SIRS, sepsis, and multiple organ dysfunction syndrome demystified (Proceedings)

According to Webster's dictionary, inflammation is defined as "a local response to cellular injury that is marked by capillary dilatation, leukocytic infiltration, redness, heat, and pain and that serves as a mechanism initiating the elimination of noxious agents and of damaged tissue." Based upon this definition, inflammation is a good thing and is necessary for the body to heal from injury. Unfortunately, if inflammation goes unchecked and spirals out of control, it can be damaging and lead to increased morbidity and mortality. It is the purpose of these proceedings to demystify how such a good thing can become so bad.

In general, when an injury happens, local inflammation occurs in order to rid the body of the injury and allow repair to start happening. The body has natural anti-inflammatory mechanisms that keeps this proinflammatory stage in check and prevents it from going out of control. Recall that the components of inflammation release noxious substances in order to kill or remove damaged tissue. When inflammation spirals out of control, the release of an overwhelming number of noxious substances may cause normal, healthy tissue to be damaged. This newly damaged tissue can induce more inflammation and a vicious cycle begins. Occasionally, the inflammation is overwhelming to the point that the anti-inflammatory systems in the body can no longer keep things under control. This occurs more frequently if the injury/inflammation is ongoing, if there are new insults to the body (such as hypoxia, surgery), or if the immune system is compromised (such as with immune mediated diseases). Activated neutrophils can then travel to other parts of the body and accumulate in organs. In essence, the whole body starts to become inflamed and normal tissue, even at distant sites from the original injury, are targeted and destroyed. This out-of-control inflammation causes clinical signs that can be observed and has been given the term the systemic inflammatory response syndrome (SIRS).

When SIRS occurs, the body responds in various ways to the excess release of cytokines, or hypercytokinemia, that is occurring in the body. Most cytokines are released from activated monocytes, macrophages, and neutrophils. Thermoregulation, heart rate, respiratory rate, and white blood cell counts frequently become altered. Pyrexia occurs due to release of the cytokines interleukin-1 (IL-1), and IL-6. Tachycardia and tachypnea are stimulated by IL-1 and tumor necrosis factor (TNF)-α. Leukocytosis can occur due to granulocyte colony stimulating factor, granulocyte monocyte stimulating factor, and IL-6. In addition, the circulating cytokines further activate neutrophils, which can result in end-organ damage. Because of these systemic responses that occur due to the excessive inflammation, SIRS can be defined when certain clinical criteria are met. In veterinary medicine, these clinical criteria for SIRS are based upon an adaptation of 1991 human SIRS criteria. In order to meet SIRS criteria, a dog must have two or more of the following:

     • Tachycardia (HR > 120 bpm)

     • Tachypnea (RR > 20 bpm)

     • Fever (> 104.0°F) or Hypothermia (<100.4°F)

     • Leukopenia (<5,000 WBC/μL) or Leukocytosis (>18,000 WBC/μL)

Unfortunately, depending on the criteria used, the sensitivity is only 77-97% and the specificity is only 64-77% in dogs meeting SIRS criteria. There are some sources that argue that tachypnea in the dog should be considered at a RR > 40 bpm and/or a PaCO2 < 30 mmHg, instead of 20 bpm. The reasoning behind this is that many dogs have a normal respiratory rate up to 30 bpm, so making the SIRS criteria more stringent would make the likelihood of diagnosing SIRS a lot greater. Additionally, some clinicians consider using three out of four criteria necessary to diagnose SIRS. SIRS criteria in the cat are slightly different than the dog and the cat must have two or more of the following in order to meet SIRS criteria:

     • Bradycardia (HR < 140 bpm) or Tachycardia (HR > 225 bpm)

     • Tachypnea (RR > 40 bpm)

     • Fever (> 104.0°F) or Hypothermia (<100.0°F)

     • Leukopenia (<5,000 WBC/μL) or Leukocytosis (>19,000 WBC/μL)

Some sources indicate that greater than 5 or 10% bands should also be considered one of the criteria for SIRS.

Due to the lack of sensitivity and specificity for the SIRS criteria that were created in 1991, the human medical field has attempted to expand the classification scheme in order to better identify septic patients. This new scheme uses the old SIRS criteria plus other physical parameters and biomarkers in order to identify septic patients. This has lead to the 2001 PIRO classification as a model of recognizing sepsis. PIRO stands for Predisposition, Insult, Response, and Organ dysfunction. Predisposition may include genetic factors, age, concurrent conditions, or gender. Insult may include the type of bacteria, the extent of infection, and location of infection. Response uses biomarkers to look for evidence of things like excessive proinflammation, hypoinflammatory states, adrenal dysfunction, and coagulation abnormalities. Organ dysfunction would include things such as renal failure and the acute respiratory distress syndrome. Further studies in both human and veterinary medicine need to be performed in order to determine the ultimate usefulness of the PIRO classification scheme.

So, why is it important to be able to identify a patient that is in SIRS? It is important because SIRS is frequently associated with sepsis. In people, severe sepsis is the 3rd leading cause of death, with a mortality rate between 28-50% or greater. If sepsis can be recognized in its early stages, there is a higher probability of being able to save that patient. However, once sepsis leads to septic shock and multiple organ failure, the mortality rate skyrockets. Therefore, it is necessary to be able to recognize sepsis/SIRS in the early stages. Before proceeding, a few terms need to be defined. These terms are from the ACCP/SCCM Consensus Conference Definitions:

     1. Sepsis: The systemic inflammatory response (SIRS) to a documented infection.

     2. Severe sepsis/SIRS: Sepsis (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.

     3. Sepsis (SIRS)-induced hypotension: A systolic blood pressure <90 mmHg or a reduction of ≥ 40 mmHg from baseline in the absence of other causes for hypotension.

     4. Septic shock/SIRS shock: A subset of severe sepsis (SIRS) and defined as sepsis (SIRS) induced hypotension despite adequate fluid resuscitation along with the presence of perfusion abnormalities that may include, but are not limited to, lactic acidosis, oliguria, or an acute alteration in mental status.

     5. Multiple organ dysfunction syndrome (MODS): Presence of altered organ function in an acutely ill patient such that homeostasis cannot be maintained without intervention.

Based upon these definitions, sepsis is SIRS with infection. It is important to realize that in certain situations, SIRS itself can lead to shock and MODS, without infection being present. The most common causes of SIRS-related shock and MODS are pancreatitis, trauma, and burns.

Once sepsis occurs, the body either heals or it ultimately dies. The septic process has been grouped into 5 different stages by Bone, et. al. The first stage is the establishment of infection. This is the stage where the infection sets up the initial inflammation and cytokine release. The body quickly begins regulating the proinflammatory mediators with the compensatory anti-inflammatory response, in order to prevent excessive cytokine release and inflammation. Stage 2 is the preliminary systemic response. This is an indication that the infection has not been able to be maintained at a local level. Fever is the most consistent systemic response at this stage. The 3rd stage is an overwhelming systemic response. This is caused by excessive release of proinflammatory cytokines and mediators that produce the clinical syndrome of SIRS: tachycardia (or bradycardia in the cat), tachypnea, pyrexia or hypothermia, and leukocytosis, leukopenia, or a significant left shift. Stage 4 is the compensatory anti-inflammatory reaction. This is when the body tries to down-regulate the proinflammatory mediators and many of the signs of sepsis resolve. However, if this anti-inflammatory reaction goes too far, a syndrome called compensatory anti-inflammatory response syndrome (CARS) occurs. This essentially causes the immune system to become paralyzed and potentially allows the initial infection to spiral out of control or allows for superinfection to set in. The 5th and last stage is immunomodulatory failure. This is a failure of the immune system to return to a healthy homeostasis. Monocytes become deactivated and can no longer respond, the infection progresses, organ failure ensues, and death occurs.

In sepsis, the presence of multiple organ dysfunction is a very bad prognostic indicator. MODS is frequently the beginning of the end and it is not uncommon for a patient that develops MODS to die. The more organs that are dysfunctioning, the higher the mortality rate. MODS is a multifactorial syndrome that is a result of many insults and injuries that have occurred throughout the body secondary to SIRS or sepsis. One of the major causes of MODS is the damage that is occurring to the endothelial cells secondary to the overwhelming proinflammatory cytokines. When endothelial cells are damaged, it exposes substances that activate the clotting cascade. Therefore, platelets aggregate, the secondary hemostatic pathways are stimulated, clots form, and clots are then ultimately broken down. When there is an overabundance of clotting happening, thrombosis occurs and clotting factors are used up. Once a significant number of clotting factors are used up, bleeding can occur. This unbalance of clotting and bleeding is the concept behind disseminated intravascular coagulation (DIC). Microthrombosis from excessive clotting can lead to local tissue hypoxia and death, leading to more inflammation. It is ultimately this dysfunction in the coagulation system (coagulation activation, abnormalities in fibrinolysis, and microcirculatory thrombosis), in addition to bacterial factors and excessive inflammatory mediators that leads to organ death. If excessive organ death occurs, then the whole body is unable to function, and death of the animal occurs.

Clinically, most septic patients go through a hyperdynamic phase and then a hypodynamic phase. During the hyperdynamic phase, the patient will have a fever, brick red mucous membranes, a quick capillary refill time (CRT), bounding pulses, tachypnea, and tachycardia. During the hypodynamic phase, the patient will be hypothermic, have pale/white mucous membranes, have a prolonged CRT, be tachypneic, tachycardic (or bradycardic in the cat), and have refractory hypotension. It is important to note that myocardial depression occurs during all stages of sepsis.

Diagnostics that should be performed in SIRS/Sepsis patients include: CBC, Chemistry, UA + culture (pre-fluids if possible), PCV/TP, Glucose, Lactate, Acid-base status, Oxygenation/Ventilation status, Blood smear, and Coagulation profile (PT, PTT, D-dimers, FDP's, Antithrombin). If sepsis is suspected, then diagnostic tests need to be performed to search for a source of infection. These tests may include: Chest/Abdominal radiographs, abdominal ultrasound, abdominocentesis/DPL, cultures (urine, blood, effusions, transtracheal washes, aspirates, wounds), spinal radiographs, CSF tap, joint taps, and infectious disease testing (rickettsial, protozoal, viral, fungal).

Monitoring and treatment is intense in these patients and experienced nursing care is a must. Frequently these patients need aggressive fluid therapy, oxygen, possibly ventilation, pharmacologic blood pressure support, central venous pressure monitoring, direct arterial blood pressure monitoring, frequent blood gas analysis, blood products, and intravenous or enteral nutrition. Many of these animals are non-ambulatory, so bladder/urinary care, colon care, passive range of motion, oral care, and prevention of pressure sores is absolutely necessary. Since these patients are so dynamic, experienced personnel are needed in order to recognize sudden, frequent changes in an animal's status.

SIRS, sepsis, and MODS are all very serious syndromes and can quickly lead to patient death if clinical signs go unrecognized. Understanding the pathophysiology and consequences of these syndromes is imperative to understanding why early recognition of clinical signs is so important. Although early recognition and goal directed therapy may lead to more positive outcomes, the survival outcome of septic patients remains poor.

References

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Brady C, Otto C, Van Winkle T, et al: Severe sepsis in cats: A retrospective study of 29 cases (1986-1998). JAVMA 2000;217:531-535.

Bone RC, Balk RA, Cerra FB, et al. American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference: definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Chest 1992;101:1644-55.

Balk RA, Ely, WE, Goyette RE. Sepsis Handbook, 2nd ed. Thomson Advanced Therapeutics Communications and Vanderbilt University School of Medicine; 2004.

Dellinger RP, Carlet JM, Masur H, et al. Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock. Critical Care Medicine 2004;32:858-73.

Okano S, Yoshida M, Fukushima, et al. Usefulness of systemic inflammatory response syndrome criteria as an index for prognosis judgement. Veterinary Record 2002;150:245-246.