British Journal of Surgery 1997,84,269-272

For debate

Abdominal contamination, infection and sepsis: a continuum M . S C H E I N , D . H. W I T T M A N N * , L. W I S E and R. E. CONDON* Department of Surgery, New York Methodist and Cornell University Medical College, New York, and *Department of Sueery, Medical College of Wisconsin, Milwaukee, Wisconsin, USA Correspondence to: Dr M. Schein, Department of Surgery, New York Methodist Hospital, 506 Sixth Street, Brooklyn, New York 11 215-9008, USA

The evolving concept that the term infection does not mean sepsis, and that sepsis is one form of systemic inflammatory response syndrome (SIRS) but that SIRS also includes non-infective causes, may appear complicated but was developed to simplify and explain matters. That some surgeons use the terms ‘infection’ and ‘sepsis’ interchangeably is evident in the literature where abdominal sepsis and wound sepsis seem to mean abdominal and wound infection respectively. It has been said that ‘changing terminology results from the evolution of patient care, and from attempts to clarify or better describe what is happening. . .’l. This has occurred in the past decade, during which an immense body of new data has increased understanding of the biological events that generate the SIRS, now a common denominator for sepsis, septic shock, organ dysfunction and, eventually, death in critically ill medical, surgical and severely traumatized patients2.

The ‘old’ meaning of sepsis Until the past decade it was presumed that the physiological response to infection represented a consequence of the proliferation of or toxin production by micro-organisms3. This understanding still prevails in updated medical dictionaries in which ‘septic’ is ‘pertaining to an infection with pyogenic micr~organisms’~ and ‘sepsis’ is described as ‘the presence of pathogenic microorganisms or their toxins in the blood or other tissues . .

increased respiratory rate, altered mentation, hyperdynamic circulation, hypermetabolic response, and, at the cellular level, defects in oxygenation, represents a non-specific systemic host-determined response. Thus, the present notion is that whereas infection is the local host response to invasion of micro-organisms, sepsis is the systemic response of the host to the same challenge. This septic response can follow any infection irrespective of the specific causative bacteria, fungus or and may persist for a variable time despite control of the primary infection’*. Notably, a response identical to the septic response may be triggered by multiple non-infective conditions such as traumaI3, burns14, acute pancreatiti~’~,aspiration pneumoniaI6, necrotic tissueI7 and tissue inflammation” as reviewed recentlyI9. Experimentally, clinical sepsis and histological evidence of multiorgan inflammation are produced by intraperitoneal injection of an inflammation stimulant, zymosan20*21. Marshall and Sweenef studied the differential roles of infection and sepsis, and demonstrated that the magnitude of the host response, independent of the presence of bacteria, bacteriological characteristics or control of infection, is the major determinant of outcome in critically ill surgical patients’. Moreover, microorganisms isolated from patients with advanced sepsis may represent a consequence of the physiological derangement rather than a causezz. A hypothesis has matured to suggest that sepsis represents an exaggerated host immune response leading to generalized autodestructive inflammationz3. This concept has been substantiated by recent advances in molecular biology which have unravelled the biological mechanisms producing clinical sepsis and tissue damage through the final common pathway of endogenous proinflammatory mediators, and activation of leucocytes at the endothelial le~el’~.~~.

Current terminology in clinical sepsis

Paper accepted 27 April 1996

The recognition that clinical sepsis can arise in the absence of infection has created confusion for those using this term to imply infection. New terminology was thus required to cover the newly accumulated perception. The term ‘SIRS’ was coined to encompass the non-infectious situations producing clinical se sis, replacing the terms ‘septic state’ or ‘septic response’ 5. Sepsis was redefined as the systemic response to an infective stimulus, consisting of SIRS with microbiological evidence of infection. In other words, SIRS and sepsis represent an identical hostdetermined response, the former in culture-negative or culture-positive patients, and the latter only when infection is documented. Both manifest a continuum of clinical and pathophysiological ~ e v e r i t y ~ ~ . ~ ~ . The term ‘septicaemia’ has been defined as a systemic disease caused by the presence of micro-organisms or their toxins in the blood5, but has been used clinically to cover a spectrum of conditions associated with SIRS and sepsisz5. To reduce confusion, the presence of viable micro-organisms in the blood is preferably termed bacteraemia, viraemia or fungaemia, according to the causative organismE. The term ‘bloodstream infection’,

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Emergence of the ‘new’meaning of sepsis In the late 1970s, the absence of infective foci in patients with intra-abdominal infection and dying a ‘septic death’ led to the evolution of the concept of ‘sepsis without infection’. Meakins et aL7 termed this phenomenon ‘nonbacteraemic clinical sepsis’, while others named it ‘sepsis without ba~teria’~, ‘hypermetabolic organ failure c~mplex’~, the ‘systemic septic or ‘defense failure syndrome’I2.It has become recognized that clinical sepsis, manifesting all the signs that traditionally were associated with infection such as tachycardia, fever,

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270 M . S C H E I N , D . H . W I T T M A N N , L. W I S E and R . E . C O N D O N describing signs of systemic infection when a pathogen is isolated from the blood, should replace ‘~epticaemia’~~.

Intra-abdominal infection versus abdominal sepsis It is proposed that the aforementioned arguments which clarify the nomenclature of systemic infection and sepsis apply also to local surgical conditions. The terms ‘intraabdominal infection’ and ‘intra-abdominal sepsis’, used interchangeably by surgeons, serve as an example. Both terms are not identical; more accurate classification may be valuable clinically as well as academically. Currently the term ‘abdominal sepsis’ is confusing and not specific enough because it describes the systemic inflammatory response only and does not address local events within the peritoneal cavity. Instead, a nomenclature is offered in Tables 1 and 2, and explained below.

Abdominal sepsis The term ‘abdominal sepsis’ has been used to emphasize the systemic response to an initially localized infectious process. Sepsis is only one component of the SIRS, and SIRS is a systemic rather than localized phenomenon; the term ‘abdominak sepsis’ is obsolete because it does not address the important initial local inflammatory response. Furthermore, it does not address the non-infectious local inflammatory response seen in peritonitis. Analogous to systemic sepsis, ‘abdominal sepsis’ represents the nonspecific peritoneal inflammatory response of the host to microbial invasion. Although the peritoneal inflammatory response is comparable to the systemic inflammatory response and utilizes identical mechanisms of humoral and cellular interaction, the two responses occur in functionally separate peritoneal and systemic compartments. Studies in e ~ p e r i m e n t a l ~ ~ p ,r~i ~ m, a ~ y ~ and ~,~~, ~ e c o n d a r y bacterial ~ ~ - ~ peritonitis have demonstrated that bacterial invasion of the peritoneum is associated with a local outpouring of proinflammatory cytokines such as tumour necrosis factor (TNF)a, interleukin (IL) 1, IL-6 and others, with their intraperitoneal concentrations inversely correlating with survival. Peritoneal levels of cytokines in peritonitis are many times higher than systemic levels measured simultaneously, indicating a compartmentalized inflammatory process with plasma levels of cytokines (a ‘spill-over’from the peritoneal cavity or produced systemically) representing the tip of the iceberg. Non-infectious abdominal conditions can also trigger an identical cytokine-mediated response. Levels of IL-1 and

IL-6 are raised after major abdominal operations, the extent of the response increases with the magnitude of the operative t r a ~ m a ~ and ~ - ~portal ~ , vein levels are higher than those measured systemically3*. Also, acute pancreatitis represents a local, intra-abdominal, ‘mediator disease’ in which portal vein levels of TNF-a are higher than those in the hepatic vein39. Peritpnitis may be associated with infective and non-infective stimuli alike; the term ‘peritonitis’ represents a local inflammatory response syndrome (LIRS), an intra-abdominal analogue of SIRS (Table I).

Intra-abdominal contamination Abdominal contamination indicates the presence of micro-organisms in the peritoneal cavity (Table 2). It occurs before tissue invasion has developed, as shown by the lack of a local inflammatory response4*.An example is traumatic colonic perforation with peritoneal soiling. Surgeons still mix cases of abdominal contamination with those of infection or sepsis, as in a study entitled ‘severe intra-abdominal ~epsis’~’.Consequently, many clinical trials are ‘diluted’ with cases of penetrating trauma that represent contamination rather than infection and have a low risk of death. For example, Solomkin et aL42pointed out that the average mortality rate in antibiotic studies was only 3.5 per cent, in sharp contrast with the higher rate of about 30 per cent seen in current surgical practice43+””’

Intra-abdominal infection Intra-abdominal infection is an inflammatory response to micro-organisms associated with invasion of normal sterile peritoneal tissues by organisms (Table 2). In clinically relevant terms it may be useful to distinguish between ‘resectable’ infection, contained within the visceral peritoneum of a removable organ (e.g. gangrenous appendicitis), and ‘non-resectable’ infection which has invaded beyond (e.g. perforated appendicitis).

Contamination, infection and sepsis: a continuum Clearly, local contamination, infection and sepsis mean different things. These specific conditions, however, may co-exist in the same patient, developing simultaneously or consecutively. The instillation of faeces into the peritoneal cavity may involve a continuum of local and systemic conditions ranging from local contamination to septic shock. Untreated or neglected abdominal contamination

Table 1 Terminology, description and examples of systemic and localized inflammation using peritonitis as an example of a local host remonse Mainly systemic

Mainly localized

Term

Systemic inflammatory response syndrome

Description

Systemic inflammatory response to infective and non-infective causes Severe trauma Severe pancreatitis Severe burns Severe infection

Peritonitis (local inflammatory response syndrome) Local peritoneal inflammatory response to infective and non-infective causes

Examples (non-infective) Examples (infective)

Operative trauma Mild pancreatitis Sterile chemical peritonitis Localized intra-abdominal infection

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Table 2 Classification of abdominal contamination, infection and sepsis

Term

Description

Intra-abdominal contamination

Presence of micro-organisms in the peritoneal cavity. Gastroduodenal perforation having surgery within 12 h No tissue invasion as evident by lack of local Traumatic enteric perforation having surgery within inflammatory response 12 h Peritoneal contamination with bowel contents during elective or emergency procedures

Mild intra-abdominal infection

Local inflammatory response to pathogenic microorganisms or invasion of normal sterile peritoneal tissues by these organisms

Localized resectable infection, such as gangrenous appendicitis or gangrenous ischaemic or strangulated bowel without frank perforation; acute cholecystitis Localized non-resectable infection, such as intraperitoneal abscess or peritonitis early after contamination

Severe intra-abdominal infection

Local inflammatory response to pathogenic microorganisms or invasion of normal sterile peritoneal tissues by these organisms

Diffuse peritonitis after perforation of an infectious process into the free abdominal cavity that cannot be contained locally Peritonitis following an abdominal operation with leakage of intestinal bacteria into the abdominal cavity Infected pancreatic necrosis

ends in intra-abdominal infection; the latter is invariably associated with a systemic septic response. More significantly, abdominal inflammation may persist after the infection is cured. Surgical and antimicrobial therapy addresses the infectious component but does not always halt the inflammation. Two or three planned reoperations supplemented with a short course of antibiotics are sufficient to sterilize the peritoneum in cases of severe peritonitis but the inflammatory process continue^^^,^^. A scenario in which bacterial peritonitis is cured, but local and systemic inflammation persists, represents ‘tertiary peritonitis’, a term coined to describe the condition of a subgroup of patients who develop multiple organ dysfunction and die despite ‘successful’ operations, effective antibiotic treatment and maximal supportive therapf’. After adequate treatment of less advanced abdominal infection, residual abdominal inflammation is self-limited. It may be manifest after operation as persistent fever or leucocytosis and usually reflects local residual cytokine-mediated inflammation rather than continuing infection48. Defining when contamination is replaced by infection, and when infection is cured but inflammation persists, must be clarified more precisely.

Clinical relevance Clinicians will adopt the new terminology only if it is meaningful in daily clinical practice. Accurate use of the terms ‘contamination’, ‘infection’ and ‘sepsis’ is of importance in the study and treatment of these conditions since they may represent a continuum but are approached differently (Table 2). Abdominal contamination is controlled by local peritoneal defence mechanisms, assisted by operative peritoneal toilet and prophylactic antibiotics. ‘Resectable’ infection is managed by removal of the contained focus of infection, supplemented with a short perioperative course of antibiotics. Infection that is not ‘resectable’ is treated by surgical control of its source; in this situation therapeutic antibiotics are continued after operation. The term ‘sepsis’ should be used only to denote a systemic

Examples

inflammatory response that is associated with intraabdominal infection. Persistent inflammation after infection is cured should be treated expectantly and without antibiotic^^^. Current therapy deals adequately with some of the initiators of contamination, infection and sepsis. To improve results further, the biological consequences of peritoneal (LIRS) and systemic (SIRS) inflammatory processes should be also addressed.

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