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GENERAL DESIGN: Presentation of a new type of a study protocol for evaluation of the effectiveness of an immune modifier (rhG-CSF, filgrastim): prevention of postoperative infectious complications and of sub-optimal recovery from operation in patients with colorectal cancer and increased preoperative risk (ASA 3 and 4). This part describes the design of the randomised, placebo controlled, double-blinded, single-centre study performed at an university hospital (n = 40 patients for each group). OBJECTIVE: The trial design includes the following elements for a prototype protocol: * The study population is restricted to patients with colorectal cancer, including a left sided resection and an increased perioperative risk (ASA 3 and 4). * Patients are allocated by random to the control or treatment group. * The double blinding strategy of the trial is assessed by psychometric indices. * An endpoint construct with quality of life (EORTC QLQ-C30) and a recovery index (modified Mc Peek index) are used as primary endpoints. Qualitative analysis of clinical relevance of the endpoints is performed by both patients and doctors. * Statistical analysis uses an area under the curve (AUC) model for improvement of quality of life on leaving hospital and two and six months after operation. A confirmatory statistical model with quality of life as the first primary endpoint in the hierarchic test procedure is used. Expectations of patients and surgeons and the negative affect are analysed by social psychological scales. CONCLUSION: This study design differs from other trials on preoperative prophylaxis and postoperative recovery, and has been developed to try a new concept and avoid previous failures.

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GENERAL DESIGN: Presentation of a novel study protocol to evalue the effectiveness of an immune modifier (rhG-CSF, filgrastim): prevention of postoperative infectious complications and sub-optimal recovery from operation in patients with colorectal cancer and increased preoperative risk (ASA 3 and 4). The rationale and hypothesis are presented in this part of the protocol of the randomised, placebo controlled, double-blinded, single-centre study performed at an university hospital (n = 40 patients for each group). OBJECTIVE: Part one of this protocol describes the concepts of three major sections of the study: Definition of optimum and sub-optimal recovery after operation. Recovery, as an outcome, is not a simple univariate endpoint, but a complex construction of mechanistic variables (i. e. death, complications and health status assessed by the surgeon), quality of life expressed by the patient, and finally a weighted outcome judgement by both the patient and the surgeon (true endpoint). Its conventional early assessment within 14-28 days is artificial: longer periods (such as 6 months) are needed for the patient to state: "I am now as well as I was before". Identification of suitable target patients: the use of biological response modifiers (immune modulators) in addition to traditional prophylaxes (i. e. antibiotics, heparin, volume substitutes) may improve postoperative outcome in appropriate selected patients with reduced host defence and increased immunological stress response, but these have to be defined. Patients classified as ASA 3 and 4 (American Society for Anaesthesiologists) and with colorectal cancer will be studied to prove this hypothesis. Choice of biological response modifier: Filgrastim has been chosen as an example of a biological response modifier because it was effective in a new study type, clinic-modelling randomised trials in rodents, and has shown promise in some clinical trials for indications other than preoperative prophylaxis. It has also enhanced host defence and has been anti-inflammatory in basic research. CONCLUSION: The following hypothesis will be tested in patients with operations for colorectal cancer and increased preoperative risk (ASA 3 and 4): is the outcome as evaluated by the hermeneutic endpoint (quality of life expressed by the patient) and mechanistic endpoints (mortality rate, complication rate, relative hospital stay, assessed by the doctor) improved in the group receiving filgrastim prophylaxis in comparison with the placebo group? Quality of life will be the first primary endpoint in the hierarchical, statistical testing of confirmatory analysis.

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The basic principles for treating intraabdominal infections are fourfold: (1) to obliterate the infectious source; (2) to purge bacteria and toxins; (3) to maintain organ system function and (4) to tame the inflammatory process. Operative and nonoperative treatment options are available. Operative therapy includes different strategies: (1) the standard operation; (2) advanced procedures to decompress the abdominal compartment syndrome and (3) percutaneous drainage of abscesses. Nonoperative management includes: (1) antibiotic therapy; (2) hemodynamic and pulmonary support; (3) nutrition and metabolic support; (4) detoxification support (including support of renal and hepatic function) and (5) inflammation modulating therapy. Standard operative management addresses the first two principles and has been shown to reduce mortality by more than 50%. A recent extensive series of studies reports mortality rates around 20%. Patients with an abdominal compartment syndrome (intraabdominal pressure over 25 torr) and patients with advanced disease and compounding risk factors best documented by high APACHE-II scores are candidates for more advanced operations. The mortality rate following abdominostomy (leaving the abdomen open) in 869 patients participating in 37 studies was 42%, when the abdomen was simply left open for decompression (open abdominostomy). When a mesh was used to cover the abdominal wound (mesh abdominostomy) 39% of 439 patients enrolled in 12 studies died. Patients who underwent staged abdominal repair (STAR abdominostomy) faired better. Of 385 patients in 11 studies 28% died. Data from antibiotic studies as well as from immunomodulating therapy are nonconclusive at this point with respect to reducing mortality in intraabdominal infection.

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OBJECTIVE: The goal of antibiotic therapy for surgical sepsis is to kill bacteria that intermittently or continuously reach the bloodstream from the residue of an operatively treated focus. While sepsis and conditions leading to sepsis compromise the immune system, antibiotics may become a fundamental determinant of the host's defense. No data from sound prospective randomized clinical antibiotic trials dealing with sepsis are available. Therefore we tested the hypothesis that treatment recommendations can be based on pharmacodynamics comparing in vitro activity of commonly used antimicrobials with concentrations sustained in vivo to provide for full coverage for bacteria of concern. RESULTS: The application of strict criteria for antibiotic choice to avoid selection of primary resistant strains reveals that most commonly used antibiotics render insufficient activity to eliminate pathogens that commonly cause surgical sepsis. Antibiotics that sustain in vivo concentration exceeding fourfold the MIC100 (highest minimal inhibitory concentration for all (100%) species tested) of Escherichia coli, for example, are 400 mg ciprofloxacin IV (MIC100 of 1224 strains=0.06 mg/dl, in vivo concentration=1 mg/dl for 12 h), and 1000 mg imipenem/cilastatin (MIC100 of 3142 strains=0.14 mg/dl, in vivo concentration=2 mg/dl for 6 h). The third choice is one of the fourth- or, less convincingly, third-generation cephalosporins. Similar data for most pathogens causing sepsis are provided. First- and second-generation cephalosporins and penicillin beta-lactamase inhibitor combinations generally do not achieve sufficient concentrations to cover the most important pathogens of sepsis. CONCLUSION: Sepsis is defined as a whole body's inflammatory response that is characterized by systemic signs and symptoms secondary to a focal infection. While many antibiotic trials have dealt with a focal infection, no prospective randomized antibiotic trial has dealt with sepsis per se. Antibiotic trials on focal infections generally exclude patients when their focal infection has progressed to sepsis. To circumvent the lack of controlled clinical trials we show that pharmacodynamics may provide sound foundation for antibiotic choice for sepsis.

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Cefotaxime has retained its broad-spectrum activity against the key pathogens in surgical infection, despite 15 years of widespread use. It has good activity against a wide range of Gram-positive and Gram-negative aerobes and most anaerobes, except Bacteroides fragilis but, combined with metronidazole, it offers clinically complete coverage of B. fragilis and Escherichia coli, the two most important species involved in intra-abdominal infections. For mixed infections involving B. fragilis, 500 mg metronidazole 12-hourly should be added to the cefotaxime regimen. Cefotaxime therapy is simple, generally inexpensive and has a relatively broad spectrum of activity compared to many other antimicrobials used for postoperative nosocomial pneumonia. Treatment with cefotaxime at 1 g or 2 g can be 12-hourly. Surgical prophylaxis with single-dose cefotaxime (1 g or 2 g) is as effective as with many other agents, with no documented selection of resistance. Clinical experience gained worldwide strongly supports the use of cefotaxime for the treatment of prophylaxis and surgical infections.

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OBJECTIVE: The authors determine if any aspects of the treatment of renal transplant patients with pancreatitis were of particular benefit with regard to graft and patient survival. BACKGROUND: The incidence of pancreatitis in renal transplant patients is low (1%-2%), but the mortality of the disease approaches 100%. Although several descriptive reports have been published, there is no consensus-regarding management. METHODS: The authors conduct a retrospective chart review. RESULTS: Twenty-one patients were identified with posttransplant pancreatitis (1.3% incidence). The cause of pancreatitis was presumed to be maintenance immunosuppression in all cases. Patients were classified by dynamic computed tomography (CT) scans having 1) mild/edematous disease (4 patients), 2) localized abscess or pseudocyst (6 patients), or 3) severe disease (11 patients). Patients with mild/edematous pancreatitis did well with medical management. The six patients with localized abscess or pseudocyst were successfully treated with standard operative intervention. Of the 11 patients with severe disease, 6 had several days of intensive medical management before operation, and all died. The other five patients underwent early operative intervention based principally on CT scan findings, and all survived. The latter group had multiple operations and four of five had functioning renal allografts at discharge. CONCLUSION: The severity of pancreatitis in the posttranplant patients may be difficult to assess by clinical criteria. Dynamic CT scanning is, therefore, essential in defining the extent of disease. Early, and perhaps repeated, operations may be lifesaving in those patients having CT scan findings of severe pancreatitis.

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Excessive duration of antibiotics for prophylaxis and treatment of surgical infection appears to be the principal reason for "inappropriate" administration in current surgical practice. The main factors to blame are the inability of the clinician to distinguish between contamination, infection, and inflammation. Failure to distinguish between contamination and infection is the reason that prophylaxis is unnecessarily carried through into the postoperative phase for prolonged periods. Failure to distinguish between infection and inflammation misguides surgeons to continue antibiotics for unnecessarily long treatment periods. The concept for shortening courses of antibiotic administration is supported by a forum of experts. The majority of experts also favored a trend away from the use of therapeutic courses of fixed duration, by tailoring the duration of administration to the intraoperative findings to shorten treatment courses. Specific recommendations are (1) contamination: single dose prophylaxis (gastroduodenal peptic perforations operated within 12 hours, traumatic enteric perforations operated within 12 hours, peritoneal contamination with bowel contents during elective or emergency procedures, early or phlegmonous appendicitis, or phlegmonous cholecystitis); (2) resectable infection: 24-hour postoperative antibiotics (appendectomy for gangrenous appendicitis, cholecystectomy for gangrenous cholecystitis, bowel resection for ischemic or strangulated "dead" bowel without frank perforation); (3) advanced infection: 48 hours to 5 days, based on operative findings and patient's condition (intra-abdominal infection from diverse sources); (4) severe infection with the source not easily controllable: longer administration periods may be necessary (e.g., infected pancreatic necrosis).

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Acquired immunodeficiency syndrome (AIDS) caused by the human immunodeficiency virus (HIV) may turn out to be the largest lethal epidemic of infection ever. The estimated global number of HIV-infected adults in 1993 was 13 million, with projections of up to 40 million by the year 2000. Human immunodeficiency virus infections and AIDS are relevant to surgeons with respect to the surgical management of AIDS patients in general, the treatment of the increasingly long list of surgical complications specific to AIDS patients in particular, and the risks of patient-to-surgeon and surgeon-to-patient HIV transmission. Because of migration of individuals and populations throughout the world, even surgeons practicing in relatively unaffected regions should be familiar with the potential surgical implications of AIDS. Ethical considerations arise, as well. Are surgeons obliged to operate on HIV-positive or AIDS patients? Some surgeons adhere strictly to the Hippocratic Oath, whereas others reserve the right to be selective on whom they operate, except in emergencies. Other common ethical considerations in the AIDS patient are similar to those arising in the terminal cancer case: whether to operate or not; whether to provide advanced support such as total parenteral nutrition or hemodialysis. Answers are not simple and require close collaboration between the surgeon, the AIDS specialist, and involved members of other specialties. Emergency operations become necessary to treat AIDS independent disease such as acute cholecystitis and appendicitis or AIDS-related life-threatening conditions such as gastrointestinal bleeding, obstruction, perforation, or ischemia complicating Kaposi's sarcoma, lymphoma, and cytomegalovirus or disseminated nontuberculous mycobacterial infections. Delays and errors in diagnosis are frequent. Poor nutritional state with weight loss, low serum albumin, and leukocyte count prevails in most patients requiring emergency operations and account for a high mortality. By applying solid judgment and selecting management appropriately, the surgeon has the ability to prolong life and to improve the quality of life for these unfortunate patients, and to do so with extremely minimal risk to himself and his team.

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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. METHODS: 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.

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BACKGROUND: Although the proximal role of systemic cytokines in the infectious-inflammatory cascades is well recognized, the magnitude and meaning of its intraperitoneal levels in peritonitis have received little attention. We hypothesized that in peritonitis a significant and clinically relevant cytokine-mediated inflammatory response is compartmentalized in the peritoneal cavity. METHODS: MEDLINE was used to search the literature for all articles dealing with experimental, primary, and secondary bacterial peritonitis and cytokines. RESULTS: Bacterial peritonitis is associated with an immense intraperitoneally compartmentalized cytokine response, with plasma levels of cytokines representing only the tip of the iceberg. Although certain amount of cytokines may be beneficial to the peritoneal defense mechanisms, higher levels correlate with adverse outcome. Thus it is plausible to look at acute peritonitis as initially a combined infective (microorganism) and inflammatory (cytokines) process. The clinical significance of the distinction between peritoneal inflammation and infection and the relevance of our findings to the stratification and treatment of peritonitis are discussed. CONCLUSIONS: Current surgical and antibiotic therapy for peritonitis is able to clear the peritoneal cavity of infective concentration of bacteria, but many patients continue to die of an uncontrolled activation of the inflammatory cascade. We suggest that one potential venue for therapeutic progress is the modulation of the compartmentalized peritoneal inflammatory response.

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Pharmacokinetics relate to distribution of drugs between various body compartments; pharmacodynamics pertain to antimicrobial action at the site of infection. In this review the pharmacokinetic/pharmacodynamic justification for short courses of antibiotics is presented. A simplified pharmacokinetic model for most antimicrobials divides the body into a central compartment, the bloodstream, and a peripheral compartment consisting of extravascular fluid. The latter is the site of most infections. Adequate drug concentrations have to be achieved and sustained within the peripheral compartment to kill bacteria, or at least to inhibit bacterial growth and enhance killing by host defence mechanisms. Laboratory data with standardised bacterial inocula suggest that bacteria need to be exposed to either the minimal inhibitory concentration (MIC) or the minimal bactericidal concentration (MBC) for 16-24 hours to inhibit growth or to kill 99.9% of bacteria, respectively. Antimicrobials that yield tissue compartment concentrations in excess of the MIC or MBC, therefore, may be equally effective, and eliminate bacteria within 16-24 hours, once operation has reduced the bacterial inoculum. From this standpoint pharmacokinetics variables such as the time above MIC, which express the antibiotic-microbial-time relationship, become more important. The duration of administration, therefore, must be tailored by clinical judgement to the magnitude of the remaining bacterial inoculum, and the condition of the patient. Pharmacokinetics indicate that courses of treatment can be shortened.

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Excessive duration of antibiotics appears to be the principal reason for their inappropriate use in current surgical practice. The main factors to blame are the inability of the clinician to distinguish between contamination and infection, infection and inflammation, and failure to stratify the latter. Consequently, and unnecessarily, prophylactic drugs are carried through into the postoperative period and treatment is continued for long periods. Most experts who contributed to this Discussion Forum favour a trend away from the use of therapeutic courses of fixed duration, and towards attempts to stratify the infective processes, minimising administration by tailoring the duration to the clinical findings. As a consensus of this forum specific recommendations are: Contamination (gastroduodenal peptic perforations operated within 12 hours, traumatic enteric perforations operated with 12 hours, peritoneal contamination with bowel contents during elective or emergency procedures, early or phlegmonous appendicitis or phlegmonous cholecystitis): single dose prophylaxis. Resectable infection (appendicectomy for gangrenous appendicitis, cholecystectomy for gangrenous cholecystitis, bowel resection for ischaemic or strangulated dead bowel without frank perforation): 24 hours postoperative antibiotics. Advanced infection (intra-abdominal infection from diverse sources): 48 hours to 5 days, based on operative findings and patient's condition. Severe intra-abdominal infection with the source not easily controllable (infected pancreatic necrosis, postoperative intra-abdominal infection): longer courses may be necessary.

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OBJECTIVE: To study the pattern of intraperitoneal cytokine release in secondary peritonitis and its correlation with plasma levels and prognosis. DESIGN: Noncomparative descriptive case series. SETTING: Department of surgery in a university hospital. PATIENTS: Seventeen consecutive patients undergoing planned relaparotomy for severe intra-abdominal infection (Acute Physiological and Chronic Health Evaluation [APACHE II] score > 10; mean score, 17.5). INTERVENTIONS: The following were measured at the first and last serial operations in the peritoneal exudate and plasma: endotoxin, tumor necrosis factor alpha (TNF-alpha), interleukin-1 (IL-1), interleukin-6 (IL-6), elastase, and neopterin. MAIN OUTCOME MEASURES: Survival and death. RESULTS: Six patients died. Peritoneal endotoxin levels were significantly higher than in the plasma and were significantly higher in the nonsurvivors. Plasma TNF-alpha, IL-6, elastase, and neopterin levels remained elevated in the nonsurvivors prior to death. Levels of TNF-alpha, IL-6, elastase, and endotoxin were 19, 993, 239, and 7 times higher, respectively, in the peritoneal exudate than in plasma, all significant differences. Elastase and TNF-alpha levels decreased in survivors during the operative treatment but remained elevated in the nonsurvivors. CONCLUSIONS: Secondary peritonitis is associated with a significant cytokine-mediated inflammatory response that is compartmentalized in the peritoneal cavity and indicates an adverse prognosis. Levels of cytokines in the exudate of peritonitis may be used to better stratify the severity of peritonitis and, in future, to guide local therapy.

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Ischemic complications associated with hemorrhagic shock after blunt or penetrating trauma can result in acute renal, pulmonary, or hepatic failure. Less well described is the association between hemorrhagic shock and ischemic necrosis of the right colon, with only 14 cases reported in the literature. Herein, we report three previously healthy young trauma victims with shock-associated right colon necrosis. Each patient suffered a period of hypotension after injury. Diagnosis and operation took place within 2 days of initial injury in all three cases. In each patient, a right colectomy and primary anastomosis was performed without complication. Pathologic examination of the resected specimens showed ischemic necrosis, but no evidence of vascular thrombosis or embolic occlusion of the mesenteric vessels. The etiology of this type of ischemic colitis is not clear, but seems to represent a form of nonocclusive mesenteric ischemia. Knowledge of this disease process will lead to early recognition, prompt treatment, and a satisfactory outcome.

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Abscess formation at the site of drug injection is the commonest infectious complication in drug addicts. This study characterizes the clinical presentation of the condition, its current microbiology, and treatment outcome. All patients presenting for treatment of soft tissue abscesses associated with parenteral drug abuse over a 21-month period were studied. Sixty-six patients with 70 subcutaneous abscesses after injection of cocaine (85%), heroin (5%), or unreported drugs (10%) were identified. Only 42% were febrile (T > 37.5 degrees C), 54 percent had leukocytosis, and 47 percent had wound fluctuance. Wound cultures (243 isolates in 57 patients) grew predominately anaerobes (143 isolates) and facultative gram-positive cocci (88 isolates). Twenty-six blood cultures were obtained, and five (19%) were positive, two with the same bacteria isolated from the wound. Of the patients tested, 29 percent were positive for hepatitis B surface antigen and 9 percent for HIV. Simple incision and drainage was effective in all cases. Classical signs and symptoms of infection and abscess formation may be absent in this patient population. Many of these patients carry other blood-borne infections which the health professional must guard against. Cocaine injection, and "mixed" aerobic-anaerobic infections predominated, in contrast to earlier reports, when narcotics and aerobes predominated. Simple incision and drainage is adequate treatment; antibiotics, when given, should cover gram-positive and anaerobic bacteria; gram-negative coverage is unnecessary.

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Pyoderma fistulans sinifica (PFS, also referred to as fox den disease because its multiple fistulae and sinuses resemble the structure of a fox den) is a distinct chronic infectious disease in which epithelialized tracts form within the subdermal fatty tissue. PFS, which has not been previously described in the English-language literature, must be differentiated from hidradenitis suppurativa, pilonidal sinus, and perianal fistula. The fistulous tracts of PFS are always lined by stratified squamous-cell epithelium but, unlike those of hidradenitis, reach deep into the subcutaneous fat, run epifascially for long distances, and have no relation to skin appendices. We report on 10 men (mean age +/- SD, 36 +/- 5 years) with PFS (mean duration +/- SD, 11 +/- 7 years). Bacterial cultures of affected tissue from these patients yielded a total of 14 facultative and 31 obligate anaerobic species. Treatment consisted of wide en-bloc excision down to the fascia, including all fistulae. Antibiotic therapy temporarily reduced purulent discharge but did not eradicate the infection. Two patients who underwent fistulotomy without wide en-bloc excision developed recurrences.

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UNLABELLED: The necessity of preoperative or intraoperative mechanical bowel preparation of the colon, before primary anastomosis, has been recently challenged in clinical elective and emergency situations. PURPOSE: This experimental study in dogs investigated the safety of segmental resection and primary anastomosis in the unprepared or loaded colon. METHODS: Two segments of the descended colon were resected and anastomosed in each animal. Group I (12 anastomoses) received preoperative mechanical bowel preparation; the colon was not prepared in Group II (16 anastomoses); in Group III (12 anastomoses), a preliminary distal colonic obstruction was produced, and during the subsequent resection the colon was loaded. Postoperatively, animals were observed clinically, and anastomoses were assessed at autopsy on the ninth day. RESULTS: All animals recovered uneventfully. At autopsy there was no evidence of anastomotic leakage. CONCLUSIONS: In light of recent clinical reports and this experimental study, the ritual of mechanical bowel preparation should be further scrutinized.

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