixed ratio of red cells to plasma to platelets. High plasma- and platelet-to–red cell ratio has been shown to increase survival in retrospective studies.¹¹ Military data showed an increase in survival with a red cell/plasma ratio approaching 1 : 1.¹² Civilian trauma centers are increasingly adopting a 1 : 1 : 1 ratio for massive transfusion protocols.

Use of Recombinant Activated Factor VII as An Adjuvant for Resuscitation in the Coagulopathic Patient

Patients with diffuse bleeding enter a coagulopathy leading to decreased levels of fibrinogen, factor VIII, and platelets. The low levels of fibrinogen lead to a loose fibrin structure. Low levels of factor XIII, the fibrin-stabilizing factor, decreases the strength of the fibrin clot by limiting the development of complex branching clots.¹³ Trauma patients with massive bleeding thus may benefit from recombinant activated factor VII (rFVIIa), because it works to increase thrombin peak, allowing for a stable fibrin plug.

Mechanism of Action

Hemostasis is initiated by the formation of a complex between tissue factor (TF), exposed as a result of a vessel wall injury, and activated factor VII (FVIIa) that is normally present in circulating blood. The TF-FVIIa complex converts factor X into FXa on the TF-bearing cell. FXa then activates prothrombin into thrombin. This limited amount of thrombin activates FVII, FV, FXI, and platelets. Thrombin-activated platelets change shape, resulting in exposure of negatively charged phospholipids which form a template for thrombin generation involving FVIII and FIX. Full thrombin generation is necessary for complete activation of FXIII and thrombin activatable fibrinolytic inhibitor (TAFI) to occur. Furthermore, full thrombin generation is important for the fibrin structure of the hemostatic plug.

The addition of rFVIIa to FVIII- or FIX-deficient plasma has been shown to increase thrombin generation in a cell-based in vitro model. Furthermore, extra rFVIIa was found to normalize fibrin clot permeability in vitro and to tighten the fibrin structure as studied by three-dimensional confocal microscopy. These findings indicate that administration of rFVIIa can compensate for the lack of FVIII and FIX. Accordingly, administration of exogenous rFVIIa has been found to stop bleeding in hemophilia patients and, provided it is given in high enough doses, to allow major surgery to be performed in severe hemophiliacs with inhibitors. Because rFVIIa enhances thrombin generation on already activated platelets, it has been suggested that rFVIIa may also help improve hemostasis in other situations involving impaired thrombin generation, such as platelet disorders (thrombocytopenia and functional platelet defects); the immediate result is an increase in generation of thrombin. Furthermore, exogenous rFVIIa induces hemostasis independently of tissue factor and factors VIII and IX by binding directly to activated platelet surfaces with low affinity to generate thrombin in a dose-dependent manner.

Pharmacology

Intravenous administration of rFVIIa does not induce systemic activation of coagulation. Administration of rFVIIa shortens prothrombin time (PT) and partial thromboplastin time (PTT) but does not affect levels of thrombin, fibrinogen, or platelet count. The half-life of rFVIIa ranges between 1.3 and 2.7 hours, being shorter for children younger than 15 years; however, there is considerable individual variation. Initial work in humans indicates that a dose of 90 to 110 µg/kg of rFVIIa (given as a bolus) should be repeated every 2 hours over a 24-hour period. Intervals may be increased thereafter according to the response and severity of bleeding.

Safety

There are case series and reports of thromboembolic events associated with the use of rFVIIa.¹⁴ Tissue factor is expressed under pathologic conditions such as atherosclerosis, sepsis, or cancer, so the risk of thromboembolic complications such as stroke, myocardial infarction, deep venous thrombosis (DVT), and pulmonary embolism (PE) is increased.