Biomedical subjects
Publications and source records attributed to W G Cheadle.
Infection remains a dreaded complication after elective operations and repeated surgical procedures may be necessary in those who present with severe infection. The immune response to such infection is becoming increasingly understood and new therapies are being developed based on this knowledge.
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.
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.
External abdominal fistulas that arise from the digestive tract are associated with high mortality and prolonged morbidity in terms of infection, malnutrition, and skin excoriation. Such external fistulas most commonly follow anastomotic leak after gastrointestinal surgery. We identified 58 patients seen over a 5-year period at the University of Louisville Hospitals because of external abdominal fistulas that arose from the stomach (8), duodenum (4), small intestine (26), colon (14), biliary tract (9), and pancreas (7). Fifteen patients had multiple fistulas and 32 had high-output fistulas (greater than 200 mL/day). Closure was achieved in 48 patients, and eight of the 10 patients whose fistulas remained open died. Overall mortality was 19%. Principles of management include control of infection, correction of fluid and electrolyte imbalance, nutritional support, proper wound care, and often operative intervention. Multiple staged operations over many months were particularly important in managing complex wounds with large abdominal wall defects and multiple fistulas. Fistula closure is the ultimate goal, and patience is important to achieve it.
Polymyxin B, when bound to a polystyrene fiber (PMX-F), has been used experimentally as an extracorporeal blood filter to reduce serum lipopolysaccharide levels, which are believed to be responsible for physiologic alterations in the septic state. To validate our theory that a combination of PMX-F, systemic antibiotics, and immune stimulation would improve survival, 78 rats were given intravenous doses of Escherichia coli (range, 4.6 to 6.2 X 10(8) colony-forming units/ml). They were then randomized into groups receiving either systemic gentamicin (n = 10); pretreatment with muramyl dipeptide (n = 11); or extracorporeal hemoperfusion through either a sham column (n = 8), PMX-F-packed column with systemic gentamicin (n = 8); or PMX-F-packed column with systemic gentamicin and muramyl dipeptide pretreatment (n = 8). Thirty-three control rats received no treatment. Sham hemoperfusion (13%) and control (21%) rats had the lowest survival rate, although increased improvement was noted in rats treated with gentamicin (30%) or the combination of PMX-F filtration and gentamicin (50%). The most significant improvements occurred in rats pretreated with muramyl dipeptide (53%) and in rats treated with a combination of PMX-F, gentamicin, and muramyl dipeptide (88%). These data show that lipopolysaccharide filtration and nonspecific immune stimulation are additive to antibiotic therapy and are useful as adjunctive measures in the multimodal treatment of experimental gram-negative bacterial infection.
The charts of all patients with colonic volvulus at the University of Louisville Hospitals between 1983 and 1988 were reviewed. A total of 45 patients were identified, and there were 17 with cecal volvulus and 29 with sigmoid volvulus (1 had both). Two-thirds of the patients were either demented, bedridden, or used constipating drugs. Initial nonoperative decompression was achieved in 26 of 29 patients with sigmoid volvulus but in only three of nine patients in which it was attempted with cecal volvulus. Two of these recurred, and 16 of the 17 cecal volvulus patients underwent operation. One-third of the sigmoid volvulus patients had at least one recurrent episode on the index admission. Fourteen of the 29 had an operation, and half of these patients died following surgery. Fifteen sigmoid volvulus patients chosen to be treated with successive nonoperative treatment had no mortality. Mortality was higher following emergent (4 of 5) than elective (2 of 9) operation for sigmoid volvulus, and one of three died after operation for a successfully decompressed first episode. Mortality for nonoperative reduction of an early recurrence was zero of four patients, while operative mortality for recurrence was two of seven (all had successful preoperative deflation). There was no mortality or recurrence in four patients with cecal volvulus treated by cecopexy alone, but all three patients died in whom tube cecostomy was performed. Two of nine patients died following right hemicolectomy. These data suggest that if an elective operation is to be performed for sigmoid volvulus, it should be done following one or more recurrences and that nonoperative decompression can be safely performed on successive occasions.(ABSTRACT TRUNCATED AT 250 WORDS)
Immunological assessment is important to characterize the host defence response of trauma patients as infection is the most common cause of severe morbidity and late death. Sixty trauma patients were followed serially and divided into three groups: those with an uneventful recovery (n = 17), those with recovery after major sepsis (n = 27) and those who died (n = 16). The ability of peripheral blood monocytes to express the antigen HLA-DR was measured and compared to the results from 77 asymptomatic volunteers. After initial injury, there was a significant reduction from normal in the three trauma groups. It took one week for HLA-DR antigen expression to return to the normal range in the first group, three weeks in the second group, and in the third group it never returned to normal. Monocyte HLA-DR antigen expression, after incubation with lipopolysaccharide, distinguished those patients who survived from those who died. There was no difference in HLA-DR antigen expression between a high transfusion group of 31 patients who received 10 or more units of blood and a low transfusion group of 29 patients who received less than 10 units. The ability of monocytes to express HLA-DR antigen correlated directly with the clinical course in these patients and its measurement identified a group of patients at high risk of infection and death following trauma.
Enterogastric reflux has been implicated as a possible etiologic mechanism in gastritis both after partial gastrectomy and in those with an intact pylorus. We studied the effects of cimetidine on bile acid concentration and composition by high-performance liquid chromatography. The gastric aspirates collected for this study came from 27 prospectively randomized patients receiving intravenous cimetidine (200 mg every 6 hours) and 25 patients given a placebo. Total bile acid concentration of aspirates was determined spectrophotometrically. Marked differences were noted in conjugated bile acids. Glycochenodeoxycholic acid, a toxic dihydroxy bile acid, was decreased after cimetidine compared with results from the placebo. The ratio of less toxic trihydroxylated to more toxic dihydroxylated bile acids was significantly increased. Enterogastric reflux itself seemed unaltered by cimetidine; likewise, the concentration of total bile acids in the cimetidine group was similar to that among patients receiving placebo. These changes in bile salt composition with cimetidine may help explain its salutary effects in gastritis, over and above its ability to reduce gastric hydrogen ion secretion.
Protein binding, serum kinetics and minimum inhibitory concentrations (MICs) for Staphylococcus aureus were determined for cefoxitin, cefazolin, ceftazidime and ceftriaxone in the rabbit. MICs of cefazolin and cefoxitin were also measured for Escherichia coli. Varying concentrations of the bacteria were administered intradermally to create areas of cellulitis, which were quantified as mean erythematous areas (EAs). Despite large differences in protein binding of the antibiotics (range 12-88%) and antibiotic dosing to allow serum concentrations to drop below the respective MICs, there was no statistical difference in the mean EAs of the animals after bacterial challenge. Antibiotic protein binding did not alter the course of cellulitis nor correlate with bacterial MIC in this model.
Twenty-seven severely injured patients had antibody response to gram-negative organisms measured of whom 25 also had skin testing. Twenty-three patients (92%) were anergic at admission. Injury Severity Scores were greater in patients who remained anergic for three weeks compared with patients whose skin tests became positive. Patients with major infection had longer anergy duration than uninfected patients. Twenty-two (81%) of 27 anergic patients mounted antibody responses. Initial bacterial contamination determined the clinical outcome and antibody response. Six of eight patients with moderate contamination mounted IgM responses to all organisms and/or an IgG response to Escherichia coli, and they remained uninfected. Of the other two patients, one died, and the other developed chronic infection. Seven of eight patients with heavy contamination developed major sepsis despite mounting several antibody responses. Six patients without contamination mounted no antibody responses and remained uninfected.
Forty-three consecutive trauma patients with an injury severity score greater than 20 were studied prospectively for evidence of cytomegalovirus (CMV) infection. Twenty-one patients had serologic conversion: 3 with primary CMV infections, 18 with reactivation of CMV infection (CMV group). Twenty-two patients had no serologic conversion (no CMV group). To differentiate the effects of CMV and transfusion, the CMV group and the no CMV group were each divided into high (more than 10 units) and low (less than 10 units) transfusion subgroups. Similar fever peaks, leukocyte counts, lymphocyte counts, and incidence of major bacterial sepsis were recorded for the four subgroups. Several factors were significantly associated with CMV infection independent of transfusion, including increased duration of major bacterial sepsis and number of septic episodes per patient; prolonged duration of anergy; increased duration of intensive care unit and hospital stay; increased duration of ventilatory assistance and rate of tracheostomy; and increased suppressor cells, decreased helper: suppressor ratios, increased functional suppressor cells, and increased natural killer cells. Although mortality was not increased with CMV infection, our data suggest that such infection after trauma may delay recovery from major bacterial infection, often resulting in a major increase in morbidity.
Previous studies using cholescintigraphy and measurement of bile salts in gastric juice have demonstrated that duodenogastric reflux is increased after cholecystectomy, a factor that may contribute to postoperative complaints in some patients. We studied 24-hour continuous gastric pH in healthy subjects, patients with cholelithiasis, and patients who had undergone cholecystectomy. Cholecystectomy decreased the percentage of time that gastric pH is below 2 and increased the time it is above 4 and 6. Furthermore, there was a greater increase in the more alkaline pH values in patients who were symptomatic than in those who were asymptomatic. The results demonstrated that cholecystectomy is associated with an alkaline shift in the 24-hour gastric pH profile that is most marked in symptomatic patients. This suggests that gastric alkaline episodes may be related to some postcholecystectomy symptoms.
Muramyl dipeptide (MDP), a purified synthetic immune adjuvant, has been shown to increase murine intraabdominal abscess formation in a monomicrobial model using Bacteroides fragilis. This effect required live bacteria and was abolished by appropriate antibiotics. A polymicrobial model of peritonitis and abdominal abscess formation using Streptococcus fecalis, Escherichia coli, and B. fragilis was initially used to determine mortality rates at various concentrations and obtain an appropriate LD50. Animals were then pretreated with MDP or its inert buffer and underwent intraperitoneal injection of the appropriate bacterial suspension. Mortality and abdominal abscess formation were then assessed at 2 weeks after injection. There was a significant reduction in mortality (P less than 0.03) in mice treated with MDP compared to the controls. In surviving animals, there was also a significant increase in the number of animals forming abscesses (P less than 0.05) following treatment with MDP. This study has shown that nonspecific immune stimulation by MDP provided enhanced protection against a polymicrobial intraperitoneal challenge and paradoxically increased the formation of abdominal abscesses at the same time. This may be regarded as enhancement of the natural history of survival from peritonitis via bacterial containment through intraabdominal abscess formation, a manifestation of beneficial outcome in experimental peritonitis.
Current trauma assessment scores do not include an assessment of immune competence and have not been designed to predict late death from or risk of infection. We have compared the use of the Outcome Predictive Score (OPS) with other standard scales to predict clinical outcome after trauma. The OPS combines the Injury Severity Score (ISS) corrected for age (%LD50), degree of bacterial contamination, and monocyte HLA-DR antigen expression on hospital admission. The OPS was compared to the ISS, %LD50, Revised Trauma Score (RTS), Combined Trauma Score-ISS (TRISS), and Anatomical Index (AI). Sixty-one seriously ill patients were studied. Patient outcome was defined as uneventful recovery (n = 18), major infection (n = 27), and death (13 of 16 deaths resulted from infection). The assessment scores were compared for their use in prediction of these outcomes, as well as their ability to distinguish patients with good outcome from those patients who developed major infection or died, and to differentiate survival from death. Only the OPS was able to significantly segregate all five outcome groups (p less than 0.05). Although the age-adjusted ISS distinguished between survival and death (p less than 0.05), only OPS consistently distinguished between good outcome and sepsis/death (p less than 0.05), and therefore best identified the patients who developed infection. AI, RTS, and TRISS had little predictive value.
Copovithane (CPV), a synthetic polymer, has been shown to have antitumor activity and also to reduce mortality in experimental murine peritonitis. The purpose of this study was to compare CPV with muramyl dipeptide (MDP), an immunomodulator of proven efficacy in simulated surgical infection. Six groups of CBA/J mice were compared; they received intramuscular injections of normal saline (controls), MDP (100 micrograms), or CPV (100, 200, and 400 mg/kg) 24 h prior to bacterial challenge. The challenge consisted of a Klebsiella-impregnated thigh suture. The first experiment assessed survival after bacterial challenge. The MDP and the CPV groups both had median survival times of 3 days, significantly longer than the control group (1 day, p less than .05). In the second experiment, animals were sacrificed at 6, 24, and 48 h following bacterial challenge, and blood and infected muscle were taken for quantitative bacteriology. At 6 h, there was no difference between groups. Both the MDP and CPV groups had significantly (p less than .05) lower blood bacterial counts than the control group at 24 and 48 h. Both the MDP and CVP groups had significantly lower local bacterial recovery than controls at 48 h (p less than .05), and local bacterial recovery of the MDP group was significantly lower than the control group at 24 h (p less than .05). CPV improved survival and reduced local and systemic bacterial recovery compared with controls. Although the effect of CPV was similar to MDP in this model, it consistently was of lower magnitude and had a narrow dose range.
We determined the natural history of experimental abscess formation and had a secondary interest in the effect of muramyl dipeptide. Swiss-Webster mice were injected intraperitoneally with autoclaved mouse fecal suspension and either Bacteroides fragilis (10(8) colony-forming units [cfu]/mL) alone or Escherichia coli (10(4) cfu/mL), enterococcus (10(3) cfu/mL), and B fragilis (10(5) cfu/mL) after pretreatment with muramyl dipeptide or saline solution. All deaths occurred within 48 hours of injection and surviving mice, including those bearing abscesses, appeared to be healthy throughout the study. The number of mice with abscesses and the number of abscesses per group were at their maximum at two to four weeks. Groups with live bacteria had a substantial reduction in the number of abscesses between eight and 26 weeks, compared with two- and four-week values. Manual rupture of palpably large eight-week-old abscesses in 21 mice produced only one death and at autopsy two weeks later, all of the mice showed multiple smaller abscesses. Abscess formation appeared to be beneficial and the natural history of such may include spontaneous resolution without mortality.
Injury is an important cause of both morbidity and mortality, particularly in the young. Scoring systems have been developed to establish guidelines of transfer and compare patient outcome, but no scoring system as yet has been constructed that focuses upon immune capability of these patients. We report an outcome predictive score (OPS) which appears to distinguish good outcome from sepsis in patients who survive, and between patients with sepsis who survive from patients with sepsis who die. The score is based on (1) Injury severity score (ISS) expressed as percentage of the 50 per cent lethal dose of injury for age (%LD50), (2) Degree of bacterial contamination at initial injury, (3) The patient's monocyte DR antigen expression. Fifty-one severely injured patients were divided into three groups: (1) A group without infection (N = 15), (2) A major sepsis group which survived (N = 24), (3) A group who died (N = 12). There was no difference between the ISS of these groups. The mean OPS of the good outcome group was significantly less than the mean OPS of both the septic (P less than 0.0002) and dead (P less than 0.00001) groups. The mean OPS of the septic group was also significantly less than the mean of the group that died (P less than 0.002). Identification of high risk patients may be important to determine priority of patient care and to institute additional therapeutic measures.
Fifty asymptomatic volunteer subjects underwent prolonged computerized ambulatory distal esophageal pH monitoring to characterize acid reflux patterns. A bimodal distribution of data, which corresponded to the erect and supine positions, occurred in 45 subjects, and separate mean baseline pH values were noted for the erect and supine positions (pH 6.46 and pH 5.46, respectively, p less than 0.001). At esophageal pH 4, reflux episodes occurred more commonly in the erect position (44 percent) than in the supine position (20 percent). There were also significantly greater numbers of reflux events and longer durations when the pH was below 3 (p less than 0.02) and 4 (p less than 0.001) in the erect compared with the supine position, but prolonged events (more than 10 minutes) occurred in both positions. Postprandial reflux occurred in 78.7 percent of the subjects, with an average of 5.1 episodes. A slight but significant correlation between age and erect reflux was seen (p less than 0.04). In the pH 3 to 5 range, 18 percent of the subjects had acid exposure in excess of the group mean plus 2 standard deviations and 10 percent in excess of the mean plus 3 standard deviations. Overall, a nonnormal distribution of pH data was found with 28 subjects having less than 1.6 percent of their values below pH 4. This finding may represent either the true spectrum of normal acid reflux or a subclinical pathologic state that will become symptomatic over time.