ANNALS OF SURGERY Vol. 224, No.

1, 10-18 1996 Lippincott-Raven Publishers

Management of Secondary Peritonitis

Dietmar H. Wittmann, M.D., Ph.D., F.A.C.S., Moshe Schein, M.D., F.C.S. (S.A.), and Robert E. Condon, M.D., F.A.C.S. From the Department of Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin

Objective
The authors review current definition, classification, scoring, microbiology, inflammatory response, and goals of management of secondary peritonitis.

Summary Background Data

Despite improved diagnostic modalities, potent antibiotics, modern intensive care, and aggressive surgical treatment, up to one third of patients still die of severe secondary peritonitis. Against the background of current understanding of the local and systemic inflammatory response associated with peritonitis, there is growing controversy concerning the optimal antibiotic and operative therapy, intensified by lack of properly conducted randomized studies. In this overview the authors attempt to outline controversies, suggest a practical clinical approach, and highlight issues necessitating further research.

Method
The authors review the literature and report their experience.

Results
The emerging concepts concerning antibiotic treatment suggest that less-in terms of the number of drugs and the duration of treatment-is better. The classical single operation for peritonitis, which obliterates the source of infection and purges the peritoneal cavity, may be inadequate for severe forms of peritonitis; for the latter, more aggressive surgical techniques are necessary to decompress increased intra-abdominal pressure and prevent or treat persistent and recurrent infection. The widespread acceptance of the more aggressive and demanding surgical methods has been hampered by the lack of randomized trials and reportedly high associated morbidity rates.

Conclusions
Sepsis represents the host's systemic inflammatory response to bacterial peritonitis. To improve results, both the initiator and the biologic consequences of the peritoneal infective-inflammatory process should be addressed. The initiator may be better controlled in severe forms of peritonitis by aggressive surgical methods, whereas the search for methods to abort its systemic consequences is continuing.

Intra-abdominal infections after spontaneous gastrointestinal perforation and those resulting from injuries or complicating abdominal operations, still represent the "bread and butter" for surgeons. The purpose of this
Address reprint requests to Dietmar H. Wittmann, M.D., Ph.D., F.A.C.S., Department of Surgery, Medical College of Wisconsin,

overview is to present the "state of the art" in the management of secondary peritonitis, to emphasize persisting controversies, and to identify the gaps in our knowledge that require further study.

CLASSIFICATION AND STRATIFICATION

9200 W. Wisconsin Avenue, Milwaukee, WI 53226. Definition Peritonitis and intra-abdominal infection are not syn-

Accepted for publication August 10, 1995. 10

onymous. Peritonitis denotes inflammation of the peri-

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Management of Secondary Peritonitis

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toneum from any cause. It may be regarded as the localized equivalent of the systemic inflammatory response seen after any trigger of inflammation,",2 which recently has been described as systemic inflammatory response syndrome.3 Intra-abdominal infection denotes peritonitis caused by bacteria (e.g., a local inflammatory process initiated by bacteria and their toxins). It may be regarded as the localized equivalent of systemic sepsis (Fig. 1). Intra-abdominal abscess is an intra-abdominal infection that has been confined within the abdominal cavity. Because the vast majority of clinically significant peritonitis is caused by bacteria, both terms are used interchangeably. Intra-abdominal infection is defined as an inflammatory response of the peritoneum to micro-organisms and their toxins, which results in purulent exudate in the abdominal cavity. Conditions without such peritoneal inflammatory response, in which contamination has occurred but infection is not established (e.g., early traumatic bowel perforation), or in which the infectious process remains contained within a diseased, but resectable, organ (e.g., gallbladder or appendix), represent "simple" forms of peritonitis, easily cured by an operation and not requiring prolonged additional antibiotic therapy.4

Table 1. CLASSIFICATION OF INTRAABDOMINAL INFECTIONS

1. Primary peritonitis Diffuse bacterial peritonitis in the absence of disruption of intraabdominal hollow viscera 11. Secondary peritonitis Localized (abscess) or diffuse peritonitis originating from a defect in abdominal viscus
A. Spontaneous peritonitis in children B. Spontaneous peritonitis in adults C. Peritonitis in patients with CAPD D. Tuberculous and other granulomatous peritonitis

Ill. Tertiary peritonitis

Peritonitislike syndrome occurring late due to disturbance in the host's immune response

A. Acute perforation peritonitis 1. Gastrointestinal perforation 2. Intestinal ischemia 3. Pelviperitonitis and other forms B. Postoperative peritonitis 1. Anastomotic leak 2. Accidental perforation and devascularization C. Post-traumatic peritonitis 1. After blunt abdominal trauma 2. After penetrating abdominal trauma A. Peritonitis without evidence for pathogens B. Peritonitis with fungi C. Peritonitis with low-grade pathogenic bacteria

CAPD = continued ambulatory peritoneal dialysis.

Classification
Many attempts have been made to classify peritonitis in general, and secondary peritonitis in particular, which include a large variety of different pathologic conditions

ranging in severity from a local problem such as gangrenous appendicitis to a devastating disease such as diffuse postoperative peritonitis due to a dehiscence of a gastroduodenal anastomosis.5-8 A simplified version is presented in Table 1. It differentiates between the relatively rare forms of primary peritonitis, which usually respond to medical treatment, and tertiary peritonitis, which does not respond to any treatment, from the commonly occurring secondary peritonitis that mandates surgical intervention.

Scoring
The multifaceted nature of abdominal surgical infections makes it difficult to precisely define the disease and to assess its severity and therapeutic progress. Both the anatomic source of infection, and to a greater degree, the physiologic compromise it inflicts, affects the outcome.9 " The mortality of intra-abdominal infection is related mainly to the severity of the patient's systemic response and his premorbid physiologic reserves, estimated best using the Acute Physiology and Chronic Health Evaluation II (APACHE-II) scoring system (Fig. 2).6,12 The APACHE-II score has been validated prospectively in a large number of patients and has been adopted by the Surgical Infection Society as the best available

PERITOS NEITIS
RSPONSE TO ANY CAUSE
RSPONSE TO INFECTIOI

Figure 1. Relation between systemic inflammatory response syndrome and sepsis vs. peritonitis and intra-abdominal infection.

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100%

Wittmann, Schein, and Condon

Ann. Surg. -July 1996

90%
80%
M 70%

0
R
T A

60%c Lo R+
50%

40%
T
y

30%
20%10%

0% 0
2
4

bacteria invade the peritoneal cavity. Only a few are involved in the ensuing infection (Table 3).5"6 Postoperative state, administration of systemic and luminal antibiotics, and the invasive environment of the intensive care unit may drastically modify patients ecology, resulting in colonization of the foregut with peculiar microorganisms (e.g, fungi, coagulase-negative staphylococci and gram-negative bacteria of low pathogenicity). These are the organisms that may be found in tertiary peritonitis, in intensive care unit infections, and in multiple-organ failure. '7
6 8 10 121416 1820 2224 26 283032 3436 38

APACHE-11
Figure
tified

2.

Mortality Log
R

of intra-abdominal infections

in

924 APACHE
X

stra-

Biphasic Infection
A series of experimental studies in rodents has clarified the bacteriology of secondary peritonitis, emphasizing the key process of bacterial simplification and nsvergil.'5 From the initial plethora of contaminating bacteria, the inoculum is spontaneously reduced to include only a few organisms that survive well outside their natural environment: endotoxin-generating facultative anaerobes such as Esclerichici coli, responsible for the acute peritonitis phase with positive blood cultures, and obligate anaerobes, such as Bacteroides.s fagilis, for late abscess formation. These bacteria act in sIvncegr: both are necessary to produce an abscess, and the obligate anaerobe can increase the lethality of an otherwise nonlethal inoculum of the facultative micro-organism.

cases.

+ (1

R)

=-4.333

(APACHE 11

0.226).

method of risk stratification

tion
.

in

intra-abdominal infec-

MICROBIOLOGY OF PERITONITIS
The micro-organisms associated with secondarv and tertiary peritonitis are summarized in Table 2. Typically. primary peritonitis is a monomicrobial, aerobic infection. The presence of obligate anaerobes, or a mixed flora. suggests secondary peritonitis. The latter- represents a polymicrobial infection after a spontaneous or traumatic breach in a micro-organism-containing viscus. or because of a postoperative breakdown of intestinal anastomosis. The number and types of bacteria increase progressively down the gastrointestinal tract. Proximally, it contains a sparse aerobe (coliforms) and oral anaerobe flora (< 104), with the stomach and duodenum normallv sterile. However, diseases of the stomach (e.g., carcinoma. gastric outlet obstruction) or acidreducing drugs may result in its colonization. 14 Distally, the colon contains the largest concentration of bacteria-in I g of stool, up to 10 - obligate anaerobes and 10' facultative anaerobes (formerly aerobes). After a perforation of the colon, more than 400 different species of

INFLAMMATORY RESPONSE IN PERITONITIS

The outcome of peritonitis depends on the results of a struggle between two main forces: the patient's systemic and peritoneal defenses on one hand and the volume, nature, and duration of the contamination on the other. The exact events that follow the invasion of the peritoneal cavity with bacteria and adjuvants of infection (e.g, blood, bile, barium sulfate) and, subsequently, its translymphatic systemic spread, are subjects of excellent re-

Table 2. MICROBIOLOGY AND ANTIBIOTIC TREATMENT RECOMMENDATIONS

Microbiology
Recommended Therapy
Third generation cephalosporins/ metronidazole combination or penicillin/ beta-lactamase inhibitor combinations or imipenem/cilastatin or ciprofloxacin/ clindamycin combination
Antibiotics no help

Secondary peritonitis
All forms including infected pancreatic necroses

Gram-negative and gram-positive facultative and obligate anaerobic bacteria; predominant are

Escherichia co/i and Bacteriodes fragilis

Tertiary peritonitis Microorganisms do not cause tertiary peritonitis

Fungi, Pseudomonas spp.- Entrococcus gram-negative of low pathogenicity

spp.-

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Table 3. BACTERIA FROM 255 PATIENTS WITH INTRA-ABDOMINAL INFECTIONS FROM THE DEPARTMENT OF SURGERY AT THE MEDICAL COLLEGE OF WISCONSIN
Bacterium
Bacteroides Fusobacterium Porphyromonas Prevotella Clostridium Peptostreptococcus Escherichia co/i Klebsiella Enterobacter Citrobacter Proteus Kluyvera ascorbata Koserella trabulsii Morganella morganii Providencia alcalifaciens Cedecea lapagei Yersinia enterocolitica Pseudomonas No. of Isolates 305 48 18 27 35 78 140 33 19 12 15 2 3 3
1 1

and not reflect their tissue concentration or biological activity. Local estimation of cytokines in the peritoneal exudate may thus better reflect the severity of an initially local process (i.e, peritonitis). Certain levels of peritoneal cytokines, at a particular point in time, stimulate the peritoneal defenses against infection. In different (higher?) levels and certain phases (late?) peritoneal cytokines possess an adverse, end-organ damaging effect.2' Timely therapeutic intervention is crucial to abort the ensuing, self-perpetuating "mediator disease" (systemic inflammatory response syndrome) before the overproduced "terminal" mediator nitric oxide (NO) completely asphyxiates cells by blocking the Krebs-cycle, inflicting advanced injury at the cellular and microvascular level, leading to sequential multiple-organ failure and death. 12627

MANAGEMENT
The management of primary peritonitis, an essentially "nonsurgical," antibiotic-treated disease is referred to 6 elsewhere.< 7 Goals of management of secondary peritonitis are summarized in Table 4.2x The sine qlua non of success is timely surgical intervention to stop delivery of bacteria and adjuvants into the peritoneal cavity. All other measures are of little use if the operation does not successfully abort the infective source and quantitatively reduce the inoculum of micro-organisms and adjuvants of infection so that they can be effectively handled by the patient's defenses, supported by antibiotic therapy. As yet, effective "antimediator" therapy to modulate the local and systemic inflammatory repercussions of peritonitis is not available. Consequently, intensive measures to support tissue oxygenation and maintain organ function are necessary while awaiting recovery brought on trough antibiotic and surgical therapy.

Staphylococcus Gemella
Enterococcus

Streptococcus
*

2 33 34 26 35 184

No antibiotics had been administered for at least 3 days before specimen collection. For bacteriological methods. see: Krepel CJ, Gohr CM, Edmiston CE, Condon RE. Surgial sepsis constancy of antibiotic susceptibility of causative organisms.

Surgery 1995, 17:505-509.

views.'9-'2 The microorganisms and their products (e.g, endotoxins) stimulate the host's cellular defenses to activate a myriad of inflammatory mediators that are responsible for the sepsis (e.g, systemic response to infec-

tion).2"
The recent explosion in molecular biology has increased our understanding of the cytokine-mediated inflammatory response in peritonitis. During peritonitis, cytokines (tumor necrosis factor-a, interleukin-l, interleukin-6, elastase, and others) are measurable in the systemic circulation,-2 and in much greater concentrations in the peritoneal exudate22; the magnitude of the phenomena negatively correlates with outcome. Bacterial peritonitis appears to induce an intense compartmentalized inflammatory process. The largest part of peritoneal cytokines probably derive from macrophages exposed to endotoxin liberated from infecting bacteria. Other potential sources are direct translocation of cytokines through the intestinal barrier-23 or production by tissues traumatized during the operative trauma for peritonitis.24 The compartmentalization of the cytokine cascades in peritonitis corroborates the concept that circulating concentrations of cytokines may be misleading
Table 4. MANAGEMENT PRINCIPLES OF PERITONITIS
1. Supportive measures A. To combat hypovolemia and shock and maintain adequate tissue oxygenation B. To treat bacteria, not eliminated by surgery, with antibiotics C. To support failing organ systems D. To provide adequate nutrition II. Operative treatment Principle 1 (Repair) Control the source of infection Principle 2 (Purge) Evacuate bacterial inoculum, pus, and adluvants (peritoneal 'toilet'')

Principle 3 (Decompress)
Treat abdominal compartment syndrome Principle 4 (Control) Prevent or treat persistent and recurrent infection or verify both repair and purge

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Antibiotic Therapy
Advances in bacteriology and the introduction, during the 1960s and 1970s, of antibiotics (e.g., aminoglycosides, cephalosporins) with limited activity against obligate anaerobes have refocused the attention on the anaerobic nature of secondary peritonitis. This prompted the aforementioned experimental studies that identified E. coli and B. ftagi/is as the main target organisms for therapy. The current practice of early empirical administration of antibiotics targeted against these bacteria is well established.42" However, issues concerning the choice and timing of drugs, the need for operative cultures, and the duration of postoperative administration are controversial. Unfortunately, the numerous prospective randomized studies concerned with antibiotic management of"peritonitis" do not provide the information they promise because thle patients whose illnesses are most severe usually are excluded by study design. Many trials are "diluted" witlh low mor-tality-penetrating trauma cases that represenit contamination rather than infection. Consequently, the aver-age mortality rate in the antibiotics studies reviewed by Solomkin et al.3") was only 3.5%. This sharply contrasts with the 32% and 29% mortality rates of 569 and 924 cases, respectively, which consistently are associated with severe intra-abdominal infections.6 3' Nevertheless, and despite of the numerous options advertised, antibiotic therapy for secondary peritonitis is simple. The emerging concepts suggest that less, in terms ofthe number of drugs and the duration of treatment, is better.32 To hit the primary endotoxin-producing target organism E. coli, an antibiotic that kills all strains and thus does not induce resistance, is required. Third-generation cephalosporins such as cefotaxime sodium, ceftizoxime sodium, cefmenoxime hydrochloride, and ceftriaxone sodium meet this requirement. In 104 studies, none of 10,478 strains of E. coli tested had a minimal inhibitory concentration in excess of the concentrations sustained over 12 hours in the peritoneum with a 2-g dose of cefotaxime sodium.2933 The once popular "triple" regimen of the 1 970s (ampicillin, an aminoglycoside, and metronidazole or clindamycin) has become obsolete. Aminoglycosides are significantly more nephrotoxic than third-generation cephalosporins, are inefficient in the low pH level ofthe infected peritoneal environment,34 and are no longer the first choice of antibiotics in the initial treatment of intra-abdominal infection.2932 The enterococctus, which frequently is isolated in experimental and clinical peritonitis, is almost (may transfer resistant genes to other bacteria) clinically insignificant except for its role as a cofactor for B. fragilis in the formation of abscesses.'8 Thus, it does not require coverage with ampicillin if the obligate anaerobes (e.g., Bfragilis) are adequately covered by metronidazole or clindamycin. A few low-mortality35,36 or retrospective studies37 sug-

gest that monotherapy with a single broad-spectrum antibiotic that includes full activity against E. coli may be equal or superior to polytherapy with multiple drug combinations. We are not convinced by studies that claim that agents only partially effective against the obligate anaerobes represent an effective monotherapy. Half of the patients in one series35 have been cured of infection with antibiotics to which even their aerobic bacteria were resistant. This suggests that in many instances, operation alone may be curative, a well-known reality in the preantimicrobial era, when the mortality rate was reduced from 90% to 40% by introducing operative manage-

ment.38
Because monotherapy has not been studied adequately in patients with established peritonitis from an intestinal or postoperative source, and because many of the 3-Lactam antibiotics are not fully effective against obligate anaerobes in the peritoneal cavity,29 we advocate the addition of metronidazole to an effective, nontoxic, antiaerobic agent. The active compound of cilastatin-imipenem is an effective sole agent for severe intraabdominal infection.39 It should be reserved, however, as a "second-line" agent for the nosocomially altered spectrum of postoperative peritonitis. Our general recommendations are summarized in Table 2. The value of obtaining routine intraoperative peritoneal cultures has become questionable because the results rarely influence clinical decisions29.36.37.40 and usually are available only when therapy is no longer necessary. The trend to continue administration of antibiotics for fixed periods4' 42 is no longer justified. Recommendations of the Surgical Infection Society that the conditions representing "simple" (simple cholecystitis, appendicitis, etc.) intra-abdominal infection, or contamination only (early operated-on spontaneous or traumatic gastrointestinal lesions) do not require prolonged therapeutic postoperative antibiotics4 is an important step toward limiting the currently prevailing practices of excessive antibiotic prescription.4344 Further changes in the current practices are being examined to possibly minimize postoperative administration by intraoperative stratification of the extent of infection, tailoring the duration of therapy to operative findings.45 It still is widely believed-and practiced-that anti-infective agents should be continued until temperature and leukocyte count are within normal limits, but there is no evidence that continuing therapy aborts the potentially developing infective complications. Surgeons who stopped antibiotics according to a protocol, despite continued fever, did not observe an excessive rate ofinfectious complications; the pyrexia resolved spontaneously in the vast majority of the patients.45 Microbiological studies in patients undergoing relaparotomies for diffuse peritonitis demonstrated that the peritoneal cavity becomes almost sterile

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after a few days.46 Thus, it appears that at a certain stage, infection is cured; however, the fever, fueled by ongoing, usually self-limited hypercytokinemia, persists. We believe that the persistence of postoperative pyrexia or other clinical and laboratory signs of infection is not an indication to continue, restart, or change antibiotics. Instead, while awaiting a spontaneous remittance, a search should be conducted for a treatable extra-abdominal and especially intraperitoneal cause. Further studies are necessary to better define the exact point in time in which the transition from infection to "inflammation-only" occurs and beyond which antibiotics are obsolete. An unresolved issue remains the clinical significance of antibiotic-induced endotoxemia. Several studies suggest that some antibiotics possess greater endotoxin-liberating abilities and cytokine production.47 This phenomenon has been claimed to be of clinical importance in patients with sepsis,48 but its relevance was never examined in the setup of peritonitis. If evidence were produced that intraperitoneal killing of bacteria with antibiotics excessively triggers the cascades of inflammation, then there would be a case for withholding the drugs until the source of infection is dealt with, and the pus is evacuated operatively.

Table 5. INDICATIONS FOR STAGED ABDOMINAL REPAIR

Critical patient's condition (hemodynamic instability) precluding definitive repair Excessive peritoneal edema (abdominal compartment syndrome: pulmonary, cardiac, renal, or hepatic dysfunction, and decreased visceral perfusion) preventing abdominal closure without undue tension, intra-abdominal pressure > 15 mmHg Massive abdominal wall loss Impossibility to eliminate or to control the source of infection Incomplete debridement of necrotic tissue Uncertainty of viability of remaining bowel Uncontrolled bleeding (the need for "packing")

Operative Therapy
The classical, single operation for intra-abdominal infection (principles 1 and 2, Table 3) was established during the early decades of this century and reduced overall mortality from 90% (19th century) to approximately 40% in 1926.38 Principle 1 eliminates the source of infection; frequently, it involves a simple procedure, such as appendectomy or omentopexy of a perforated peptic ulcer. Occasionally, major resections to remove the infective focus are indicated, such as gastrectomy or colectomy, for perforated gastric carcinoma or colonic diverticulitis, respectively. Generally, the choice of the procedure, and whether the ends of resected bowel are anastomosed, exteriorized, or simply closed depends on the anatomic source of infection, the degree of peritoneal inflammation and generalized septic response, and the patient's premorbid reserves. No formula is available, but the prevailing trend has been to minimize the immediate risk of complications by avoiding any intestinal suture lines in the presence of severe peritonitis.3: Principle 2 purges the infected abdominal cavity. All infectious fluids should be aspirated, and particulate matter should be removed by swabbing. Although cosmetically appealing and popular with surgeons, there is no evidence that intraoperative peritoneal lavage reduces mortality or the incidence of septic complications in patients receiving adequate systemic antibiotics.49'50 Peritoneal irrigation with antibiotics is not advantageous because bacteria need to be exposed to the antibiotic for

hours to be effective. The addition of antiseptics may produce toxic effects.49 Intraperitoneal instillation of heparin has decreased mortality in a few experimental studies, but clinical trials are lacking.5' The concept of radical debridement of the peritoneal cavity did not withstand the test of a prospective randomized study52 because aggressive debridement caused excessive bleeding from the denuded peritoneum and endangered the integrity of the friable intestine. The role of postoperative peritoneal lavage is at best questionable53 because the basic question remains whether it is possible to irrigate the whole abdominal cavity; do we irrigate the abdomen or only the drain tract?54 Despite the dictum that it is impossible to effectively drain the free peritoneal cavity, drains still are commonly used and misused. In addition to the false sense of security and reassurance they provide, drains can erode into intestine or blood vessels and promote infective complications.54 Their use should be limited to the evacuation of an established abscess, to allow escape of potential visceral secretions (e.g., biliary, pancreatic) and to establish a controlled intestinal fistula when the latter cannot be exteriorized.754 Despite gradual improvement in critical care and antimicrobial therapy, the mortality rate of intra-abdominal infection remained unacceptably high until the 1980s. True progress may have been hidden because in later decades, more patients with advanced types of intra-abdominal infection (e.g., postoperative peritonitis) were treated actively. Nevertheless, it became clear that if the initial standard operation fails, persisting or recurrent intra-abdominal infection sometimes is overlooked or the diagnosis is delayed.55 Waiting for the appearance of signs of persisting infection or organ failure as the indication for re-exploration ("on demand") of the abdomen often proved futile.56 To improve results, methods to affect principles 3 and 4 (Table 3) had to be addressed. The 1980s witnessed the evolution of two therapeutic concepts: open management (laparostomy) 57.58 and "planned" relaparotomies.5960 Planned relaparotomy addresses principle 4: multiple operative interventions

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are planned before or during (but not after) the first procedure for peritonitis. The commitment is made to return to the abdominal cavity to re-explore, evacuate, debride, or resect, until those disease processes indicating the need for serial relaparotomies are resolved. Moreover, planned relaparotomy allows verification of the integrity of anastomoses, fashioned at the first operation, or their eventual construction during subsequent relaparotomy,61 62 as opposed to the routine avoidance of suture-lines advocated by the single operation propo-

ities required to address principles 3 and 428.61.68.73,74 However, we believe these techniques to be beneficial if initiated early, in well-selected patients, for specific indications (Table 5), performed by a team of dedicated surgeons. Conversely, indiscriminate use at "the end of the operative list," often by ever-changing members of junior staff, represents a recipe for disasters.70

Management of Intra-Abdominal Abscess

Erroneously, the term intra-abdominal abscess has been used as a synonym for peritonitis. This is not true because abscesses develop from effective host defenses and represent a relatively successful outcome of peritonitis. Abscesses may be visceral and nonvisceral, intraor extraperitoneal. Nonvisceral abscesses arise after resolution of diffuse peritonitis in which a loculated area of infection and suppuration is "walled off" and persists, or after a perforation of a viscus (or an intestinal anastomosis) that is effectively localized by peritoneal defenses.7 The mainstay of treatment is drainage. Percutaneous, ultrasound, or computed tomography-guided drainage is the method of choice for single "simple" abscesses. Although retrospective studies attribute no lesser mortality or morbidity rates to percutaneous drainage versuis surgical drainage,75 the former represents a minimally invasive procedure that can spare the patient the unpleasantness of another open abdominal operation. Multiple and complex abscesses (i.e., mutiloculated, associated with tissue necrosis, enteric communication or tumor) require laparotomy for drainage and the eradication of the source.76 Failure to improve or clinical evidence of deterioration after percutaneous drainage should prompt an urgent operation.

nents.63
Open management addresses principle 3 and facilitates frequent re-exploration. It serves to decompress the high intra-abdominal pressure caused by peritoneal edema associated w'ttl inflammation and fluid resuscitation, thus obviating the deleterious systemic consequences of the abdominal compartment syndrome.64 Early results of these methods were promising, particularly in the management of infected pancreatic necrosis, but were less favorable in cases of postoperative peritonitis.65 Simple open management was plagued by intestinal fistulas and abdominal-wall defects,66 problems that were almost eliminated by introduction of temporary abdominal closure devices such as the artificial burr or mesh-zipper techniques.6'67 Staged abdominal repair as a conceptual operative approach combines the advantages of planned relaparotomy and of open management with a minimal rate of complications.6 Using the indications presented in Table 4, approximately 10% to 15% of all patients undergoing intra-abdominal infection surgery will qualify for this management policy.6'68 A prospective nonrandomized attempt to compare "closed" and "open" abdomen techniques did not demonstrate an advantage of the latter.69 Recent nonrandomized series failed to to demonstrate the benefits of planned relaparotomies.7" However, another prospective study showed the staged abdominal repair approach to be superior to conventional operative therapy when patients at equal mortality risk were compared.68 It has been shown in trauma cases that repeated operations performed in patients in whom the inflammatory response is already "switched-on" by the traumatic event (and their macrophages thus primed) may act as a "second hit," escalating the and precipitating multiorgan dysfunction.7" The "second hit" issue in the setup of reoperative therapy for peritonitis should be clarified; namely, what should be the interval between relaparotomies to avoid adding wood to the inflammatory fire? A 24-hour interval is supported by collected clinical experience and by bacteriological studies. Bacteria regrow to their initial inoculum 24 hours after peritoneal irrigation.72 A prospective, randomized, multicenter study (recently approved by the Surgical Infection Society) will be necessary to further document the value of the demanding. potentially harmful, and costly management modal-

Tertiary Peritonitis
Aggressive supportive and operative measures allow the salvage of patients who previously would have died of uncontrolled peritonitis. However, delays in management and iatrogenic factors during the 1 980s produced a "new" subgroup of patients who died of "sepsis" and multiple-organ failure despite having a "clean" abdo2 men. 765 However, occasionally at surgery, some thin, cloudy,, micro-organism-containing peritoneal fluid was found. The term tertiary peritonitis was coined to describe this situation, which develops late in the postoperative phase, presents clinically as sepsis, and is associated with a sterile peritoneal cavity or peculiar microbiology (Table 2). Two or three planned reoperations, supplemented with a short course of antibiotics, are sufficient to sterilize the peritoneum in the most severe peritonitis.46 This phase, when infection is cured but severe peritoneal and systemic inflammation persists, represents tertiary peritonitis. Further antimicrobial admin-

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istration and operative interventions are futile and may contribute to the peritoneal superinfection with yeasts and other commensuals. The low virulence of these organisms, which represent a marker of tertiary peritonitis and not its cause, reflects the global immunodepression of the affected patients.7'7 The usually fatal outcome of tertiary peritonitis, which conceptually falls within the systemic inflammatory response syndrome-multiorgan failure complex, indicates that current antibiotic-assisted, mechanical answers to severe peritonitis have about reached their limits. To further improve results, both the initiator and the biologic consequences of the peritoneal infective-inflammatory process should be addressed. Current therapy deals adequately with the initiator. The search for a magic bullet (or bullets) to abort its systemic consequences continues.

16.
17.

18. 19. 20.

21.
22.

References
1. Goris RJA, te Boekhorst TPA. Nuytinck JKS, Gimbrere JSF. Multiple-organ failure: generalized autodestructive inflammation? Arch Surg 1985; 120:1109-1115. 2. Marshall JC, Sweeney D. Microbial infection and the septic response in critical illness. Arch Surg 1990; 125:17-23. 3. Bone RG. Sepsis. SIRS and MODS: the new definition. Proceedings of Sepsis/SIRS. Washington, DC, February 21-22, 1995. 4. Bohnen JMA, Solomkin JS, Dellinger EP, et al. Guidelines for clinical care: anti-infective agents for intra-abdominal infection: a Surgical Infection Society policy statement. Arch Surg 1992; 127:

23. 24. 25. 26.

27.

83-89. 5. Wittmann DH. Symposium of intra-abdominal infections: introduction. World J Surg 1990; 14:145-230. 6. Wittmann DH, Walker AP, Condon RE. Peritonitis, intra-abdominal infection, and intra-abdominal abscess. In: Schwartz SI, Shires GT. Spencer FC, eds. Principles of Surgery. 6th ed. New York: McGraw Hill: 1993:1449-1484. 7. Rotstein OD, Meakins JL. Diagnostic and therapeutic challenges of intra-abdominal infections. World J Surg 1990; 14:159-166. 8. Rotstein OD, Simmons RL. Peritonitis and intraabdominal abscess. In: Barne PS. Shires GT, eds. Surgical Intensive Care. Boston: Little Brown & Co; 1994:1043-1063. 9. Bohnen J, Boulanger M, Meakins JL, McLean AP. Prognosis in generalized peritonitis: relation to cause and risk factors. Arch Surg 1983: 118:285-290. 10. Meakins JL, Solomkin JS, Allo MD, et al. A Proposed classification of intra-abdominal infections. Arch Surg 1984: 119:13721378. 11. Dellinger EP, Wertz MJ, MeakinsJL, et al. Surgical infection stratification system for intra-abdominal infection. Arch Surg 1985;

28.
29.

30.
31. 32.

33. 34. 35.

36. 37. 38.
39.

120:21-29. 12. Knaus WA. Draper EA. Wagner DP, Zimmerman JE. APACHE 11: a severity of disease classification system. Crit Care Med 1985; 13:818-829. 13. Nystrom PO, Bax R. Dellinger EP, et al. Proposed definitions for diagnosis, severity scoring, stratifications, and outcome for trials on intra-abdominal infection. World J Surg 1990; 14:148-158. 14. Finegold SM. Microflora of the gastrointestinal tract. In: Wilson SE. Finegold SM, Williams RA, eds. Intra-Abdominal Infection.
New York: McGraw-Hill: 1982:1-22. 15. Bentley DW. Nichols RL, Condon RE. Gorbach SL. The mi-

croflora of the human ileum and intra-abdominal colon: results of direct needle aspiration at surgery and evaluation of technique. J Lab Clin Med 1972: 79:421-426. Krepel CJ. Gohr CM. Edmiston CE, Condon RE. Surgical sepsis: constancy of antibiotic susceptibility of causative organisms. Surgery 1995; 117:505-509. Marshall JC. Christou NV, Meakins JL. The gastrointestinal tract: the "undrained abscess" of multiple organ failure. Ann Surg 1993; 218:111-119. Bartlett JG, Onderdonk AB, Louie TJ, Kasper DL. A review: lesson from an animal model of intra-abdominal sepsis. Arch Surg 1978: 113:853-857. Maddaus MA, Ahrenholz D, Simmons RL. The biology of peritonitis and implications for treatment. Surg Clin North Am 1988: 68:431-433. Parrillo JE. Pathogenic mechanisms of septic shock. New Engl J Med 1993: 328:1471-1477. Patel RT, Deen KI, Youngs J, et al. Interleukin 6 is a prognostic indicator of ourcome in severe intra-abdominal sepsis. Br J Surg 1994: 81:1306-1308 Holzheimer RG, Schein M, Wittmann DH. Inflammatory Mediators in Plasma and Peritoneal Exudate of Patients Undergoing Staged Abdominal Repair (STAR) for Severe Peritonitis. Arch Surg 1995: 130:1314-1320. Deitch EA. Cytokines yes. cytokines no, cytokines maybe? Crit Care Med 1993: 21:817-819 Baigrie RJ. Lamont PM, Kwiatowski D. et al. Systemic cytokine response after major surgery. Br J Surg 1992: 79:757-760 Schein M. Solomkin J. Wittmann DH. Cytokines in peritonitis. Curr Opinion Surg Infect 1995: 3:123-127. Lancaster JR. Hibbs JB. EPR demonstration of iron-nitrosyl complex formation by cytotoxic activated macrophages. Proc NatI Acad Sci 1990: 87:1223-1227. Palmer RMJ. The discovery of nitric oxide in the vessel wall. Arch Surg 1993: 128:396-401. Wittmann DH. Newer methods of operative therapy for peritonitis. In: Nyhus LM. Baker RG, Fischer JE. Mastery of Surgery. Boston, MA: Little Brown and Co: 1996 (in press). Wittmann DH. Bergstein JM. Frantzides CT. Calculated empiric antimicrobial therapy for mixed surgical infections. Infection 1991: 19(suppl 6):345-350. Solomkin JS. Meakins JL. Dellinger EP. Antibiotics trials in intraabdominal infections: a critical evaluation of study design and outcome reporting. Ann Surg 1984: 201:29-39. Schein M. Management of severe intra-abdominal infection. Surg Annu 1992: 24:47-68. Gorbach SL. Intra-abdominal infections: state of the art clinical article. Clin Infect Dis 1993: 17:961-967. Wittmann DH, Schassan HH. Penetration of eight beta-lactam antibiotics into peritoneal fluid. Arch Surg 1983: 112:205-212. Simmen HP. Battaglia H. Kossmann T. Blaser J. Effect of pH in peritoneal fluid on outcome of aminoglycoside treatment in intraabdominal infections. World J Surg 1993: 17:393-397. Stone HH. Strom PR. Fabian TC. Dunlop WE. The third-generation cephalosporins for polymicrobial surgical sepsis. Arch Surg 1983: 118:193-200. Hopkins JA. Wilson SE. Bobey DO. Adjunctive antimicrobial therapy for complicated appendicitis: bacterial overkill by combination therapy. World J Surg 1994: 18:933-938. Mosdell DM. Morris DM. Voltura A. et al. Antibiotic treatment for surgical peritonitis. Ann Surg 1991: 214:543-549. Kirschner M. Die Behandlung der akuten eitrigen freien Bauchfellentzuendung. Langenb Arch Chir 1926: 142:53-267. Solomkin JSI Dellinger EP. Christou NV. Busuttil RW. Results of a multicenter trial comparing imipenem/cilastatin to tobramnycin/

18

Wittmann, Schein, and Condon clindamycin for intra-abdominal infections. Ann Surg 1990: 212: 581-591. Mosdell DM, Morris D, Fry DE. Peritoneal cultures and antibiotic therapy in pediatric perforated appendicitis. Am J Surg 1994; 167: 313-316. Condon RE, Wittmann DH. The use of antibiotics in general surgery. Curr Prob Surg 1991; 28:803-949. Lennard E, Dellinger E, Wertz MJ, Minshew BH. Implications of leukocytosis and fever at conclusion of antibiotic therapy of intraabdominal sepsis. Ann Surg 1982; 195:19-23. Schein M, Karban A, Assalia A, Eldar S. Current attitudes concerning the duration of antibiotic therapy following operations for abdominal contamination and infection: results of an Israeli national survey. Theor Surg 1994; 9:160-164. Hadjiminas D, Cheadle W, Spain D, et al. Antibiotic overkill of trauma victims. Am J Surg 1994; 168:288-290. Schein M, Assalia A, Bachus H. Minimal antibiotic therapy after emergency abdominal surgery: a prospective study. Br J Surg 1994; 81:989-991. Aprahamian C, Schein M, Wittmann DH. Cefotaxime and metronidazole in severe intra-abdominal infection. Diag Microbiol Infect Dis 1995; 22:183-188. Prins JM, Deventer S.J.H., Deventer SJH, et al. Clinical relevance of antibiotic-induced endotoxin release. Antimirob Agents Chemother 1994: 38:121-1218. Mock C, Dries D, Jurkovich GJ, Maier RV. Antibiotics which result in greater endotoxin release are associated with greater mortality in septic trauma patients. Arch Surg 1995; 130:1234-1241. Schein M, Saadia R, Decker GG. Intraoperative peritoneal lavage. Surg Gynecol Obstet 1988; 166:187-195. Schein M, Cecelter G, Freinkel W, Gerding H. Peritoneal lavage in abdominal sepsis: a controlled clinical study. Arch Surg 1990; 125: 1132-1135. Shar T, Schein M. The role of fibrin and heparin in intra-abdominal infection. Surg Res Comm 1991; 10:299-303. Polk HC, Fry DE. Radical peritoneal debridement for established peritonitis. Ann Surg 1980; 192:350-355. LeiboffAR, SoroffHS. The treatment of generalized peritonitis by closed postoperative peritoneal lavage. Arch Surg 1987: 122:10051010. Farthmann EH, Schoffel U. Principles and limitations of operative management of intraabdominal infections. World J Surg 1990; 14: 210-217. Barendregt W, de Bower H, Kubat K. The results of autopsy of patients with surgical disease of the digestive tract. Surg Gynecol Obstet 1992; 175:227-232. Norton LW. Does drainage of intraabdominal pus reverse multiple organ failure? Am J Surg 1985; 149:347-350. Steinberg D. On leaving the peritoneal cavity open in acute generalized suppurative peritonitis. Am J Surg 1979; 137:216-220. Schein M, Saadia R. Decker GG. The open management of the septic abdomen. Surg Gynecol Obstet 1986: 163:587-591. Penninckx FM, Kerremans RPJ. Lauwers PM. Planned relaparot-

Ann. Surg. -July 1996

40.
41.

60.
61.

42.

62.
63.
64.

43.

44.
45.

65.
66.

46.

47.

67.

48. 49.

68.

69.

50.
51.

70.

52. 53.
54. 55. 56. 57. 58. 59.

71.

72. 73.

omies in the surgical treatment of severe generalized peritonitis from intestinal origin. World J Surg 1983: 7:762-766. Teichmann W. Wittmann DH. Andreone A. Scheduled reoperations(Etappenlavage) for diffuse peritonitis. Arch Surg 1986: 121: 147-152. Wittmann DH. Aprahamian C, Bergstein JM. Etappenlavage, advanced diffuse peritonitis managed by planned multiple laparotomies utilizing zippers. slide fastener, and velcro analogue for temporary abdominal closure. World J Surg 1990: 14:218-226. Ivatury R. Nallathambi M. Prakaschanda R. et al. Open management of the septic abdomen: therapeutic and prognostic consideration based on APACHE I1. Crit Care Med 1989: 17:511-515. L&vy E, Palmer D. Frileux P. et al. Septic necrosis of the midline wound in postoperative peritonitis. Ann Surg 1988: 207:470-479. Schein M. Wittmann DH, Aprahamian C. Condon RE. Abdominal compartment syndrome: the physiological and clinical consequences of elevated intra-abdominal pressure. J Am Coll Surg 1995: 180:745-753. Schein M. Planned reoperations and open management in critical intra-abdominal infections: prospective experience in 52 cases. World J Surg 1991: 15:537-545. Kinney EV. Polk HC. Open treatment of peritonitis: an argument against. Adv Surg 1987: 21:19-28. Garcia-Sabrido JL. Tellado JM. Christou NW, et al. Treatment of severe intra-abdominal sepsis and/or necrotic foci by an "open abdomen' approach. Arch Surg 1988: 123:152-156. Wittmann DH. Bansal N, Bergstein JM, et al. Staged abdominal repair compares favorably with conventional operative therapy for intra-abdominal infections when adjusting for prognostic factors with a logistic model. Theor Surg 1994: 9:201-207. Christou NV. Barie PS. Dellinger EP. et al. Surgical Infection Society intra-abdominal infection study: prospective evaluation of management techniques and outcome. Arch Surg 1993: 128:193199. Hau T. Ohmann C. Wolmershauser H. et al. Planned reaparotomy *.s relaparotomy on demand in the treatment of intraperitoneal infections: a case controlled study. Curr Opinion Surg Infect 1995; 3(suppl):28 (abstract). Waydhas C. Nast-Kolb D, Kick M, et al. Traumatic inflammatory response, secondary operations, and late multiple organ failure. J Trauma 1994: 74:164 (abstract). Edmiston CE, Goheen MP, Kornhall S, et al. Fecal peritonitis: microbial adherence to serosal mesothelium and resistance to peritoneal lavage. World J Surg 1990; 14:176-183. Bohnen JMA, Mustard R. A critical look at scheduled relaparotomy for secondary bacterial peritonitis. Surg Gyencol Obstet 1992;

172(suppl):25-29.
74. Schein M. Assalia A. The role of planned reoperations and laparostomy in severe intraabdominal infection: is a prospective randomized trial possible? Theor Surg 1994; 9:38-42. 75. Levison MA, Zeigler D. Correlation of APACHE 11 score, drainage technique and outcome in postoperative intra-abdominal abscess. Surg Gynecol Obstet 1991: 172:89-94. 76. Malangoni MA. Shumate CR, Thomas HA, Richardson JD. Factors influencing the treatment of intra-abdominal abscesses. Am J Surg 190: 159:167-171.