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Septic shock
Incidence
Septic shock is a form of acute circulatory shock that occurs secondary to severe infection. The incidence of septic shock may be rising, partly related to medical progress that allows individuals to survive longer, resulting in increased numbers of older, debilitated, or immunocompromised patients passing through the intensive care unit (ICU). Some 15% of ICU patients develop septic shock at one time or another, and the mortality rate is 40%–50%. , Somewhat lower mortality rates have been reported in some trials evaluating the effects of new therapeutic interventions, but such studies include a number of exclusion criteria that are often associated with high mortality rates—cirrhosis, immunosuppression, and “do-not-resuscitate orders,” for example—so it is perhaps not surprising that mortality rates are lower in these therapeutic trials than in “real life.”
Etiology of septic shock
Septic shock is most often bacterial, but it can also be caused by a fungal, parasitic, or viral infection. In one-third of patients, no infectious agent is identified. About half of the infections are nosocomial in origin. Although an infection can originate anywhere, the lung is the most common source of infection (40%), followed by the abdomen (20%), indwelling venous and arterial catheters and primary bacteremias (15%), and the urinary tract (10%).
Pathophysiology of septic shock
The pathophysiology of septic shock is complex. Essentially, the systemic sepsis response starts with the body’s recognition of an invading organism or its toxins. Among the bacterial factors, one of the best known toxins is lipopolysaccharide, which is part of the outer gram-negative bacterial membrane, but other bacteria-derived factors include lipoteichoic acid and peptidoglycan. In certain cases, especially infections involving Staphylococcus aureus or beta-hemolytic group A streptococcus, the formation of superantigens results in toxic shock syndrome.
The early humoral response involves the complement and contact (kinin-kallikrein) systems. Immune cells, principally monocytes/macrophages and polymorphonuclear neutrophils (PMNs), are not only able to recognize pathogenic agents and their products so they can phagocytose and destroy them but also to release a series of mediators that can activate other cells. Among cell membrane receptors implicated in the recognition of pathogenic agents are the Toll-like receptors. In response to cellular stimulation, intracellular signaling is activated, resulting largely in the activation of transcriptional factors, including nuclear factor kappa B, which in turn are responsible for the initiation of proinflammatory reactions. A number of cytokines that interact synergistically are released by macrophages and other cells. Two of the key players are tumor necrosis factor alpha (TNF-α) and interleukin (IL)-1. TNF-α and IL-1 are particularly important proinflammatory cytokines whose administration in animals can reproduce all features of septic shock, including hypotension and development of multiple organ failure. A host of secondary mediators, including lipid mediators, oxygen free radicals, proteases, and arachidonic acid metabolites, are also released by macrophages, PMNs, and other cells. Vasodilator substances such as nitric oxide (NO) and prostaglandins are released by endothelial cells and are responsible for the early hemodynamic changes of sepsis. NO, in particular, acts as a powerful vasodilator on vascular smooth muscle. Increased NO production is essentially the result of the induction of inducible NO synthase by proinflammatory cytokines. The formation of large quantities of NO can also have secondary toxic effects on cells. It is important to note that the inflammatory response also causes release of vasoconstrictor substances, including thromboxane and endothelins.
Other effects of the inflammatory reaction that accompanies septic shock include expression of adhesion molecules on vascular endothelium and circulating cells (platelets, PMNs, and monocytes), allowing adhesion of activated leukocytes and their migration to subendothelial tissues. Alterations in intercellular endothelial junctions result in increased capillary permeability and generalized edema. Alterations in coagulation and fibrinolysis complete the picture, with proinflammatory mediators creating a procoagulant state. In addition, sepsis causes a significant reduction in plasma levels of natural anticoagulants such as protein C, protein S, and antithrombin by reducing their synthesis and increasing their consumption and clearance. Thrombolysis is also stimulated with an increase in the levels of plasminogen activator inhibitor-1. The net result is a balance that favors procoagulant processes, often leading to disseminated intravascular coagulation and contributing to the microcirculatory disorder that leads to multiple organ failure and death in many patients with sepsis. Antiinflammatory mediators including IL-4 and IL-10 are also released, which limit the effects of proinflammatory mediators and can lead to a state of relative immunosuppression sometimes called immunoparalysis . Many patients are already immunosuppressed when sepsis is diagnosed.
Classification
Patients with septic shock may be classified according to the letters PIRO :
P = Predisposing factors
Each patient has specific characteristics. For example, an individual receiving long-term immunosuppressant therapy requires a different approach than someone who was previously healthy. Factors associated with lifestyle, such as alcoholism, may influence the course of septic shock. Patient age and gender may also be important. Increasingly, genetics is being considered, and studies are discovering the genetic factors that can influence the development of and survival from sepsis. Improved understanding of these aspects should help better direct therapeutic strategies.
I = Infectious insult
This refers to the specific characteristics of the infection, that is, the agent or pathogen involved (e.g., gram-positive vs. gram-negative, bacteria vs. virus or fungus), the source of sepsis (e.g., urinary tract vs. respiratory tract), and the degree of extension of the infection (e.g., pneumonia confined to one lobe of one lung vs. generalized bilateral lung involvement, appendicitis vs. generalized peritonitis). All of these factors can influence the severity of sepsis response and the patient’s likely response to therapy.
R = Host response
This refers to factors involved in the inflammatory response of the host to the infection and is assessed largely by the presence or absence of the signs and symptoms of sepsis (e.g., degree of elevation of white blood cell count, C-reactive protein [CRP], or procalcitonin). Each patient mounts a different response dependent on various factors, including those previously discussed, and a patient’s response will vary with his or her clinical course and treatment.
O = Organ dysfunction
This refers to the degree of organ dysfunction related to sepsis and can be evaluated using the Sequential Organ Failure Assessment (SOFA) score, which uses objective, readily available measures to quantify the dysfunction of six organ systems ( Table 112.1 ). Dysfunction of each organ is rated according to a scale (0 [normal function] to 4 [organ failure]), and individual scores can then be summed to provide a total. Individual organ function and a composite score can thus be followed during the course of the disease and treatment.
TABLE 112.1
The Sequential Organ Failure Assessment Score
From Vincent JL, de Mendonca A, Cantraine F, et al. Use of the SOFA score to assess the incidence of organ dysfunction/failure in intensive care units. Results of a multicenter, prospective study. Crit Care Med. 1988;26:1793–1800.
| SOFA Score | 0 | 1 | 2 | 3 | 4 |
|---|---|---|---|---|---|
| Respiration | |||||
| PaO 2 /FiO 2 , mm Hg | >400 | ≤400 | ≤300 | ≤200 with respiratory support | ≤100 with respiratory support |
| Coagulation | |||||
| Platelets × 10 3 /mm 3 | >150 | ≤150 | ≤100 | ≤50 | ≤20 |
| Liver | |||||
| Bilirubin, mg/dL (μmol/L) | <1.2 (<20) | 1.2–1.9 (20–32) | 2.0–5.9 (33–101) | 6.0–11.9 (102–204) | >12.0 (>204) |
| Cardiovascular | |||||
| Hypotension | No hypotension | MAP <70 mm Hg | Dopamine ≤5 or dobutamine (any dose) * | Dopamine >5 or epinephrine ≤0.1 or norepinephrine ≤0.1 * | Dopamine >15 or epinephrine >0.1 or norepinephrine >0.1 * |
| Central Nervous System | |||||
| Glasgow Coma Score | 15 | 13–14 | 10–12 | 6–9 | <6 |
| Renal | |||||
| Creatinine, mg/dL (μmol/L) or urine output | <1.2 (<110) | 1.2–1.9 (110–170) | 2.0–3.4 (171–299) | 3.5–4.9 (300–440) or <500 mL/d | >5.0 (>440) or <200 mL/d |
* Adrenergic agents administered for at least 1 hour (doses given are in μg/kg/min).
Clinical presentation
It has been suggested that sepsis progresses in a continuum through to septic shock, but in the clinical situation, such a progression is not always so clear-cut or constant, and it is difficult to predict which patients are going to develop septic shock and when. Septic shock can develop very abruptly, without evidence of signs of sepsis in the preceding hours.
Septic shock is characterized by the persistence of severe arterial hypotension requiring vasopressor support, despite adequate fluid resuscitation, and the presence of perfusion abnormalities manifested by oliguria, reduced peripheral perfusion, and altered mental status. Septic shock is typically associated with hyperlactatemia (blood lactate concentrations greater than 2 mEq/L).
One may anticipate that patients with septic shock will have fever, leukocytosis, and other typical features of sepsis, but this is not always true. Fever may be an important clue, but moderate fever can be found in other types of shock as well. More importantly, fever is often absent in patients with septic shock; in fact, hypothermia may be present in 10%–15% of cases, and this feature is associated with higher mortality rates. Tachycardia can be the result of circulatory alterations associated with any type of shock. Leukocytosis is also nonspecific and can be found in other types of circulatory failure; moreover, acute leukopenia may occur in sepsis because of peripheral trapping of activated leukocytes and is also associated with a worse prognosis. Lactic acidosis, a hallmark of all types of circulatory failure, is usually compensated for by hyperventilation, so tachypnea is not specific for septic shock.
A more typical characteristic of septic shock is the hyperkinetic pattern characterized by high cardiac output. Although such a hemodynamic pattern is not entirely specific—it can be found in other inflammatory states such as polytrauma, pancreatitis, or even anaphylactic shock—it should alert the attending physician to a likely diagnosis of septic shock.
Hemodynamic changes
The inflammatory reaction causes intense vasodilation that increases vascular capacity and results in a fall in arterial blood pressure. Hypovolemia caused by fluid loss (e.g., diarrhea, vomiting, or sweating) and alterations in capillary permeability contribute to hypotension, and reduced myocardial contractility can further aggravate the hemodynamic situation, although it is completely reversible when the septic shock resolves. The pathophysiology of reduced myocardial contractility includes alterations in endothelial function, beta-adrenergic receptors, and myocardial calcium metabolism. These effects are caused largely by sepsis mediators such as TNF-α and IL-1, oxygen free radicals, platelet activating factor, and NO, which all have negative inotropic effects.
After vascular filling as a result of volume resuscitation, the hemodynamic status in septic shock is characterized by reduced vascular tone associated with reduced systemic vascular resistance and a raised cardiac output. In addition, impaired myocardial contractility causes a fall in the ventricular ejection fraction. Ejection volume and cardiac output may be maintained by an increase in diastolic volumes. Hence, there is myocardial depression or dysfunction without any true cardiac failure (which would be associated with reduced cardiac output).
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