Definitions

It is important, both among clinicians and researchers, to use common nomenclature and definitions with a complicated syndrome like sepsis and its related topics. This facilitates a meaningful discussion on the subject. A first attempt to define sepsis was undertaken in 1991 and was revisited in 2002. Based on these consensus meetings, an attempt has also been made to define sepsis in dogs and cats. In this process six major terms have been defined:

 Infection: A pathological process caused by the invasion of normally sterile tissue, fluid or a body cavity by pathogenic or potentially pathogenic microorganisms.

 Systemic inflammatory response syndrome (SIRS): A systemic inflammatory response to different insults including heat stroke, extensive trauma, disseminated cancer, immune-mediated disease, infection, pancreatitis, burns.

 Sepsis: The clinical syndrome defined by the presence of both infection and a systemic inflammatory response.

 Multiple organ dysfunction/failure syndrome (MODS/ MOFS): The dysfunction of multiple organs.

 Severe sepsis: Sepsis complicated by organ dysfunction, e.g., MODS.

 Septic shock: Septic shock in human adults refers to sepsis in combination with acute circulatory failure characterised by persistent arterial hypotension unexplained by other causes. If infection is not proven it is appropriate to speak of 'distributive shock'.

Both in human and companion animal medicine (Figure 1) an attempt has been made to define clinical and laboratory parameters that help in identifying the above defined syndromes. Recently, these clinical markers have been expanded in human medicine in order to facilitate bedside recognition of the syndromes. Such a new appraisal has not yet been undertaken in veterinary medicine.

Figure 1. Veterinary criteria for the definition of SIRS.

In dogs at least two out of four criteria should be present and in cats three out of four (WBC, white blood cell count.)

Pathophysiology of Sepsis

Sepsis is the culmination of complex interactions between the infecting microorganism and the host's immune, inflammatory and coagulation responses. An inflammatory response is traditionally characterised by redness, increased local heat, swelling/oedema, pain and loss of function. These symptoms are the end result of a cascade of events that starts with the activation of the innate immune system of the host by the invading microorganism and the opsonisation of organisms by acute phase proteins (e.g., complement) and phagocytosis by macrophages and dendritic cells. This results in activation of inflammatory cells and production and release of inflammatory cytokines (tumour necrosis factor alpha (TNFα), interleukin (IL)-1 and -6), arachidonic acid metabolites, free radicals, lysosomal enzymes, and tissue factor. These inflammatory mediators are responsible for further attraction and activation of inflammatory cells and for the activation of procoagulant factors, and they are mainly responsible for the clinical symptoms described before.

All these responses are beneficial in a localised inflammatory response, but when the response becomes systemic, i.e., SIRS or sepsis, the situation often becomes life-threatening. A local response can develop into a systemic one in two different ways: either the host is unable to contain the primary infection and the microorganism (mostly bacteria) can replicate in the bloodstream, or there is leakage of the locally produced toxins and related pro-inflammatory mediators into the blood stream.

The loss of control over precapillary sphincter tone and systemic vasodilatory effects (with nitrous oxide in a pivotal role), can lead to distributive shock that is characterised by maldistribution of blood to different organs and vascular beds. Initially cardiac output can be increased by two to four times to maintain normal arterial pressures (hyperdynamic phase) but if shock progresses hypotension, cardiac systolic dysfunction (hypodynamic phase) and organ failure ensues. The inflammatory response will also change homeostasis and metabolism, leading to increased dependence on proteins as an energy source and muscle wasting in a very short period of time. Also several other endocrinological and metabolic functions can be altered by the disease process: septic patients often develop peripheral insulin resistance, critical illness-related corticosteroid insufficiency (CIRCI) and the syndrome of inappropriate antidiuretic hormone (SIADH) secretion. As many proinflammatory mediators are also procoagulant and vice versa, coagulation is often activated in SIRS and sepsis, leading to the clinical picture of disseminated intravascular coagulation (DIC).

Treatment

Management

Despite an enormous increase in evidence-based knowledge on the sepsis syndrome, mortality in human medicine has decreased little over the last several decades. This appears to have changed dramatically since structural attention has been given to how to implement this knowledge clinically. With the complicated and multifactorial impact of sepsis and related problems such as SIRS, MODS and shock, it is no surprise that treatment can become complex and has to consist of many different approaches to be successful. In 2004 the 'Surviving Sepsis Campaign Guidelines' were published (www.survivingsepsis.org ) as part of an international effort to increase awareness and improve outcome.

The current management guidelines for humans have several key characteristics:

 Evidence-based treatment recommendations.

 Standardisation of a 'cocktail' of treatment options that are addressed simultaneously.

 Early, goal-directed therapy with an improvement of the initial resuscitation phase (Figure 2). The protocols developed for this focus mainly on restoration of systemic oxygen delivery through manipulation of preload (volume), contractility (stroke volume) and afterload (blood pressure).

 Implementation of this unified approach by education of medical professionals, development of protocols and checklists.

These starting points seem to be rather basic but their impact has been substantial with mortality reductions of up to 30% in certain human hospitals. They demonstrate the importance of early, effective/aggressive and protocol-driven treatment. Not all goals and treatment options that have been described in these guidelines can be implemented in veterinary medicine. But from the guidelines we can definitely learn the basic management 'attitude' and implement some recommendations, such as the prompt recognition of the disease and of the infectious source, the correct and efficient use of fluid therapy to restore tissue perfusion and the early use of broad-spectrum antibiotics.

Figure 2. Goal-directed treatment of severe sepsis and septic shock in humans.

This protocol should be used in the first 6 hours after presentation. ScvO₂ is measured in blood from the pulmonic artery.

Treatment Options

The treatment consists of a dual approach of source identification and (surgical) control of the infection, and the treatment of the debilitatory effects of the systemic inflammation. To establish a comprehensive treatment plan the following aspects have to be considered: fluid therapy, antibiotic therapy, oxygen therapy, glucose control, maintenance of urine output and renal integrity, treatment of acid-base disturbances (pH < 7.15), vasopressors and inotropic therapy, treatment of coagulopathies and the use of blood products, support of the gastrointestinal tract (stress ulcer prophylaxis), sedation and analgesia, mechanical ventilation and nutritional support. This list is far from complete and depending on the cause of the severe sepsis and septic shock other treatment modalities also have to be considered.

The administration of broad-spectrum antibiotics, within the first hour of presentation, is considered to have a positive effect on outcome. Once the causative organism has been identified, the initial antibiotic regimen may need to be changed to a more narrow and specific antibiotic regimen. Antibiotics should be stopped if the cause is non-infectious.

New treatment modalities in human medicine such as the use of activated protein C, anti-prostaglandins and anti-oxidants are either too expensive for routine use in veterinary medicine, unavailable or their efficacy is still under debate.

The author would like to acknowledge Dr C. Valtolina DipACVECC for her help in the preparation of these notes.

References

1.  Christ M. How to manage sepsis in the emergency department leading to a decreased mortalitity in ICU - the Critical Care Cascade. www.acutecaretesting.org.

2.  Dellinger RP, Levy MM, et al. Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock: 2008 [published correction appears in Critical Care Medicine 2008;36:1394–1396]. Critical Care Medicine 2008;36:296–327.

3.  Levy MM, Fink MP, et al. (SCCM/ESICM/ACCP/ATS/SIS) SCCM/ESICM/ ACCP/ATS/SIS International Sepsis Definitions Conference. Critical Care Medicine 2003;31(4):1250–1256.

4.  Members of the American College of Chest Physicians/Society of Crit Care Med Consensus Conference Committee: American College of Chest Physicians/Society of Crit Care Med Consensus Conference. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Critical Care Medicine 1992;20:864–874.

5.  Rivers EM, Ryant B, et al. (Early Goal-directed Therapy Collaborative Group). Early goal-directed therapy in the treatment of severe sepsis and septic shock. New England Journal of Medicine 2001;345:1368–1377.