The Systemic Inflammatory Response Syndrome

Inflammation is good. A protective series of events, the inflammatory response is - under normal circumstances - an amazing dance. Infectious agents, external stimuli, even intrinsic disease can stimulate a cascade of events resulting in inflammation. The four signs of inflammation were recorded in Latin by Cornelius Celsus in first century Rome: Rubor (redness), calor (heat), tumor (swelling), and dolor (pain). It was understood later that the increased circulation, fever, and swelling were the results of potentially beneficial physiologic responses. In the 19th century, Rudolf Virchow added a fifth sign of inflammation: Functio laesa (loss of function), a suggestion that the temporary loss of function may be an adaptive response to limit use and allow healing.

This response is due to locally produced mediators that recruit and activate cells of the immune system (recognition, release, and recruitment). As these defenders arrive, they recruit and activate other proteins and chemical messengers. Some of these messengers are pyrogens. Others act on local vasculature, increasing circulation; the cause of redness. Circulation to the area brings oxygen, nutrients, and primarily neutrophilic cellular infiltrate. Some factors increase vascular permeability; the cause of local swelling. Increased permeability allows agents of the immune system to enter damaged tissues. As these cellular, chemical, and protein messengers stimulate the proinflammatory cascade, a simultaneous anti-inflammatory cascade acts to limit the process to the affected area. If it all works, the infection is vanquished, the damaged tissues heal, the inflammatory response is confined to the local area, and the organism survives (removal, resolution, and restoration).

When the inflammatory stimulus is extensive, or for other reasons the proinflammatory forces are not contained, this protective process can lead to systemic manifestations. When the inflammatory cascade results in systemic signs of inflammation the process is called the systemic inflammatory response syndrome (SIRS). Clinical criteria of SIRS in veterinary patients are listed in Table 1-1. SIRS can be caused by invasion of normally sterile host tissues by microorganisms. Septicemia occurs when bacteria are found in the bloodstream. When the systemic inflammatory response is associated with bacterial infection of normally sterile host tissues, the process is called sepsis. Septic shock is a state of inadequate oxygen delivery and organ dysfunction. Unlike other causes of circulatory shock, septic shock is characterized by hypotension often unresponsive to fluid and vasoactive therapies. While infection is a common cause of SIRS, there are many noninfectious causes. Any stimulus that initiates the production and release of circulating inflammatory mediators can cause systemic inflammatory changes. Examples of noninfectious causes of SIRS include pancreatitis, heat stroke, multiple trauma, rattlesnake envenomation, and neoplasia.

SIRS can occur preoperatively and may, in fact, be an indication for emergency surgery. SIRS can also result from the trauma of surgery itself. The inclusion criteria for SIRS have been criticized as being too sensitive and insufficiently specific. This is especially true in surgical patients. SIRS may also be mimicked by certain events that are commonplace in the immediate postoperative period. These signs will likely subside in the hours following surgery and are not caused by underlying physiologic derangements.

Epidemiology

In the United States it is estimated that 750,000 patients suffer annually from sepsis and septic shock. Sixty percent of people suffering from severe sepsis and septic shock will develop circulatory shock with hypotension and organ failure. Traditionally, septic shock has been closely associated with gram-negative bacteria. The incidence of gram-negative sepsis in the United States has steadily increased. The endotoxin produced by gram-negative bacteria has long been known to cause many of the signs associated with SIRS. Since the late 1980s, however, the incidence of gram-positive and fungal sepsis has increased. Reasons given for the increased incidence include an aging of the population and a rise in the incidence of geriatric diseases. With better medical care, patients live longer and succumb to the effects of chronic organ failure.

The incidence of sepsis in veterinary medicine also appears to be increasing. As in people, this may be a result of good preventative medicine and better medical care. Pets surviving into their golden years face chronic dysfunction of vital organs. When these animals present with surgical disease they may not have the physiologic reserve to mount an appropriate inflammatory response. Septicemia is found in critically ill veterinary patients. One study of 100 critically ill dogs and cats found 49 had bacteremia (positive blood cultures). Bacteremic patients in this study also had an increased mortality rate.

Patients with SIRS may experience dysfunction of one or more organ systems. This process is termed the multiple organ dysfunction syndrome (MODS). Human patients with sepsis experience dysfunction of at least one organ, with multiple organ dysfunction occurring in 30% of such patients. MODS can also be found in more than 30% of trauma patients, 24% of patients with acute pancreatitis, and 33% of burn victims. A massive inflammatory reaction resulting from systemic cytokine release is the common pathway underlying multiple organ dysfunction. Despite the availability of more potent antibiotic and sophisticated critical care, mortality rates from sepsis still range from 20% to 75%.

Pathophysiology

Several factors have been identified that increase the risk of SIRS. These include the presence of infectious diseases or debilitating conditions (trauma, neoplasia, diabetes mellitus), immunosuppression (viral diseases, chemotherapy or other immunosuppressive treatments), advanced age, and malnutrition. Invasive therapeutic and diagnostic procedures can also increase the risk of acquiring a serious infection. Indwelling vascular and urinary catheters or chest tubes can let pathogens past natural protective mechanisms. General anesthesia can depress normal defenses directly by inhibiting the reticuloendothelial system. Anesthesia can also result in systemic hypotension, further depressing host defenses. A controlled inflammatory response can increase the risk of developing an exaggerated response to a second event. Called the "two hit" phenomenon this is of particular concern to the veterinary surgeon who may unwittingly supply the second "hit" when the patient is taken to surgery.

Surgical Stress and the Neurohormonal Response

Tissue injury is injury whether the cause is the front end of an automobile or the surgeon's knife. The neurohormonal response to tissue injury begins with adrenocorticotropin release by the anterior pituitary gland. The anterior pituitary also secretes growth hormone, prolactin, and endorphin. Arginine vasopressin is released by the posterior pituitary while the adrenal gland responds with cortisol and epinephrine. This fight-or-flight response is basic to survival and results in a variety of physiologic effects including tachycardia, tachyarrhythmias, hypertension, myocardial ischemia, congestive heart failure, hypokalemia, hypomagnesemia, hyperglycemia, altered immune function, and hypercoagulability.

Biochemical Mediators of SIRS

Mediators of the inflammatory response include endotoxin, cytokines, complement, kinins, endorphins, and myocardial depressant factor. These products contribute to hemodynamic changes, cardiopulmonary dysfunction, and multiple organ dysfunction associated with SIRS. Cellular messengers initiate a complex signaling sequence involving the release of secondary mediators (Fig. 1.1). Surface receptors on macrophages recognize a variety of pathogens. While acquired immunity helps to fight a previously encountered pathogen, there are primitive, innate Toll-like receptors (TLRs) conserved across species that can also mount an immune response. Secondary mediators include platelet activating factor and metabolites of the arachidonic acid, cyclooxygenase, and lipoxygenase pathways. Induction of inducible nitric oxide synthetase, endothelial tissue factor expression, microvascular coagulation, and cell-adhesion molecule upregulation are also considered secondary events.

Figure 1.1. Intercellular Communication. Some of the cells and mediators involved in the inflammatory response. Direction of the arrow indicates which cells activate other cells of the immune system and the mediators involved. GM-CSF = Granulocyte monocyte-colony stimulating factor, IL = Interleukin, INF = Interferon, NK = Natural killer cell, PAF = Platelet activating factor, TGF = Tissue growth factor, TNF = Tumor necrosis factor.

The substance most extensively investigated has been endotoxin, the lipopolysaccharide (LPS) moiety of the gram-negative bacterial cell wall. Endotoxin is detectable in the serum of nearly half the patients with septic shock. When endotoxin is given to experimental animals or to normal human volunteers, it can produce the same cardiovascular abnormalities as those seen in human septic shock. These and other observations lent support to the hypothesis that endotoxin represented the "Final Common Pathway" of sepsis. However, recent experiments have proven that endotoxin is not essential to the development of SIRS. Studies in dogs have demonstrated that Staphylococcus aureus, an organism without endotoxin, produces the same cardiovascular abnormalities as does E. coli.

LPS is delivered to immune cells and the CD14 cell surface receptor. Acute phase proteins and specific LPS binding proteins play a roll in presenting the LPS to the macrophage. Along with a Toll-like receptor, the LPS binding to the CD14 receptor signals the activation of the nuclear transcription factor NF-Kb, a transcription factor for many of the proinflammatory cellular glycoproteins or cytokines.

Cytokines, released from activated white blood cells, include tumor necrosis factor (TNF) alpha; interleukin (IL)-1, IL-6, IL-8; and platelet activating factor (PAF) (Fig. 1.2). TNF is detectable in the serum of septic shock patients, as well as in healthy animals given endotoxin. TNF is now thought to be one of the primary mediators because the levels peak very early in sepsis and SIRS. TNF given experimentally to healthy animals produces fever, hypotension, anorexia, leukopenia, increased capillary permeability, and granulocyte colony-stimulating factor release.

Figure 1.2. Pro- and anti-inflammatory cytokine interactions. Arrow direction indicates which cytokines activate (in proinflammatory cascade) or inhibit (in the anti-inflammatory cascade) other cytokines. Dashed lines indicate stimulating and suppressing functions. GM-CSF = Granulocyte monocyte-colony stimulating factor, IL = Interleukin, INF = Interferon, PAF = Platelet activating factor, TGF = Tissue growth factor, TNF = Tumor necrosis factor.

Resolution occurs when soluble receptors contain TNF, and IL-1 or specific anti-inflammatory cytokines (IL-4, IL-10, IL-11, IL-13, and some of the colony-stimulating factors) counteract the effects of proinflammatory cytokines (Fig. 1.2). Other mechanisms include an intracellular suppressor of cytokine signaling and elimination of circulating cytokines through normal systemic metabolic pathways.

Clinical Features

SIRS becomes detrimental with arterial hypotension and evidence of inadequate perfusion in the setting of a systemic insult. Patients with SIRS experience three types of circulatory shock. Hypovolemia as a result of increased vascular permeability and fluid loss into the tissues, distributive shock because of inappropriate vasodilatation and shunting of blood from vital areas, and a cardiogenic component due to depressed cardiac function. Many features, such as tachycardia, depressed mentation, and oliguria, are nonspecific: presentations vary from hypothermia with cold extremities and weak pulses to hyperthermia with warm extremities and bounding pulses. Cardiovascular instability may last from hours to days, but typically it will respond to therapy within 1 to 4 days in patients destined to survive the acute phase of the illness. An early change in septic shock and uncompensated SIRS is altered blood flow regulation. The coagulation cascade may also play a role in this response. Overexpression of proinflammatory cytokines is thought to upset the balance toward procoagulation. Decreased circulating levels of protein C and antithrombin are found in patients with severe sepsis and septic shock. Capillaries become blocked with activated white blood cells and microthrombi. Systemic release of inflammatory mediators also contributes to inappropriate shunting of blood around important vascular beds. Many systems are affected, and signs of progressive multiple organ system dysfunction may begin to appear.

Diagnosis

Suspicion of infectious causes of SIRS requires that diagnostic material be collected early while appropriate therapy and monitoring are instituted. SIRS is not a diagnosis but a syndrome with multiple causes. Possible causes must be excluded through history, physical examination, and diagnostic testing. Patients should be expected to do better if the source of the inflammation can be quickly identified and removed or drained. This means surgical disease should be ruled out first. Imaging of the abdomen may reveal mass lesions, organomegally, or local fluid accumulation. Loss of abdominal detail on plain radiographs would suggest abdominal fluid. Ultrasound may be more sensitive for abnormal fluid and useful for sampling. Radiographs of the chest and echocardiography help to evaluate the heart and lungs. When fluid is suspected in the chest or abdomen, sterile collection (either thoracocentesis, abdominocentesis, or diagnostic peritoneal lavage) for fluid analysis should be performed. It should be noted that abdominocentesis alone is relatively insensitive and a diagnostic peritoneal lavage with 10 to 20 ml/kg of sterile physiologic crystalloid fluid can increase sensitivity. Nonsurgical infectious and noninfectious causes of SIRS require intensive reassessment of therapy. Where (as with bacterial culture) a positive diagnosis may take days, therapy should be directed at likely pathogens. Areas of particular concern include the urinary tract, reproductive tract, abdominal cavity, respiratory tract, teeth and gums, and the heart valves. A thorough physical examination is performed with attention to oral examination, cardiac and thoracic auscultation, and abdominal palpation. Blood samples are drawn for CBC, serum biochemical profile, coagulation testing, rickettsial, fungal, and immune testing if indicated. Urine is collected for analysis and culture. Blood cultures should be taken from the jugular vein after surgically preparing the skin. Because blood cultures can have a relatively low yield, multiple samples should be taken 15 minutes to 1 hour apart, ideally during peak rises in body temperature. Antibiotic administration should be withheld until samples are collected but no significant delay should occur in starting therapy. If interstitial changes in the lung fields and clinical findings support possible pulmonary disease, bronchoscopy or a transtracheal wash may provide samples for a diagnosis.

Treatment/Monitoring

Standard sepsis treatment strategies include volume support to maintain cardiac output, the use of antibiotics to kill invading bacteria, surgical procedures to eradicate the nidus of infection, and intensive life-support procedures such as dialysis, mechanical ventilation, and the use of vasoactive drugs. Despite these approaches the mortality rate from septic shock is high, ranging from 25% to 75%. In addition, the incidence of sepsis syndrome in hospitals in the United States increased 139% between 1979 and 1987. This increase may be caused by several medical trends: improved life-support technology that keeps patients who have a high risk for infection alive at the extremes of age; increased use of invasive medical procedures; advances in cancer chemotherapy and immunotherapy; and the prevalence of acquired immunodeficiency syndrome. The increasing incidence of sepsis and its high mortality rate have charged the search for additional therapies.

Advances in cytokine biology have stimulated research to mitigate the biologic activity of cytokines on target cells. Binding cytokines with neutralizing molecules in circulation and blocking the interaction between cytokines and their cell-surface receptors in the target tissues are the two strategies employed. Repeating experiments performed on anti-endotoxin antibody, researchers used anti-TNF antibodies with significant success in protecting mice against lethal doses of endotoxin. However to date no convincing studies exist that anti-TNF antibodies are effective in clinical SIRS. The same can be said for similar work with other proinflammatory cytokines. All of these studies have failed to take into account the natural anti-inflammatory counterpart to these cytokines and other mediators. Interleukin-4, 10, 11, and 13 as well as the colony-stimulating factors and natural receptor antagonists are induced by TNF, IL-1, and other proinflammatory compounds. These anti-inflammatory mediators suppress many of the inflammatory effects of TNF and cytokines. New therapies for sepsis and SIRS should be directed at restoring homeostasis and not simply suppressing inflammation.

The management of patients with life-threatening infections and systemic inflammation still largely consists of hemodynamic and pulmonary support, appropriate antibiotics, and timely surgical intervention. Despite the exponential growth in our understanding of the basic biology of inflammation, our arsenal does not yet include a magic bullet to normalize the mediators of the proinflammatory and anti-inflammatory response.