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Pathophysiology and Management

Created: 16/5/2007

Pathophysiology and Management

Dr John Griffiths DICM MRCP FRCA MA
CriticalCareUK Editor

Focus on the definition of sepsis

Sepsis is part of the body’s response to infection and remains one of the most important challenges to modern day intensive care treatment. Early understanding of the mechanisms that drive the septic process was hampered by a lack of consensus as to the definitions of the disease processes that form the septic spectrum. To address this problem, experts recruited by the American College of Chest Physicians and Society of Critical Care Medicine met in 1991 to reach a consensus on the diagnosis of sepsis and its sequelae (Box 1). These definitions have provided a foundation for the common reporting and discussion of sepsis, its complications and treatment. Sepsis remains a common cause of death in intensive care units. Data from the Intensive Care National Audit and Research Centre (ICNARC) suggest that in the UK, 27% of intensive care patients either present with sepsis initially or develop sepsis during the first 24 hours of ICU admission. The mortality of severe sepsis and septic shock remains high (30% and over 50%, respectively).

Box 1. Consensus Conference of the American College of Chest Physicians and Society of Critical Care Medicine definitions for the various manifestations of infection.

 • Systemic Inflammatory Response Syndrome (SIRS):
Manifest by two or more of the following conditions:
1. A temperature >38oC or <36oC
2. An heart rate >90 beats per minute
3. A respiratory rate >20 breaths per minute or a PaCO2 <32 mmHg
4. A white blood cell count >12,000/mm3 or <4000/mm3, or the presence of >10% immature forms.

Infection:Microbial phenomenon characterised by an inflammatory response to the presence of microorganisms or the invasion of normally sterile host tissue by these organisms.

Bacteraemia: The presence of viable bacteria in the blood.

Sepsis (Simple): The systemic response to infection, manifested by two or more of the SIRS criteria pus an infection.

Sepsis (Severe): Sepsis associated with organ dysfunction, hypoperfusion, or hypotension. Hypoperfusion and perfusion abnormalities that may include, but are not limited to lactic acidosis, oliguria or an acute alteration in mental status.

Septic shock: Sepsis-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. Patients who are receiving inotropic or vasopressor agents may not be hypotensive at the time that the perfusion abnormalities are measured. This is a subset of severe sepsis.

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

Adapted from Bone RC et al. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Chest 1992; 101: 1644-1655.

Focus on the pathophysiology of sepsis

The pathophysiology of sepsis has been divided into five stages:

• the infectious insult
• the preliminary systemic response
• the overwhelming systemic response
• compensatory anti-inflammatory reaction
• immunomodulatory failure.

Sepsis is characterised by a systemic inflammatory response (SIRS) to an infective insult (Figure 1). The inflammatory response results in systemic vasodilatation, hypotension, increased cardiac output and, eventually, reduced oxygen extraction by the tissues. The key pathological features driving this process are abnormalities of endothelial function and disordered coagulation homeostasis. These result in the release of a variety of cytokines and tissue factors, an activation of the clotting cascade and a reduction in the natural inhibitors of clotting (e.g. activated protein C). Once triggered, the downward spiral of severe sepsis is believed to be independent of the underlying infectious disease process. The combination of increased thrombosis and reduced fibrinolysis leads to disturbed microcirculatory blood flow, microcirculatory ischaemia, and multiple organ dysfunction and eventual multiple organ failure.

Figure 1 .The relationship of infection, SIRS, severe sepsis and sepsis.

[Adapted from Bone RC et al. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Chest 1992; 101:1644-55]

Focus on the multiple organ dysfunction syndrome (MODS)

MODS was first described in patients with massive acute blood loss secondary to ruptured aortic aneurysms. It is now evident that MODS accompanies a diverse group of disorders that include sepsis and its spectrum of disease, pre-eclampsia, trauma and pancreatitis. Once initiated, MODS follows a predictable clinical course, irrespective of the precipitating disorder or event. The first evidence of organ dysfunction is usually changes in the cardiovascular and respiratory systems, with the appearance of acute lung injury or the acute respiratory distress syndrome (ARDS). The resulting pulmonary failure and ensuing hypoxaemia are followed by hepatic and renal dysfunction and disorders of the haemostatic, gastrointestinal and central nervous systems. Delirium is an acute disorder of attention and cognition. It develops in more than 80% of patients in the ICU. Bone marrow failure and myocardial dysfunction are usually late manifestations of MODS. Support for the failing organs is the cornerstone of modern ICU practice, and prognosis is most directly related to the number of failed organs (Table 1).

Table 1. Clinical and laboratory markers of organ dysfunction.

Organ System






Cardiac arrest


Haemodynamic support

Altered CVP, PCWP

Reduced cardiac output


Weight loss






Increased D-dimers

Abnormal white cell count

Abnormal clotting profile



GI bleeding

Acute pancreatitis

Acalculous cholecystitis

Decreased intestinal pH

Elevated amylase




Increased PT

Elevated LFTs





Altered consciousness

Altered EEG




Renal replacement therapy

Elevated creatinine

Elevated urea




Mechanical ventilation

PaO2 <70 mmHg

SaO2 <90%

PaO2/FiO2 <300



Nosocomial infection

Altered white cell count

Impaired white cell function

Adapted from Balk RA. Pathogenesis and management of multiple organ dysfunction or failure in severe sepsis and septic shock. Crit Care Clin 2000; 16: 337-352.

Focus on the management of the septic patient

Despite evidence of the significant role of inflammatory mediators and haemostasis in the evolution of sepsis and acute organ dysfunction, the treatment of severe sepsis has remained the same for more than 30 years: examine and stabilise the patient, diagnose and treat infection and support organ function. Intra-abdominal signs should prompt surgical review. Early recognition of the septic process is the cornerstone to good management and may be aided by the use of a “track and trigger” system. The aim of the early supportive management is to return as many of the physiological parameters towards the normal range. Many patients will require ventilation to maximise oxygenation and minimise the work of breathing. Following work in patients with ARDS, a “lung protective strategy” is advocated (see Ventilation section). Targeted and protocol-driven early “goal-directed therapy” of fluid and inotropic support has been shown to improve the outcome from sepsis possibly by augmenting the SIRS response driven by tissue hypoxia. A standardised approach to the management of the septic patient has recently been formulated into “The Surviving Sepsis Campaign”.

Inotropic therapy

There is little evidence to support the use of a particular inotrope in sepsis. In the face of the vasodilatation and reduced systemic vascular resistance that characterises “warm sepsis”, most clinicians would opt for noradrenaline (norepinephrine). As sepsis can dampen myocardial function, dobutamine is often introduced to provide inotropy and chronotropy. Adrenaline (epinephrine) is a useful agent when simplicity of treatment is required and is therefore often used during the initial stages of resuscitation on the ward or in theatre prior to transfer to the ICU.

Renal replacement therapy

Acute renal failure often develops during the sepsis and may require renal replacement therapy. Even if renal function is normal in a septic patient, early high volume continuous veno-venous haemofiltration may still be advocated. It is thought that this process may remove some of the pro-inflammatory or pro-coagulant cytokines that drive the septic cascade.

Novel therapies

Activated protein C (APC)

This endogenous protein plays an important physiological role in the body’s normal response to injury or insult. APC helps to maintain the balance between the coagulation and fibrinolytic pathways and helps to reduce the inflammatory response through inhibition of thrombin-mediated inflammatory activities and leucocyte attachment to the endothelium. Levels of APC are reduced during sepsis. The PROWESS study showed that APC could significantly reduce mortality in sepsis. Despite the high cost of APC, the National Institute for Clinical Excellence (NICE) has recently advocated its use. Longer-term outcome data are awaited.


The circulatory shock seen in sepsis can often become resistant to treatment with the traditional catecholamine inotropes (noradrenaline and adrenaline). In this situation, treatment with vasopressin or vasopressin analogues can lead to restoration of an adequate blood pressure and reduction in the dose of existing inotropes.

Focus on outcome from sepsis

Severe sepsis is now the third leading cause of infectious death. The mortality rate in patients with severe sepsis ranges from 30-50%. Mortality rates increase by 15-20% for each additional organ failure. As highlighted above the use of APC in the PROWESS study reduced absolute mortality risk by 6.1%. There is hope that by earlier recognition of the septic patient, physiological parameters and organ function can be normalised and maintained, while agents such as APC are administered to reduce the septic and inflammatory response. Through these processes, mortality from sepsis may then be reduced further. At the present time, however, the “magic bullet” for sepsis does not exist.

Key references

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. Crit Care Med 1992; 20: 864-874.

Bernard GR, Artigas A, Brigham KL, et al. Am J Respir crit Care Med 1994;149:818-824.
The American-European consensus Conference on ARDS: definitions, mechanisms, relevant outcomes, and clinical trial coordination.

Bone RC, Grodzin CJ, Balk RA. Chest 1997; 112: 235-243.
Sepsis: a new hypothesis for pathogenesis of the disease process.

Wheeler AP, Bernard GR. NEJM 1999; 340: 207-214.
Treating Patients with Severe Sepsis.

Balk RA. Crit Care Clin 2000; 16: 337-352.
Pathogenesis and management of multiple organ dysfunction or failure in severe sepsis and septic shock.

Rivers E, Nguyen B, Havstad S et al. N Engl J Med 2001; 345: 1368-1377.
Early goal-directed therapy in the treatment of severe sepsis and septic shock.

Dellinger RP, Carlet JM, Masur H et al. Crit Care Med 2004; 32: 858-873.
Surviving sepsis campaign guidelines for management of severe sepsis and septic shock.

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