SYSTEMIC INFLAMMATORY RESPONSE SYNDROME AND MULTIPLE-ORGAN DYSFUNCTION SYNDROME: DEFINITION, DIAGNOSIS, AND MANAGEMENT

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CHAPTER 93 SYSTEMIC INFLAMMATORY RESPONSE SYNDROME AND MULTIPLE-ORGAN DYSFUNCTION SYNDROME: DEFINITION, DIAGNOSIS, AND MANAGEMENT

Anthony Watkins, Edwin A. Deitch

In 1973, Tilney et al.¹ described 18 patients who developed “sequential system failure” following surgery for ruptured abdominal aneurysms. It was at this time that the idea that severe physiologic insults could lead to multiple-organ failure (MOF) was first established. Several decades later, MOF (or multiple organ dysfunction syndrome [MODS]) remains a major source of postinjury morbidity and a leading cause of death in surgical intensive care units (SICUs). Although the pathogenesis of this syndrome remains to be fully defined, it is evident that sepsis, systemic inflammatory response syndrome (SIRS), acute respiratory distress syndrome (ARDS), and MODS are closely related phenomena. Consequently, the goal of this chapter is to review SIRS and MODS, focusing on current strategies for diagnosing, managing, and (most importantly) preventing these syndromes.

INCIDENCE

The concept that death from trauma has a trimodal distribution (with these deaths being caused by hemorrhage, head injury, and sepsis/organ failure) is well established. Because MODS is the most common cause of late trauma deaths, it has been the subject of intense investigation. It is now clear that certain clinical risk factors can be used to predict the likelihood of a patient developing MODS. These include age, injury severity score (ISS), number of blood transfusions, and lactate/base deficit levels.² However, it is only over the last decade that the incidence of MODS in high-risk trauma patients appears to have decreased. This decrease appears to be due to a better knowledge of the factors predisposing patients to its development, as well as to the immunoinflammatory response to shock and trauma. For example, a 12-year prospective study examining 1344 trauma patients noted that the actual incidence of MODS (25%) was lower than its predicted rate.³

The authors concluded that this decrease was likely due to the concomitant drop in the liberal use of blood transfusions, which have been shown to be an independent predictor of MODS, SIRS, and mortality.^4,⁵ Not only does the incidence of MODS appear to be decreasing but there is emerging data to suggest that the mortality rate of patients with MODS is also declining—as reflected in a retrospective study of MODS-related death after blunt multiple trauma during a 25-year period. This study revealed an approximately 50% reduction in MODS-related mortality, from 29% to 14% over this time period.⁶ As will be discussed later in this chapter, several therapeutic interventions have been developed that have been shown to reduce mortality or to attenuate organ dysfunction, which would help explain this decline in mortality. In spite of these improvements, once MODS has become established the risk of death is significant—with the patient’s prognosis being more closely related to the number of organs that have failed than to any other variable, including the underlying processes that initiated the MODS.⁷

MECHANISMS OF MODS

The clinical picture of MOF is indicative of a generalized systemic inflammatory response, which typically occurs as a result of infection or uncontrolled inflammation in the patient with severe trauma. Several distinct and often conflicting hypotheses have been proposed to explain the mechanisms underlying MODS.⁷ Nonetheless, MOF can be viewed as a systemic process involving the excessive stimulation of certain inflammatory responses mediated by circulating factors whose effects contribute to injury or dysfunction in organs not involved in the initial insult. To a large extent, the cascade of events culminating in MOF is likely to be mediated by the same factors irrespective of the exact nature of the triggering insult. In fact, it is the host’s inflammatory response to injury or infection that is probably more important in the genesis of SIRS, ARDS, and MODS than the microbial agent or the initiating insult. Thus, an appreciation of the role of the inflammatory response of the host in the pathogenesis of MOF is vital in order to develop new and effective modalities for the prevention and treatment of this syndrome.

The earliest reports of postinjury MODS identified occult intra-abdominal infection as the etiology in approximately half of the cases. However, the recognition that more than 50%–70% of patients with MOF do not have an identifiable focus of infection meant that uncontrolled infection could not be the universal cause of MODS. From this early work came the recognition that only a fraction of septic-appearing patients were infected and that the host’s own response to tissue injury or shock could result in a noninfectious septic state. In turn, this recognition that the host’s immunoinflammatory response to microbial infection, tissue injury, necrotic tissue, or shock was similar led to the hypotheses that immune cell products, such as cytokines, contributed to the development of MODS.

This hypothesis was based on the concept that an excessive immuno-inflammatory response due to activated macrophages and other immune cells led to cytokine-mediated tissue injury and thereby the development of SIRS and MODS. This hypothesis was supported by several experimental and clinical observations. For example, cytokine levels were increased in trauma patients and the administration of tumor necrosis factor alpha (TNF-α) to humans elicited a clinical response similar to SIRS, whereas preclinical animal studies documented that TNF-neutralization improved survival in animals receiving a lethal dose of endotoxin. However, things were not this simple—as soon became apparent from multiple failed clinical trials of anti-inflammatory agents and the results of more complex preclinical animal studies. In fact, it is now recognized that cytokines have many beneficial functions, such as the control of infection. It is also recognized that elevated cytokine levels appear to be more markers or predictors of the host response than inducers of MODS.

Another mechanism by which hemorrhagic shock and trauma could predispose to the developments of MODS is through an ischemia-reperfusion injury and/or damage to the microcirculation. Because shock is essentially a total-body ischemia-reperfusion insult and the microcirculation of various tissues and organs are highly susceptible to ischemia-reperfusion–mediated insults, this process has been termed the microcirculatory hypothesis of MODS.⁷ Physiologically, circulatory shock could contribute to MOF through inadequate global oxygen delivery, the ischemia-reperfusion phenomenon, and/or the promotion of deleterious endothelial-leukocyte interactions.

Although prolonged tissue hypoxia leads to inadequate ATP generation and potentially irreversible cell damage, under most clinical conditions the shock period is not long enough for this process to occur. Thus, in clinical situations it appears that most of the tissue damage occurs after ischemia is relieved by reperfusion and that this damage is due to the production of reperfusion-induced oxygen radicals and proinflammatory factors (such as oxidants, nitric oxide, chemokines, and cytokines). In fact, recent studies show that the combination of reperfusion-induced increased levels of nitric oxide and superoxide anion synergistically increase cell injury via the production of peroxynitrite, which is a long-lasting and potent oxidant that causes direct cell injury through lipid peroxidation. This notion that increased nitric oxide production is important in the pathogenesis of MODS is supported by clinical studies showing that serum nitrate levels (an index for the systemic production of nitric oxide) correlated well with MOF scores in critically ill patients.⁸

Endothelial-leukocyte interactions leading to tissue injury also seem to be a key step in the pathogenesis of SIRS, ARDS, and MODS. Many factors related to shock and tissue injury, including cytokines, necrotic tissue, endotoxins, and oxidants, can convert endothelial cells from a quiescent state to a proinflammatory procoagulant one and can activate neutrophils. The combination of these changes in endothelial cell phenotype and neutrophil activation has been documented to lead to increased neutrophil adherence to the microcirculatory endothelium, thereby promoting neutrophil-mediated microvascular injury.⁷ Experimentally, inhibition of neutrophil-endothelial interactions has been shown to limit shock- and sepsis-induced injury to a number of organs, including the lung. Furthermore, neutrophil activation in trauma patients has been identified as a predictor of the development of SIRS, ARDS, and MODS. Therefore, endothelial cell–neutrophil interactions, whether induced by shock, sepsis, or an augmented inflammatory response, appear to be an important effector mechanism in the development of ARDS and MODS.

The gut hypothesis of MOF has been used to explain why no identifiable focus of infection can be found in as many as 30% of bacteremic patients who die from MOF.⁹ An extensive body of experimental as well as clinical studies supports this hypothesis. For example, clinical studies indicate that intestinal permeability is increased in patients with sepsis after major thermal injury or trauma and that loss of intestinal barrier function correlates with the development of systemic infection, ARDS, and MODS.¹⁰ Likewise, studies in intensive care unit (ICU) and trauma patients indicated that gut ischemia, as measured by gastric tonometry, is a better predictor of the development of ARDS and MODS than global indices of oxygen delivery.¹¹ Although both clinical and experimental studies implicated intestinal injury and bacterial translocation in the development of SIRS and MODS, a study by Moore et al.¹² began to cast doubt on the clinical relevance of bacterial translocation.

These investigators failed to find bacteria or endotoxin in the portal blood of severely injured patients, including a subgroup of patients developing MODS. One potential explanation for this failure to find endotoxin or bacteria in the portal blood was that the gut-derived factors contributing to SIRS, ARDS, and MODS were exiting the gut via the lymphatics. Studies testing this possibility have documented that nonbacterial factors exiting the ischemic gut contribute to acute ARDS, MODS, neutrophil activation, and endothelial cell injury/activation in both rodent and primate models of trauma-hemorrhagic shock and have led to the gut-lymph hypothesis of MODS.¹⁰ This gut lymph hypothesis of MODS proposes that nonbacterial noncytokine factors released from the stressed gut via the lymphatic system activate neutrophils and endothelial cells, thereby leading to organ dysfunction. Thus, over the last several years the gut hypothesis has expanded beyond bacterial translocation and now also implicates gut-derived nonbacterial proinflammatory and tissue-injurious factors in the pathogenesis of SIRS, ARDS, and MODS.

Although each of the various MODS hypotheses was presented individually, in patients many of these pathways overlap and the induction of one pathway can lead to activation of others. For example, severe bacterial infection activates the immuno-inflammatory response, which in turn leads to microcirculatory dysfunction and gut ischemia. Likewise, nonbacterial gut-derived factors have been shown to activate neutrophils, lead to an augmented inflammatory response, and promote microcirculatory dysfunction. Furthermore, shock states are associated with microcirculatory failure, gut injury, induction of an inflammatory response, and augmented neutrophil-endothelial cell interactions. In addition, in many patients who develop MOF no one major insult seems to have occurred. Instead, it appears that the development of MODS is related to the summation of several minor insults rather than one major event.

This clinical observation has led to the “two-hit” hypothesis of MODS, where potentially clinically modest events prime the host so that the host’s response to subsequent secondary events becomes exaggerated, culminating in SIRS, ARDS, and MOF. Although this two-hit theory needs to be further understood, it is a feasible explanation of how trauma or burn injury can convert a nonlethal infectious or hypoxic challenge into a lethal insult. In fact, as illustrated in Figure 1 it is clear that the difficulty in finding an effective therapy to prevent or treat MODS relates to the overlapping nature of the multiple systems activated by shock and trauma as well as the ability of one system to prime other systems for an exaggerated physiologic response to secondary insults. Nonetheless, the knowledge gained from these basic studies of the physiology of inflammation and MODS have provided important therapeutic insights. For example, they highlight the importance of prompt and adequate volume resuscitation and microcirculatory blood flow to prevent organ ischemia, the need for early excision of nonviable tissue to limit systemic inflammation, and the need for therapies to better preserve gut barrier dysfunction and limit uncontrolled inflammation.

Figure 1 Overlapping nature of multiple hypotheses believed to be responsible for causing MODS.

DIAGNOSIS

A key step in the treatment of a disease process is the establishment of an accurate diagnosis. To that end, a number of consensus conferences have been held in an attempt to provide classification schemes that allow SIRS, ARDS, and MODS to be accurately diagnosed. Based on these conferences, SIRS is defined as the response to a variety of severe clinical insults, which is manifested by two or more of the four conditions listed in Table 1.¹³ Furthermore, SIRS should be viewed as an evolved dynamic process that has adaptive survival value for the host under most circumstances because it signals the body to respond to injury or to an external threat such as a bacterial infection. However, if this protective inflammatory response becomes uncontrolled or excessive it has maladaptive consequences due to its potential to injure the host’s own tissues.

Table 1 Definition of Systemic Inflammatory Response Syndrome

Temperature >38°C or <36°C

Heart rate >90 bpm

PaCO₂ <32 torr (<4.3 kPa)

WBC of >12,000 or <4,000 cells/mm ³; >10% immature forms

The term “MODS” was introduced by a consensus conference of the American College of Chest Physicians (ACCP) and the Society of Critical Care Medicine (SCCM) in 1991.¹⁴ Prior to that time, this syndrome had many different names, including sequential organ dysfunction syndrome and multiple-organ failure syndrome. Several MODS scoring systems have been established that grade the severity of MODS and emphasize the concept that there exists a continuous spectrum from mild to full-blown dysfunction that correlates, on a patient population level, with mortality and morbidity (Table 2).¹⁵^–¹⁸

Table 2 Comparison of Scores Evaluating Multiple-Organ Dysfunction

These systems, much like the sequential organ failure assessment (SOFA) score developed by Vincent et al.,¹⁸ score organ failure by assigning a numerical scale in which more points are given to the higher degree of organ dysfunction in several organ systems (Table 3).^16,¹⁹ Although not developed to predict mortality in individual patients, there are several areas where the use of such scoring systems can be beneficial in critically ill patients. This includes their use in the daily clinical evaluation of a patient’s response, in research involving epidemiologic studies, and in the assessment of new therapies in clinical trials. Although these scoring systems use slightly different parameters to grade organ failure, most studies have found that the clinical utility of these scoring systems is comparable.^20,²¹

Table 3 The Sequential Organ Failure Assessment (SOFA) Score

MANAGEMENT

At the current time, the treatment of patients with established MODS is largely symptomatic and dedicated to supporting organs and systems that have failed. Because there is no “cure” for MODS, once it is present—and because the mortality rate of patients with established MODS is high—prevention becomes a key strategy in the care of the high-risk trauma patient. Therefore, it is important to understand and utilize certain strategies and approaches that have been shown to reduce the risk for developing MODS. In trauma patients, prevention begins in the field, with rapid transport to a medical facility, and extends throughout the resuscitative, operative, and ICU phases of care (Table 4). Because the approaches and strategies used at different phases of patient care may vary to some extent, each of these phases is discussed individually—although in actual clinical practice these phases often overlap.

Table 4 Prevention of Multiple Organ Failure

Resuscitative Phase

Shock resuscitation

Base deficit and lactate monitoring

Restrictive strategy for blood transfusion

Operative Phase

Vigilance in preventing missed injuries

Damage-control laparotomy

Early fracture fixation

ICU Phase

Infection-related issues

Early nutritional support and glucose control

Specific organ support

Recognition of abdominal compartment syndrome

Pharmacologic therapy

ICU, Intensive care unit.

Resuscitative Phase

The resuscitative phase has as its central goal the restoration of an effective blood volume, optimization of microcirculatory blood flow (and hence tissue perfusion), and the prevention/limitation of ischemia-reperfusion injury. Recognition that shock causes a global ischemia-reperfusion injury, which directly and indirectly leads to cellular and hence organ injury, has led to an increasing emphasis on the adequacy of volume resuscitation as well as a search for more effective resuscitation fluids. The primary endpoint of resuscitation, however, remains controversial. Parameters such as base deficit and lactate levels, oxygen delivery, gastric intramucosal pH (pHi), and invasive monitoring using pulmonary artery catheters have all been used in an attempt to optimize volume resuscitation.

This is because blood pressure and urine output may not reflect the adequacy of volume resuscitation in the severely injured trauma patient. In this setting, arterial blood base deficit and serum lactate levels have been shown to be useful markers with which to monitor the response to resuscitation. A worsening base deficit or serum lactate has been shown to correlate with ongoing blood loss or inadequate volume resuscitation, whereas improvements in these parameters are indicative of adequate volume resuscitation. Because in severely injured patients the period of volume resuscitation may last up to 48 hours, serial measurements are important. Based on prospective studies demonstrating that patients who cleared their base deficient or lactate levels within 48 hours had a reduced incidence of ARDS and MODS plus a higher survival rate than those who did not,^22,²³ the resuscitative goal should be to reduce and keep the base deficit below −2 mmol/l and/or the serum lactate less than 1.5 mEq/l.

The choice of resuscitative fluid has become a more controversial subject with the recognition that Ringers lactate is proinflammatory and thus may exacerbate the inflammatory response and contribute to the development of organ injury in shock states.²⁴^–²⁷ Given these concerns, plus the recent recognition that large-volume resuscitation with crystalloid solutions contributes to the development of the abdominal compartment syndrome (ACS),²⁸ attention has refocused on the early resuscitation of trauma patients with hypertonic (7.5%) saline. The largest clinical trial comparing hypertonic saline versus Ringer’s lactate when administered in the field demonstrated similar survival between the two groups.²⁹ However, there were decreased complications (such as renal failure and ARDS) in the hypertonic saline group.²⁹

Nonetheless, at the current time due to the paucity of clinical trials there is not enough data to determine whether or not initial hypertonic saline resuscitation is superior to standard crystalloid resuscitation of the trauma patient. Another encouraging approach is the use of resuscitation fluids containing antioxidants, with three clinical trials, including a recent prospective randomized trial, showing that splanchnic-directed antioxidant therapy helps prevents MODS in trauma patients.³⁰ As investigations into novel resuscitation fluids with pharmacologic actions (i.e., gut-protective, immune modulatory) continues, it is likely that the initial resuscitative approach of the trauma patient will evolve from Ringer’s lactate to include new fluid formulas.

The role of blood transfusions in trauma patients has also undergone an intense reevaluation based on clinical studies showing that blood is immune-suppressive and that blood transfusions are an independent predictor of MODS, especially when blood older than 2 weeks is administered.³¹ These observations, plus the fact that ICU patients as well as trauma patients can be safely managed with hemoglobin levels in the range of 7 g/dl, has led to the emergence of a selective transfusion policy in which prophylactic transfusions for anemia are no longer routinely administered. In fact, the TRICC trial demonstrated a significant reduction in the severity of new organ dysfunction in a critical care setting when transfusion was withheld unless the hemoglobin concentration was less than 7 g/dl.^32,³³

Thus, based on the existing literature regarding the clinical efficacy of prophylactic red blood cell (RBC) transfusions for anemia in the critically ill two general conclusions can be made:prophylactic RBC transfusions to raise the hemoglobin above 7 g/dl does not improve tissue oxygen consumption consistently in critically ill patients, either globally or at the level of the microcirculation, and prophylactic RBC transfusion is not associated with improvements in clinical outcome in the critically ill and may result in worse outcomes in several patient subgroups.

A large amount of the research that was carried out on the physiology of volume resuscitation involved attempts to identify optimal central hemodynamic values, especially cardiac index, oxygen delivery, and oxygen consumption values. This research also attempted to identify tissue-specific regional resuscitation endpoints, such as the gastric pH using gastric tonometry. Although the early studies suggested that resuscitating patients to supranormal levels of cardiac output and oxygen delivery to meet increased tissue oxygen demands will improve survival, these early results have been refuted by numerous prospective randomized trials. In fact, it is now clear that the use of prophylactic blood transfusions, inotropes, and large volumes of crystalloids to reach supranormal levels of oxygen delivery may be deleterious rather than beneficial. Likewise, although there is data suggesting that patients with low gastric mucosal pHs have a worse outcome measuring gastric mucosal pH has not been shown to be as effective as measuring base deficit or lactate as markers of the adequacy of volume resuscitation. Thus, at the current time there is no compelling reason to use gastric tonometry to guide resuscitation effects.

Operative Intervention

In an early article on multiple organ failure, Eiseman et al. described a series of 42 surgical patients with MODS, 24 of whom developed MODS as a result of intraoperative error or postoperative mismanagement.³⁴ This study emphasizes one of the key elements in the perioperative care of trauma patients: missed injuries are not uncommon in trauma patients and they can have dire consequences, including the development of ARDS, MODS, and death.³⁵^–³⁷ Although the specifics of the operative care of the trauma patient are covered elsewhere, certain aspects are important in the context of MODS. An example is the judicious use of damage-control laparotomy to limit both acute and delayed MODS. The rationale behind a damage-control laparotomy is the clinical observation that prolonged attempts at definitive control of intra-abdominal injuries can result in hemodynamic instability, acidosis, and coagulopathy.

If the patient survives the operation, the incidence of postoperative MODS is high. In contrast, a planned reoperation is safer and easier in patients who have been warmed and fully resuscitated and have had their acidosis and coagulopathy corrected. Although the morbidity and mortality rate of patients undergoing damage-control laparotomies is significant, the incidence of MODS appears to be reduced and survival increased.³⁶ A second example of operative intervention to reduce the incidence of ARDS and MODS is early fixation of long-bone fractures.³⁸ In fact, beginning as early as 1985, numerous prospective and retrospective clinical trials have documented that early fixation of long-bone fractures compared with delayed fracture fixation is associated with lower rates of renal, respiratory, and liver failure and lower rates of death.

Early fracture fixation in the presence of major thoracic or head injury is controversial. Proponents of early fixation have shown no added morbidity in the presence of either chest or head injury, whereas opponents have cited increases in the risk for secondary brain injury and ARDS associated with early orthopedic intervention in these specific patient subpopulations. Despite these subgroups, most evidence supports early fracture fixation as an effective method of reducing organ failure in patients with long-bone fractures, although in the individual patient caution must be exercised in the timing of secondary operations.

Intensive Care Unit Management Phase

The incidence of postoperative and postinjury MOF can be prevented through strategies such as continued resuscitation, management of infectious complications, and early nutritional and specific organ support. Although some organs (such as the pulmonary system) have randomized prospective data supporting certain therapies that improve outcome, other systems (such as the hepatic system) rarely require specific treatment. In this section we focus on preventive and therapeutic strategies that appear to have reduced the incidence of MODS and/or improved outcome in patients with MODS (Tables 4 and 5).

Table 5 ICU Interventions That Reduce Mortality or Attenuate Organ Dysfunction

Objective	Intervention
Resuscitation	Early goal-directed resuscitation
Prophylaxis	SDD
ICU support	Restrictive transfusion strategy
	Low tidal volume ventilation
	Daily awakening
	Tight glucose control
	Enteral feeding
Mediator-targeted therapy	Activated protein C
Mediator-targeted therapy	Low-dose corticosteroids

ICU, Intensive care unit; SDD, selective decontamination of digestive tract.

Because infections can contribute to the development of MODS and can increase mortality, several key concepts must be kept in mind to limit infection-related MODS. The use of early empiric antibiotics in patients suspected of having pneumonia is important because the use of early adequate empiric antibiotic has been shown to reduce pneumonia-related mortality.³⁹ Interestingly, although not used much in the United States it appears that selective decontamination of the digestive tract (SDD) reduces infectious complications as well as mortality in critically ill trauma and other surgical patients.⁴⁰

The concept behind SDD is that the gut is a major reservoir for organisms causing pneumonias and bacteremias. By controlling the intestinal bacterial flora, including the upper gastrointestinal tract flora, the incidence of infections and hence mortality will be reduced. The reason for the failure to employ SDD appears to relate to the fact that this therapy is very labor intensive and has only recently been shown by meta-analyses to improve survival. In addition, when MODS develops in the postoperative or post-trauma period a meticulous search for a source of infection should be made, with particular attention to wounds, incisions, sites of previous injury or surgery, and intravenous catheter sites because the development of ARDS or MODS is not an uncommon manifestation of an occult infection. Despite extensive research involving various pharmacologic therapies of severe sepsis, with the exception of activated protein C, the results of clinical trials of immunomodulatory agents have been distressing.

In contrast, a prospective randomized trial documented that the recombinant form of activated protein C improved 28-day survival and led to a more rapid resolution of cardiovascular, respiratory, and hematologic dysfunction in patients with severe sepsis.⁴¹ The reason activated protein C was effective where other agents were not may relate to the fact that it has both anticoagulant and anti-inflammatory activity, thereby protecting the microcirculation as well as limiting the inflammatory response. Last, the use of low-dose steroids has emerged as an effective therapy in patients with pressor-refractory septic shock and an impaired response to ACTH stimulation because controlled trials have documented that in this patient group the administration of 50 mg of hydrocortisone every 6 hours and 50 mcg of fludrocortisone improves survival.⁴²

In addition to infectious issues, other non organ-specific therapies that appear to be beneficial include early enteral alimentation, glucose control, elevation of the head of the bed, and daily cessation of sedative infusions in ventilated patients. The notion of early enteral feeding is based on the concept of limiting gut-origin sepsis because the fed gut is more resistant to stress-induced injury and parenteral alimentation is associated with gut atrophy, increased permeability, and loss of barrier function.⁷ Based on the results of multiple prospective randomized trials, early enteral nutrition has been found to effectively reduce infectious complications, ICU, and total hospital length of stay, although it does not appear to improve survival.⁴³ Thus, in an attempt to further improve the beneficial effects of enteral feedings a number of immune-enhancing enteral formulas were produced and tested in trauma and ICU patients.

Although some studies comparing standard to immune-enhancing enteral formulas suggested that immune-enhancing diets are associated with a further decrease in infectious complications, others did not.⁴⁴ Thus, at the current time the institution of early enteral feeding seems to be the key factor in reducing infectious complications—with the composition of the enteral formula being of secondary importance. A second metabolic approach has been the institution of tight glucose control in which insulin is liberally used to keep the serum glucose less than 120 mg/dl.

Since the original prospective randomized controlled study showing that tight glucose control (<120 mg/dl) was associated with a survival advantage compared to a more liberal glucose control regimen (<215 mg/dl),⁴⁵ numerous other studies (including several in trauma patients) have validated the concept that elevated serum glucose levels are associated with an increased incidence of infectious complications and poorer clinical outcomes.⁴⁶ Other easily instituted ICU therapies have been shown to reduce complications. For example, daily interruption of sedative infusions in critically ill patients undergoing mechanical ventilation reduces ICU length of stay and morbidity,⁴⁷ whereas elevation of the head of the bed of ventilated patients reduces the incidence of pneumonia and helps to preserve pulmonary function.⁴⁸

In addition to elevating the head of the bed and daily sedative cessation, other advances in the care of the patient with respiratory failure have been made over the last several years. The most important of these was the recognition that high tidal volumes and increased airway pressures cause, rather than prevent, lung injury by inducing lung inflammation. This process has been termed ventilator-induced lung injury (VILI). Consistent with this physiologic concept, multicenter randomized controlled trials confirmed that mechanical ventilation of patients with acute lung injury and ARDS with a lower tidal volume (i.e., 6 ml/kg) than traditionally used results in decreased mortality and attenuates the local and systemic release of proinflammatory mediators.^49,⁵⁰ In addition, further clinical trials documented that outcomes in patients with acute lung injury or ARDS are similar whether lower or higher PEEP levels are used when an end-inspiratory plateau-pressure limit of 30 cm of water is maintained.⁵¹

While oxygenation is maintained with low tidal volumes, permissive hypercapnia and increased CO₂ levels may develop as a result of decreased ventilation, but this does not appear to be harmful.^52,⁵³ Thus, the use of low-tidal volume ventilation that maintains the inspiratory plateau pressure below 30 cm of water is effective both in the prevention and treatment of acute lung injury and ARDS. A number of other ventilatory strategies have either failed to show consistent benefit (such as inhaled nitric oxide) or remain to be proven beneficial (such as prone ventilation or high-frequency ventilation).

Renal replacement therapy has been effective in critically ill patients with MODS by allowing regulation of fluid and electrolytes. Renal replacement therapy also has the potential to remove toxins and circulating mediators of inflammation. Methods of supporting renal function, such as the prophylactic use of low-dose dopamine, have not been found to be effective.⁵⁴ Thus, currently the best way to limit renal failure is to avoid underresuscitation and to promptly diagnose and treat infectious complications. Once renal failure has occurred, continuous venovenous hemodialysis appears to be superior to hemodialysis because it avoids the need for systemic anticoagulation and is less likely to cause hypotensive episodes in the fragile patient.⁵⁵

A recently recognized and important treatable cause of MODS is the abdominal compartment syndrome (ACS). The ACS can be viewed as a reversible mechanical cause of MODS that is related to increased intra-abdominal pressure.^56,⁵⁷ As the intra-abdominal pressure rises, abdominal visceral perfusion decreases, ventilation is impaired, and cardiac output declines. Clinically, the ACS is manifested as a decreasing urine output, inadequate ventilation associated with elevated peak airway pressures, and hypotension. Patients at highest risk of developing ACS are those suffering from multiple trauma, massive hemorrhage, and prolonged operations with massive volume resuscitation, as well as those requiring intra-abdominal packing to control bleeding.

ACS can also develop in patients after severe hemorrhagic shock without an abdominal or retroperitoneal injury, and this phenomenon is known as secondary ACS. Secondary ACS is due to progressive visceral and retroperitoneal edema in shocked patients with the capillary leak syndrome who receive massive crystalloid fluid resuscitation. The diagnosis of ACS is made or confirmed by measuring the abdominal pressure through a Foley catheter placed in the bladder, with ACS being defined as the combination of a urinary bladder pressure >25 mm Hg, progressive organ dysfunction (urinary output <0.5 ml/kg/hr or PaO₂/F_IO₂ <150 or peak airway pressure >45 cm H₂O or cardiac index <3 L/min/m² despite resuscitation), and improved organ function after surgical abdominal decompression. Surgical treatment, consisting of opening the abdomen, leads to rapid and profound correction of the physiologic abnormalities in most cases, whereas untreated the ACS is highly lethal, with a mortality rate approaching 100%.