GYNECOLOGIC
ONCOLOGY
4,
40-47 (1992)
Infectious Complications after Gastrointestinal Surgery in Patients with Ovarian Carcinoma and Malignant Ascites D. DONATO, M.D.,*,’ *Division
of Gynecologic
A. ANGELIDES, Oncology,
M.D.,*
H. IRANI, M.D.,?
Department of Obstetrics 016310, University of Miami
M. PENALVER, M.D. ,* AND H. AVERETTE,
and Gynecology, P. 0. Box 016960, School of Medicine, Miami, Florida
and TDepartment 33101
of Surgery,
M.D.* P. 0. Box
Received March 11, 1991
plications
in this patient population
[1,3,7]. After an ex-
One hundred four patients with ovarian cancer underwent intestinal reconstruction as part of a cytoreductive effort or for tensive search of the English literature, no articles could relief of intestinal obstruction from July 1980 to June 1990. be found that addressed the infectious complications ocTwenty-four percent~of patients were obstructedpreoperatively, curring in ovarian cancer patients with ascites who while the remainingseventy-sixpercenthad bowelresectionsper- undergo various bowel reconstructive procedures. It is formed in concert with a debulking procedure. The overall in- well known from the literature that patients with cirrhosis fectious complication rate was 14.4%. No statistical association and ascites have an 8-10% incidence of spontaneous bacwas found betweenthe presenceof ascitesat the time of lapa- terial peritonitis [9-121. These patients are also at sigrotomy and infectiousmorbidity (P = 0.58). The useof a pre- nificant risk for septic morbidity and mortality with the operative mechanicalbowel preparation was associatedwith a performance of even minor surgical procedures such as significant reduction in infectious morbidity (P = 0.01). Addi- upper endoscopy, colonoscopy, or paracentesis [9,10,13tionally, patients consideredin adequatenutritional condition 18]. However, patients with cirrhosis have multiple deexperiencedsignificantly lessinfectious complicationsthan those fects that contribute to their increased susceptibility to patients in poor nutritional condition (P = 0.03). Intestinal proinfection. For example, the loss of significant liver parceduresinvolving the large bowelweremarginally associatedwith increasedinfectious complications(P = 0.13). Neither preop- enchyma results in major impairments in the synthesis of erative radiotherapy, the presenceof preoperative obstruction, vital proteins such as clotting factors and albumin [9,19]. these patients have multiple immunological diseasepresence,extent of debulking, number of intestinal pro- Additionally, cedures,or hand versus stapled anastomosiswas found to be defects, including diminished portal clearance of bacteria, significantly associatedwith infectious complications.It is con- and deficiencies in both complement and neutrophilic cludedthat the presenceof ascitesdoesnot increasethe infectious function [9,19,20]. complication rate in ovarian cancer patients who undergo small Taking the above information into consideration, the or large bowel reconstructive procedures.Additionally, patients fundamental goal of this report was to retrospectively with preoperative bowel obstruction or previous abdominal raexamine our clinical experience with ovarian cancer padiation therapy werenot found to experiencea significantincrease tients who underwent various gastrointestinal procedures in the infectious complication rate in the current series. 0 1992 Academic
in the presence of ascites. It is hypothetically possible that ascites may produce an increase in infectious morbidity in this group, as it is a potential culture medium for bacteria and also has the inherent capability to distribute pathogenic bacteria throughout the abdominal cavity and surgical wound. Several other important parameters potentially involved in the infectious complications of ovarian cancer patients undergoing intestinal reconstructive surgery were also investigated. These factors included age, nutritional status, previous radiotherapy, presence and site of ob-
Press, Inc.
INTRODUCTION
Numerous articles have been written about the performance of gastrointestinal procedures on patients with ovarian carcinoma [l-S]. The majority of articles have concentrated on survival statistics and quality of life, while only a few have focused specifically on postoperative com’ To whom correspondence and reprint requests should be addressed.
40 $1.50 Copyright 0 1992 by Academic Press, Inc. All rights of reproduction in any form reserved. 0090~8258/92
INTESTINAL
SURGERY
AND ASCITES IN OVARIAN
struction preoperatively, use of various bowel preparations, number and type of anastomosis performed, whether the anastomosis was hand sewn or stapled, and the extent of debulking, if performed. MATERIALS
AND METHODS
From July 1980 to June 1990,597 patients with ovarian carcinoma were treated at the Division of Gynecologic Oncology, University of Miami School of Medicine. During this time, we were able to identify 104 patients who underwent intestinal reconstruction as part of a debulking procedure and/or to relieve a clinically evident intestinal obstruction. The majority of patients (93%) had stage III or IV disease, and almost all (99%) had epithelial carcinomas of the ovary. A retrospective chart review was carried out on all patients to determine the specific pre-, intra-, and postoperative characteristics depicted in Table 1. Nutritional status was defined as adequate versus poor on the basis of preoperative serum values of albumin and transferrin and amount of weight loss during the preceding 3-4 months [24]. Patients with adequate nutritional status were defined as having had less than 20% usual body weight loss over the previous 3-4 months, a serum albumin >3.0 gm/dl, and serum transferrin ~200 mg/dl. Conversely, patients with poor nutritional status had more than 20% usual body weight loss, serum aibumin ~3.0 g/dl, and/or a serum transferrin ~200 mg/dl. As the half-life of serum transferrin is approximately 8 days, more credence was placed in this value. If a discrepancy occurred in nutritional measurements, the serum transferrin value was taken as the most accurate measure of current nutritional status [24,25]. The serum protein values were obtained within the same 24-hr period to minimize hydration-related inaccuracies. Preoperative nutritional support was employed in patients with poor nutritional indices, as well as in all patients who were obstructed preoperatively. Patients with preoperative bowel obstruction were considered at increased risk nutritionally, as they typically remained NPO during the preoperative period and for several days postoperatively until normal bowel function returned. It was obvious that despite having initial adequate nutritional parameters, these patients would undergo significant vital protein catabolism during this period of prolonged fasting if nutritional repletion were not instituted. Therefore, preoperative nutritional support was employed in all obstructed patients regardless of initial nutritional parameters. Patients were considered obstructed preoperatively if clinical signs and symptoms of obstruction were substantiated by radiographic findings, or a contrast study of the intestinal tract. In oatients with ascites. no evidence of an infectious
41
CANCER TABLE
1
Distribution of Population Characteristics Characteristic Age 40 50-60 >60 Preop radiotherapy Yes No Preop obstruction Yes No Site of obstruction Small bowel Large bowel Adequate nutrition Yes No Preop hyperalimen Yes No Mechanical prep Yes No Oral prep Yes No Preop antibiotics Yes No Disease present Yes No Debulking performed Yes No Large bowel reconstr Yes No No. anastamosis/patient 1 >l Hand anastomosis Yes No Presence of ascites Yes No
N
%
20 33 51
19.2 31.7 49.1
11 93
10.6 89.4
25 19
24.0 76.0
17 8
68.0 32.0
90
92.8 7.2
27 77
26.0 74.0
76 28
73.1 26.9
68 36
65.4 34.6
93 11
89.4 10.6
99 5
95.2 4.8
92 12
93.0 1.0
82 22
78.9 21.1
83 21
79.8 20.2
16 88
15.4 84.6
41 63
39.4 60.6
n 97 of 104 patients with complete nutritional
evaluation
or hepatic etiology was suspected or confirmed in any case. All patients had malignant ascites documented by either current or previous cytologic findings. Therefore, fluid cultures, protein content, and specific gravity evaluations were not performed on ascitic fluid from any patient. An adequate mechanical bowel preparation consisted of a clear liauid diet at least 24 hr nrior to sureerv. A
42
DONATO
full bottle of magnesium citrate was given orally the night prior to surgery. In addition, multiple enemas were given rectally until the return was clear the night prior to surgery. The only modification in this schema occurred in patients who were obstructed preoperatively. For patients who had evidence of small bowel obstruction, the magnesium citrate was omitted, and preoperative nasogastric suction was employed prior to laparotomy. The colon was usually evacuated with enemas the night prior to surgery. Patients with large bowel obstruction were placed on elemental diets, and enemas were not routinely performed. Catharsis was accomplished with magnesium citrate the night prior to surgery. The oral antibiotic bowel preparation utilized in this study consisted of erythromycin base (1 g) and neomycin sulfate (1 g) given at 1 PM, 2 PM, and 11 PM the day prior to surgery. Preoperative intravenous antibiotic selection included broad spectrum coverage of gram-negative and anaerobic organisms. A single agent (cefoxitin) was utilized in the majority of patients, and the antibiotic was given on call to the operating room. Prophylactic intravenous antibiotics (gentamycin and clindamycin) were given for a median of 3 days postoperatively to all patients who underwent bowel reconstruction. Patients with preoperative small or large bowel obstruction received a therapeutic course of postoperative antibiotics, as they were felt to be at high risk for infection due to stasis and bacterial overgrowth in obstructed segments. Obviously, patients who met the criteria for febrile morbidity as defined below also received a therapeutic course of antibiotics. Patients who did not meet the definition of febrile morbidity but had a clinical suspicion of infection (fever with subsequent negative blood cultures) or documented urinary, pulmonary, or intravenous catheter-related infections were usually given extended antibiotic coverage postoperatively. As the main goal of this paper was to evaluate the effect of malignant ascites on infectious morbidity after bowel reconstructive surgery, the definition of postoperative infectious morbidity purposefully excludes pulmonary and urinary sources. Specifically, the definition of infectious morbidity for the purpose of this paper includes any case of wound infection, wound dehiscence, anastomotic leakage accompanied by sepsis, intraabdominal abscess formation, enterocutaneous fistulae formation, or culture-positive bacteremia/septicemia (excluding pulmonary or urinary sources) occurring within the first 30 days after surgery. Surgical mortality was defined as any postoperative death within this time period. Statistical Analysis
The dependent variable was infectious morbidity as defined above. As all of the independent variables are cat-
ET AL.
egorical, or can be categorized, crude odds ratio estimates and corresponding 95% confidence intervals were calculated. Stratified analysis was utilized in the analysis of possible confounding or effect-modifying variables. For each stratified variable, the stratum-specific odds ratio estimates and the Mantel-Haenszel common odds ratio estimates were calculated. Hypothesis testing was performed using the Mantel-Haenszel x2 statistic. As all stratum-specific estimates were uniform in this series, the Mantel-Haenszel odds ratio estimates and corresponding 95% confidence intervals are reported. Logistic regression analysis was also utilized to adjust for potential confounding variables where appropriate. RESULTS One hundred twenty-seven bowel procedures were performed on one hundred-four patients. The median age of the patients in this series was 60 with a range of 19 to 81. Seventy-two (69%) patients underwent their gastrointestinal procedures as part of an initial debulking procedure, while thirty-two (31%) had at least one prior surgical procedure. Twenty-five (24%) patients had clinical and/or radiographic evidence of bowel obstruction preoperatively. Seventeen (68%) patients had obstruction of the small intestine, while the remaining eight (32%) patients had a colonic obstruction. Eleven (11%) patients had a previous history of radiation therapy. Nine patients received whole abdominal radiotherapy, while two patients received intraperitoneal 32P prior to laparotomy. Ninety-nine (95%) patients had disease present at the time of laparotomy, and of these, ninety-two (93%) had some concerted attempt at surgical debulking in addition to the intestinal procedure. Ninety-seven patients had a nutritional assessment preoperatively. Of these, 90 patients (93%) were judged to be in adequate nutritional condition, while 7 patients (7%) were deemed to be in poor nutritional condition. The median values for serum albumin and transferrin in our patients were 3.80 g/d1 and 239 mg/dl, respectively. Twenty-seven patients (26%) received preoperative hyperalimentation for a median of 4 days with a range of l-23 days. All seven patients in the poor nutritional group received preoperative hyperalimentation for a median of 6 days. Seventy-six (73%) patients had a mechanical bowel preparation prior to surgery, while sixty-eight (65%) patients had oral antibiotics to help reduce intestinal bacterial flora preoperatively. A preoperative dose of intravenous antibiotic (cefoxitin) was given to 93 (90%) patients. The remaining 11 (10%) patients did not receive any preoperative intravenous antibiotics. All patients received postoperative gentamycin and
INTESTINAL
SURGERY
AND ASCITES IN OVARIAN
TABLE 2 Infectious Morbidity/Mortality: Obstructed Patients Pt.
anastam.
Leak/ sepsis
AB MH CM AW
Enterocolic Enterocolic Enterocohc Enterocolic
y -
Type
Wound Y Y Y
Gr t-1 batter.
Fistula
Death
Y -
-
Y -
-
Y
-
clindamycin. The 1.5 patients who meet the criteria for infectious morbidity received a median of 7 days of therapeutic antibiotics. Twenty-two patients did not develop febrile morbidity post operatively. However, all had clinical evidence of small or large bowel obstruction prior to surgery. These patients were treated therapeutically with a median of 7 days of postoperative antibiotics. Fourteen patients did not meet the criteria for febrile morbidity. However, clinically they were either suspected of harboring an infection (8 patients with fever and negative blood cultures) or had documented urinary, pulmonary, or intravenous catheter-related infections (3, 1, and 2 patients, respectively). These patients were all treated with an extended course of postoperative antibiotics (median, 7 days). The remaining 53 patients had no evidence of infection and were treated prophylactically with a median of 3 days of postoperative antibiotics. Eighty-two (79%) intestinal reconstructive procedures involved large bowel in the form of enterocolic anastomosis, colocolostomies, or formation of diversionary colostomies. Only 21% of procedures involved the small bowel exclusively (enteroenterostomies, or illiostomies). Twenty-one (20%) patients had more than one gastrointestinal procedure at the same laparotomy. Sixteen (15%) patients had a total of 18 hand-sewn anastomosis, while the remaining eighty-eight (85%) patients had stapled anastomosis/resections. In the 17 patients with small bowel obstruction, 15 (88%) had primary anastomosis performed while 2 (12%) patients had proximal diversions without anastomosis. Of the 8 patients with large bowel obstruction, 5 (63%) had primary anastomosis without proximal diversion while 3 (37%) had colostomy formation without anastomosis. The median blood loss was 1100 cc with a range of 100-5000 cc. Forty-one patients (39%) had ascites present at the time of intestinal reconstruction. In 36 patients the amount of ascites was quantitated. The median amount of ascites present in these patients was 1750 cc, with a range of 100-9000 cc. Fifteen patients (14.4%) sustained 19 infectious complications postoperatively (Tables 2 and 3). Four patients developed anastomotic leaks and sepsis, eight patients developed wound infections (five of which developed fas-
43
CANCER
cial dehiscences requiring reclosure), four patients developed enterocutaneous fistulae, and three patients were found to have gram-negative bacteremia. Of the four patients who developed enterocutaneous fistulae, only one had a prior history of radiotherapy, and she was without evidence of disease at the time of surgery. The other three patients were found to have bulky, unresectable disease at the time of laparotomy. There were five postoperative deaths. Three were due to sepsis, one was due to progressive cancer, and the last was due to pulmonary emboli. Two of the three patients who died of sepsis had anastomotic leaks, while the third had a high output enterocutaneous fistula. Univariate analysis was performed for each variable to detect possible relationships with infectious morbidity. The results of these analyses and calculated P values are summarized in Table 4. As can be seen, no significant association could be found between the presence of ascites at the time of laparotomy and infectious morbidity (P = 0.58). However, a significant association was found between the use of a mechanical bowel preparation and a reduction in the infectious complication rate (P = 0.01). Additionally, patients with an adequate preoperative nutritional status sustained significantly fewer infectious complications than those patients in poor nutritional condition (P = 0.03). Patients who underwent colonic reconstructive procedures were found to have a marginally significant increase in infectious morbidity over patients whose sole procedure involved small bowel reconstruction (P = 0.14). When the remaining parameters were individually analyzed with respect to infectious morbidity, no other significant associations could be established. As a majority of patients who had a preoperative mechanical bowel preparation also had oral antibiotics to reduce intestinal flora, logistic regression analysis was performed to elucidate the most important parameter re-
TABLE 3 Infectious Morbidity/Mortality: Nonobstructed Patients Pt. ES SR CO JB CB MC TF HL ML MK JM
Type
anastam Enterocolic Colocolonic Enteroentero Enterocolic Enterocolic Colocolonic Colocolonic Enteroentero Enteroentero Enterocohc Enteroentero
Leak/ sepsis Y y y
Wound Y Y Y Y Y -
Gr t-1 batter.
Fistula
Death
Y -
Y -
Y -
Y -
Y Y -
Y -
44
DONATO
TABLE 4 Correlation of Study Parametersand Infectious Morbidity (Crude Odds Ratio Estimates) Characteristic
OR
95% CI
P
Age
60
50-60 Xi0 Preop radiation No Yes Preop obstruction No Yes Adequate nutrition No Yes Preop hyperalimen No Yes Mechanical prep No Yes Oral prep No Yes Preop antibiotics No Yes Disease present No Yes Debulking performed No Yes Large bowel reconstr No Yes No. of procedures 1 >l Hand anastomosis No Yes Ascites present No Yes
0.57 1.21
0.08-4.07 0.25-6.49
0.51 0.79
2.50
0.45-12.70
0.21
1.16
0.28-4.56
0.86
0.19
0.03-1.23
0.03
1.52
0.4-5.60
0.48
0.25
0.07-0.89
0.01”
0.76
0.22-2.70
0.64
0.40
0.08-2.19
0.20
0.67
0.06-16.85
0.73
0.82
0.14-6.13
0.82
4.32
0.54-93.23
o.14b
0.99
0.20-4.37
0.98
2.33
0.52-9.88
0.20
0.72
0.19-2.57
0.58
ET AL.
patients received postoperative antibiotics for a median of at least 3 days, the relative contribution of intravenous antibiotics to the diminution in infectious morbidity could not be addressed. Due to the variability in duration of postoperative antibiotic usage, statistical analysis was employed to be sure that ascites patients received a duration of antibiotic usage similar to that of patients without ascites. In fact, no statistical difference in duration of postoperative antibiotic usage was found between patients with and without ascites (P = 0.70). The presence of obstruction was not found to be significantly associated with infectious morbidity (P = 0.86). Additionally, no relationship could be found between the site of obstruction and infectious outcome. Infections occurred in 3 of 17 patients with small bowel obstruction and in 1 of 8 patients with large bowel obstruction (P = 0.78). Thus, the overall infection rate for patients with clinical obstruction was 16.0% (4 of 25 patients). To determine whether the presence of obstruction was responsible for modifying the activity of other parameters on infectious outcome, stratification analysis was performed. Mantel-Haenszel adjusted odds ratios and the corresponding P values for all remaining variables are listed in Table 5. Once again, the utilization of a mechanical preparation (P = 0.01) and the presence of an adequate preoperative nutritional status (P = 0.03) were the only factors significantly associated with a reduction in the infectious complication rate for both obstructed and nonobstructed patients. DISCUSSION
’ Statistically significant. ’ Borderline significant.
sponsible for the reduction in infectious morbidity. When the use of oral antibiotics was controlled for in the logistic model, a mechanical preparation was the only parameter significantly associated with a reduction in infectious morbidity (P = 0.01). All but 11 patients received a preoperative dose of an intravenous antibiotic. However, no significant association was found between the use of preoperative antibiotics and infectious outcome (P = 0.20). As all noninfected
The current report has demonstrated that in a series of ovarian cancer patients who undergo intestinal reconstructive procedures, the presence of ascites was not associated with an increase in the infectious complication rate. Although ascitic fluid can be a potential growth medium for bacteria, it has been shown that malignant ascitic fluid possess a significant amount of antimicrobial activity [9]. Both opsonic activity and complement protein content are higher in malignant ascitic fluid than in ascites from cirrhotics [9,15,21-231. Therefore, it is not surprising that the presence of malignant ascites did not contribute to the infectious complications in our patient population. In a report by Clarke-Pearson et al., 49 ovarian cancer patients with intestinal obstruction were investigated [7]. The authors reported that of all variables examined, the only factor found to be significantly associated with major postoperative complications was the presence of clinical ascites [7]. Unfortunately, the specific complications incurred by the patients with ascites are not delineated, and both noninfectious and infectious complications are reported collectively. As 12% of patients
INTESTINAL
SURGERY
AND ASCITES IN OVARIAN
TABLE 5 ParameterCorrelationswith InfectiousMorbidity Stratification by Obstruction Status (Mantel-HaenszelAdjusted Odds Ratios) Parameter Age 40 50-60 >60 Preop radiation No Yes Adequate nutrition No Yes Preop hyperalimen No Yes Mechanical prep No Yes Oral prep No Yes Preop antibiotics No Yes Disease present No Yes Debulking performed No Yes Large bowel reconstr No Yes No. of procedures 1 >l Hand anastomosis No Yes Ascites present No Yes
Adjusted OR
95% CI
P
0.57 1.26
0.08-4.12 0.26-7.07
0.52 0.73
3.42
0.28-23.89
0.21
0.20
0.03-0.95
0.03
1.58
0.41-5.93
0.46
0.21
0.06-0.89
0.01”
0.71
0.19-3.06
0.64
0.40
0.08-2.20
0.20
0.70
0.05-20.42
0.78
0.84
0.14-6.36
0.84
4.36
0.54-94.44
o.14b
0.98
0.20-4.37
0.98
2.29
0.51-9.73
0.21
0.74
0.20-2.63
0.61
’ Statistically significant. b Borderline significant.
in this study were severely malnourished and none received preoperative nutritional therapy, it is very possible that the increased postoperative complication rate in the ascites group may have resulted from significant fluid abnormalities (congestive failure and prolonged ventilatory support). A significant reduction in infectious morbidity was noted in patients who received a mechanical bowel preparation prior to laparotomy. This is consistent with other reports that clearly show the importance of reducing the fecal load of the colon prior to intestinal surgery [26-281.
CANCER
45
The ideal prophylactic antibiotic regime for elective intestinal surgery remains controversial [26-301. However, the utilization of an initial preoperative intravenous dose followed by at least 24 hr of postoperative coverage has been recommended [26]. Although oral antibiotics have been advocated by some, intravenous antibiotics have the advantage of achieving both a local intestinal and a systemic tissue level prior to the planned procedure. Obtaining adequate tissue levels prior to intestinal manipulation seems to be essential for the reduction of bacterial contamination at the time of surgery [26,27]. Although the current study did not demonstrate a significant association between the use of preoperative intravenous antibiotics and infectious morbidity, the results must be considered in light of the fact that a majority of patients received concurrent oral antibiotics, and all received a median of at least 3 days of postoperative intravenous antibiotics. Due to the small patient numbers in each of these categories, it was impossible to statistically analyze the effect of each individual parameter on infectious morbidity. Therefore, confirmation of the ideal method of prophylaxis for elective intestinal surgery cannot be addressed in this study. It has been established that patients with severe nutritional deficits are at increased risk for postoperative morbidity and mortality [24,25,31-331. In our series, patients who were judged to be in adequate nutritional condition sustained statistically fewer infectious complications than did patients who were deemed to be in poor nutritional condition. This trend has been previously reported in a similar population of patients with ovarian cancer [7]. The use of preoperative nutritional support has still not been conclusively shown to reduce postoperative morbidity and mortality [24,31,33]. As there were only seven patients in the poor nutritional group and all received preoperative hyperalimentation, we were unable to demonstrate the efficacy of preoperative therapy in our patient population. Furthermore, it has been stated that patients ‘with severe malnutrition require at least 14 days of nutritional support consisting of at least 35 kcal/kg/day and 1.5 g/kg of protein daily for adequate repletion [31,33]. The severely depleted patients in our series received a median of only 6 days of preoperative hyperalimentation. Therefore, the efficacy of preoperative nutritional support awaits the results of a randomized, prospective trial. A marginal increase in the infectious complication rate was noted in patients who underwent large bowel reconstruction relative to patients whose sole procedure involved small bowel reconstruction. This is not surprising, as the majority of our patients were not obstructed, and it would be anticipated that small bowel reconstructive procedures would be associated with less bacterial contamination than those involving large bowel [34].
46
DONATOETAL.
The presence of preoperative obstruction was not shown to increase the infectious morbidity in the current series of ovarian cancer patients undergoing various intestinal reconstructive procedures. This finding is contrary to that of Castaldo et al. [l]. The authors found that the highest incidence of infectious morbidity and mortality occurred in patients with preoperative obstruction. It is our opinion that the aggressive utilization of hyperalimentation and employment of a therapeutic postoperative antibiotic regime contributed to the low infectious morbidity in our subgroup of obstructed patients. Recall that all patients in the current series who were obstructed received preoperative hyperalimentation and a therapeutic course of postoperative antibiotics for a median of 7 days. These patients were felt to be at high risk for the development of intraabdominal infections due to mechanical stasis and bacterial overgrowth in affected intestinal segments. Castaldo et al. did not employ preoperative hyperalimentation in any patient and do not even address the issue of antibiotic usage in their patients [l]. Obviously, the precise employment of hyperalimentation and antibiotics in patients with clinical bowel obstruction has not been established. Although it is believed that aggressive utilization of these two therapeutic modalities will reduce infectious morbidity in this population, definitive proof awaits the completion of prospective clinical trials. In those patients with preoperative bowel obstruction, no statistical difference in infectious morbidity was noted between those with small and those with large bowel obstruction (P = 0.78). However, our numbers are small, and we would hesitate to draw any definitive conclusion from these data. In fact, two previous series have reported an increased postoperative complication rate in patients with small versus large bowel obstruction [1,7]. In the series of Castaldo et al., 10% of patients with large bowel obstruction versus 44% with small bowel obstruction sustained major postoperative complications [ 11. In study of Clarke-Pearson et al., 25% of patients with large bowel obstruction versus 63% of patients with small bowel obstruction sustained major postoperative complications [7]. There are at least two explanations for the contradictory findings noted between the current series and the two reports previously discussed. First, the collective majority of patients (90%) with small bowel obstruction in both previous studies had primary anastomosis performed. In contrast, only 1 of 26 patients (4%) with large bowel obstruction in these studies had primary anastomosis performed (96% had proximal colostomy formation without anastomosis). In our series, 63% of patients with large bowel obstruction and 88% of patients with small bowel obstruction had primary anastomosis. As any anastomosis performed in the context of an obstructed gastrointestinal tract carries a greater risk of dehiscence [35], it is not
surprising that the patients with small bowel obstruction in the above two series sustained more complications than did patients with large bowel obstruction. Second, as previously discussed, the nutritional status of the patients in the above two studies appears to be very different than that in the current study. For example, the percentage of patients with severe nutritional deficits in the study by Clarke-Pearson et al. was almost twice that of the current series. Closer inspection of this series reveals that the albumin was the only serum protein utilized for the calculation of nutritional status. As the half-life of serum albumin is relatively long (20-30 days), it is considered insensitive to acute nutritional deficits [25]. Therefore, the number of patients with severe nutritional deficits may well have been underestimated by the authors. Castaldo et al. do not discuss the preoperative nutritional status of their patients. It appears that only 8 of 49 (16%) patients received any form of nutritional support pre- or postoperatively. The authors concede that the addition of nutritional support may well have improved the high postoperative complication rate encountered in their series
111.
Finally, we were unable to demonstrate a significant relationship between infectious morbidity and parameters such as age, prior radiotherapy, disease presence, performance of concurrent debulking, number of bowel procedures, and the use of hand versus stapled anastomotic techniques. These factors were not shown to be significantly correlated with postoperative complications in a previous study [7]. Although Castaldo et al. reported a possible trend toward increased postoperative complications in patients with multiple anastomosis or previous radiotherapy, the association was not found to be significant [l]. In summary, our findings suggest that both large and small bowel reconstructive procedures can be performed safely in patients with ovarian cancer who have ascites present at the time of laparotomy. The utilization of a mechanical bowel preparation and an adequate nutritional status were both significantly associated with a reduction in infectious morbidity in this patient population. The presence of intestinal obstruction was not found to be significantly associated with infectious morbidity, nor was it shown to modify the effects of other variables on infectious outcome in the current report. Although it is believed that the aggressive use of preoperative hyperalimentation and the employment of a therapeutic antibiotic regime may have contributed to the limited infectious morbidity in our patients with preoperative obstruction, definitive statements cannot be made at this time. A previous history of abdominal radiation therapy was also not found to be significantly associated with infectious
INTESTINAL
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CANCER
47
upper gastrointestinal endoscopy. A reappraisal, Endoscopy 15, Zl23 (1983). 18. Camara, D. S. Transient bacteremia following endoscopic injection of esophageal varices, Arch. Intern. Med. 143,1350-1352 (1983). 19. Isner, J., Macdonald, J. S., and Schein, P. Spontaneous streptococcus pneumonia peritonitis in a patient with metastatic gastric REFERENCES cancer, Cancer 39, 2306-2309 (1977). 1. Castaldo, T. W., Petrilli, E. S., Ballon, S. C., and Lagasse, L. D. 20. Kurtz, R. C., and Bronzo, R. L. Does spontaneous bacterial perIntestinal operations in patients with ovarian carcinoma, Am. J. itonitis occur in malignant ascites? Am. J. Gustroenterol. 77, 146Obsfet. Gynecol. 139, 80-84 (1981). 148 (1982). 21. Fromkes, J. J., Thomas, F. B., Mekhjian, H. S., and Evans, M. 2. Tunca, J. C., Buchler, D. A., Mack, E. A., Ruzicka, F. F., Crowley, J. J., and Carr, W. F. The management of ovarian-cancerAntimicrobial activity of human ascitic fluid, Gustroenterology 73, 668-672 (1977). caused bowel obstruction, Gynecol. Oncol. 12, 186-192 (1981). 22. Simberkoff, M. S., Moldover, N. H., and Weiss, G. Bactericidal 3. Piver, M. S., Barlow, J. J., Lele, S. B., and Frank, A. Survival and opsonic activity of cirrhotic ascites and non-ascitic peritoneal after ovarian cancer induced intestinal obstruction, Gynecol. Oncol. fluid, J. Lab. Clin. Med. 91, 831-839 (1978). 13, 44-49 (1982). 23. Akalin, G., Laleli, Y., and Telatar, H. Bactericidal and opsonic 4. Krebs, H. B., and Goplerud, D. R. Surgical management of bowel activity of ascitic iluid from cirrhotic and non-cirrhotic patients, J. obstruction in advanced ovarian carcinoma, O&et. Gynecoi. 61, Infect. Dis. 147, 1011-1017 (1983). 327-330 (1983). 24. Albina, J. E., Ioruda, M. J., and Rombeau, J. L. Perioperative 5. Clarke-Pearson, D. L., Chin, N. O., DeLong, E. R., Rice, R., and total parenteral nutrition, in Parental nutrition (.I. L. Rombeau and Creasman, W. T. Surgical management of intestinal obstruction in M. D. Caldwell, Eds.), Saunders, Philadelphia, pp. 370-379 (1986). ovarian cancer, Gynecol. Oncol. 26, 11-18 (1987). 25. Cerra, F. B. Assessment of nutritional and metabolic status, in 6. Fernandez, J. R., Seymour, R. J., and Suissa, S. Bowel obstruction Surgical nutrition (F. B. Cerra, Ed.), Mosby, St. Louis, pp. 24-48 in patients with ovarian cancer. A search for prognostic factors, (1984). Am. J. Obstet. Gynecol. 158, 244-249 (1988). 26. Smith, L. E. Preoperative bowel preparation, in Current surgical I. Clarke-Pearson, D. L., DeLong, E. R., Chin, N., Rice, R., and therapy (J. L. Cameron, Ed.), B. C. Decker, Philadelphia, Vol. 3, Creasman, W. T. Intestinal obstruction in patients with ovarian pp. 164-167 (1989). cancer, Arch. Surg. 123, 42-45 (1988). 27. Shackelford, R. T., and Zuidema, G. D. (Eds.), in Bowel prepu8. Rubin, S., Hoskins, W., Benjamin, I., and Lewis, J. Surgery for ration in surgery of the alimentary tract, Saunders, Philadelphia, intestinal obstruction in advanced ovarian cancer, Gynecol. Oncol. Vol. 3, pp. 191-193 (1982). 39, 16-19 (1989). 28. Beck, D. E., Harford, F. J.. Dipalma, J. A., et al. Bowel cleaning 9. Runyon, B. A. Spontaneous bacterial peritonitis: An explosion of with polyethylene glycol electrolyte lavage solution, South. Med. J. information, Hepatology 8, 171-175 (1988). 78, 1414-1416 (1985). 10. Carey, W. D., Boayke, A., and Leatherman, J. Spontaneous bac- 29. Brass, C. L., Richards, G. K., and Ruedy, J. The effect of metroterial peritonitis: Clinical and laboratory features with reference to nidazole on the incidence of postoperative wound infection in elechospital-acquired cases, Am. J. Gustroenterol. 81,1156-1161 (1986). tive colon surgery, Am. J. Surg. 135, 91-96 (1978). 30. Washington, J. A., Dearing, W. H., Judd, E. S., et al. Effect of 11. Almadal, T. P., and Skinhoh, P. Spontaneous bacterial peritonitis preoperative antibiotic regimen on development of infection after in cirrhosis: Incidence, diagnosis, and prognosis, Stand. J. Gusrroenterol. 22, 295-300 (1987). intestinal surgery, Ann. Surg. 180, 567-572 (1974). 31 Mullen, J. L., Buzby, G. P., Matthews, D. C., Smale, B. F., and 12. Hoefs, J. C., and Runyon, B. A. Spontaneous bacterial peritonitis, Rosato, E. F. Reduction of operative morbidity and mortality by Dis.-A-Month 31, l-48 (1985). combined preoperative and postoperative nutritional support, Ann. 13. Metcalf, A. M., Dozois, R. R., Wolff, B. G., and Beart, R. W. Surg. 192, 604-613 (1980). The surgical risk of colectomy in patients with cirrhosis, Dis. Colon 32. Kaminski, M. V., Fitzgerald, M. J., and Murphy, R. J. Correlation Rectum. 30, 529-531 (1987). of mortality with serum transferrin and anergy, J. Purenter. Enterol. 14. Brinson, R. R., Kolts, B. E., and Monif, G. R. Spontaneous bacNutr. 1, 27-32 (1973). terial peritonitis associated with an intrauterine device, J. Clin. 33. Mullen, J. H. L., Buzby, G. P., Waldman, T. G., et al. Prediction Gastroenterol. 8, 82-84 (1986). of operative morbidity and mortality by preoperative nutritional 15. Runyon, B. A., Morrissey, R. L., Hoefs, J. C., and Wyle, F. A. assessment, Surg. Forum 30, 80-82 (1979). Opsonic activity of human ascitic fluid: A potentially important 34. Russell, J. C., and Welch, J. P. Pathophysiology of bowel obstrucprotective mechanism against spontaneous bacterial peritonitis, Hetion, in Bowel obstruction (J. P. Welch, Ed.), Saunders, Philadelpatology 5, 634-637 (1985). phia, pp. 28-58 (1990). 16. Liebowitz, H. R. Hazards of abdominal paracentesis in the cirrhotic 35. Welch, J. P. (Ed.). Operative techniques, decisions, and complipatient, N. Y. State J. Med. 154, 20-25 (1962). cations, in Bowel obstruction, Saunders, Philadelphia, pp. 423-448 17. O’Conner, H. T., Hamilton, I., and Lincoln, C. Bacteremia with (1990).
morbidity in this series. However, patient numbers in these categories are small, and definitive conclusions must await the recruitment of a larger clinical series.
ONCOLOGY
4,
40-47 (1992)
Infectious Complications after Gastrointestinal Surgery in Patients with Ovarian Carcinoma and Malignant Ascites D. DONATO, M.D.,*,’ *Division
of Gynecologic
A. ANGELIDES, Oncology,
M.D.,*
H. IRANI, M.D.,?
Department of Obstetrics 016310, University of Miami
M. PENALVER, M.D. ,* AND H. AVERETTE,
and Gynecology, P. 0. Box 016960, School of Medicine, Miami, Florida
and TDepartment 33101
of Surgery,
M.D.* P. 0. Box
Received March 11, 1991
plications
in this patient population
[1,3,7]. After an ex-
One hundred four patients with ovarian cancer underwent intestinal reconstruction as part of a cytoreductive effort or for tensive search of the English literature, no articles could relief of intestinal obstruction from July 1980 to June 1990. be found that addressed the infectious complications ocTwenty-four percent~of patients were obstructedpreoperatively, curring in ovarian cancer patients with ascites who while the remainingseventy-sixpercenthad bowelresectionsper- undergo various bowel reconstructive procedures. It is formed in concert with a debulking procedure. The overall in- well known from the literature that patients with cirrhosis fectious complication rate was 14.4%. No statistical association and ascites have an 8-10% incidence of spontaneous bacwas found betweenthe presenceof ascitesat the time of lapa- terial peritonitis [9-121. These patients are also at sigrotomy and infectiousmorbidity (P = 0.58). The useof a pre- nificant risk for septic morbidity and mortality with the operative mechanicalbowel preparation was associatedwith a performance of even minor surgical procedures such as significant reduction in infectious morbidity (P = 0.01). Addi- upper endoscopy, colonoscopy, or paracentesis [9,10,13tionally, patients consideredin adequatenutritional condition 18]. However, patients with cirrhosis have multiple deexperiencedsignificantly lessinfectious complicationsthan those fects that contribute to their increased susceptibility to patients in poor nutritional condition (P = 0.03). Intestinal proinfection. For example, the loss of significant liver parceduresinvolving the large bowelweremarginally associatedwith increasedinfectious complications(P = 0.13). Neither preop- enchyma results in major impairments in the synthesis of erative radiotherapy, the presenceof preoperative obstruction, vital proteins such as clotting factors and albumin [9,19]. these patients have multiple immunological diseasepresence,extent of debulking, number of intestinal pro- Additionally, cedures,or hand versus stapled anastomosiswas found to be defects, including diminished portal clearance of bacteria, significantly associatedwith infectious complications.It is con- and deficiencies in both complement and neutrophilic cludedthat the presenceof ascitesdoesnot increasethe infectious function [9,19,20]. complication rate in ovarian cancer patients who undergo small Taking the above information into consideration, the or large bowel reconstructive procedures.Additionally, patients fundamental goal of this report was to retrospectively with preoperative bowel obstruction or previous abdominal raexamine our clinical experience with ovarian cancer padiation therapy werenot found to experiencea significantincrease tients who underwent various gastrointestinal procedures in the infectious complication rate in the current series. 0 1992 Academic
in the presence of ascites. It is hypothetically possible that ascites may produce an increase in infectious morbidity in this group, as it is a potential culture medium for bacteria and also has the inherent capability to distribute pathogenic bacteria throughout the abdominal cavity and surgical wound. Several other important parameters potentially involved in the infectious complications of ovarian cancer patients undergoing intestinal reconstructive surgery were also investigated. These factors included age, nutritional status, previous radiotherapy, presence and site of ob-
Press, Inc.
INTRODUCTION
Numerous articles have been written about the performance of gastrointestinal procedures on patients with ovarian carcinoma [l-S]. The majority of articles have concentrated on survival statistics and quality of life, while only a few have focused specifically on postoperative com’ To whom correspondence and reprint requests should be addressed.
40 $1.50 Copyright 0 1992 by Academic Press, Inc. All rights of reproduction in any form reserved. 0090~8258/92
INTESTINAL
SURGERY
AND ASCITES IN OVARIAN
struction preoperatively, use of various bowel preparations, number and type of anastomosis performed, whether the anastomosis was hand sewn or stapled, and the extent of debulking, if performed. MATERIALS
AND METHODS
From July 1980 to June 1990,597 patients with ovarian carcinoma were treated at the Division of Gynecologic Oncology, University of Miami School of Medicine. During this time, we were able to identify 104 patients who underwent intestinal reconstruction as part of a debulking procedure and/or to relieve a clinically evident intestinal obstruction. The majority of patients (93%) had stage III or IV disease, and almost all (99%) had epithelial carcinomas of the ovary. A retrospective chart review was carried out on all patients to determine the specific pre-, intra-, and postoperative characteristics depicted in Table 1. Nutritional status was defined as adequate versus poor on the basis of preoperative serum values of albumin and transferrin and amount of weight loss during the preceding 3-4 months [24]. Patients with adequate nutritional status were defined as having had less than 20% usual body weight loss over the previous 3-4 months, a serum albumin >3.0 gm/dl, and serum transferrin ~200 mg/dl. Conversely, patients with poor nutritional status had more than 20% usual body weight loss, serum aibumin ~3.0 g/dl, and/or a serum transferrin ~200 mg/dl. As the half-life of serum transferrin is approximately 8 days, more credence was placed in this value. If a discrepancy occurred in nutritional measurements, the serum transferrin value was taken as the most accurate measure of current nutritional status [24,25]. The serum protein values were obtained within the same 24-hr period to minimize hydration-related inaccuracies. Preoperative nutritional support was employed in patients with poor nutritional indices, as well as in all patients who were obstructed preoperatively. Patients with preoperative bowel obstruction were considered at increased risk nutritionally, as they typically remained NPO during the preoperative period and for several days postoperatively until normal bowel function returned. It was obvious that despite having initial adequate nutritional parameters, these patients would undergo significant vital protein catabolism during this period of prolonged fasting if nutritional repletion were not instituted. Therefore, preoperative nutritional support was employed in all obstructed patients regardless of initial nutritional parameters. Patients were considered obstructed preoperatively if clinical signs and symptoms of obstruction were substantiated by radiographic findings, or a contrast study of the intestinal tract. In oatients with ascites. no evidence of an infectious
41
CANCER TABLE
1
Distribution of Population Characteristics Characteristic Age 40 50-60 >60 Preop radiotherapy Yes No Preop obstruction Yes No Site of obstruction Small bowel Large bowel Adequate nutrition Yes No Preop hyperalimen Yes No Mechanical prep Yes No Oral prep Yes No Preop antibiotics Yes No Disease present Yes No Debulking performed Yes No Large bowel reconstr Yes No No. anastamosis/patient 1 >l Hand anastomosis Yes No Presence of ascites Yes No
N
%
20 33 51
19.2 31.7 49.1
11 93
10.6 89.4
25 19
24.0 76.0
17 8
68.0 32.0
90
92.8 7.2
27 77
26.0 74.0
76 28
73.1 26.9
68 36
65.4 34.6
93 11
89.4 10.6
99 5
95.2 4.8
92 12
93.0 1.0
82 22
78.9 21.1
83 21
79.8 20.2
16 88
15.4 84.6
41 63
39.4 60.6
n 97 of 104 patients with complete nutritional
evaluation
or hepatic etiology was suspected or confirmed in any case. All patients had malignant ascites documented by either current or previous cytologic findings. Therefore, fluid cultures, protein content, and specific gravity evaluations were not performed on ascitic fluid from any patient. An adequate mechanical bowel preparation consisted of a clear liauid diet at least 24 hr nrior to sureerv. A
42
DONATO
full bottle of magnesium citrate was given orally the night prior to surgery. In addition, multiple enemas were given rectally until the return was clear the night prior to surgery. The only modification in this schema occurred in patients who were obstructed preoperatively. For patients who had evidence of small bowel obstruction, the magnesium citrate was omitted, and preoperative nasogastric suction was employed prior to laparotomy. The colon was usually evacuated with enemas the night prior to surgery. Patients with large bowel obstruction were placed on elemental diets, and enemas were not routinely performed. Catharsis was accomplished with magnesium citrate the night prior to surgery. The oral antibiotic bowel preparation utilized in this study consisted of erythromycin base (1 g) and neomycin sulfate (1 g) given at 1 PM, 2 PM, and 11 PM the day prior to surgery. Preoperative intravenous antibiotic selection included broad spectrum coverage of gram-negative and anaerobic organisms. A single agent (cefoxitin) was utilized in the majority of patients, and the antibiotic was given on call to the operating room. Prophylactic intravenous antibiotics (gentamycin and clindamycin) were given for a median of 3 days postoperatively to all patients who underwent bowel reconstruction. Patients with preoperative small or large bowel obstruction received a therapeutic course of postoperative antibiotics, as they were felt to be at high risk for infection due to stasis and bacterial overgrowth in obstructed segments. Obviously, patients who met the criteria for febrile morbidity as defined below also received a therapeutic course of antibiotics. Patients who did not meet the definition of febrile morbidity but had a clinical suspicion of infection (fever with subsequent negative blood cultures) or documented urinary, pulmonary, or intravenous catheter-related infections were usually given extended antibiotic coverage postoperatively. As the main goal of this paper was to evaluate the effect of malignant ascites on infectious morbidity after bowel reconstructive surgery, the definition of postoperative infectious morbidity purposefully excludes pulmonary and urinary sources. Specifically, the definition of infectious morbidity for the purpose of this paper includes any case of wound infection, wound dehiscence, anastomotic leakage accompanied by sepsis, intraabdominal abscess formation, enterocutaneous fistulae formation, or culture-positive bacteremia/septicemia (excluding pulmonary or urinary sources) occurring within the first 30 days after surgery. Surgical mortality was defined as any postoperative death within this time period. Statistical Analysis
The dependent variable was infectious morbidity as defined above. As all of the independent variables are cat-
ET AL.
egorical, or can be categorized, crude odds ratio estimates and corresponding 95% confidence intervals were calculated. Stratified analysis was utilized in the analysis of possible confounding or effect-modifying variables. For each stratified variable, the stratum-specific odds ratio estimates and the Mantel-Haenszel common odds ratio estimates were calculated. Hypothesis testing was performed using the Mantel-Haenszel x2 statistic. As all stratum-specific estimates were uniform in this series, the Mantel-Haenszel odds ratio estimates and corresponding 95% confidence intervals are reported. Logistic regression analysis was also utilized to adjust for potential confounding variables where appropriate. RESULTS One hundred twenty-seven bowel procedures were performed on one hundred-four patients. The median age of the patients in this series was 60 with a range of 19 to 81. Seventy-two (69%) patients underwent their gastrointestinal procedures as part of an initial debulking procedure, while thirty-two (31%) had at least one prior surgical procedure. Twenty-five (24%) patients had clinical and/or radiographic evidence of bowel obstruction preoperatively. Seventeen (68%) patients had obstruction of the small intestine, while the remaining eight (32%) patients had a colonic obstruction. Eleven (11%) patients had a previous history of radiation therapy. Nine patients received whole abdominal radiotherapy, while two patients received intraperitoneal 32P prior to laparotomy. Ninety-nine (95%) patients had disease present at the time of laparotomy, and of these, ninety-two (93%) had some concerted attempt at surgical debulking in addition to the intestinal procedure. Ninety-seven patients had a nutritional assessment preoperatively. Of these, 90 patients (93%) were judged to be in adequate nutritional condition, while 7 patients (7%) were deemed to be in poor nutritional condition. The median values for serum albumin and transferrin in our patients were 3.80 g/d1 and 239 mg/dl, respectively. Twenty-seven patients (26%) received preoperative hyperalimentation for a median of 4 days with a range of l-23 days. All seven patients in the poor nutritional group received preoperative hyperalimentation for a median of 6 days. Seventy-six (73%) patients had a mechanical bowel preparation prior to surgery, while sixty-eight (65%) patients had oral antibiotics to help reduce intestinal bacterial flora preoperatively. A preoperative dose of intravenous antibiotic (cefoxitin) was given to 93 (90%) patients. The remaining 11 (10%) patients did not receive any preoperative intravenous antibiotics. All patients received postoperative gentamycin and
INTESTINAL
SURGERY
AND ASCITES IN OVARIAN
TABLE 2 Infectious Morbidity/Mortality: Obstructed Patients Pt.
anastam.
Leak/ sepsis
AB MH CM AW
Enterocolic Enterocolic Enterocohc Enterocolic
y -
Type
Wound Y Y Y
Gr t-1 batter.
Fistula
Death
Y -
-
Y -
-
Y
-
clindamycin. The 1.5 patients who meet the criteria for infectious morbidity received a median of 7 days of therapeutic antibiotics. Twenty-two patients did not develop febrile morbidity post operatively. However, all had clinical evidence of small or large bowel obstruction prior to surgery. These patients were treated therapeutically with a median of 7 days of postoperative antibiotics. Fourteen patients did not meet the criteria for febrile morbidity. However, clinically they were either suspected of harboring an infection (8 patients with fever and negative blood cultures) or had documented urinary, pulmonary, or intravenous catheter-related infections (3, 1, and 2 patients, respectively). These patients were all treated with an extended course of postoperative antibiotics (median, 7 days). The remaining 53 patients had no evidence of infection and were treated prophylactically with a median of 3 days of postoperative antibiotics. Eighty-two (79%) intestinal reconstructive procedures involved large bowel in the form of enterocolic anastomosis, colocolostomies, or formation of diversionary colostomies. Only 21% of procedures involved the small bowel exclusively (enteroenterostomies, or illiostomies). Twenty-one (20%) patients had more than one gastrointestinal procedure at the same laparotomy. Sixteen (15%) patients had a total of 18 hand-sewn anastomosis, while the remaining eighty-eight (85%) patients had stapled anastomosis/resections. In the 17 patients with small bowel obstruction, 15 (88%) had primary anastomosis performed while 2 (12%) patients had proximal diversions without anastomosis. Of the 8 patients with large bowel obstruction, 5 (63%) had primary anastomosis without proximal diversion while 3 (37%) had colostomy formation without anastomosis. The median blood loss was 1100 cc with a range of 100-5000 cc. Forty-one patients (39%) had ascites present at the time of intestinal reconstruction. In 36 patients the amount of ascites was quantitated. The median amount of ascites present in these patients was 1750 cc, with a range of 100-9000 cc. Fifteen patients (14.4%) sustained 19 infectious complications postoperatively (Tables 2 and 3). Four patients developed anastomotic leaks and sepsis, eight patients developed wound infections (five of which developed fas-
43
CANCER
cial dehiscences requiring reclosure), four patients developed enterocutaneous fistulae, and three patients were found to have gram-negative bacteremia. Of the four patients who developed enterocutaneous fistulae, only one had a prior history of radiotherapy, and she was without evidence of disease at the time of surgery. The other three patients were found to have bulky, unresectable disease at the time of laparotomy. There were five postoperative deaths. Three were due to sepsis, one was due to progressive cancer, and the last was due to pulmonary emboli. Two of the three patients who died of sepsis had anastomotic leaks, while the third had a high output enterocutaneous fistula. Univariate analysis was performed for each variable to detect possible relationships with infectious morbidity. The results of these analyses and calculated P values are summarized in Table 4. As can be seen, no significant association could be found between the presence of ascites at the time of laparotomy and infectious morbidity (P = 0.58). However, a significant association was found between the use of a mechanical bowel preparation and a reduction in the infectious complication rate (P = 0.01). Additionally, patients with an adequate preoperative nutritional status sustained significantly fewer infectious complications than those patients in poor nutritional condition (P = 0.03). Patients who underwent colonic reconstructive procedures were found to have a marginally significant increase in infectious morbidity over patients whose sole procedure involved small bowel reconstruction (P = 0.14). When the remaining parameters were individually analyzed with respect to infectious morbidity, no other significant associations could be established. As a majority of patients who had a preoperative mechanical bowel preparation also had oral antibiotics to reduce intestinal flora, logistic regression analysis was performed to elucidate the most important parameter re-
TABLE 3 Infectious Morbidity/Mortality: Nonobstructed Patients Pt. ES SR CO JB CB MC TF HL ML MK JM
Type
anastam Enterocolic Colocolonic Enteroentero Enterocolic Enterocolic Colocolonic Colocolonic Enteroentero Enteroentero Enterocohc Enteroentero
Leak/ sepsis Y y y
Wound Y Y Y Y Y -
Gr t-1 batter.
Fistula
Death
Y -
Y -
Y -
Y -
Y Y -
Y -
44
DONATO
TABLE 4 Correlation of Study Parametersand Infectious Morbidity (Crude Odds Ratio Estimates) Characteristic
OR
95% CI
P
Age
60
50-60 Xi0 Preop radiation No Yes Preop obstruction No Yes Adequate nutrition No Yes Preop hyperalimen No Yes Mechanical prep No Yes Oral prep No Yes Preop antibiotics No Yes Disease present No Yes Debulking performed No Yes Large bowel reconstr No Yes No. of procedures 1 >l Hand anastomosis No Yes Ascites present No Yes
0.57 1.21
0.08-4.07 0.25-6.49
0.51 0.79
2.50
0.45-12.70
0.21
1.16
0.28-4.56
0.86
0.19
0.03-1.23
0.03
1.52
0.4-5.60
0.48
0.25
0.07-0.89
0.01”
0.76
0.22-2.70
0.64
0.40
0.08-2.19
0.20
0.67
0.06-16.85
0.73
0.82
0.14-6.13
0.82
4.32
0.54-93.23
o.14b
0.99
0.20-4.37
0.98
2.33
0.52-9.88
0.20
0.72
0.19-2.57
0.58
ET AL.
patients received postoperative antibiotics for a median of at least 3 days, the relative contribution of intravenous antibiotics to the diminution in infectious morbidity could not be addressed. Due to the variability in duration of postoperative antibiotic usage, statistical analysis was employed to be sure that ascites patients received a duration of antibiotic usage similar to that of patients without ascites. In fact, no statistical difference in duration of postoperative antibiotic usage was found between patients with and without ascites (P = 0.70). The presence of obstruction was not found to be significantly associated with infectious morbidity (P = 0.86). Additionally, no relationship could be found between the site of obstruction and infectious outcome. Infections occurred in 3 of 17 patients with small bowel obstruction and in 1 of 8 patients with large bowel obstruction (P = 0.78). Thus, the overall infection rate for patients with clinical obstruction was 16.0% (4 of 25 patients). To determine whether the presence of obstruction was responsible for modifying the activity of other parameters on infectious outcome, stratification analysis was performed. Mantel-Haenszel adjusted odds ratios and the corresponding P values for all remaining variables are listed in Table 5. Once again, the utilization of a mechanical preparation (P = 0.01) and the presence of an adequate preoperative nutritional status (P = 0.03) were the only factors significantly associated with a reduction in the infectious complication rate for both obstructed and nonobstructed patients. DISCUSSION
’ Statistically significant. ’ Borderline significant.
sponsible for the reduction in infectious morbidity. When the use of oral antibiotics was controlled for in the logistic model, a mechanical preparation was the only parameter significantly associated with a reduction in infectious morbidity (P = 0.01). All but 11 patients received a preoperative dose of an intravenous antibiotic. However, no significant association was found between the use of preoperative antibiotics and infectious outcome (P = 0.20). As all noninfected
The current report has demonstrated that in a series of ovarian cancer patients who undergo intestinal reconstructive procedures, the presence of ascites was not associated with an increase in the infectious complication rate. Although ascitic fluid can be a potential growth medium for bacteria, it has been shown that malignant ascitic fluid possess a significant amount of antimicrobial activity [9]. Both opsonic activity and complement protein content are higher in malignant ascitic fluid than in ascites from cirrhotics [9,15,21-231. Therefore, it is not surprising that the presence of malignant ascites did not contribute to the infectious complications in our patient population. In a report by Clarke-Pearson et al., 49 ovarian cancer patients with intestinal obstruction were investigated [7]. The authors reported that of all variables examined, the only factor found to be significantly associated with major postoperative complications was the presence of clinical ascites [7]. Unfortunately, the specific complications incurred by the patients with ascites are not delineated, and both noninfectious and infectious complications are reported collectively. As 12% of patients
INTESTINAL
SURGERY
AND ASCITES IN OVARIAN
TABLE 5 ParameterCorrelationswith InfectiousMorbidity Stratification by Obstruction Status (Mantel-HaenszelAdjusted Odds Ratios) Parameter Age 40 50-60 >60 Preop radiation No Yes Adequate nutrition No Yes Preop hyperalimen No Yes Mechanical prep No Yes Oral prep No Yes Preop antibiotics No Yes Disease present No Yes Debulking performed No Yes Large bowel reconstr No Yes No. of procedures 1 >l Hand anastomosis No Yes Ascites present No Yes
Adjusted OR
95% CI
P
0.57 1.26
0.08-4.12 0.26-7.07
0.52 0.73
3.42
0.28-23.89
0.21
0.20
0.03-0.95
0.03
1.58
0.41-5.93
0.46
0.21
0.06-0.89
0.01”
0.71
0.19-3.06
0.64
0.40
0.08-2.20
0.20
0.70
0.05-20.42
0.78
0.84
0.14-6.36
0.84
4.36
0.54-94.44
o.14b
0.98
0.20-4.37
0.98
2.29
0.51-9.73
0.21
0.74
0.20-2.63
0.61
’ Statistically significant. b Borderline significant.
in this study were severely malnourished and none received preoperative nutritional therapy, it is very possible that the increased postoperative complication rate in the ascites group may have resulted from significant fluid abnormalities (congestive failure and prolonged ventilatory support). A significant reduction in infectious morbidity was noted in patients who received a mechanical bowel preparation prior to laparotomy. This is consistent with other reports that clearly show the importance of reducing the fecal load of the colon prior to intestinal surgery [26-281.
CANCER
45
The ideal prophylactic antibiotic regime for elective intestinal surgery remains controversial [26-301. However, the utilization of an initial preoperative intravenous dose followed by at least 24 hr of postoperative coverage has been recommended [26]. Although oral antibiotics have been advocated by some, intravenous antibiotics have the advantage of achieving both a local intestinal and a systemic tissue level prior to the planned procedure. Obtaining adequate tissue levels prior to intestinal manipulation seems to be essential for the reduction of bacterial contamination at the time of surgery [26,27]. Although the current study did not demonstrate a significant association between the use of preoperative intravenous antibiotics and infectious morbidity, the results must be considered in light of the fact that a majority of patients received concurrent oral antibiotics, and all received a median of at least 3 days of postoperative intravenous antibiotics. Due to the small patient numbers in each of these categories, it was impossible to statistically analyze the effect of each individual parameter on infectious morbidity. Therefore, confirmation of the ideal method of prophylaxis for elective intestinal surgery cannot be addressed in this study. It has been established that patients with severe nutritional deficits are at increased risk for postoperative morbidity and mortality [24,25,31-331. In our series, patients who were judged to be in adequate nutritional condition sustained statistically fewer infectious complications than did patients who were deemed to be in poor nutritional condition. This trend has been previously reported in a similar population of patients with ovarian cancer [7]. The use of preoperative nutritional support has still not been conclusively shown to reduce postoperative morbidity and mortality [24,31,33]. As there were only seven patients in the poor nutritional group and all received preoperative hyperalimentation, we were unable to demonstrate the efficacy of preoperative therapy in our patient population. Furthermore, it has been stated that patients ‘with severe malnutrition require at least 14 days of nutritional support consisting of at least 35 kcal/kg/day and 1.5 g/kg of protein daily for adequate repletion [31,33]. The severely depleted patients in our series received a median of only 6 days of preoperative hyperalimentation. Therefore, the efficacy of preoperative nutritional support awaits the results of a randomized, prospective trial. A marginal increase in the infectious complication rate was noted in patients who underwent large bowel reconstruction relative to patients whose sole procedure involved small bowel reconstruction. This is not surprising, as the majority of our patients were not obstructed, and it would be anticipated that small bowel reconstructive procedures would be associated with less bacterial contamination than those involving large bowel [34].
46
DONATOETAL.
The presence of preoperative obstruction was not shown to increase the infectious morbidity in the current series of ovarian cancer patients undergoing various intestinal reconstructive procedures. This finding is contrary to that of Castaldo et al. [l]. The authors found that the highest incidence of infectious morbidity and mortality occurred in patients with preoperative obstruction. It is our opinion that the aggressive utilization of hyperalimentation and employment of a therapeutic postoperative antibiotic regime contributed to the low infectious morbidity in our subgroup of obstructed patients. Recall that all patients in the current series who were obstructed received preoperative hyperalimentation and a therapeutic course of postoperative antibiotics for a median of 7 days. These patients were felt to be at high risk for the development of intraabdominal infections due to mechanical stasis and bacterial overgrowth in affected intestinal segments. Castaldo et al. did not employ preoperative hyperalimentation in any patient and do not even address the issue of antibiotic usage in their patients [l]. Obviously, the precise employment of hyperalimentation and antibiotics in patients with clinical bowel obstruction has not been established. Although it is believed that aggressive utilization of these two therapeutic modalities will reduce infectious morbidity in this population, definitive proof awaits the completion of prospective clinical trials. In those patients with preoperative bowel obstruction, no statistical difference in infectious morbidity was noted between those with small and those with large bowel obstruction (P = 0.78). However, our numbers are small, and we would hesitate to draw any definitive conclusion from these data. In fact, two previous series have reported an increased postoperative complication rate in patients with small versus large bowel obstruction [1,7]. In the series of Castaldo et al., 10% of patients with large bowel obstruction versus 44% with small bowel obstruction sustained major postoperative complications [ 11. In study of Clarke-Pearson et al., 25% of patients with large bowel obstruction versus 63% of patients with small bowel obstruction sustained major postoperative complications [7]. There are at least two explanations for the contradictory findings noted between the current series and the two reports previously discussed. First, the collective majority of patients (90%) with small bowel obstruction in both previous studies had primary anastomosis performed. In contrast, only 1 of 26 patients (4%) with large bowel obstruction in these studies had primary anastomosis performed (96% had proximal colostomy formation without anastomosis). In our series, 63% of patients with large bowel obstruction and 88% of patients with small bowel obstruction had primary anastomosis. As any anastomosis performed in the context of an obstructed gastrointestinal tract carries a greater risk of dehiscence [35], it is not
surprising that the patients with small bowel obstruction in the above two series sustained more complications than did patients with large bowel obstruction. Second, as previously discussed, the nutritional status of the patients in the above two studies appears to be very different than that in the current study. For example, the percentage of patients with severe nutritional deficits in the study by Clarke-Pearson et al. was almost twice that of the current series. Closer inspection of this series reveals that the albumin was the only serum protein utilized for the calculation of nutritional status. As the half-life of serum albumin is relatively long (20-30 days), it is considered insensitive to acute nutritional deficits [25]. Therefore, the number of patients with severe nutritional deficits may well have been underestimated by the authors. Castaldo et al. do not discuss the preoperative nutritional status of their patients. It appears that only 8 of 49 (16%) patients received any form of nutritional support pre- or postoperatively. The authors concede that the addition of nutritional support may well have improved the high postoperative complication rate encountered in their series
111.
Finally, we were unable to demonstrate a significant relationship between infectious morbidity and parameters such as age, prior radiotherapy, disease presence, performance of concurrent debulking, number of bowel procedures, and the use of hand versus stapled anastomotic techniques. These factors were not shown to be significantly correlated with postoperative complications in a previous study [7]. Although Castaldo et al. reported a possible trend toward increased postoperative complications in patients with multiple anastomosis or previous radiotherapy, the association was not found to be significant [l]. In summary, our findings suggest that both large and small bowel reconstructive procedures can be performed safely in patients with ovarian cancer who have ascites present at the time of laparotomy. The utilization of a mechanical bowel preparation and an adequate nutritional status were both significantly associated with a reduction in infectious morbidity in this patient population. The presence of intestinal obstruction was not found to be significantly associated with infectious morbidity, nor was it shown to modify the effects of other variables on infectious outcome in the current report. Although it is believed that the aggressive use of preoperative hyperalimentation and the employment of a therapeutic antibiotic regime may have contributed to the limited infectious morbidity in our patients with preoperative obstruction, definitive statements cannot be made at this time. A previous history of abdominal radiation therapy was also not found to be significantly associated with infectious
INTESTINAL
SURGERY
AND ASCITES IN OVARIAN
CANCER
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morbidity in this series. However, patient numbers in these categories are small, and definitive conclusions must await the recruitment of a larger clinical series.
