In the mid 1980s, after the recognition of sequential organ failure as a syndrome was recognized, multiple terms were used inconsistently by the medical community [11]. These disparate definitions attempting to describe the same physiologic phenomena led to the 1991 consensus conference. The societies of the American College of Chest Physicians (ACCP) and the Society of Critical Care Medicine (SCCM) were present. The goal of this conference was to establish a definition to describe what is now known as the spectrum of physiologic response to infection and/or inflammation. The term “systemic inflammatory response syndrome” (SIRS) was introduced at this conference. Additionally the terms sepsis, severe sepsis, septic shock and multiple organ dysfunction were defined as a result of this meeting (Table 7.2). The term “SIRS” was established to differentiate sepsis from a noninfectious, inflammatory state [12]. SIRS was defined as two or more of the following conditions:

SIRS could represent the symptoms from an infectious or noninfectious source. Infection was described as the invasion of normally sterile tissue by organisms. The term ­“sepsis” was defined as SIRS in conjunction with a confirmed infection. “Severe sepsis” was defined as sepsis associated with organ dysfunction, hypotension or hypoperfusion as evidenced by: elevated lactate, acute renal failure, liver failure, altered mental status and/or hematalogic abnormalities. “Septic shock” was the term established as a subset of severe sepsis with the added additional clinical information of persistent hypotension, despite adequate fluid resuscitation. Hypotension was defined as systolic blood pressure (SBP) <90 mmHg, mean arterial pressure (MAP) <70 mmHg, or a decrease in SBP >40 mmHg from baseline.

MODS was defined as the presence of altered organ function in an acutely ill patient such that homeostasis cannot be maintained without intervention and is the culmination of septic shock and multiple end-organ failure [13]. The 2001 Consensus Conference further expanded on these definitions [14]. A problem similar to the disparate use of the word “sepsis” in the early 1980s remains a problem in regard to the definition of MOF. This is evidenced by a lack of consensus with regard to the innumerable scoring systems available to assess mortality.

Sepsis, severe sepsis, septic shock, and MOF are commonplace in intensive care units and afflict 1.1 million people annually. Moreover, MOF results in 215,000 deaths in the United States alone. Mortality from the spectrum of sepsis is estimated to be 9.3% of all deaths in the United States [15]. The individual costs of treating a single patient with MOF can be upwards of $150,000 per patient [16]. In the United States alone the costs of treating sepsis and its related sequelae is approximately $24 billion annually [17]. Additionally, the cost of critical care can account for as much as 1% of the gross national product of some countries. The resultant morbidity from this disease and consequent loss of wages and quality of life are difficult to quantify. These costs illustrate the substantial financial and societal burden this disease process inflicts. The irony of MOF is that it emerged as a result of improvements in critical care but that it has remained a substantial encumbrance in terms of morbidity, mortality, and cost despite numerous improvements made in critical care in regard to resuscitation and supportive measures.

The overall mortality ranges between 40 and 60% for MOF in all patients and this mortality increases as more organ systems are affected [18, 19]. The incidence of any organ failure in all ICUs ranges from 30 to 60% [20]. In a 1985 study of intensive care patients by Knaus, single organ failure occurred in approximately one-third of all patients at some point during their ICU stay and MOF occurred in 15% of these patients [21]. MOF following septic shock remains the leading contributor to mortality in ICU patients. In a study by Mayr that looked at causes of death in 3,700 ICU patients, the most common cause of death in a single ICU was MOF (47%) [20]. Specifically regarding trauma patients, traumatic brain injury and uncontrolled hemorrhage remain the leading causes of early death after trauma. MOF is, however, the number one cause of late deaths in trauma patients [22]. Despite our improved understanding of the pathophysiology of this disease, the use of antibiotic agents, and more innovative therapies, there continues to be a high mortality rate for MOF.

Regarding the demographics of sepsis and organ failure, a study by Martin et al. in 2003 elucidated some important differences. This study revealed that men are more likely to have sepsis and are more frequently enrolled in clinical trials despite the predominance of women in the population of the United States. Additionally, African-American men had the youngest age of onset in this study as well as the highest mortality. The reason for these demographic differences is not known; however, genetic differences and socioeconomic factors most likely contribute to these disparities [23]. Recently, research has confirmed a lower overall incidence of MOF [24]. The incidence of early single organ dysfunction has not changed but there has been a decrease in early MOF from 22 to 7%. The incidence of MOF in 1992 was 1.8 times the incidence in 2002 [25, 26]. A similar study of trauma patients by Durham also revealed a lower overall mortality for single organ failure as well as a decrease in the overall incidence of MOF [27].

MOF resides at the most severe end of a spectrum of illness that includes SIRS, sepsis, severe sepsis and septic shock. Any point along this constellation of criteria puts the patient at risk for MOF. The risks of organ failure are multiple and due to lack of consensus regarding a scoring system, it is difficult to ascertain which risk factors are most specific. MOF was originally thought to be catalyzed by an infectious process. While the majority of patients with MOF will have an infectious source, it is also known that MOF occurs without an infection, per se, and can be solely due to unregulated inflammation, as occurs with severe pancreatitis, trauma or burns [28]. Immunosuppression, pneumonia, blood transfusions and bacteremia are all associated with increased risk for developing sepsis, severe sepsis, or septic shock and therefore also increases a patient’s risk for MOF [29, 30].

A demographic risk factor for MOF includes advanced age. Advanced age, defined as greater than 65, has likewise been associated with worse quality of life indicators in survivors of sepsis. These patients more often require extensive rehabilitation as well as skilled nursing facility admission upon their hospital discharge from their acute septic event [31]. In a multivariate analysis, adjusted for age, sex, and severe head injury, patients with MOF had four times greater odds of requiring assistance from others in activities of daily living more than 2 years after trauma as compared to trauma patients without organ failure. There was no statistically significant difference regarding self-care between patients who did not have a history of organ failure when compared with those patients who had a history of a single organ failure [32]. Obese patients, in general, have been found to have higher post-traumatic morbidity and mortality. Obesity is defined as body mass index (BMI) >30 kg/m and as the BMI goes up, the incidence of MOF increases as well [33]. Moreover, when age, injury severity score (ISS), and transfusions are adjusted for, obesity is associated with an 80% increased risk of MOF [22, 34]. This is likely associated to the pro-inflammatory state that obesity confers to patients [35]. Additionally, patients with nonoperative diagnoses—for example, patients admitted postacute myocardial infarction—have also been found to have a higher likelihood of developing MOF [21].

In trauma patients, Balk and colleagues aptly identified several major risk factors for the development of postinjury MOF. These included prolonged periods of hypotension, trauma, bowel infarction, hepatic insufficiency, advanced age, and alcohol abuse [36]. Additionally, ISS, number of units of packed red blood cells transfused, base deficit, and lactate levels are all associated with an increased risk of developing MOF [37, 38] (Table 7.3). Blood transfusions have independently been shown to be predictors of SIRS, MODS and mortality [39]. Furthermore, Durham et al. also validated that total blood products infused in the first 24 h after injury in addition to higher Acute Physiology and Chronic Health Evaluation (APACHE) III scores, amplified the risk for MOF occurrence [27].

Genetic factors also play a role in determining the severity and progression of organ failure. Genetic variants, particularly single-nucleotide polymorphisms (SNPs), are critical determinants for individual differences in both inflammatory responses as well as clinical outcomes in trauma patients [40]. Individuals who possess specific genetic polymorphisms in genes controlling the synthesis of cytokines or toll like receptors (TLR) may be predisposed to excessive inflammatory response to sepsis which increases their risk for the development of MODS [41]. For example, toll-like receptor 9 (TLR9) signaling plays an important role in the innate immune response. Trauma patients with SNPs of TLR9 have been found to have a greater responsiveness of their peripheral blood leukocytes as well as a higher risk of sepsis and multiple organ dysfunction [42]. Henckaerts and colleagues furthermore showed that these functional polymorphisms involved in innate immunity predispose patients to severe infections and death. Further study and elucidation could contribute to formation of a risk model where patients could be stratified as to who could benefit from specific preventative or therapeutic options [43].

MOF does not have a consensus definition and there are a variety of scoring systems used to categorize the severity of organ dysfunction. Trending these scores during a patient’s hospital course enables physicians to prognosticate the patient’s risk of mortality [44]. There is also a direct ­relationship between the number of organ failures and ICU mortality. Moreover, improvements in cardiovascular, respiratory and renal function during an ICU course can predict a better survival [45].

Scoring systems like the Acute Physiology and Chronic Health Evaluation (APACHE) score are based on measured laboratory values that enable staging of the severity of organ dysfunction. One of the most commonly used scoring systems is the Sequential Organ Failure Assessment Score (SOFA) (Table 7.4). Clinical and laboratory variables in six organ systems (respiratory, hematologic, liver, cardiovascular, central nervous system, renal) are utilized to calculate a total score [46]. Patients with no organ failure defined by a SOFA score below or equal to two for each organ at admission have an ICU mortality rate of 6% compared to 65–100% for those with four or more organ failures [34]. The Denver MOF score is also a frequently used and well validated score. It is defined as two or more organ systems failing greater than 48 h after injury. The Denver score looks at dysfunction in the cardiac, respiratory, renal and hepatic systems [47] (Table 7.5). When comparing the Denver postinjury MOF score with the SOFA score, the SOFA score is very sensitive but not as specific as the Denver MOF score, whereas the Denver postinjury MOF score is more specific and less sensitive than the SOFA score when dealing with the trauma population. This distinction is important when analyzing epidemiologic data as more sensitive scores will have a higher incidence of MOF, while a more specific score will have a higher mortality rate [48–50]. Regardless of what score is used to evaluate the various physiologic and clinical parameters, it is an underlying theme in all organ failure scores, that as the number of organ systems that are affected increase, so does the mortality [51, 52]. Moreover, these scoring systems were developed to quantify the severity of illness and the risk of mortality in ICU patients. These prognostic scores will not tell how a patient will respond to therapy and are best utilized to predict outcomes in certain homogenous groups of patients. Additionally, these scores are unable to provide details regarding how a patient will respond to treatment. However, they can be repeatedly assessed to evaluate a patient’s progress and used to identify patients for enrollment and to assess morbidity in clinical trials [53].

The common clinical manifestations leading to multiple organ dysfunction are included in the ACCP-SCCM guidelines and can fall anywhere within the continuum of SIRS to MOF. These most commonly include alterations in body temperature (hyper or hypothermia), tachypnea or hypocarbia, tachycardia, leukocytosis, leukopenia or bandemia, hypotension, thrombocytopenia or coagulopathy, and ­alterations in mental status [54]. Fever is the most common ­presenting symptom of sepsis and should be an impetus for further evaluation the patient as well as identification of a source. Elderly patients with sepsis or those that are immunosuppressed may not mount a febrile response or conversely may be hypothermic [55]. In sepsis, common sites of infection are the pulmonary, gastrointestinal, and urinary tract systems. Other nosocomial causes of sepsis are intravenous catheter infections, ventilator-associated pneumonia, and sinusitis. As approximately 20% of patients will not have an identifiable source, noninfectious etiologies for SIRS should be considered [56]. These may include surgery, trauma, hematoma, subarachnoid hemorrhage, venous thrombosis, pancreatitis, myocardial infarction, transplant rejection, thyroid storm, acute renal or adrenal insufficiency, lymphoma, tumor lysis syndrome, transfusion reaction, opiates, benzodiazepines, anesthetic related malignant hyperpyrexia, and neuroleptic malignant ­syndrome [57].

A thorough physical examination should include a head-to-toe exam as well as inspection of indwelling catheters, a rectal exam, and examination of all wounds, including those under casts/fixation devices. Potential atypical causes of sepsis should be given consideration when an obvious source is identified. These potential causes of sepsis include sinusitis, meningitis, septic joint, acalculous cholecystitis, septic thrombophlebitis, deep muscular abscess, or a viral infection. Corresponding laboratory values based on the suspected differential diagnoses should be obtained.

Infections leading to sepsis can also arise in surgical sites from the skin to the deep muscle layers. Physical examination should be repeated if no source is identified. An investigation of all organ systems should be thorough and systematic. Subtle findings of end organ hypoperfusion such as altered mental status, tachypnea, hypoxia, hypotension, oliguria may be missed if the physician does not have a high index of suspicion and an incomplete exam is performed; i.e., failure to remove a dressing to inspect a wound. Failure to investigate thoroughly can lead to a delay in diagnosis and increased morbidity and mortality. Physical examination should include a rapid review of the patient’s hemodynamic condition and should include continuous monitoring. Patients in shock should have arterial catheters placed for blood pressure monitoring. Persistent clinical signs of SIRS may suggest ongoing inflammation or infection. In addition to the patient’s hemodynamic status, clinical signs of poor end organ perfusion, such as change in mental status, low urine output, mottling, and poor capillary refill, should be taken into consideration and used to guide resuscitation [58]. Initiation of resuscitation should take place immediately upon recognition of SIRS or sepsis symptoms and should not wait for transport to the next level of care.

The pathophysiology of MOF is at best a nebulous interaction of multiple inflammatory mediators. Our understanding of this process and the innumerable interactions is in its infancy. A complete discussion of the immunology of this process is beyond the scope of this chapter as entire books have been dedicated to this task [62–64]. This section highlights some salient points regarding the pathophysiology of MOF.

Initially, SIRS was thought to be an overwhelming, uncontrolled response to infection. While MOF frequently is the end point of the spectrum of SIRS and severe sepsis, severe inflammation is also a mitigating factor and can result in the same endpoint of organ failure. This indicates overlap in the pathophysiology between inflammation and infection. The progression to MOF from SIRS from either cause is likely the result of an unbalanced interaction between the pro and anti inflammatory mediators. In most patients, the initial SIRS response is physiologically followed by a compensatory anti-inflammatory response syndrome (CARS). This acts to limit the SIRS response so that it is not ­counterproductive. The subsequent balance between the pro-inflammatory (SIRS) and anti-inflammatory (CARS) response has been referred to as the mixed antagonistic response syndrome or MARS [36]. If the balance of these two systems is disturbed the inflammatory response becomes systemic and deregulated. The result is whole-body activation of the inflammatory response, with resultant disruption of normal cellular metabolism and microcirculatory perfusion. Both of these responses, if unchecked can result in complications, the former leading to MOF and the later secondary infections. At the site of injury, endothelial cells and leukocytes coordinate the local release of mediators of the inflammatory response, including cytokines interleukins, interferons, leukotrienes, prostaglandins, nitric oxide, reactive oxygen species, and products of the classic inflammation pathway. It is this usually functional biologic response that becomes unregulated and leads to MOF [65].

In 1996, Moore and colleagues recognized MOF is not necessarily related to an infectious process and follows a bimodal distribution. Early MOF is now defined as organ failure that develops within 72 h of the initial diagnosis of sepsis (Table 7.6). Late MOF was defined as organ failure that develops after 72 h after the initial diagnosis of sepsis [66]. When compared to the late MOF group, patients with early organ failure died sooner, had more cardiac dysfunction and had greater evidence of hyper inflammation. In contrast, patients with late MOF were older, had greater evidence of hepatic failure, and were more likely to have an infection as a “second hit” [67].

Multiple theories exist regarding the cause for MOF and it is likely that these pathways overlap to cause initially organ insufficiency that, unless reverses, ultimately leads to failure. Four overlapping categories have been proposed to the complex pathophysiology of MOF. These are the cytokine hypothesis, the microcirculatory hypotheses, the gut hypothesis and the two-hit hypothesis [63].