Background
History of infectious diseases
During thousands of years of human existence, epidemic infectious diseases probably were rare, with most infections occurring as a result of trauma or from physical contact with animals. In 2735 BC, Chinese emperor Sheng Nung recorded the use of an herbal remedy to treat fever. Over the next 2 millennia, pandemics of cholera, plague (black death), smallpox, measles, tuberculosis, and gonorrhea spread worldwide, wiping out huge segments of the population. In 1546, Hieronymus Fracastorius suggested germ theory for infections.
John Pringle, a British army surgeon, proposed the concept of antisepsis for the first time. In the 19th century, antiseptic practices lead to a reduction in mortality from puerperal fever from 13.6% to 1.5% in a Vienna hospital. In 1879, Louis Pasteur identified Streptococcus bacteria as the cause of puerperal sepsis. In 1892, Richard Pfeiffer identified the toxin that causes shock in patients. In 1928, Alexander Fleming recognized that his bacterial cultures were killed by a blue mold, Penicillium notatum. Thus, with the discovery of penicillin, a new era began, with antibiotics used to treat bacterial infections. In 1944 in the United States, Waksman discovered that streptomycin was effective in the treatment of tuberculosis.
Further advances in medical sciences in the late 20th century enhanced our understanding of sepsis and septic shock—recognition of inflammatory mediators stimulating nitric oxide production; producing endothelial injury; activating coagulation cascade; and eventually leading to organ ischemia, damage, and, ultimately, death. This knowledge will lead to novel approaches to treat severe sepsis in the future.
Sepsis and septic shock
In 1914, Schottmueller wrote, "Septicemia is a state of microbial invasion from a portal of entry into the blood stream which causes sign of illness." The definition did not change much over the years because the terms sepsis and septicemia referred to several ill-defined clinical conditions present in a patient with bacteremia. In practice, the terms often were used interchangeably; however, less than one half of the patients with signs and symptoms of sepsis have positive results on blood culture. Furthermore, not all patients with bacteriemia have signs of sepsis; therefore, sepsis and septicemia are not identical. In the last few decades, discovery of endogenous mediators of the host response have led to the recognition that the clinical syndrome of sepsis is the result of excessive activation of host defense mechanisms rather than the direct effect of microorganisms. Sepsis and its sequelae represent a continuum of clinical and pathophysiologic severity.
Serious bacterial infections at any body site, with or without bacteremia, usually are associated with important changes in the function of every organ system in the body. These changes are mediated mostly by elements of the host immune system against infection. Shock is deemed present when volume replacement fails to increase blood pressure to acceptable levels and associated clinical evidence indicates inadequate perfusion of major organ systems, with progressive failure of organ system functions.
Multiple organ dysfunctions, the extreme end of the continuum, are incremental degrees of physiological derangements in individual organs (a process rather than an event). Alteration in organ function can vary widely from a mild degree of organ dysfunction to frank organ failure.
The American College of Chest Physicians (ACCP)/Society of Critical Care Medicine (SCCM) consensus conference definitions of sepsis, severe sepsis, and septic shock (Bone, 1992) are outlined below.
Systemic inflammatory response syndrome (SIRS): The systemic inflammatory response to a wide variety of severe clinical insults manifests by 2 or more of the following conditions:
- Temperature greater than 38°C or less than 36°C
- Heart rate greater than 90 beats per minute (bpm)
- Respiratory rate greater than 20 breaths per minute or PaCO2 less than 32 mm Hg
- White blood cell count greater than 12,000/µL, less than 4000/µL, or 10% immature (band) forms
Sepsis: This is a systemic inflammatory response to a documented infection. The manifestations of sepsis are the same as those previously defined for SIRS. The clinical features include 2 or more of the following conditions as a result of a documented infection:
- Rectal temperature greater than 38°C or less than 36°C
- Tachycardia (>90 bpm)
- Tachypnea (>20 breaths per min)
With sepsis, at least 1 of the following manifestations of inadequate organ function/perfusion also must be included:
- Alteration in mental state
- Hypoxemia (PaO2 <72>2 [fraction of inspired oxygen] 0.21; overt pulmonary disease not the direct cause of hypoxemia)
- Elevated plasma lactate level
- Oliguria (urine output <30>
Severe sepsis: This is sepsis and SIRS associated with organ dysfunction, hypoperfusion, or hypotension. Hypoperfusion and perfusion abnormalities may include, but are not limited to, lactic acidosis, oliguria, or an acute alteration in mental status. The systemic response to infection is manifested by 2 or more of the following conditions:
- Temperature greater than 38°C or less than 36°C
- Heart rate greater than 90 bpm
- Respiratory rate greater than 20 breaths per minute or PaCO2 less than 32 mm Hg
- White blood cell count greater than 12,000/µL, less than 4000/µL, or 10% immature (band) forms
Sepsis-induced hypotension (ie, systolic blood pressure <90>40 mm Hg from baseline): This may develop despite adequate fluid resuscitation, along with the presence of perfusion abnormalities that may include lactic acidosis, oliguria, or an acute alteration in mental state.
Septic shock: A subset of people with severe sepsis develop hypotension despite adequate fluid resuscitation, along with the presence of perfusion abnormalities that may include lactic acidosis, oliguria, or an acute alteration in mental status. Patients receiving inotropic or vasopressor agents may not be hypotensive by the time that they manifest hypoperfusion abnormalities or organ dysfunction.
Multiple organ dysfunction syndrome (MODS): This is the presence of altered organ function in a patient who is acutely ill and in whom homeostasis cannot be maintained without intervention.
Pathophysiology
Mediator-induced cellular injury
The evidence that sepsis results from an exaggerated systemic inflammatory response induced by infecting organisms is compelling; inflammatory mediators are the key players in the pathogenesis.
The gram-positive and gram-negative bacteria induce a variety of proinflammatory mediators, including cytokines. Such cytokines play a pivotal role in initiating sepsis and shock. The bacterial cell wall components are known to release the cytokines; these include lipopolysaccharide (gram-negative bacteria), peptidoglycan (gram-positive and gram-negative bacteria), and lipoteichoic acid (gram-positive bacteria).
Several of the harmful effects of bacteria are mediated by proinflammatory cytokines induced in host cells (macrophages/monocytes and neutrophils) by the bacterial cell wall component. The most toxic component of the gram-negative bacteria is the lipid A moiety of lipopolysaccharide. The gram-positive bacteria cell wall leads to cytokine induction via lipoteichoic acid. Additionally, gram-positive bacteria may secrete the super antigen cytotoxins that bind directly to the major histocompatibility complex (MHC) molecules and T-cell receptors, leading to massive cytokine production.
An initial step in the activation of innate immunity is the synthesis de novo of small polypeptides, called cytokines, that induce protean manifestations on most cell types, from immune effector cells to vascular smooth muscle and parenchymal cells. Several cytokines are induced, including tumor necrosis factor (TNF) and interleukins, especially IL-1. Both of these factors also help to keep infections localized, but, once the infection becomes systemic, the effects can also be detrimental. Circulating levels of IL-6 correlate well with the outcome. High levels of IL-6 are associated with mortality, but its role in pathogeneses is not clear. IL-8 is an important regulator of neutrophil function, synthesized and released in significant amounts during sepsis. IL-8 contributes to the lung injury and dysfunction of other organs. The chemokines (monocyte chemoattractant protein–1) orchestrate the migration of leukocytes during endotoxemia and sepsis. The other cytokines that have a supposed role in
sepsis areIL-10, interferon-gamma, IL-12, macrophage migration inhibition factor, granulocyte colony-stimulating factor (G-CSF), and granulocyte macrophage colony-stimulating factor (GM-CSF).
The complement system is activated and contributes to the clearance of the infecting microorganisms but probably also enhances the tissue damage. The contact systems become activated; consequently, bradykinin is generated. Hypotension, the cardinal manifestation of sepsis, occurs via induction of nitric oxide. Nitric oxide plays a major role in hemodynamic alteration of septic shock, which is hyperdynamic shock. A dual role exists for neutrophils; they are necessary for defense against microorganisms but also may become toxic inflammatory mediators contributing to tissue damage and organ dysfunction.
The lipid mediators (eicosanoids), platelet activating factor, and phospholipase A2 are generated during sepsis, but their contributions to the sepsis syndrome remain to be established.
Table 1. Mediators of Sepsis
| Type | Mediator | Activity |
| Cellular mediators | Lipopolysaccharide | Activation of macrophages, neutrophils, platelets, and endothelium releases various cytokines and other mediators |
| Lipoteichoic acid |
| Peptidoglycan |
| Superantigens |
| Endotoxin |
| Humoral mediators | Cytokines | Potent proinflammatory effect Neutrophil chemotactic factor Acts as pyrogen, stimulates B and T lymphocyte proliferation, inhibits cytokine production, induces immunosuppression Activation and degranulation of neutrophils Cytotoxic, augments vascular permeability, contributes to shock Involved in hemodynamic alterations of septic shock Promote neutrophil and macrophage, platelet activation and chemotaxis, other proinflammatory effects Enhance vascular permeability and contributes to lung injury Enhance neutrophil-endothelial cell interaction, regulate leukocyte migration and adhesion, and play a role in pathogenesis of sepsis |
| TNF-alpha and IL-1b |
Abnormalities of coagulation and fibrinolysis homeostasis in sepsis
An imbalance of homeostatic mechanisms lead to disseminated intravascular coagulopathy (DIC) and microvascular thrombosis causing organ dysfunction and death (Lorente, 1993; McGillvary, 1998; Levi, 1999). Inflammatory mediators instigate direct injury to the vascular endothelium; the endothelial cells release tissue factor (TF), triggering the extrinsic coagulation cascade and accelerating production of thrombin (Carvalho, 1994). The coagulation factors are activated as a result of endothelial damage, the process is initiated via binding of factor XII to the subendothelial surface. This activates factor XII, and then factor XI and, eventually, factor 10 are activated by a complex of factor IX, factor VIII, calcium, and phospholipid. The final product of the coagulation pathway is the production of thrombin, which converts soluble fibrinogen to fibrin. The insoluble fibrin, along with aggregated platelets, forms intravascular clots.
Inflammatory cytokines, such as IL-1a, IL-1b, and TNF-alpha initiate coagulation by activation of TF, which is the principle activator of coagulation. TF interacts with factor VIIa, forming factor VIIa-TF complex, which activates factor X and IX. Activation of coagulation in sepsis has been confirmed by marked increases in thrombin-antithrombin complex (Levi, 1993) and the presence of D-dimer in plasma, indicating activation of clotting system and fibrinolysis (Mammen, 1998). Tissue plasminogen activator (t-PA) facilitates conversion of plasminogen to plasmin, a natural fibrinolytic.
Endotoxins increase the activity of inhibitors of fibrinolysis, which are plasminogen activator inhibitor (PAI-1) and thrombin activatable fibrinolysis inhibitor (TAFI). Furthermore, the levels of protein C and endogenous activated protein C also are decreased in sepsis. Endogenous activated protein C is an important proteolytic inhibitor of coagulation cofactors Va and VIIa. Thrombin via thrombomodulin activates protein C that functions as an antithrombotic in the microvasculature. Endogenous activated protein C also enhances fibrinolysis by neutralizing PAI-1 and by accelerating t-PA–dependent clot lysis.
The imbalance among inflammation, coagulation, and fibrinolysis results in widespread coagulopathy and microvascular thrombosis and suppressed fibrinolysis, ultimately leading to multiple organ dysfunction and death.
Circulatory and metabolic pathophysiology of septic shock
The predominant hemodynamic feature of septic shock is arterial vasodilation. Diminished peripheral arterial vascular tone may result in dependency of blood pressure on cardiac output, causing vasodilation to result in hypotension and shock if insufficiently compensated by a rise in cardiac output. Early in septic shock, the rise in cardiac output often is limited by hypovolemia and a fall in preload because of low cardiac filling pressures. When intravascular volume is augmented, the cardiac output usually is elevated (the hyperdynamic phase of sepsis and shock). Even though the cardiac output is elevated, the performance of the heart, reflected by stroke work as calculated from stroke volume and blood pressure, usually is depressed. Factors responsible for myocardial depression of sepsis are myocardial depressant substances, coronary blood flow abnormalities, pulmonary hypertension, various cytokines, nitric oxide, and beta-receptor down-regulation.
Peripheral circulation during septic shock
An elevation of cardiac output occurs; however, the arterial-mixed venous oxygen difference usually is narrow, and the blood lactate level is elevated. This implies that low global tissue oxygen extraction is the mechanism that may limit total body oxygen uptake in septic shock. The basic pathophysiologic problem seems to be a disparity between the uptake and oxygen demand in the tissues, which may be more pronounced in some areas than in others. This is termed maldistribution of blood flow, either between or within organs, with a resultant defect in capacity to extract oxygen locally. During a fall in oxygen supply, cardiac output becomes distributed so that most vital organs, such as the heart and brain, remain relatively better perfused than nonvital organs. However, sepsis leads to regional changes in oxygen demand and regional alteration in blood flow of various organs.
The peripheral blood flow abnormalities result from the balance between local regulation of arterial tone and the activity of central mechanisms (eg, autonomic nervous system). The regional regulation, release of vasodilating substances (eg, nitric oxide, prostacyclin), and vasoconstricting substances (eg, endothelin) affect the regional blood flow. Development of increased systemic microvascular permeability also occurs, remote from the infectious focus, contributing to edema of various organs, particularly the lung microcirculation and development of acute respiratory distress syndrome (ARDS).
In patients experiencing septic shock, the delivery of oxygen is relatively high, but the global oxygen extraction ratio is relatively low. The oxygen uptake increases with a rise in body temperature despite a fall in oxygen extraction.
In patients with sepsis who have low oxygen extraction and elevated arterial blood lactate levels, oxygen uptake depends on oxygen supply over a much wider range than normal. Therefore, oxygen extraction may be too low for tissue needs at a given oxygen supply, and oxygen uptake may increase with a boost in oxygen supply, a phenomenon termed oxygen uptake supply dependence or pathological supply dependence. However, this concept is controversial because other investigators argue that supply dependence is artifactual rather than a real phenomenon.
Maldistribution of blood flow, disturbances in the microcirculation, and, consequently, peripheral shunting of oxygen are responsible for diminished oxygen extraction and uptake, pathological supply dependency of oxygen, and lactate acidemia in patients experiencing septic shock.
Multiorgan dysfunction syndrome
Sepsis is described as an autodestructive process that permits the extension of normal pathophysiologic response to infection (involving otherwise normal tissues), resulting in multiple organ dysfunction syndrome. Organ dysfunction or organ failure may be the first clinical sign of sepsis, and no organ system is immune to the consequences of the inflammatory excesses of sepsis.
Circulation
Significant derangement in the autoregulation of circulation is typical in patients with sepsis. Vasoactive mediators cause vasodilatation and increase the microvascular permeability at the site of infection. Nitric oxide plays a central role in the vasodilatation of septic shock. Impaired secretion of vasopressin also may occur, which may permit the persistence of vasodilatation.
Central circulation
Changes in both systolic and diastolic ventricular performance occur in patients with sepsis. Through the use of the Frank Starling mechanism, the cardiac output often is increased to maintain the blood pressure in the presence of systemic vasodilatation. Patients with preexisting cardiac disease are unable to increase their cardiac output appropriately.
Regional circulation
Sepsis interferes with the normal distribution of systemic blood flow to organ systems; therefore, core organs may not receive appropriate oxygen delivery.
The microcirculation is the key target organ for injury in patients with sepsis syndrome. A decrease in the number of functional capillaries causes an inability to extract oxygen maximally; intrinsic and extrinsic compression of capillaries and plugging of the capillary lumen by blood cells cause the inability. Increased endothelial permeability leads to widespread tissue edema of protein-rich fluid.
Hypotension is caused by the redistribution of intravascular fluid volume resulting from reduced arterial vascular tone, diminished venous return from venous dilation, and release of myocardial depressant substances.
Pulmonary dysfunction
Endothelial injury in the pulmonary vasculature leads to disturbed capillary blood flow and enhanced microvascular permeability, resulting in interstitial and alveolar edema. Neutrophil entrapment within the pulmonary microcirculation initiates and amplifies the injury to alveolar capillary membrane. ARDS is a frequent manifestation of these effects. As many as 40% of patients with severe sepsis develop acute lung injury.
Acute lung injury is a spectrum of pulmonary dysfunction secondary to parenchymal cellular damage characterized by endothelial cell injury and destruction, deposition of platelet and leukocyte aggregates, destruction of type I alveolar pneumocytes, an acute inflammatory response through all the phases of injury, and repair and hyperplasia of type II pneumocytes. The migration of macrophages and neutrophils into the interstitium and alveoli produces many different mediators, which contribute to the alveolar and epithelial cell damage.
The acute lung injury may be reversible at an early stage, but, in many cases, the host response is uncontrolled, and the acute lung injury progresses to ARDS. Continued infiltration occurs with neutrophils and mononuclear cells, lymphocytes, and fibroblasts. An alveolar inflammatory exudate persists, and type II pneumocyte proliferation is evident. If this process can be halted, complete resolution may occur. In other patients, a progressive respiratory failure and pulmonary fibrosis develop. The late stage of ARDS is characterized by an aggressive repair process, infiltration with an excess number of fibroblasts, and synthesis of the extracellular matrix (ECM) protein, including collagen. Subsequent deposition of metrics in the alveolar wall impedes gas exchange and results in a restrictive defect leading to irreversible respiratory failure.
Gastrointestinal dysfunction and nutrition
The gastrointestinal tract may help to propagate the injury of sepsis. Overgrowth of bacteria in the upper gastrointestinal tract may aspirate into the lungs and produce nosocomial pneumonia. The gut's normal barrier function may be affected, thereby allowing translocation of bacteria and endotoxin into the systemic circulation and extending the septic response. Septic shock usually causes ileus, and the use of narcotics and sedatives delays the institution of enteral feeding. The optimal level of nutritional intake is interfered with in the face of high protein and energy requirements.
Liver dysfunction
By virtue of the liver's role in the host defense, the abnormal synthetic functions caused by liver dysfunction can contribute to both the initiation and progression of sepsis. The reticuloendothelial system of the liver acts as a first line of defense in clearing bacteria and their products; liver dysfunction leads to a spillover of these products into the systemic circulation.
Renal dysfunction
Sepsis often is accompanied by acute renal failure caused by acute tubular necrosis. The mechanism is by systemic hypotension, direct renal vasoconstriction, release of cytokines (eg, TNF), and activations of neutrophils by endotoxins and other peptides, which contribute to renal injury.
Central nervous system dysfunction
Involvement of the central nervous system (CNS) in sepsis produces encephalopathy and peripheral neuropathy. The pathogeneses is poorly defined.
Mechanisms of organ dysfunction and injury
The precise mechanisms of cell injury and resulting organ dysfunction in patients with sepsis are not understood fully. Multiorgan dysfunction syndrome is associated with widespread endothelial and parenchymal cell injury because of the falling proposed mechanisms.
Hypoxic hypoxia
The septic circulatory lesion disrupts tissue oxygenation, alters the metabolic regulation of tissue oxygen delivery, and contributes to organ dysfunction. Microvascular and endothelial abnormalities contribute to the septic microcirculatory defect in sepsis. The reactive oxygen sepsis, lytic enzymes, vasoactive substances (nitric oxide), and endothelial growth factors lead to microcirculatory injury, which is compounded by the inability of the erythrocytes to navigate the septic microcirculation.
Direct cytotoxicity
The endotoxin, TNF-alpha, and nitric oxide may cause damage to mitochondrial electron transport, leading to disordered energy metabolism. This is called cytopathic or histotoxic anoxia, an inability to use oxygen even when present.
Apoptosis
Apoptosis (programmed cell death) is the principal mechanism by which dysfunctional cells normally are eliminated. The proinflammatory cytokines may delay apoptosis in activated macrophages and neutrophils, but other tissues, such as the gut epithelium, may undergo accelerated apoptosis. Therefore, derangement of apoptosis plays a critical role in tissue injury of patients with sepsis.
Immunosuppression
The interaction between proinflammatory and anti-inflammatory mediators may lead to an imbalance and inflammatory reaction, immunodeficiency may predominate, or both may be present.
Coagulopathy
Subclinical coagulopathy signified by mild elevation of the thrombin or activated partial thromboplastin time (aPTT) or a moderate reduction in platelet count is extremely common, but overt DIC is rare. Coagulopathy is caused by deficiencies of coagulation system proteins, including protein C, antithrombin 3, and tissue factor inhibitors.
Characteristics of sepsis that influence outcomes
Clinical characteristics that relate to the severity of sepsis include the following:
- An abnormal host response to infection
- Site and type of infection
- Timing and type of antimicrobial therapy
- Offending organism
- Development of shock
- Any underlying disease
- Patient's long-term health condition
- Location of the patient at the time of septic shock
Frequency
United States
Since the 1930s, studies have shown an increasing incidence of sepsis. In 1 study, the incidence of bacteremic sepsis (both gram-positive and gram-negative sepsis) increased from 3.8 cases per 1000 admissions in 1970 to 8.7 cases per 1000 admissions in 1987. The incidences of nosocomial blood stream infection in 1 institution from 1980-1992 increased from 6.7 to 18.4 cases per 1000 discharges. The increase in the number of patients who are immunocompromised and an increasing use of invasive diagnostic and therapeutic devices predisposing to infection are major reasons for the increase in incidences of sepsis.
The incidence of sepsis syndrome and septic shock in patients admitted to a university hospital was reportedly 13.6 and 4.6 cases per 1000 persons, respectively. In the United States, 200,000 cases of septic shock and 100,000 deaths per year occur from this disease.
A recently published article reported the incidence, cost, and outcome of severe sepsis in the United States. Analysis of a large sample from the major centres reported the incidence of severe sepsis as 3 cases per 1000 population, and 2.26 cases per 100 hospital discharges. Out of these cases, 51.1% received intensive care admission, an additional 17.3% were cared for in intermediate care or coronary care unit. Incidence ranged from 0.2 cases per 1000 admissions in children to 26.2 cases per 1000 admissions in individuals older than 85 years. The mortality rate was 28.6% and ranged from 10% in children to 38.4% in elderly people. Severe sepsis resulted in an average cost of $ 2200 per case, with an annual total cost of $16.7 billion nationally (Angus, 2001).
International
A Dutch surveillance study reported that 1.36 cases per 100 hospital admissions were secondary to severe sepsis.
Mortality/Morbidity
The mortality rate in patients with sepsis varies in the reported series from 21.6-50.8%. Over the last decade, mortality rates seem to have decreased. In some studies, the mortality rate specifically caused by the septic episode itself is specified and is 14.3-20%.
Sex
Most studies of septic shock report a male preponderance. The percentage of male patients varies from 52-66%.
Age
Sepsis and septic shock occur at all ages but most often in elderly patients. At present, most sepsis episodes are observed in patients older than 60 years. Advanced age is a risk factor for acquiring nosocomial blood stream infection in the development of severe forms of sepsis.
Treatment
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