Systemic inflammation is the common pathway by which severe illness and injury can lead to organ dysfunction and death. It is extremely common in our patients and an understanding of the causes and pathophysiology of this response will improve management and hopefully survival of these patients.

Systemic Inflammation

The systemic inflammatory response syndrome (SIRS) occurs when there is release of inflammatory mediators into the systemic circulation. These trigger the clinical signs that are described in Table 1. The systemic inflammatory response occurs when a local site of inflammation is severe enough to allow 'overflow' of mediators into the circulation instead of restricting them to the region of injured tissue only. Systemic release of mediators can also occur in response to a systemic insult such as bacteremia or endotoxemia.

Systemic circulation of inflammatory mediators results in numerous global abnormalities that, if severe enough, can have life threatening consequences. Pathologic effects of inflammatory mediators include:

 Increased capillary permeability

 Vasodilation

 Activation of white blood cells

 Activation of coagulation

 Myocardial dysfunction

 Mitochondrial dysfunction

The consequences of these effects can include:

 Hypovolemia

 Hypotension

 Decreased oxygen delivery to the tissues

 Interstitial edema

 Disseminated intravascular coagulation

 Indiscriminate cell damage

 Global cellular/organ dysfunction

The magnitude of SIRS varies from mild to severe; in general mild to moderate SIRS is a normal and beneficial response to a significant insult. It is vital for immunocompetency and without it there is increased morbidity and mortality. A severe or over exuberant SIRS response may be detrimental causing cellular dysfunction and tissue damage that is more significant than the primary insult itself.

Table 1. Clinical recognition of SIRS.

*Brady CA et al. JAVMA 2000;217(4):531-535

The major causes of SIRS are infection, trauma, pancreatitis, burn injury, neoplasia and immune reactions. Effectively any insult that leads to cell damage will produce an inflammatory response and has the potential to cause SIRS. It is important to note that although infection is a common cause of SIRS it is not the only cause.

Sepsis

Sepsis refers to a specific subset of SIRS patients that are believed to have an infection as the primary disease process.

Multiple Organ Dysfunction Syndrome

Mortality from severe SIRS or sepsis occurs as a result of acquired, progressive abnormalities in organ function, a process known as multiple organ dysfunction syndrome (MODS). The cause of MODS is not fully understood at this time but is believed to be the result of many different effects of circulating inflammatory mediators as described above. This syndrome is characterized by abnormalities developing in organs that were not affected by the original insult and is associated with high morbidity and mortality rates. Clinical management of severe SIRS/septic patients is complex and challenging. It requires initial identification of at risk animals, intense monitoring and nursing care and aggressive management of any abnormalities that develop.

Organ systems at risk of dysfunction in severe SIRS/sepsis:

 Pulmonary

 Acute, severe hypoxemia (acute respiratory distress syndrome)

 Cardiovascular

 Hypovolemia

 Hypotension

 Arrhythmias

 Renal

 Acute renal failure (oliguria, anuria, hyperkalemia, azotemia)

 Hematological

 White blood cells (leukocytosis, leukopenia)

 Thrombocytopenia

 Disseminated intravascular coagulation (prolonged bleeding times, schistocytes, low fibrinogen, thrombocytopenia, elevated fibrin(ogen) degradation products

 Gastrointestinal

 Ileus

 Bacterial translocation

 Lack of nutrition

 Blood glucose

 Hypoglycemia

At Risk Patients

The severity of SIRS and likelihood of the development of MODS is variable. The factors contributing to the severity of sepsis include the virulence and magnitude of the injury or infection, the degree of associated tissue injury, the age and concurrent diseases of the patient and the animal's genetic makeup. An important aspect of critical care medicine is the identification of 'at risk' patients. Intensive monitoring and aggressive supportive care is the corner stone of management for these animals.

Some disease processes are well recognized to be severe and often life threatening. These would include septic peritonitis, pancreatitis, severe aspiration pneumonia, endocarditis and massive trauma. Such patients should receive aggressive initial resuscitation as any period of hypoperfusion will worsen the inflammatory insult. Intensive monitoring and supportive care is indicated in these patients. In patients with less severe disease processes there should be regular re-evaluation. If at any time they appear to be developing SIRS or MODS their level of care should be increased accordingly.

Monitoring

The frequency at which monitoring is performed depends on the severity of the patient illness, the availability of equipment and staff and the owner's financial commitment. The frequency recommended below is for a severely ill patient, this can be modified in less compromised patients.

 Physical examination (4 x daily)

 Arterial blood pressure measurement (continuous/hourly)

 Body weight (3 x daily)

 Continuous ECG

 Temperature (continuous/every 2 hours)

 Central venous pressure (continuous/hourly)

 Urine output with urinary catheter and closed collection system (every 2-4 hours)

 Pulse oximetry (every 4 hours)

 Blood glucose, venous blood gases, lactate and electrolytes (every 4 hours)

 Packed cell volume, total protein every 8 hours

 Complete blood count / hemogram--daily

 Coagulation screen--daily

 Biochemistry profile--every 2 days

 Thoracic radiographs--initially and at any sign of respiratory distress

Treatment

The most important aspect of therapy is resolution of the primary disease which is causing the systemic inflammation. This includes surgical removal of necrotic tissue, surgical excision of a septic focus, lavage of infected tissues, etc.

Antibiotic Therapy

If a septic process is suspected early, appropriate antibiotic therapy is essential. Empirical intravenous broad spectrum, bacteriocidal antibiotics are indicated with gram-positive, gram-negative and anaerobic coverage until such time that culture and sensitivity results can guide the treatment more specifically. If a primary infectious process is not evident, broad spectrum antibiotic therapy may still be indicated if there is any concern of compromised gastrointestinal barrier function and bacterial translocation. Most severely ill patients have poor gastrointestinal perfusion and systemic inflammation that will place them at high risk of bacterial translocation.

Corticosteroids

In experimental studies, corticosteroids have been shown to have numerous beneficial effects including anti-inflammatory activity, improved membrane stability, improved microcirculation and enhancement of gluconeogenesis. In many of the studies that reported these beneficial effects in patients with circulatory shock and sepsis, very high doses of corticosteroids were administered prior to or at the time of the insult. Early administration of short courses of high dose steroids was found to decrease survival during sepsis in human clinical trials. The adverse effects of corticosteroids are well documented including increased susceptibility to infection, especially pneumonia, gastrointestinal hemorrhage and hyperglycemia. Currently corticosteroid administration is not recommended in septic patients.

Physiological doses of hydrocortisone may be indicated in the treatment of catecholamine resistant septic shock. Benefits of this therapy have been demonstrated in human medicine but are yet to be evaluated in veterinary medicine.

Supportive Care

Intravenous fluid therapy is essential to maintain tissue perfusion. Any evidence of hypoperfusion requires rapid intervention. Initially it is important to restore blood volume. Hypovolemia may be evidenced by vasoconstriction and a low or normal central venous pressure (-5 to +4 cm H₂O). Often it is very difficult to determine if the animal's blood volume is adequate or not, so a 'test' fluid bolus is commonly given. This can be an isotonic crystalloid (20 ml/kg) or a colloid (5 ml/kg). If there is an improvement in cardiovascular parameters as a result, further fluid administration may be indicated.

Patients with hypotension despite aggressive fluid resuscitation require a vasopressor with α-adrenergic effects; dopamine is a popular choice. Norepinephrine is a more potent α receptor agonist for patients that do not respond adequately to dopamine. If there is evidence of decreased cardiac contractility (echocardiography) a positive inotrope such as dobutamine may also be indicated.

Oxygen therapy is indicated for any animal with evidence of reduced pulmonary function. As long term, high levels of oxygen therapy can have detrimental effects, the fraction of inspired oxygen (F_IO₂) should be titrated to the lowest level required to prevent the patient from being hypoxemic; that is to maintain 80 mm Hg < PaO₂ < 120 mm Hg or SpO₂ > 95%. When animals have severe hypoxemia (PaO₂ <60 mm Hg, SpO₂ < 90%) despite oxygen therapy, require high levels of oxygen (>60%) for more than 1-2 days or have excessive respiratory effort despite oxygen therapy, they are candidates for mechanical ventilation.

Any other abnormalities noted from the monitoring listed above should be treated appropriately. Intensive nursing care is essential for successful management of these cases.

References

1.  Dellinger RP, et al. Surviving sepsis campaign guidelines for management of severe sepsis and septic shock. Criti Care Med 2004;32:858-873

2.  De Laforcade AM. Systemic inflammatory response syndrome. In: Silverstein DC, Hopper K (eds). Textbook of small animal critical care medicine, Saunders, St Louis, 2009, p46

3.  Fenton KE, Parker MM. Severe sepsis: recent advances in management and the need to do more. Advances in Sepsis 2004;3(3):75-82

4.  Hotchkiss RS, Karl IE. The pathophysiology and treatment of sepsis. N Engl J Med 2003;348(2):138-150

5.  Mittleman Boller E, Otto CM. Sepsis. In: Silverstein DC, Hopper K (eds). Textbook of small animal critical care medicine, Saunders, St Louis, 2009, p454

6.  Riedemann NC, et al. The enigma of sepsis. J of Clin Invest 2003;112(4):460-467

7.  Schrier RW, Wang W. Acute renal failure in sepsis. N Engl J Med 2004;352(2):159-169