Intensive Care Doctor-Community

Background

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 significantly over the years because sepsis and septicemia were considered to refer to a number of ill-defined clinical conditions in addition to bacteriemia. In practice, the terms were often used interchangeably; however, less than one half of the patients who have signs and symptoms of sepsis have positive blood culture results.

In the late 1960s, several reports appeared describing remote organ failure (eg, pulmonary failure, liver failure) as a complication of severe sepsis. In 1975, a classic editorial by Baue was entitled "Multiple, progressive or sequential systems failure, a syndrome of the 1970s." This concept was formulated as the basis of a new clinical syndrome. Several terms were cloned thereafter, such as multiple organ failure, multiple system organ failure, and multiple organ system failure, to describe this evolving clinical syndrome of otherwise unexplained progressive physiological failure of several interdependent organ systems. More recently, the term multiple organ dysfunction syndrome (MODS) has been proposed as a more appropriate description.

Multiorgan failure from sepsis

Sepsis is a clinical syndrome that complicates severe infection and is characterized by systemic inflammation and widespread tissue injury. In this syndrome, tissue is removed from the original insult that displayed the signs of inflammation, such as vasodilatation, increased microvascular permeability, and leukocyte accumulation. Multiple organ dysfunction is a continuum, with incremental degrees of physiological derangements in individual organs; it is 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 degree of organ dysfunction has a major clinical impact. The term MODS is defined as a clinical syndrome in which the development of progressive and potentially reversible physiological dysfunction in 2 or more organs or organ systems induced by a variety of acute insults, including sepsis, is characteristic.

In 1991, the American College of Chest Physicians/Society of Critical Care Medicine Consensus Panel developed definitions of the various stages of sepsis, which are as follows:

• Infection is a microbial phenomenon in which an inflammatory response to the presence of microorganisms or the invasion of normally sterile host tissue by these organisms is characteristic.
• Bacteremia is the presence of viable bacteria in the blood.
• Systemic inflammatory response syndrome (SIRS) may follow a variety of clinical insults, including infection, pancreatitis, ischemia, multiple trauma, tissue injury, hemorrhagic shock, or immune-mediated organ injury.
• Sepsis is a systemic response to infection. This is identical to SIRS, except that it must result from infection.
• Septic shock is sepsis with hypotension (systolic BP <90>
• MODS is the presence of altered organ function in a patient who is acutely ill such that homeostasis cannot be maintained without intervention. Primary MODS is the direct result of a well-defined insult in which organ dysfunction occurs early and can be directly attributable to the insult itself. Secondary MODS develops as a consequence of a host response and is identified within the context of SIRS. The inflammatory response of the body to toxins and other components of microorganisms causes the clinical manifestations of sepsis.

The sepsis syndrome is recognized clinically by the presence of 2 or more of the following:

• Temperature greater than 38°C or less than 36°C
• Heart rate greater than 90 beats per minute
• Respiratory rate greater than 20 breaths per minute or a PaCO2 in arterial gas less than 32 mm Hg
• WBC count greater than 12,000 cells/µL, less than 4000 cells/µL, or greater than 10% band forms

Pathophysiology

Pathogenesis

Sepsis has been referred to as a process of malignant intravascular inflammation. Normally, a potent, complex, immunologic cascade ensures a prompt protective response to microorganism invasion in humans. A deficient immunologic defense may allow infection to become established; however, an excessive or poorly regulated response may harm the host through maladaptive release of indigenously generated inflammatory compounds.

Lipid A and other bacterial products release cytokines and other immune modulators that mediate the clinical manifestations of sepsis. Interleukins, tumor necrosis factor-alpha (TNF-alpha), interferon gamma (IFN-gamma), and other colony-stimulating factors are produced rapidly within minutes or hours after interactions of monocytes and macrophages with lipid A. TNF release becomes a self-stimulating process (an autocrine), and release of other inflammatory mediators, including interleukin-1 (IL-1), platelet activating factor, IL-2, IL-6, IL-8, IL-10, INF, and eicosanoids, further increases cytokine levels. This leads to continued activation of polymorphonuclear leukocytes (PMNs), macrophages, and lymphocytes; proinflammatory mediators recruit more of these cells (a paracrine process). All of these processes create a state of destructive immunologic dissonance.

Sepsis is described as an autodestructive process that permits extension of the normal pathophysiologic response to infection to involve otherwise normal tissues and results in MODS.

Specific organ involvement

Organ dysfunction or organ failure may be the first clinical sign of sepsis, and no organ system is immune from the consequences of the inflammatory excesses of sepsis.

Circulation

Significant derangement in autoregulation of circulation is typical of 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. Also, impaired secretion of vasopressin may occur, which may permit persistence of vasodilatation.

Central circulation: Changes in both systolic and diastolic ventricular performance occur in sepsis. Through the use of the Frank Starling mechanism, cardiac output often is increased to maintain the BP 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.

Microcirculation is the key target organ for injury in sepsis syndrome. A decrease in the number of functional capillaries causes an inability to extract oxygen maximally, which is caused by intrinsic and extrinsic compression of capillaries and plugging of the capillary lumen by blood cells. Increased endothelial permeability leads to widespread tissue edema of protein-rich fluid.

In severe sepsis and septic shock, microcirculatory dysfunction and mitochondrial depression cause regional tissue distress, therefore, regional hypoxia persists. This condition is termed microcirculatory and mitochondrial distress syndrome (MMDS). Sepsis-induced inflammatory autoregulatory dysfunction persists and oxygen need is not matched by supply, leading to multiorgan system dysfunction.

Redistribution of intravascular fluid volume resulting from reduced arterial vascular tone, diminished venous return from venous dilation, and release of myocardial depressant substances causes hypotension.

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 membranes. Acute respiratory distress syndrome (ARDS) is a frequent manifestation of these effects.

Gastrointestinal dysfunction and nutrition

The GI tract may help propagate the injury of sepsis. Overgrowth of bacteria in the upper GI tract may be aspirated into the lungs, producing nosocomial pneumonia. The normal barrier function of the gut may be affected, allowing translocation of bacteria and endotoxins into the systemic circulation and extending the septic response. Septic shock usually causes ileus, and the use of narcotics and sedatives delays institution of enteral feeding. The optimal level of nutritional intake is interfered with in the face of high protein and calorie requirements.

Liver

By virtue of the role of the liver in 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 systemic circulation.

Renal dysfunction

Acute renal failure often accompanies sepsis due to acute tubular necrosis. The mechanism is by systemic hypotension, direct renal vasoconstriction, release of cytokines (eg, TNF), and activation of neutrophils by endotoxins and other peptides, which contribute to renal injury.

Central nervous system dysfunction

Involvement of the 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 sepsis are not understood fully. Multiorgan dysfunction syndrome is associated with widespread endothelial and parenchymal cell injury because of the following 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, and vasoactive substances (nitric oxide, 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 utilize oxygen even when it is present.
• Apoptosis: Apoptosis (programmed cell death) is the principal mechanism by which dysfunctional cells are eliminated normally. 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 sepsis.
• Immunosuppression: The interaction between proinflammatory and anti-inflammatory mediators may lead to an imbalance. An inflammatory reaction or immunodeficiency may predominate, or both may be present.

Coagulopathy

Subclinical coagulopathy signified by a mild elevation of the thrombin or activated partial thromboplastin time (aPTT) or a moderate reduction in platelet count is extremely common, but overt disseminated intravascular coagulation (DIC) is rare. Deficiencies of coagulation system proteins, including protein C, antithrombin 3, and tissue factor inhibitors, cause coagulopathy.

Characteristics of sepsis that influence outcomes

Clinical characteristics that relate to the severity of sepsis include an abnormal host response to infection, the site and type of infection, the timing and type of antimicrobial therapy, the offending organism, and the development of shock, underlying disease, and the patients' chronic health condition. The location of patient at the time of septic shock also relates to the severity of sepsis.

Frequency

United States

Current estimates suggest that the incidence of sepsis is greater than 500,000 cases per year. Approximately 40% of patients who are septic may develop shock. Patients who are at risk include those with positive blood cultures. Prevalence rates for SIRS of sepsis vary from 20-60%.

International

A French study in 1996 found that severe sepsis was present in 6.3% of all ICU admissions.

Mortality/Morbidity

Mortality from multiorgan dysfunction syndrome remains high. Mortality rates from ARDS alone is 40-50%. Once additional organ system dysfunction occurs, the mortality rate increases as much as 90%.

Clinical

History

Symptoms of sepsis usually are nonspecific and include fever, chills, and constitutional symptoms of fatigue, malaise, anxiety, or confusion. These symptoms are not pathognomonic for infection and may be observed in a wide variety of noninfectious inflammatory conditions. They may be absent in serious infections, especially in elderly individuals.

• Sepsis, SIRS, septic shock, and multiorgan dysfunction syndrome represent a clinical continuum. The specific features exhibited depend on where the patient's case falls on that continuum. SIRS is defined by the presence of 2 or more of the following:
  • Temperature greater than 38.0°C or less than 36.0°C
  • Heart rate greater than 90 beats per minute
  • Respiratory rate greater than 20 breaths per minute
  • WBC count greater than 12,000 cells/µL, less than 4000 cells/µL, or more than 10% bands
• Fever is a common feature of sepsis. Fever from an infectious etiology results from resetting the hypothalamus so that heat production and heat loss are balanced to maintain a higher temperature. An abrupt onset of fever usually is associated with a large infectious load.
• Chills are a secondary symptom associated with fever and result from increased muscular activity in an attempt to produce heat in order to raise the body temperature to the level required to reset the hypothalamus.
• Sweating occurs when the hypothalamus returns to its normal set point and senses that the body temperature is above the desired level. Perspiration is stimulated to evaporate and cool excess body heat.
• Alteration in mental function often is observed. Mild disorientation or confusion especially is common in elderly individuals. More severe manifestations include apprehension, anxiety, and agitation, and it may eventually lead to coma. The mechanism of alteration in mental function is not known, but altered amino acid metabolism has been proposed as one cause of metabolic encephalopathy.
• Hyperventilation with respiratory alkalosis is a common feature of sepsis. Stimulation of the medullary ventilatory center by endotoxins and other inflammatory mediators has been proposed as the cause of hyperventilation.
• The following localizing symptoms are some of the most useful clues to the etiology of both fever and sepsis:
  • Head and neck infections - Earache, sore throat, sinus pain, or swollen lymph glands
  • Chest and pulmonary infections - Cough, especially if productive; pleuritic chest pain; and dyspnea
  • Abdominal and GI infections - Abdominal pain, nausea, vomiting, and diarrhea
  • Pelvic and genitourinary infections - Pelvic or flank pain, vaginal or urethral discharge, urea, frequency, urgency
  • Bone and soft tissue infections - Focal pain or tenderness, focal erythema, edema

Physical

Physical examination notes the general condition of the patient first. Observe the overall hemodynamic condition to search for signs of hyperperfusion. Look for signs suggestive of a focal infection. An acutely ill, toxic appearance is a common feature in serious infections.

• The vital signs may suggest sepsis, even if fever is absent. As noted above, tachypnea is common; tachycardia with an increased pulse pressure also is common.
• Measure the body temperature accurately. Oral temperatures often are unreliable; obtain rectal temperatures.
• Investigate signs of systemic tissue perfusion. In the early stages of sepsis, cardiac output is well maintained or even increased. Along with vasodilatory mediators, this may result in warm skin, warm extremities, and normal capillary refill. As sepsis progresses, stroke volume and cardiac output fall. Patients begin to manifest signs of poor distal perfusion, including cool skin, cool extremities, and delayed capillary refill.
• The following physical signs suggest focal, usually bacterial, infection:
  • CNS infection - Profound depression in mental status and meningismus
  • Head and neck infections - Inflamed or swollen tympanic membranes, sinus tenderness, pharyngeal exudates, stridor, cervical lymphadenopathy
  • Chest and pulmonary infections - Localized rales or evidence of consolidation
  • Cardiac infections - Regurgitant valvular murmur
  • Abdominal and GI infections - Focal tenderness, guarding or rebound, rectal tenderness, or swelling
  • Pelvic and genitourinary infections - Costovertebral angle tenderness, pelvic tenderness, cervical motion pain, and adnexal tenderness
  • Bone and soft tissue infections - Focal erythema, edema, infusion, and tenderness
  • Skin infections - Petechiae and purpura