of the outcome of sepsis and septic shock. Genetic predispositions in an individual’s

immunoinflammatory response may dictate whether infection is adequately or inadequately countered.

These differences in response may be partially explained by single nucleotide polymorphisms (SNPs) in

the genetic sequences for various inflammatory mediators. These subtle nucleotide variations may affect

the transcription or translation of associated genes or the secretion or function of the corresponding

proteins.

The recognition that genetic background may regulate the response to severe sepsis and septic shock

has led to the identification of an array of genetic markers associated with enhanced risk of septic

mortality. These SNPs are in genes encoding proteins involved in pathogen recognition (toll-like

receptors 2, 4, and 5; CD14; and mannose-binding lectin), cytokine expression (TNF-α, IL-1, IL-6, and

IL-10), and several other genes involved in mediating and controlling the innate immune response and

the inflammatory cascade.58,59

Investigation into genetic polymorphisms should provide important insights into the pathophysiology

of shock. SNP identification leading to early diagnosis of individuals at risk of developing or dying from

the complications of shock may allow therapies to become more preemptive and effectively targeted.

LOSS OF COMPENSATORY RESPONSES TO SHOCK

If shock is prolonged, the arteriolar and precapillary sphincters become refractory and relax, while the

postcapillary sphincter remains in spasm. Therefore, the capillary hydrostatic pressure increases, and

Na+, Cl−, and water are moved into the interstitium, leading to depletion of intravascular volume.

Cellular membrane function is also impaired with prolonged shock. The normal negative membrane

potential approaches neutrality, leading to increased permeability and interstitial flooding by K+. This

is caused, at least in part, by a decrease in the normal function of the adenosine triphosphate–dependent

Na+-K+ membrane pump that is a result of cellular hypoxia. The loss of the membrane potential

difference leads to cellular swelling due to an intracellular influx of Na+ and fluid.

In addition to these cellular effects, severe and prolonged shock results in the development of

progressive organ dysfunction. Although the mechanisms responsible are incompletely understood, it

appears that the vital organs, in particular the lung early on, are limited in their ability to protect

themselves during shock. As a result, direct endothelial injury occurs, resulting in leakage of various

inflammatory mediators, which in turn results in accumulation of interstitial fluid and subsequent

reduction in nutrient and gaseous diffusion. This condition, along with progressive microcirculatory

thrombosis, is responsible for the late organ dysfunction characteristic of uncompensated shock.

COMPLICATIONS OF SHOCK

Ischemia–Reperfusion Injury

Inadequate microvasculature flow results in activation of leukocytes and converts local endothelial cells

to a proinflammatory, prothrombotic phenotype. On reperfusion, the reintroduction of oxygen prompts

these cells to generate superoxide anion, hydroxyl radicals, and hydrogen peroxide, further injuring

local tissue. Microvascular endothelial adherence, monolayer transmigration, and local oxidative burst

by activated neutrophils, along with the profound loss of endothelial monolayer integrity (i.e.,

microvascular capillary leak), contribute to massive interstitial edema after reperfusion. Although all

tissues are sensitive to varying degrees, ischemia–reperfusion injury appears to be most detrimental to

the pulmonary vasculature and the splanchnic circulations. Pulmonary interstitial edema and alveolar

fluid accumulation are associated with the development of ARDS, whereas extensive visceral edema

may contribute to development of ACS and mesenteric ischemia.

Second-hit Phenomena

Patients who have been successfully resuscitated from shock are at risk for what is referred to as the

second-hit phenomenon. A single episode of severe or prolonged shock may precipitate organ failure,

but, in addition, the initial insult may “prime” the inflammatory response, resulting in an augmented or

prolonged response to a subsequent insult such as an infection, a second episode of blood loss, or major

surgery.60 For example, after the primary event, circulating neutrophils demonstrate enhanced

superoxide anion production, increased endothelial cell adherence, augmented cytokine response, and

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increased cytotoxicity. Not only do circulating innate immune cells demonstrate this priming effect, but

tissue-fixed cells, in particular the macrophage, demonstrate altered phagocytosis and augmented

cytokine release.61 This dysfunctional response leads to not only diminished microbial clearance and

enhanced risk of nosocomial infection but also increased host tissue injury and subsequent development

of MODS.

Multiple Organ Dysfunction Syndrome

6 MODS rarely develops as a result of isolated cardiogenic or neurogenic shock but is most often

precipitated by septic and traumatic shock complicated by second-hit events such as repeated episodes

of hypovolemia, subsequent infection, or repeated blood transfusions. Similarly, the presence of an

unresolved inflammatory focus (such as devitalized necrotic tissue), undrained bodily fluids, or

unresolved regional perfusion deficits can be the primary causes for the persistence of SIRS and the

transition to MODS.

The effects of shock, resuscitation, and reperfusion and the subsequent development of MODS appear

to depend on changes in the splanchnic and pulmonary microcirculations. These vascular beds appear to

be major sites of the activation and subsequent immunoinflammatory mediator production that is

responsible for the SIRS response. As splanchnic microcirculatory flow decreases in response to

homeostatic vasoconstrictive responses during hypovolemia, excessive and prolonged hypoperfusion of

the gut results in extensive microvascular injury and subsequent activation of endothelium, neutrophils,

and macrophages. In addition, mucosal barrier disruption permits translocation of bacteria and bacterial

toxins to circulate and reach the large tissue-fixed macrophage population in the liver. Extensive

activation of the Kupffer cells in the liver results in the release of inflammatory mediators that cause

distant organ injury through the systemic activation of other immune cells.

Not only is a proinflammatory phase of SIRS present, but there is also a compensatory antiinflammatory phase of the SIRS response that is evolutionarily designed to counter the locally generated

hyperimmune response and check systemic spread of proinflammatory mediators. If the compensatory

anti-inflammatory response syndrome (CARS) results in excessive immunosuppression, it may contribute

to susceptibility to primary and secondary infections that can then lead to organ failure.62

Numerous clinical trials utilizing proinflammatory and anti-inflammatory mediators as therapeutic

interventions have been conducted. Unfortunately, few therapeutic agents designed to counter immune

dysfunction have had significant impact on the prevention and treatment of MODS. Although studies are

planned and undergoing, no study has demonstrated a sustained impact to date. Several potential

targets, including interferon, have been suggested but this theoretical benefit may prove incorrect as so

many other targets have in the past.63

Abdominal Compartment Syndrome

ACS is a highly morbid complication of reperfusion injury to the splanchnic viscera. This syndrome

appears to be increasingly prominent due to aggressive resuscitation techniques that enable salvage of

profoundly hypotensive and hypovolemic patients. Splanchnic ischemia and reperfusion result in

extensive visceral capillary leak and interstitial edema of the bowel. Excessive volume resuscitation

during this phase leads to grossly edematous viscera within the closed space of the abdomen, which

dramatically increases intra-abdominal pressure, and compromises intra-abdominal organ function,

increases renovascular resistance, limits diaphragmatic excursion, and may decrease cardiac output and

elevate intracranial pressure. The clinical hallmarks of ACS are a distended and tense abdomen,

diminished tidal volume, pulmonary edema, decreased cardiac output, oliguria, and elevated urinary

bladder pressure. Presence of all or a major part of this syndrome should prompt consideration of an

urgent operative laparotomy to decompress the abdomen and treat by leaving the abdomen open.

Hypothermia

Hypothermia (core temperature <35°C) is common during shock. In addition to immobilization, both

prehospital and postadmission exposure can lead to conductive, convective, and evaporative heat loss,

which should all be minimized. In addition, the administration of room temperature intravenous fluids

and of cold-stored blood also contributes to hypothermia.64 Hypothermia increases fluid requirements

and independently increases acute mortality rates.65

As the core temperature decreases, the rate of oxygen consumption also decreases, to approximately

50% of normal at 28°C. The decrease in oxygen consumption is accompanied by increased production of

acid metabolites. A leftward shift in the oxyhemoglobin dissociation curve also occurs with hypothermia

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but is partially compensated by the acidosis. CNS effects progress from confusion and loss of manual

dexterity to obtundation and frank coma as the core temperature decreases from 35°C to 26.5°C. The

heart rate decreases to approximately half of baseline at 28°C, with a concomitant decrease in cardiac

output. All cardiac electrical conduction intervals are prolonged, consistent with the changes in heart

rate, and both atrioventricular dissociation and refractory ventricular fibrillation occur at 28°C. Other

potential physiologic effects include ileus and pancreatitis (from cold enzyme activation) at

temperatures lower than 35°C.

Compensatory responses to hypothermia include increased excretion of catecholamines, resulting in

doubling of the basal metabolic rate, and increased production of thyroid hormones, further increasing

the basal metabolic rate to five times baseline. Shivering can increase heat production as well, but it

represents a significant energy expenditure and has been shown to be inhibited during episodes of

hypotension or hypoxemia.66 Compensatory responses to hypothermia are lost at temperatures below

30°C or 31°C, and a state of complete poikilothermy is reached.

The treatment for hypothermia is rewarming. The core temperature should be obtained on admission

of the trauma patient. Patients whose core temperatures are 33°C to 35°C can be treated with passive

rewarming, warm blankets, and hot packs. Patients with core temperatures lower than 33°C require

active rewarming. If the patient is unconscious, airway control should first be obtained. Because severe

hypothermia causes vasoconstriction, noninvasive blood pressure measurements may not be feasible or

accurate, and an arterial line should be placed for monitoring and blood gas sampling. The inspired gas

through the ventilator should be heated to 41°C and fully saturated with water vapor to increase heat

conductance in the lung. The intravenous fluids should also be warmed. Commercially available rapid

infusion systems with countercurrent heating elements should be used. For extreme hypothermia,

continuous mechanical arteriovenous rewarming can be performed for both circulatory support and

rewarming. Recently developed microtechnology permits core rewarming by percutaneous placement of

countercurrent warming coils directly in the inferior vena cava (IVC). Finally, other warming methods

include lavage of heated saline through nasogastric and thoracostomy tubes as well as peritoneal lavage,

but are not as effective.

Coagulopathy

Coagulopathy is a frequent problem complicating shock, especially in those patients who have received

large volumes of crystalloid solution and blood for resuscitation. Although this problem is incompletely

understood, it is clear that coagulation defects during shock are multifactorial. The presence of shock,

the fluid volume required for resuscitation, the presence of hypothermia, and pre-existing diseases all

influence the likelihood and severity of coagulopathy.67

A major factor in coagulopathy is usually due to the dilutional thrombocytopenia that occurs after

massive volume resuscitation. Although bleeding times can be prolonged with platelet counts less than

100,000 cells/mL, platelet counts of 50,000 cells/mL or greater are usually adequate for surgical

hemostasis. Dilutional thrombocytopenia becomes more likely with infusions of more than one blood

volume. Each unit of platelets administered increases the platelet count by 10,000 to 15,000 cells/mL.

Control of surgically remediable hemorrhage is prudent before platelet transfusion to prevent the loss of

the transfused platelets.

Dilution of other coagulation factors also plays a role in development of coagulopathy. Factors V and

VIII are the most labile in banked blood, but levels of less than 10% of normal for factors VII, X, XI, XII,

and XIII are all associated with abnormalities in hemostasis, as demonstrated by prolonged partial

thromboplastin time and prothrombin time. Fresh-frozen plasma can be administered as a source of all

the soluble coagulation factors. The administration of cryoprecipitate may be necessary as a

concentrated source of factor VIII and fibrinogen, particularly if adequate hemostasis is not obtained

with the use of fresh-frozen plasma. Recent support has emerged for the use of recombinant activated

factor VIIa. Although developed initially for use in hemophiliacs who developed inhibitors to factor

VIII, anecdotal evidence has suggested that recombinant activated factor VIIa may serve to quickly

reverse hemorrhage-induced coagulopathy.68 However, the use of factor VIIa is associated with

significant complications including pulmonary embolism, myocardial infarction, and stroke and thus is

no longer considered an optimal way to reverse hemorrhage-induced coagulopathy.69 Other agents have

demonstrated promise in rapidly reversing coagulopathy, such as tranexamic acid for massive

hemorrhage-induced coagulopathy and prothrombin concentrates for rapid reversal of

anticoagulants.70–71

Finally, evidence has suggested that coagulopathy and hemorrhage can be minimized following

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massive blood loss if early aggressive use of fresh-frozen plasma is administered. Military data

demonstrate that significant early coagulopathy is present after massive injury, even before blood

component therapy is begun. Both civilian and military experience with a 1:1 ratio of packed red blood

cells to fresh-frozen plasma has been associated with reduced mortality.72–74 However, this practice has

been associated with an increase in the development of ARDS and organ dysfunction due to poorly

defined mechanisms.75 Thus, generalization of this data to all patients with hemorrhage other than the

massively injured should be performed with caution as demonstrated in the PROPRR study.76

TREATMENT

Fluid Therapy

Early investigators of hemorrhagic shock noted that decreased CVP and a reduction in total-body

oxygen delivery (DO2

) were key early findings. If the decrease in oxygen delivery was severe or

prolonged, a reduction in total-body oxygen consumption ensued. After adequate fluid resuscitation,

oxygen delivery and consumption increased above the baseline value for several hours, as if the body

was paying back an “oxygen debt.” Failure of the patient to achieve this hyperdynamic response to

resuscitation was almost always fatal. Because early death from shock appeared to be explained by the

dynamics of oxygen delivery and utilization, therapy focused on restoring hemodynamics and oxygen

transport with fluid and inotropes.

The provision of additional fluid beyond the amount of blood loss was associated with improved

survival in both clinical and experimental studies of hemorrhagic shock, leading to widespread

acceptance of aggressive fluid infusion. However, some researchers have recently described a significant

increase in mortality associated with crystalloid overresuscitation and have postulated that excessive

fluid administration increases the clinical risk of ARDS, MODS, increased intracranial pressure, and

ACS.77–79 Because massive volumes of fluid are only provided to patients with severe shock, it is unclear

if it is the excessive fluid or the associated underlying shock that increases the risk of ARDS, organ

failure, or death after massive fluid resuscitation.

A minimum of two large-bore (14- to 16-gauge) intravenous catheters should be established in adults.

Isotonic fluid is then infused at the same time as blood is obtained for arterial blood gas analysis,

screening, and typing. Fluid can be infused up to 200 mL/min through a 14-gauge catheter and up to

220 mL/min through a 7-French catheter. A fluid challenge of 10 to 25 mL/kg is administered to the

hypotensive patient and the response is assessed (i.e., 2,000 mL or 40% of blood volume of a 70-kg

man). This therapeutic challenge is an effective trial in determining the amount of pre-existing or

continuing volume loss. If the blood pressure returns to normal and is stabilized, the volume loss was

relatively small, and the only treatment required may be infusion of isotonic fluid.

If the increase in blood pressure is transient after fluid bolus, then hemorrhage or continued fluid

losses are severe and ongoing. Additional crystalloid is administered, and the need for blood transfusion

is assessed. Patients who continue to require large amounts of fluid and blood to support perfusion

usually have ongoing hemorrhage and require surgical intervention. No response or a minimal response

to apparently adequate infusions of crystalloid solution and blood indicates exsanguinating hemorrhage

and the need for urgent surgery.

Crystalloids

Balanced salt solutions are the most commonly used resuscitative fluids, and their use to restore

extracellular volume significantly decreases the transfusion requirement after hemorrhagic shock.

Lactated Ringer solution is isotonic, readily available, and inexpensive. It rapidly replaces the depleted

interstitial fluid compartment and does not aggravate any pre-existing electrolyte abnormalities.

Previous investigations have shown that administration of lactated Ringer solution does not lead to

aggravation of the lactic acidosis that is present in shock.80 In fact, animal models have demonstrated

that the use of blood plus lactated Ringer solution results in a more rapid return to normal lactate and

pH than dose-shed blood alone. As volume and perfusion are restored, lactate is mobilized and

metabolized to bicarbonate in a single pass through the liver. In fact, mild metabolic alkalosis may

occur 1 or 2 days after large-volume resuscitations with lactated Ringer solution. Normal saline solution

is also effective for resuscitation of hypovolemic patients. Concerns about inducing hypernatremic,

hyperchloremic metabolic acidosis with massive resuscitation volumes remain but appear of less

relevance by further investigation with normal saline and the hypertonic saline solutions.

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