William G. Cheadle

HLA-DR antigen expression on peripheral blood monocytes correlates with surgical infection

Monocyte human leukocyte antigen-DR (HLA-DR) expression has correlated closely with clinical outcome in severely injured patients at high risk for infection. Monocytes from 77 asymptomatic volunteers expressed HLA-DR antigen with minimal variability in respect to age, gender, race, time of day or year, or serum alcohol level. Patients who developed infection after elective laparotomy had a significantly lower mean percentage of monocytes expressing HLA-DR antigen and a lower mean fluorescent intensity than uninfected patients (p less than 0.05). Severely infected nonsurgical patients had significantly lower values than normal volunteers (p less than 0.01), and the mean fluorescent intensity of those who died from infection was significantly lower than that of those who survived (p less than 0.05). Patients on immunosuppressive regimens after renal transplantation had levels of HLA-DR expression similar to those of the volunteers. Monocyte HLA-DR expression was found to be a reliable marker of clinical infection and showed remarkable reproducibility within the normal uninfected study population.

A randomized prospective clinical trial to determine the efficacy of interferon-γ in severely injured patients

Many aspects of the normal immune response are depressed after severe injury. Reduced monocyte human leukocyte antigen-DR (HLA-DR) levels have closely correlated with the development of major infection. After a pilot study with recombinant interferon-gamma (rIFN-gamma) showed restoration of depressed HLA-DR levels after major injury, a multicenter, prospective, randomized, double-blind trial was conducted. Two hundred thirteen trauma patients who were at high risk of infection received either placebo or rIFN-gamma (100 micrograms) subcutaneously each day for 10 days after admission. One hundred ninety-three patients were evaluable with respect to primary end points. Patients treated with rIFN-gamma were older (p = 0.10) and had more severe modes of injury (p = 0.02). By the third day, both monocyte HLA-DR antigen expression and outcome predictive score were significantly better in the rIFN-gamma-treated group than in the placebo group (p = 0.0001 and p = 0.0006, respectively). Nine deaths occurred in patients treated with rIFN-gamma compared with 12 deaths in the placebo group (p = 0.46). Major infections requiring surgical drainage or debridement occurred in 17 patients treated with rIFN-gamma compared with 22 treated with placebo. No difference between treatment arms was noted in overall major or minor infection rates, but there were fewer severe infections that required reoperation or computer tomographic-guided drainage in patients receiving IFN-gamma. While these results suggest that rIFN-gamma may be useful in some aspects of infection in the patient with severe trauma, a larger trial with longer treatment will be needed to prove the comprehensive value of rIFN-gamma.

Trial of Short-Course Antimicrobial Therapy for Intraabdominal Infection

BACKGROUND The successful treatment of intraabdominal infection requires a combination of anatomical source control and antibiotics. The appropriate duration of antimicrobial therapy remains unclear. METHODS We randomly assigned 518 patients with complicated intraabdominal infection and adequate source control to receive antibiotics until 2 days after the resolution of fever, leukocytosis, and ileus, with a maximum of 10 days of therapy (control group), or to receive a fixed course of antibiotics (experimental group) for 4±1 calendar days. The primary outcome was a composite of surgical-site infection, recurrent intraabdominal infection, or death within 30 days after the index source-control procedure, according to treatment group. Secondary outcomes included the duration of therapy and rates of subsequent infections. RESULTS Surgical-site infection, recurrent intraabdominal infection, or death occurred in 56 of 257 patients in the experimental group (21.8%), as compared with 58 of 260 patients in the control group (22.3%) (absolute difference, -0.5 percentage point; 95% confidence interval [CI], -7.0 to 8.0; P=0.92). The median duration of antibiotic therapy was 4.0 days (interquartile range, 4.0 to 5.0) in the experimental group, as compared with 8.0 days (interquartile range, 5.0 to 10.0) in the control group (absolute difference, -4.0 days; 95% CI, -4.7 to -3.3; P<0.001). No significant between-group differences were found in the individual rates of the components of the primary outcome or in other secondary outcomes. CONCLUSIONS In patients with intraabdominal infections who had undergone an adequate source-control procedure, the outcomes after fixed-duration antibiotic therapy (approximately 4 days) were similar to those after a longer course of antibiotics (approximately 8 days) that extended until after the resolution of physiological abnormalities. (Funded by the National Institutes of Health; STOP-IT ClinicalTrials.gov number, NCT00657566.).

Interruption of professional and home activity after laparoscopic cholecystectomy among French and American patients

With a laparoscopic approach, patients can undergo cholecystectomy with a shorter hospitalization, minimal pain, and quicker recovery. It has not been demonstrated, however, that patients actually return to work after laparoscopic cholecystectomy faster than the traditional 4- to 6-week absence from work after a standard open procedure. A survey of 104 French and 84 American patients undergoing laparoscopic cholecystectomy revealed that postoperative discomfort was completely resolved in 2 weeks in 73% of French and 93% of American patients. All but 11 French and 5 American patients were back to normal home activities by 2 weeks after the operation. Of the 35 American and 40 French patients who had professional activity outside the home, 63% and 25%, respectively, returned to work within 14 days. Five (14%) of the American patients and 12 (30%) of the French patients returned to work 4 weeks or more after the operation. The amount of physical activity on the job correlated with the period off work, but, interestingly, at least six patients with very hard physical activity at work (including construction workers) were able to return to full work activity within 1 week. These data suggest that early return to work is possible and that pain resolves quickly after laparoscopic cholecystectomy. The economic benefit of having patients back on the job quickly, however, may be less than expected until cultural norms change with regard to leave of absence after major surgery.

Lymphocyte subset responses to trauma and sepsis

One hundred five trauma patients admitted to three trauma centers with injury Severity Scores of 20 or greater had lymphocyte phenotypic subsets characterized throughout their hospital course. Total lymphocytes, pan-T (CD2), helper T (CD4), suppressor T (CD8), pan B (CD20), and DR expressing lymphocytes were quantitated by monoclonal antibodies and flow cytometric analysis. Results were analyzed between three patient groups: uninfected, uneventful recovery (n = 64); major infection (n = 26); and dead (n = 15; 7 with sepsis). A significant lymphopenia, maximal at 3 days, occurred in the first postinjury week compared with controls (p < 0.05), which recovered over the study period. A hierarchical distribution was found between the three outcome groups with the lowest numbers of several lymphocyte phenotypes in those who died. T helper and suppressor cells were similarly affected, but lowest in patients destined to develop infection or die. The helper-suppressor ratio, however, was similar in all three outcome groups. Therefore, modulation early after injury aimed at restoring these subsets may reduce the risk of subsequent infection.

Jaks, STATs, Cytokines, and Sepsis

Sepsis remains a significant cause of morbidity and mortality in the intensive care unit (68), affecting more than 500,000 patients per year in the United States (39). The incidence is increasing despite the major advances in the development of antimicrobial agents and other supportive treatments (56). Septic patients often succumb to a systemic inflammatory response, of which multiple organ failure is a main complication. There is no definitive treatment for multiple organ failure other than supportive treatment, such as assisted ventilation or renal dialysis. Research efforts now heavily focus on the mechanisms of multiple organ failure, with the hope that treatment options can be identified through a better understanding of these mechanisms. One current theory implicates an inappropriate cytokine response as the main protagonist in the development of multiple organ failure following an inflammatory stimulus (35, 48). Cytokines are low-molecular-weight polypeptides or glycoproteins that regulate numerous cellular functions and allow both autocrine and paracrine signaling. Cytokines regulate many of the pathways involved in the host inflammatory response to sepsis. They influence cell differentiation, proliferation, and activation and modulate proinflammatory and anti-inflammatory responses to allow the host to react appropriately to pathogens. The binding of a cytokine to a corresponding receptor initiates intracellular signal cascades, ultimately leading to changes in gene expression. These signals must rapidly transduce an extracellular signal to the nucleus. The Janus-kinase/ signal transducers and activators of transcription (Jak/STAT) pathway is employed in the signaling of many cytokines. Cytokine receptors do not, in general, have intrinsic tyrosine kinase activity and therefore require association with receptor-associated kinases in order to propagate a phosphorylation cascade. Jaks fulfill this function by their ability to associate with many of the cytokine receptors that are involved in regulatory pathways during a sepsis response. Cytokines bind to their receptors and cause receptor dimerization. This enables Jaks to phosphorylate each other as well as the cytokine receptors. Cytokine receptor phosphorylation allows binding of STATs via a specific binding domain. Once bound to the receptor, STATs are also phosphorylated by Jaks. STATs then dissociate from the receptors and dimerize. Dimerization enables translocation of STAT into the nucleus and binding to DNA in order to alter transcription (Fig. 1). Four Jaks and seven STATs have been identified to date in mammalian cells. Multiple Jaks and STATs, as well as the ability of STATs to homoor hetero-dimerize, allow for cytokine-specific cellular responses (47). This minireview describes a number of important cytokines involved in regulating the inflammatory response to sepsis, the importance of the Jak/STAT pathways, and how these pathways are regulated.

Peritoneal host defenses are less impaired by laparoscopy than by open operation.

There is a growing body of evidence that laparoscopic surgery is physiologically less injurious than open surgery. We hypothesized that the open technique results in a greater impairment of peritoneal and systemic defense mechanisms than does the laparoscopic technique. Nissen fundoplication, standardized in technique and duration, was performed in 16 pigs. The procedure was performed through a standard midline incision (OPEN, n=8) or with laparoscopic technique and CO2 pneumoperitoneum (LAP, n=8). The peritoneal cavity was instilled with 400 cc of normal saline, either alone (not contamined, n=8) or containing 109E. coli/ml (contaminated, n=8). Quantitative cultures, cell count, and flow cytometry were performed on blood and peritoneal fluid samples obtained at timed intervals. We found that host defense processes were better preserved after LAP than by OPEN surgery. Peritoneal and systemic monocyte class II antigen expression, and serum tumor necrosis factor-alpha activity was greater in the OPEN group compared with the LAP group, but peritoneal bacterial clearance was more efficient in the LAP group. These data may illustrate a potential benefit of laparoscopic surgery in cases of peritoneal contamination.

Computerized 24-hour ambulatory esophageal pH monitoring and esophagogastroduodenoscopy in the reflux patient. A comparative study.

Ambulatory 24-hour esophageal pH monitoring and esophagogastroduodenoscopy were performed in 72 patients with symptoms suggestive of gastroesophageal reflux. Additionally, 22 asymptomatic healthy volunteers underwent pH monitoring. In patients with classic reflux symptoms and endoscopic esophagitis, a mean of 5.41 minutes/hour of reflux below pH 4 was found compared to 0.70 minutes/hour in controls (p less than 0.0001). The mean number and duration of reflux events in this group were 1.51 events/hour and 4.0 minutes/event, compared with 0.31 events/hour and 2.26 minutes/event in volunteers (p less than 0.001, p less than 0.01). A new system for ambulatory esophageal pH monitoring is presented using a pH-sensitive radiotelemetry pill or a pH probe and computerized methods for ambulatory data collection, analysis, and storage. An overall sensitivity of 76% was obtained with a 91% selectivity for detection of acid reflux in 51 patients having classic symptoms of gastroesophageal reflux. Ambulatory pH monitoring was positive for acid reflux in seven of 11 patients with normal endoscopic findings. Conversely, eight of 12 patients with normal pH monitoring had endoscopic esophagitis. In 19 patients presenting with atypical symptoms or previous gastric surgery, endoscopic findings were normal in 15. Nine of these 15 were identified as acid refluxers by pH monitoring. A combined approach using both pH monitoring and endoscopy is warranted for maximal detection and quantification of disease. A clear clinical role for pH monitoring is seen in the early diagnosis of acid reflux, particularly in patients having normal endoscopic findings with nonspecific gastrointestinal complaints or previous gastric operations.

Prophylactic postoperative nasogastric decompression. A prospective study of its requirement and the influence of cimetidine in 200 patients.

To determine the need for prophylactic nasogastric decompression following laparotomy and the influence of cimetidine, 200 consecutive patients who underwent major abdominal procedures were prospectively randomized into one of four limbs: no tube-placebo; no tube-cimetidine; tube-placebo; and tube-cimetidine. Patients were evenly distributed among these groups with respect to age, sex, alcohol and tobacco use, previous operations, and types of operations. There was significantly longer time until passage of flatus, bowel movement, and cessation of intravenous fluids in the tube group (p less than 0.05). Duration of postoperative stay increased from 11.4 to 14.1 days in the intubated patients (p less than 0.05). There was also significantly more pain with and frequency of swallowing, and nose/throat discomfort in the tube group. Nasogastric tubes reduced the incidence of vomiting from 28 in the no-tube group to 10 in the tube group (p less than 0.05), but most had only one or two episodes. Cimetidine did not affect either the incidence of vomiting or the duration of intubation, but was associated with a significant increase in pneumonias (p less than 0.05). Five patients without tubes initially, and seven patients with tubes had to have them inserted or replaced for vomiting or abdominal distention, which occurred equally in the placebo and cimetidine limbs. There were no cases of aspiration pneumonia, gastric dilatation, or wound dehiscence in the trial, and the four anastomotic leaks were divided equally between the tube and no-tube groups. The results indicated that prophylactic decompression was unnecessary in most patients and associated with increased morbidity and delayed return of gastrointestinal function. Cimetidine lowered nasogastric output on the first postoperative day (p less than 0.05), but did not prevent vomiting.

Regulation of early peritoneal neutrophil migration by macrophage inflammatory protein-2 and mast cells in experimental peritonitis.

Neutrophil (PMN) migration into the peritoneal cavity in response to fecal peritonitis is an important mechanism of host defense against bacterial invasion. We show that the murine C‐X‐C (PMN‐specific) chemokine, macrophage inflammatory protein‐2 (MIP‐2), on intraperitoneal injection in mice, causes PMN migration into the peritoneum. MIP‐2 mRNA and protein were expressed by peritoneal leukocytes after cecal ligation and puncture (CLP) in mice and neutralization of MIP‐2 reduced peritoneal PMN migration. A prerequisite for neutrophil‐endothelial adhesion and subsequent migration from the circulation is selectin‐mediated rolling. Pretreatment of mice with an anti‐P‐selectin antibody before intraperitoneal injection of MIP‐2 significantly reduced peritoneal PMN migration. However, there are no reports that a C‐X‐C chemokine can up‐regulate endothelial selectins. We postulated that MIP‐2, when injected intraperitoneally, interacts with a cell that is known to release factors that up‐regulate endothelial selectins. A likely candidate is the mast cell, which contains histamine and tumor necrosis factor α (TNF‐α), and both of these factors induce selectins. Intraperitoneally injected MIP‐2 caused an early significant increase in peritoneal TNF‐α, whereas histamine levels were unaffected. In a subsequent experiment, mast cell‐deficient mice and their normal controls were then injected intraperitoneally with MIP‐2 or underwent CLP. Significantly fewer PMNs migrated into the peritoneal cavity in the mast cell‐deficient mice after MIP‐2 injection or CLP. Thus, our findings indicate that mast cells and MIP‐2 are necessary for PMN migration into the peritoneum in response to intra‐abdominal infection, and that MIP‐2 appears to facilitate this through an increase in TNF‐α release. J. Leukoc. Biol. 65: 249–255; 1999.