Treating sepsis (Proceedings)

Definition

Sepsis is defined as the systemic inflammatory response to an infection. We commonly see patients that have a clinical presentation that appears similar to sepsis, but no source of infection can be identified. This syndrome has been termed the systemic inflammatory response syndrome or SIRS. SIRS can result from activation of the immune and inflammatory system in response to trauma, tissue injury, heat stroke, pancreatitis, burns or hypoxia. In humans, there are established criteria for the diagnosis of SIRS. Table 1 includes proposed criteria for definition of SIRS in dogs and cats and humans. It is important to realize that only 2 of the 4 potential criteria need to be met for a patient to qualify for SIRS. Sepsis includes these SIRS criteria plus evidence of a source of infection. Because the primary source of infection may not be identified initially and SIRS can lead to secondary sepsis, for the purpose of this discussion, the term sepsis will be used to describe both conditions.

Table 1

SIRS criteria are not particularly useful in the clinical management of patients because they lack specificity and sensitivity. A more recent classification scheme called PIRO, has been proposed to attempt to identify which patients are at risk of poor outcome in sepsis.

Table 2

Overview of patients at risk

Several risk factors for sepsis have been identified in human patients. It appears that many of these risk factors are equally relevant in our veterinary patients. The most obvious risk factor is a known infectious focus, such as pneumonia, prostatitis or peritonitis. These patients should be monitored carefully for systemic signs of systemic infection and activation of the inflammatory cascade. Patients with hypotension, ischemia/reperfusion injury (e.g. gastric dilatation and volvulus), or intestinal compromise (e.g. parvovirus, infiltrative intestinal disease or cancer) are at risk for bacterial translocation and sepsis. Major trauma or surgery can predispose patients to hypotension, ischemia/reperfusion or SIRS as a result of tissue injury. Burn patients have both tissue injury and are at risk for infection. Immunosuppression from drugs or disease can also predispose patients to overwhelming infections and sepsis.

Early aggressive treatment to control infection is the first line of therapy. This includes early administration of appropriate antibiotics and removal of the infectious/inflammatory focus. For abscesses or injured tissue, this may require surgical debridement and drainage. For patients with pneumonia, this may require nebulization and coupage as well as maintaining adequate hydration. Nebulization is generally performed using humidified oxygen, this delivers moisture to the airways, which in conjunction with coupage (physical therapy involving clapping on the chest to loosen pulmonary exudates) facilitates elimination of the infection. It is recommended that animals with pneumonia are nebulized 3-4 times daily for 10-15 minutes followed by coupage. The second line of therapy is aimed at supporting the normal organ function, preserving tissue perfusion, and preventing secondary organ failure. There have been multiple attempts to identify a third line of therapy to control or inhibit the actions of the inflammatory cascade, however to date the only therapy that has been beneficial in human clinical trials, activated protein C is not feasible for use in veterinary patients.

Clinically, sepsis is associated with the development of distributive shock. This form of shock results from massive vasodilation. The consequence of this vasodilation is that the amount of blood in circulation is inadequate to fill the vascular space, creating an effective hypovolemia. As a result, there is insufficient delivery of oxygen and nutrients to vital tissues. In response to tissue hypoxia, there is an increase in heart rate (in dogs and variably in cats) and cardiac contractility (early) which provide a compensatory increase in cardiac output and tissue perfusion. In contrast to hypovolemic shock, where peripheral vasoconstriction is part of the compensatory response, sepsis leads to vasodilation and maldistribution of blood flow, resulting in regions of excess blood flow and other regions that remain underperfused. Vasodilation in septic shock is a consequence of the production and release of inflammatory mediators by the activated immune system. The vasodilation is responsible for the bright red appearance of the mucous membranes. The vasodilation leads to a decrease in peripheral vascular resistance, lower diastolic blood pressure and the sensation of hyperdynamic or bounding pulses. Bounding pulses can be thought of as a normal volume of blood (pulse duration) that is propelled forward into the vessels but the pulse wave drops off rapidly (increased intensity). The stress response triggered by sepsis will result in an initial hyperglycemia, however the inflammatory mediators subsequently promote hypoglycemia from decreased production and increased consumption of glucose.

Fever is generated centrally by inflammatory mediators and external cooling will not eliminate the increase temperature. The use of antipyretics can lead to serious complications as well as loss of monitoring of response to therapy and is generally reserved for patients with dangerously high temperatures. As sepsis progresses and the animal is no longer able to compensate, perfusion is further impaired and the rectal temperature will decrease. Septic cats in particular have a high frequency of hypothermia. Hypothermia, as measured by rectal temperature, is often a reflection of poor perfusion to the rectum. Treatment should focus first on volume resuscitation with warm fluids while preventing heat loss (e.g. wrap the patient in blankets to minimize heat loss and prevent contact with cold metal tables). Forced air warming blankets are very effective in rewarming and maintaining temperature in critically ill animals and are safer than electric heating pads.

Multiple organ dysfunction in sepsis/SIRS

If the inflammatory cascade continues unchecked, more mediators are released both locally and into the system circulation. Many of these mediators have procoagulant activities. Activation of the coagulation results in an initial hypercoagulable stage that can lead to the formation of thrombi and consumption of coagulation factors. This phase of coagulation cannot be detected by classical coagulation assays, but has been demonstrated with whole blood clotting assays like thromboelastography. Consumption of the clotting factors leads to the development of disseminated intravascular coagulation (DIC). This is often the first evidence of organ dysfunction. As with sepsis, DIC occurs in stages. Often the first observed abnormality in a patient with DIC will be a decrease in platelet number, this is frequently followed by prolongation of the clotting times (aPTT>PT) and accumulation of fibrin degradation products or D-dimers. Treatment of DIC is directed at eliminating the cause, in sepsis that requires removal of the septic focus. In addition, the use of heparin and fresh frozen plasma have been advocated, although is still controversial. DIC can further impair tissue perfusion through the accumulation of local fibrin deposits.

Endothelial cell injury contributes to both DIC and the development of tissue edema. Inflammatory mediators increase vascular permeability. This localized increase in permeability allows important plasma proteins access to areas of inflammation. However, when the systemic vasculature develops this increase in permeability, there is development of tissue edema, and further compromise of organ function. This can be seen clearly in the lung, as capillary permeability increases there is an increase in interstitial fluid and eventual alveolar flooding. This combined with the infiltration of activated neutrophils results in poor gas exchange, tachypnea and further tissue hypoxia. Third spacing of intravascular fluid as a result of increased vascular permeability will contribute to the development of hypovolemic shock, which will further impair cardiac output and tissue oxygenation. Pulses will become "thready", short in duration and of low intensity.

Dogs will often show evidence of gastrointestinal dysfunction as an early sign of multiple organ dysfunction. Vomiting may occur, but more typically, these dogs develop diarrhea often with melena. Cats appear to be more likely to develop pulmonary complications. Regardless, all organs will eventually demonstrate impaired function. Recognizing decreases in function should prompt the clinician to become more aggressive in therapy. In order to recognize the changes however, appropriate monitoring is necessary.

The heart is at risk for hypoxia as a result of the compensatory increase in heart rate. As rate increases, diastolic filling and coronary perfusion, become limited. The increased rate increases the myocardial oxygen demand, but the decreased perfusion restricts oxygen delivery setting the stage for ischemic injury and development of arrhythmias. Impaired perfusion in sepsis can result from decreased venous return resulting from vasodilation and hypovolemia, as well as the negative inotropic effects of inflammatory mediators.

Poor perfusion and local inflammation can lead to acute tubular necrosis and renal failure. Monitoring urine output and blood pressure provide early indications of compromised renal function. As dysfunction progresses to failure, serum BUN and creatinine will rise. The kidney is not the only organ affected. Sepsis frequently results in increased liver enzymes and bilirubinemia. Poor perfusion, hypoxia, DIC, and hypoglycemia can all contribute to alterations in mental status. As sepsis progresses, neurologic function will deteriorate to leading to coma, seizures or death

Treatment of sepsis

The primary goal in the treatment of sepsis is to eliminate the source of infection/inflammation. This is accomplished with appropriate antibiotic therapy and surgery as indicated. Antibiotic choice depends on several factors. The first factor is the action of the drug. Bactericidal antibiotics are preferred over bacteriostatic antibiotics; common classes of bactericidal antibiotics include aminoglycosides, cephalosporins, fluoroquinolones, lincosamides, nitroimidazoles, and penicillins. The route of administration in septic patients must be intravenous, as absorption will be erratic in oral or subcutaneous drugs. The toxicity of the drugs must also be considered. The aminoglycosides, while providing an excellent gram-negative spectrum can lead to hearing loss and renal damage, particularly in poorly perfused patients. Enrofloxacin has been reported to adversely affect cartilage in growing animals and is only labeled for intramuscular use. The penicillins should not be used in animals with a history of hypersensitivity. Some animals with hypersensitivity to penicillins will also be sensitized to cephalosporins. Clindamycin can cause intestinal upset. Metronidazole requires hepatic metabolism and can lead to neurologic effects if overdosed or used at standard doses in animals with hepatic failure. Equally importantly, the spectrum of the drugs must be considered. Initial antibiotic selection should be based on Gram stain, however if that is not available knowledge of typical bacteria associated with the site of infection will facilitate selection, while cultures are pending. Most infections that lead to sepsis are caused by Gram-negative enteric bacteria. Anaerobic bacteria are frequently associated with pulmonary and peritoneal infections. Table 5 lists the most commonly reported bacteria based on site of infection. Often a single antibiotic will not provide sufficiently broad coverage. Combined therapy can take advantage of synergistic effects of some antibiotics (metronidazole and enrofloxacin), and provide broad coverage. Common combinations include 1) a first generation cephalosporin or penicillin for gram-positive organisms, 2) a fluoroquinolone, aminoglycoside or third generation cephalosporin for gram negative organisms and 3) metronidazole, clindamycin or a penicillin for anaerobes.

Antibiotics alone, however, will not save the patient once there is evidence of a systemic inflammatory response. Therefore, concurrent aggressive supportive care is critical to improve tissue perfusion and prevent the sequelae of prolonged hypoxia, hypoglycemia, hypercarbia and lactic acidosis. Restoration of effective circulating blood volume is essential for perfusion. Volume resuscitation with crystalloids and colloids provides the cornerstone of therapy. If the animal is volume resuscitated but remains hypotensive, then vasopressors and/or inotropes must be considered. If cardiac arrhythmias are compromising perfusion, then antiarrhythmic therapy should be instituted. Supplemental oxygen therapy may be sufficient to overcome pulmonary dysfunction. However, as sepsis progresses, patients will require positive pressure ventilation to attempt to provide adequate oxygenation and elimination of carbon dioxide.

Patients that have evidence of DIC may benefit from plasma transfusion, and if there is associated blood loss, then red blood cells are indicated. Maintaining oxygen delivery and tissue perfusion will help prevent renal, gastrointestinal and neurologic dysfunction. However, specific organ directed therapy may be necessary if impairment is present. For example, diuretics or dopamine may be necessary to maintain urine production. Neurologic function requires not only sufficient perfusion and oxygen, but efficient carbon dioxide removal and normoglycemia. As resuscitation becomes prolonged, the nutritional needs of the patient and specifically the gastrointestinal tract will need to be addressed.

Specific anti-cytokine or anti-inflammatory therapies have not proven beneficial in sepsis, however, new treatment strategies continue to be evaluated. Until new agents are proven in clinical trials, treatment of sepsis will rely on 1) control of infection/inflammation and 2) aggressive supportive care to prevent continued activation of the inflammatory cascade.

References available upon request