Infectious Complications after Cytoreductive Surgery and Hyperthermic Intra-Peritoneal Chemotherapy

Abstract

Background:

The aim of this study was to review the post-operative and infectious complications and determine the risk factors associated with infections in cytoreductive surgery (CRS) and hyperthermic intra-peritoneal chemotherapy (HIPEC).

Patients and Methods:

Between October 2007 and December 2013, patients who underwent CRS and HIPEC with a curative intent were included in the study. The Centers for Disease Control and Prevention's National Nosocomial Infections Surveillance System definitions were used to identify post-operative nosocomial infections.

Results:

One hundred and sixty-nine CRS and HIPEC procedures were performed. Overall, 155 complications were observed in 82 (48.5%) patients. Grade 3–4 morbidity rate was 25.5% (n = 43). Seventy infections occurred in 47 patients. Surgical site infection was the most common infectious complication. The most common micro-organism isolated from the cultures was Escherichia coli. Age (odds ratio [OR]1.039, confidence interval [CI] 1.006–1.073), the mean total number of staff scrubbing in the operation(OR 2.241, CI 1.415–3.548), and intensive care unit stay (OR 1.325, CI 0.953–1.842) were independent risk factors for infectious complications.

Conclusions:

Infectious complications are the most important cause of peri-operative morbidity and death in CRS and HIPEC. As well as patient and tumor characteristics, surgeon/center-related factors play an important role in infectious morbidity. Patients with peritoneal carcinomatosis should be considered as a complex oncologic group at high risk of infectious complications.

Peritoneal carcinomatosis (PC) is an advanced stage manifestation of abdomino-pelvic malignancies. Since Sugarbaker [1] suggested that PC should be managed as though it is a loco-regional disease but not a metastatic process, cytoreductive surgery (CRS) with loco-regional chemotherapy is now a more common treatment tactic. Results from many studies indicate that CRS and hyperthermic intra-peritoneal chemotherapy (HIPEC) may obtain significant survival improvements and even cure in selected patients with peritoneal surface malignancies [2 –6].

Cytoreductive surgical procedures include combined multi-visceral resections and peritonectomy procedures that require meticulous surgical technique resulting in prolonged operative time, hemodynamic alterations, physiologic derangements, and occasionally the necessity for intensive care unit (ICU) stay [7]. The combination of this complex anti-cancer operation with HIPEC comes with an increased risk of post-operative complications. Infectious complications have been identified as the major cause of peri-operative morbidity and death in this specific population [8]. The aim of this study was to review the post-operative and infectious complications and determine the risk factors associated with infections in CRS and HIPEC.

Patients and Methods

Patient characteristics

The study was approved by Dokuz Eylul University ethics committee (1366637NA). A prospectively recorded database of patients who were treated for PC in our institution was reviewed. Between October 2007 and December 2013, patients who underwent CRS and HIPEC with a radical curative intent were included in the study. Informed consents for the surgical procedure and also for collecting and using data in clinical studies were received from all patients. The interval between last chemotherapy and operation was at least four weeks in all patients. Active infection within four weeks before surgery, immunosuppression, non-curative interventions, and non-elective surgery were the exclusion criteria.

Surgical procedure

All patients received mechanical bowel preparation and thromboembolic prophylaxis including low molecular weight heparin, compression stockings, and intermittent pneumatic compression. Intravenous cefuroxime axetil and metronidazole were administered 30 minutes before incision and repeated every three hours during the surgical procedure. Extent of the disease and resectability were assessed with the peritoneal carcinomatosis index (PCI) [9]. Palliative interventions such as stoma formation and/or debulking were performed when complete cytoreduction was not anticipated, and these patients were excluded from the analysis.

The goal of the surgery was to eradicate the whole macroscopic tumor tissue. En-block partial or total visceral resections and peritonectomies were performed according to the tumor-involved organs and/or peritoneal surfaces. Except for peritoneal mesothelioma, peritonectomy was not performed on uninvolved surfaces. Patients with advanced ovarian carcinoma underwent bi-template aorta-caval and pelvic therapeutic lymphadenectomy. At the end of the procedure, residual disease was scored according to Completeness of Cytoreduction classification (CC) (no residual disease: CC-0; residual disease <2.5 mm: CC-1; residual disease of 2.5 mm–2.5 cm: CC-2; and residual disease >2.5 cm: CC3) [10]. Intestinal anastomoses were performed before HIPEC application.

The total number of staff including nurses, assistants, and surgeons scrubbing in and out during the entire operation at any time was defined as crowdedness of surgical team. For learning curve analysis, we divided our procedures into two groups including first and last three years. During our first three years, we performed the first 100 procedures, which may be an adequate number for proficiency in our consideration.

Hyperthermic intra-peritoneal chemotherapy

At the end of the operation, four drains (two inflow and two outflow) and two thermal probes were placed in the abdomen, and the fascia was closed. Intra-peritoneal chemotherapy was administered with closed abdominal technique at a constant temperature of 42.5°C. Oxaliplatin (400 mg/m², 30 min) or mitomycin-C (10 mg/m²), or cisplatin (75 mg/m², 90 min) by HIPEC device. Reduced doses were considered in case of advanced age and impaired renal functions. Drains were left in the abdomen and removed gradually in the post-operative period.

Post-operative follow-up and evaluation of complications

Intravenous antibiotic agents were continued for three days in patients with enterotomy and/or gastrointestinal resection. Parenteral nutrition was administered to the patients who had delayed oral feeding because of ileus or complications. As soon as complete oral feeding was ensured, nutrition support was provided with oral nutritional supplements.

Symptoms and findings including dyspnea, dysuria, purulent drainage from wound or drains, and fever >38°C were accepted as significant in support of infections. Lymphocyte count and C-reactive protein levels that kept increasing after 48 hours from operation were also considered as suspicious for infection. Any samples clinically obtained from the patients who were suspected to have infection were cultured routinely in the microbiological laboratory.

Complications and toxicity were classified according to Common Terminology Criteria for Adverse Events criteria [10]. Major morbidity was defined as Grade 3 and 4 complications. Death within first 30 days post-operative or before discharge of the patient was accepted as peri-operative morbidity. The Centers for Disease Control and Prevention's National Nosocomial Infections Surveillance System definitions were used to identify post-operative nosocomial infections [11].

Statistical analysis

Continuous variables were expressed as means and range, and categoric variables as frequency and percentages. Association between categoric variables and morbidity was determined with the chi-square test. Association between continuous variables and morbidity was tested by independent samples t-test. Association between non-parametric variables and morbidity was tested by the Mann-Whitney U test. The p values <0.05 were defined as statistically significant. Cox proportional hazards model was used to identify risk factors in multivariable analysis.

Results

Among 217 procedures, 48 were excluded from the study. The reasons for exclusion were disagreement of the patients in five, short interval (<4 wks) between last chemotherapy and surgery in 15, non-elective surgical procedure because of mechanical bowel obstruction in 12, palliative operation in 10, and signs of active infection in six patients. In 165 patients meeting inclusion criteria, 169 CRS and HIPEC were performed. Four patients who underwent re-cytroreduction and HIPEC were re-assessed individually as new procedures. Co-morbidity was assessed with the Charlson Comorbidity Index (CCI) [12], and patients were tiered into three groups: CCI = six were group I, CCI = seven or eight were group II, and CCI nine or more were group III. Median CCI score was six (6–11). Forty-six (27.2%) patients had one or more co-morbid diseases, and 108 (64%) received median nine (3–32) cycles of previous chemotherapy. Details of patient characteristics are given in Table 1.

Table 1.

Demographic and Clinical Characteristics of the Patients

	n = 169 (%)
Age	54 (20–86)
Male/female	44 (26%)/125 (74%)
Charlson Comorbidity Index	46 (27.2%)
Group 1	123 (72.8%)
Group 2	26 (15.4%)
Group 3	20 (11.8%)
Origin of peritoneal carcinomatosis
Ovarian	64 (37.9)
Colorectal	54 (32.0)
Mesothelioma	15 (8.9)
Appendix	15 (8.9)
Other	21 (12.3)
Presentation
Synchronous	87 (51.4%)
Metachronous	74 (27.6%)
Recurrent/Residual	8 (21%)
Previous chemotherapy	108 (64%)
Operative time (median, min)	320 (45–800)
Anesthesia time (median, min)	450 (135–890)
Red blood cell transfusion	123 (72.8%)
Packs of red blood cells (median, unit)	2 (2–14)
Fresh frozen plasma transfusion	73 (43.2%)
Intra-operative albumin infusion	36 (21.3%)
Peritoneal Carcinomatosis Index (median)	14 (3–28)
Completeness of Cytoreduction
CC-0	115 (68%)
CC-1 or 2	37 (22%)
Number of resected organs (median)	3 (1–9)
Ostomy	60 (35.5%)
Gastrointestinal anastomosis	87 (51.3%)

Overall, 155 individual complications were observed in 82/166 (48.5%) procedures. Grade 3–4 morbidity was observed in 43 (25.5%) patients. The cause of morbidity was infections in 47 (27.8%) patients, surgical complications in 30 (17.7%), and HIPEC toxicity in 38 (22.4%) patients. Most of the complications were managed conservatively. Nine (5%) patients underwent re-operation, and six (3.5%) needed percutaneous drainage of intra-abdominal abscess because of surgical complications.

Patients who had hard symptoms and/or signs of infection (i.e., purulent drainage from wound or drains, bacteriuria, persistent fever) were administrated empiric antibiotherapy, and after culture results were received, antibiotic agents were stopped if the culture was negative. Grade 4–5 HIPEC toxicity was observed in 12 (7%) patients who required intensive care. Six patients needed temporary hemodialysis and none of them had chronic renal failure. Hemotoxicity was observed in 10 patients: grade 1–2 in three patients, grade 3–4 in three patients, and grade 5 in four patients who all had febrile neutropenia.

Seventy infections occurred in 47 patients (Table 2). Surgical site infection (SSI) was the most common infectious complication. The most common micro-organism isolated from the cultures was Escherichia coli (Table 3). Infection was limited to a single site in 26 patients (18 SSI, two urinary tract, and six pulmonary), and more than one source was responsible in 21 patients. Co-existing infection was not statistically associated with an increase in death (p = 0.135). Extended-spectrum beta-lactamase (ESBL) producing micro-organisms were observed in 17 patients (16 E. coli and 1 Klebsiella). Patients who received post-operative antibiotic agents because of gastrointestinal interventions tended to have ESBL (+) infections more likely than who did not receive the agents, but the difference did not reach statistical significance (12.6% vs. 8.9%, p = 0.096). The mortality rate was higher in patients with ESBL (+) infections (n = 8, 5.2% vs. n = 3, 17.6%), but the difference was not statistically significant (p = 0.056).

Table 2.

Details of the Infectious Complications According to the Centers for Disease Control and Prevention's National Nosocomial Infections Surveillance System ¹¹

Complication	n	Grade 1	Grade 2	Grade 3	Grade 4	Grade 5
SSI	36	2	11	11	6	6
Superficial	4	0	3	0	1	0
Deep	19	2	7	5	3	2
Organ/space	13	0	1	6	2	4
Blood stream	9	0	1	1	3	4
Pulmonary	11	0	3	1	4	3
Urinary tract	14	1	2	3	5	3
Patients	47	2	14	11	10	10

SSI = surgical site infection.

Table 3.

Micro-Organisms Isolated from Cultures

	Infections (n, %)
Microorganisms	Surgical site	Blood stream	Pulmonary	Urinary tract
Escherichia coli/ESBL+	19 (53)/9	4 (44)/4	-	10 (71)/3
Klebsiella pneumoniae/ESBL+	6 (17)	4 (44)/1	-	2 (14)
Enterococcus spp	10 (28)	1 (11)	-	-
Staphylococcus spp	-	1 (11)	2 (23)	-
Acinetobacter spp	-	2 (23)	2 (23)	-
Pseudomonas aeruginosa	2 (6)	1 (11)	-	2 (14)
Candida albicans	6 (17)	6 (67)	3 (27)	6 (43)
Others	2 (6)	1 (11)	-	-

The median pre-operative albumin level was 3.8 (2.4–4.7) g/dL; the mean values were 3.9 in non-infected patients and 3.7 g/dL in patients with infectious complications (p = 0.305). Thirty-six patients who had prolonged operations and aggressive resections with low albumin levels received intra-operative albumin replacement, but this did not differ infection rates (Table 4). The median hospital stay was 13 (range 4–144) days. Mean hospital stay was significantly shorter (12.1 ± 4.7 d) in patients who did not have infectious complications in comparison with patients with infections (29.3 ± 22.8 d) (p < 0.001). Forty-eight patients needed a mean of 0.8 (range 0–23) days ICU stay. The peri-operative mortality rate was 6.5% (n = 11) and significantly higher in patients who had infectious complications (21.3% vs. 0.8%, p < 0.001). Candida albicans had the highest mortality rate (54.5%). In six patients with peri-operative mortality, C. albicans was isolated from both blood and wound cultures. In three patients, ESBL+ microorganisms were isolated. Details of the patients with peri-operative mortality are given in Table 5.

Table 4.

Factors Associated with Infectious Complications

	Infectious complication (−) (n = 122)	Infectious complication (+) (n = 47)	p	Multivariate analysis OR (95% CI)
Age (mean, year)	52.8	57.7	0.023	1.039 (1.006–1.073), p = 0.042
Gender			0.926
Female	90	35
Male	32	12
CCI			0.014
Group 1	95	28
Group 2	16	10
Group 3	11	9
Smoking (+)	12	9	0.100
Neoadjuvant CT (+)	77	31	0.730
Etiology			0.372
Ovarian	46	18
Colorectal	44	10
Mesothelioma	10	5
Appendix	10	5
Other	12	9
Previous surgery (+)	62	25	0.640
BMI (mean, kg/m²)	27	26.6	0.885
Resected organs (mean)	3.4	4.4	0.003
Splenectomy (+)	15	10	0.141
GI intervention (+)	103	45	0.046
Anastomosis (+)	60	30	0.087
Iatrogenic injury	7	5	0.266
Double-J/stent (+)	6	4	0.375
Synthetic mesh (+)	7	3	0.858
PCI			0.046
Mild (<13)	68	19
Severe (≥13)	50	28
Pre-operative albumin (g/dL)	3.9	3.7	0.305
Intra-operative albumin tx (+)	26	10	0.996
Red blood cells (U, mean)	2.3	3.2	0.015
Staff (mean)	3.3	3.9	<0.001	2.241 (1.415–3.548), p = 0.012
Operative time (mean, min)	321.2	373.9	0.019
Anesthesia time (mean, min)	471.2	523.9	0.018
Pre-operative hospital stay (mean, d)	8.5	8.9	0.779
ICU stay (mean, d)	0.4	0.8	0.001	1.325 (0.953–1.842), p = 0.033
Days in ventilator (mean)	0.36	1.81	0.001
HIPEC toxicity (+)	21	17	0.008
HIPEC agent			0.055
Cisplatin	46	14
Cisplatin + mitomycin-C	61	28
Oxaliplatin	15	5
Learning curve
First 3 y	64	33	0.027
Second 3 y	58	14

OR = odds ratio; CI = confidence interval; CCI = Charlson Comorbidity Index; CT = chemotherapy; BMI = body mass index; GI = gastrointestinal; PCI = Peritoneal Carcinomatosis Index; ICU = intensive care unit; HIPEC = hyperthermic intraperitoneal chemotherapy.

Table 5.

Details of the Patients with Peri-Operative Mortality

Patient	Complications	Culture
#1	Pneumonia, nephrotoxicity	Pseudomonas aeruginosa
#2	Anastomotic leak, urinary leak, hematotoxicity (febrile neutropenia), SSI, BSI	C. albicans, K. pneumoniae (ESBL+)
#3	SSI, BSI, nephrotoxicity, hematotoxicity (febrile neutropenia)	C. albicans, E. coli (ESBL+), MR-CoNS, K. pneumoniae
#4	Anastomotic leak, SSI, BSI, UTI	C. albicans, E. coli (ESBL+), Klebsiella, S. aurius
#5	Pneumonia, UTI	C. albicans, Acinetobacter sp.
#6	Pneumonia, BSI, SSI, nephrotoxicity, hematotoxicity (febrile neutropenia)	Acinetobacter sp, E. coli
#7	Pleural effusion, SSI, BSI	C. albicans, E. coli
#8	Pneumonia, iatrogenic small bowel injury, SSI, BSI, hematotoxicity (febrile neutropenia)	C. albicans, E. coli
#9	Pneumonia, nephrotoxicity, hematotoxicity	NA
#10	Pneumonia, urinary leak	NA
#11	Stroke	-

SSI = surgical site infection; BSI = blood stream infection; ESBL = extended-spectrum beta-lactamase; MR-CoNS = methicillin-resistant coagulase-negative staphylococci; UTI = urinary tract infection' NA = not available.

C. albicans = Candida albicans; K. pneumoniae = Klebsiella pneumoniae; E. coli = Escherichia coli; S. aureus = Staphylococcus aureus.

In univariable analysis, the relation between infectious complications and 27 factors was analyzed. Age (p = 0.023), co-morbidity (p = 0.017), number of resected organs (p = 0.003), gastrointestinal interventions (p = 0.046), PCI (p = 0.046), intra-operative red blood cell transfusion (p = 0.015), number of staff in surgical team (including the scrub nurse) (p < 0.001), operative time (p = 0.019), anesthesia time (p = 0.018), ICU stay (p = 0.001), days in ventilator (p = 0.001), HIPEC toxicity (p = 0.008), and learning curve (p = 0.027) were significantly associated with infectious morbidity. The chemotherapeutic agent(s) used for HIPEC did not affect infection rate. Age (odds ratio [OR] 1.039), crowded surgical team (OR 2.241), and ICU stay (OR: 1.325) were independent risk factors in multivariable analysis (Table 4).

Discussion

The use of CRS and HIPEC has been popularized around the world based on its satisfactory oncologic results [5,6,13 –15]. Overall morbidity (12%–56%) and mortality (0%–12%) rates reported in the literature, however, remain relatively high [16 –21]. Candidates for CRS and HIPEC often have a history of multiple previous operations and several cycles of chemotherapy. The majority of these patients have poor performance with nutritional deficiency and ascites, which can predispose morbidity after ultra-aggressive multi-visceral resections. Moreover, HIPEC itself is a cause of immunologic alterations and toxicity that makes patients with PC a potentially high-risk population for infections [17,22]. Our series can be regarded as a high-risk group, because half of the patients had one or more previous abdominal operations, more than half with neoadjuvant chemotherapy history, and one third with co-morbidity.

Infectious morbidity is the major cause of prolonged hospital stay and peri-operative mortality after CRS and HIPEC [8]. In a limited number of studies focusing on this issue, infectious complication rates were reported between 24% and 36% [5,8,23,24]. Valle et al. [25] reported 44% overall morbidity and 35.8% symptomatic infections in 111 patients with PC from several origins. In the same study, colon resection and prolonged operative time were significantly associated with high risk of infection. In our study, gastrointestinal interventions were associated with an increased rate of infection, and prolonged operative time was significantly associated with a higher morbidity rate. Another study [8] with 30 patients reported a higher mortality rate in patients who had infectious morbidity (36.4% vs. 5%) comparable with our results (23.3% vs. 0.8%).

In both studies and our series, the most common microorganism isolated from the cultures was E. coli, and C. albicans was the leading cause of mortality. Compatible with the literature, multi-drug resistant microorganisms were also associated with a higher mortality rate in our patients: Of 11 peri-operative mortality cases, ESBL+ microorganisms were isolated in three [26]. The effect of beta-lactamases on infection rate was not statistically significant in our series. Maintenance of prophylactic antimicrobial therapy for three days in the post-operative period, however, may be associated with increased risk of ESBL+ infections. Antimicrobial prophylaxis may be extended until post-operative day five in some centers [7]. As observed in our cases, repetitive abdominal interventions, long-term antibiotherapy, and multiple-site infections have been well known risk factors for higher mortality from candidiasis [27]. All of these results show that taking intra-operative samples for cultures is crucial to manage intra-abdominal infection treatment more successfully.

Toxicity from HIPEC should be monitored closely after CRS and HIPEC. Side effects related to HIPEC, particularly hemotoxicity, may occur even after discharge from the hospital [17]. Sugarbaker et al. [23] reported an infection rate of 47% in patients with grade 3 toxicity. In our study, approximately half of the patients with HIPEC-related toxicity had infectious morbidity. Hemotoxicity was the cause of death in six patients (four of them had febrile neutropenia).

Performance and nutrition status are important factors that should be considered during patient selection. Prevalence of malnutrition is as high as 80% in patients with advanced stage colorectal cancer [28]. Nutrition status evaluated by Subjective Global Assessment was shown to be related to survival and hospital stay after CRS and HIPEC [29]. There are no data, however, about the relation between nutrition status and complications in PC. The prospectively recorded data predicting nutrition status in our patients were body mass index, pre-operative and intra-operative serum albumin levels; however, none was significantly associated with complications.

The drawbacks of our study include limited number of patients, retrospective design, and lack of objective data about performance and nutrition status. Some of our patients who could not start oral or enteral feeding because of ileus or complications were given parenteral nutrition, but we do not have recorded data about the number of these patients and duration of parenteral nutrition. Because parenteral access is a well-known risk factor for infections, particularly fungi, this is one of the major limitations of our study. As well as pre-operative nutrition status, other pre-operative variables including lymphocyte count, previous operation and chemotherapy are potential risk factors underlying infections. The interval between last chemotherapy and surgical was at least four weeks in our patients, and no patient had low lymphocyte or neutrophil count. Previous operation and chemotherapy history did not affect our results.

As well as patient and tumor-related issues, the experience of the surgical team plays an important role in surgical complications. Most of the risk factors associated with post-operative infections in our series were intra-operative factors, which can be enhanced by revision of some surgical aspects. Our results showed that a crowded operation team is associated with increased risk of infection. Age, the extent of disease and resection, number of resected organs, blood loss, and operative time as well as learning curve were suggested as risk factors for increased morbidity in the literature [20,21,30 –34]. A learning curve of 140 and 200 operations was recommended for better surgical outcome [35,36]. Compatible with these results, the infectious morbidity rate was lower in recent procedures in our series.

There is an increasing incidence of trained surgical oncology fellows and specialized centers in these techniques all over the world. As new and more effective systemic therapies are introduced, the selective use of CRS and HIPEC will be increased. The bulk of the experienced center-based literature, however, has been surprisingly lacking in important data about infectious complications after CRS and HIPEC. Thus, every peritoneal surface malignancy management center must audit its own morbidity and death results, particularly infectious complications.

The authors developed an interdisciplinary team approach culture with the Infection Disease Unit, Nutritional Care Team, and Intensivists to improve overall patient outcomes. Our cumulative data alerted us to realize the fatal combination of multi-drug resistant bacteria and fungi. In addition, the development of more than one complication (whether it is surgical procedure-related infectious or HIPEC-related non-infectious or not) significantly increased the overall mortality rate of these patients.

Infectious complications are the most important cause of peri-operative morbidity and mortality in CRS and HIPEC. Patients with PC should be considered as a complex oncologic group sensitive to infectious complications. Morbidity of the procedure can be reduced with an experienced surgical team and sufficient number of staff. A standard peri-operative care protocol and multi-disciplinary approach will contribute to easiness in management of complications.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

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