The surgical treatment of epithelial ovarian cancer (EOC) has been constantly evolving during the last decades toward a higher radicality, aiming at maximal cytoreduction by incorporating extensive multivisceral techniques such as upper abdominal tumor debulking, extensive peritonectomy, and en bloc resection techniques. These operations characterized by a maximal surgical effort often constitute a great challenge for both patients and physicians, recruiting high personal and institutional resources.1,2
Ascites is in general a sign of advanced disease with diffuse peritoneal tumor dissemination.3 Therefore, it constitutes an additional risk factor in terms of extreme volume shifting at cytoreduction, while it is often associated with more extensive surgical procedures so that optimal tumor debulking can be obtained. Its influence on body fluids and its loss during laparotomy may often predispose to severe hemodynamic instability.
However, no studies that evaluate the impact of ascites on the perioperative management of such patients exist so far, and hardly any data on the consequences of ascites on hospital length of stay and required intensive care exist. Therefore, the aim of this work was to assess the impact of ascites at the time of surgical cytoreduction for primary and relapsed EOC on perioperative and postoperative outcomes.
MATERIALS AND METHODS
We performed a systematic analysis of a prospectively maintained database evaluating the intraoperative tumor dissemination pattern in women undergoing laparotomy for cytoreductive surgery due to primary EOC or relapse of EOC in the Department of Gynecology, Charité, Campus Virchow Clinic, between January 2005 and December 2008. The characteristics for including patients into this study were the presence of follow-up data longer than 6 months after surgery and matching data sets from the Department of Gynecology, the Department of Anesthesiology and Intensive Care Medicine, and the hospital administration data set at Charité, Campus Virchow Clinic, between January 2005 and December 2008. Of the 580 patients during that period, we included 119 patients with matching data sets from the Department of Gynecology and Anesthesiology and Intensive Care Medicine as well as the hospital administration data set offering insurance and diagnostic data. An ethical vote was conceived from the ethical committee (Charité, Berlin, Germany, No. EA1/176/11). Of the 580 patients being operated on because of ovarian cancer, 119 consecutive patients with available tumor characteristics as well as complete anesthesiological and hospital administration data sets were included into this study.
All the relevant data for anesthesiological management such as general data, physical status according to the American Society of Anesthesiologists, comorbidities, anesthesiological techniques, perioperative vital parameters, medications, fluids, perioperatively administered volume as well as transfusion therapy, and all postoperative outcome variables for each patient were taken out of the database of the Department of Anesthesiology and Intensive Care Medicine, Charité University Hospital, Campus Virchow Clinic. The patients were evaluated according to the presence of preoperative ascites, and 3 groups were classified, namely, no ascites, presence of ascites with less than 500 mL, and presence of ascites with more than 500 mL.
Anesthesiologically, the patients were treated within a clinical pathway defined by standard operating procedures always accessible in the intranet of the Charité University Hospital, Berlin, Germany. After premedication with midazolam 3.75 to 7.5 mg, noninvasive monitoring was applied (electrocardiogram, blood pressure, and oxygen saturation monitoring) and the anti-infective therapy with 1.5-g cefuroxime and 0.5-g metronidazole was administered. An epidural catheter was placed (Th8/Th10) and equipped with an 8- to 10-mL bolus and a continuous basal rate of 6-mL/h 0.2% ropivacaine and 1.0-μg/mL sufentanil. After the induction of anesthesia with propofol 2 to 3 mg per kilogram of body weight (BW) or thiopental 3 to 5 mg per kilogram of BW and analgesia with fentanyl 1 to 2 μg per kilogram of BW, the maintenance of anesthesia was realized with a total intravenous anesthesia with propofol 6 to 10 mg per kilogram of BW per hour or a balanced anesthesia with desflurane, depending on the risk score for postoperative nausea and vomiting as well as the preoperative cardiac status. In addition, remifentanil 0.05 to 0.3 μg per kilogram of BW per minute was given intraoperatively with respect to clinical necessity. Neuromuscular blocking was performed with rocuronium or cisatracurium 0.6 mg per kilogram of BW. Intraoperative neuromuscular blocking was assessed with acceleromyography, and relaxants were given accordingly. Frequent blood gas monitoring was performed, and respiratory settings were adopted accordingly if necessary. If considered necessary, an arterial line and a central venous line were placed for the continuous measurement of blood pressure and central venous pressure. The patient was covered by a forced-air body warming system. For the administration of anesthetic drugs and replacement of perioperative fluid demands, a balanced crystalloid infusion was administered. To replace blood and intravascular volume demands during the surgery, colloid solutions (Voluven) were administered. After exceeding the administration of colloid infusion 30 to 50 mL per kilogram of BW, transfusions of fresh frozen plasma (FFP) were performed according to the clinical estimation of the responsible surgeon and anesthesiologist. The transfusion of packed red blood cells (PRBCs) was given by clinical judgment being geared to the measurements of hemoglobin level in the arterial blood.
All operations were performed by 1 of 4 gynecologic oncologic surgeons. Every operative cytoreduction was primarily aiming at a maximal tumor resection with no visible macroscopical tumor residuals. Standard procedures included midline laparotomy, peritoneal cytology, extrafascial hysterectomy, adenectomy, infragastric omentectomy, and systematic pelvic as well as para-aortic lymph node dissection if a complete tumor resection could be obtained. In cases of advanced tumor disease, additional procedures, such as peritonectomy, bowel resection, splenectomy, and/or partial resection of other affected organs (eg, urinary bladder, liver, pancreas), were performed to achieve an optimal tumor debulking.
Intraoperative Mapping of Ovarian Cancer
The intraoperative mapping of ovarian cancer represents a detailed surgical and histopathological documentation system developed in our clinic to obtain a better and more objective description of the ovarian tumor spread within the abdominal cavity and to define more precisely the histopathological features of the malignancy.2,4 Within the Tumor Bank Ovarian Cancer project (www.toc.network.de), tumor tissue, ascites, serum, and blood were collected from each patient with malignant tumors. The patients’ informed consent was given before the surgery, sample collection, and documentation.
Data were expressed according to their scaling as median (25%–75% quartiles) or frequency (percentage). After checking the distributions for normality, the differences between the regarded groups in terms of interesting clinical parameters were tested by using nonparametric exact Mann-Whitney U tests for independent groups. Frequencies were tested by the exact Mantel-Haenszel test (ordered categories) or the exact χ2 test in contingency tables.
A 2-tailed P < 0.05 was considered statistically significant. All tests have to be understood in the area of exploratory data analysis. Therefore, no adjustments for multiple testing have been made. All numerical calculations were performed with IBM SPSS Statistics, version 20, copyright 1989, 2010 (SPSS, Inc).
One hundred nineteen consecutive women who underwent cytoreductive surgery for primary or relapsed EOC were enrolled into the analysis. Fifty-six women (47%) did not present any ascites, whereas 42 women (35.3%) presented ascites less than 500 mL, and 21 women (17.6%) presented ascites more than 500 mL at the time of surgery. All 3 groups were balanced in terms of age, International Federation of Gynecology and Obstetrics stage, tumor histological diagnosis, body mass index, comorbidities, or the American Society of Anesthesiologists status. There was no significant difference between the groups regarding anesthesiological management in terms of using an epidural catheter, an arterial line, or a central venous line (Table 1).
Table 2 outlines an overview of tumor characteristics and performed surgical procedures in the 3 groups. The performed surgical procedures due to primary ovarian cancer were more frequent and more extensive in patients with ascites, especially if more than 500 mL of ascites was present. Performance of hysterectomy (26.8% vs 40.5% vs 57.1%, P = 0.044), bilateral salpingo-oophorectomy (32.1% vs 38.1% vs 66.7%, P = 0.029), resection of large (23.2% vs 47.6% vs 81%, P < 0.001) and small intestine (17.9% vs 38.1% vs 57.1%, P = 0.002), as well as peritonectomy (41.1% vs 83.3% vs 81%, P < 0.001) were significantly more frequent in patients with ascites. The rates of optimal tumor resection were significantly lower in the group of patients with ascites. In the group of patients without ascites, 75% could be operated on macroscopically tumor free, whereas the rates of total macroscopic tumor clearance were only 50% and 38% in patients with ascites less than 500 mL and more than 500 mL, respectively. The preoperative levels of the tumor marker CA-125 were significantly higher in the group of patients with ascites compared with those of the patient group with no ascites (103 vs 277 vs 760 IU/L, P < 0.001).
Intraoperative anesthesiological data are outlined in Table 3. There was no difference in the administration of crystalloid solutions. Patients without ascites at the time of surgery received an infusion of colloid solutions significantly less than that of patients with ascites (Fig. 1). Moreover, the transfusion of PRBCs and FFP was less in patients with no ascites in comparison with patients with more than 500 mL of ascites (0 vs 3 U of PRBCs and 0 vs 2 U of FFP) (Fig. 1).
Noradrenaline (NA) was used more frequently and in higher doses in patients presenting ascites to maintain perfusion pressure. Low-dose NA and high-dose NA were administered in 37.5% and 1% of patients with no ascites, in 38.1% and 4% of patients with less than 500 mL of ascites, as well as in already 57.1% and 9.5% of patients with more than 500 mL of ascites, respectively. Eligible values can be seen for episodes of tachycardia. Heart rates of more than 90 beats per minute were more frequent in patients with 500 mL or more ascites than in patients without ascites.
There was no difference in narcotics to maintain anesthesia and other medication used during surgery, and there was no difference in body temperature, duration of surgery, acid-base balance, as well as glucose and lactate values.
The postoperative outcome data show significant differences among the study groups. The intensive care unit (ICU) stay and hospital stay are significantly longer in patients with ascites at the time of surgery (Fig. 2). Of the patients with more than 500 mL of ascites at the time of surgery, 95.2% needed a postoperative stay on the ICU and the required median length of intensive care monitoring was 3 days (interquartile range [IQR], 1–9 days). On the contrary, only 63.6% of the patients without ascites were transferred to the ICU, and they stayed significantly shorter with a median stay of 1 day (IQR, 0–2 days). Moreover, the entire hospital stay was significantly prolonged in patients having more than 500 mL of ascites, with a median of 21 days (IQR, 17–40.5 days) compared with only 16 days (IQR, 13–20 days) in patients without ascites (Fig. 2). This may be attributed to the higher incidence of postoperative complications in patients with more than 500 mL of ascites such as pleural infusions, circulatory complications as well as shock, urinary tract infection, anemia, coagulopathy, need for insulin administration, and hypokalemia (Table 4).
In the present study, we could show for the first time that the presence of ascites due to EOC in patients undergoing cytoreductive surgery is associated with significantly higher rates of administered colloid infusions as well as PRBC and FFP transfusions. Furthermore, patients with both EOC and ascites required higher doses of NA administration by higher rates of hemodynamic instability in terms of more frequent episodes of tachycardia and hypotension compared with patients with no ascites. In addition, ascites was associated with a significantly prolonged hospital stay as well as postoperative intensive care treatment and with significantly higher operative complication rates.
Cytoreductive surgery is associated with an extensive perioperative management. Postoperative intensive care is often required, whereas operative morbidity can be considerable. Pulmonary complications are frequently seen and may lead to a longer hospital stay. Developing hypothermia is another complication caused by anesthetic-induced thermoregulatory impairment and wide exposition of open abdominal surgery. This condition can lead to coagulatory dysregulation, cardiac problems, and higher wound infection rates.5 Moreover, large amounts of fluid loss during surgery display another critical point of perioperative care because it frequently leads to hemodynamic instability.
Hemodynamic instability during anesthesia is a risk factor for intrahospital and long-term mortality. Intraoperative tachycardia in noncardiac surgery was associated with an increased hospital mortality.6 Episodes of hypotension during surgery were found to be a multivariate predictor of 1-year mortality in noncardiac surgery.7,8 For abdominal surgery, it is shown that restrictive fluid therapy is beneficial for the patient.9,10 However, in patients with both EOC and ascites, it has to be stated that being hemodynamically unstable compels additional administration of intravenous fluids and transfusions.
Various theories exist on the underlying mechanisms of increased hemodynamic instability at ascites. The main underlying mechanism of malignant ascites pathophysiology lies in the defective vascular permeability and neoangiogenesis of peritoneal microvascularization. Although ascites is a product of a combination of different factors such as obstructed lymph vessels and decreased plasma osmotic pressure, the main pathophysiological factor is known to be tumor-related neoangiogenesis, resulting in vascular hyperpermeability and damaged peritoneal surfaces.11,12 Peritoneal tumor cells are responsible for the secretion of the vascular endothelial growth factor (VEGF), which can be found in 40-fold increased levels in malignant ascites, when compared with the ascites of patients with liver cirrhosis.13 These high levels of VEGF in turn cause massive neoangiogenesis on the large surface of the peritoneum. The combination of increased hydrostatic pressure as an effect of peritoneal neoangiogenesis and VEGF-related hyperpermeability of these nonmatured peritoneal blood vessels can be potent enough to result in the accumulation of several liters of intraperitoneal fluids per day in patients with ovarian cancer.14,15 Besides VEGF, a number of other cytokines and immunomodulators such as prostaglandin E2, tumor necrosis factor α, interleukin 1, and interleukin 6 are secreted by the tumor cells to achieve immunosuppression and protection from T cell–mediated tumor cell destruction. On the other hand, these mediators also promote further vasodilatation and increase of microvessel permeability.16 In combination with extensive cytoreductive surgery, which per se poses a challenge to hemodynamic management, this impairment of the vascular permeability can be responsible for fluid loss to the extravascular space and consecutive hemodynamic instability. How to replace this fluid stays controversial.17 The drainage of ascites leads to a change in plasma protein levels, which can be up to 20%.5 As colloid pressure changes drastically, the intravascular volume is highly influenced. This could lead to differences in perioperative fluid and volume therapy needs.
An additional finding of the present study was the significantly more prolonged hospital and ICU stay of patients with ascites versus patients without ascites. The extended lengths of stay may be due to the higher rate of surgical and medical complications, further prolonging the need for hospital or intensive care. Khuri et al18 could show in a large collective of noncardiac surgery that the occurrence of a 30-day postoperative complication was more important than the preoperative patient risk and intraoperative factors in determining survival.
The results of the present study clearly indicate the high challenge in terms of perioperative and intraoperative volume control management in extensive ovarian cancer debulkings with ascites. The perioperative morbidity of these procedures is necessarily derived not only from the extensive resections but also from the hemodynamic imbalances that result from the instant loss of massive volumes of ascites in combination with the peritonectomy. These surgeries are feasible only under very careful and highly specialized volume control management, which makes them very challenging from an anesthesiological point of view.
A weakness of the present study is the overall low number of the patients included, which precludes multivariate analyses to uncover independent parameters associated with the surgery outcomes. Furthermore, we used in the present work the commonly used ascites classification with the cutoff limit of 500 mL, which however needs to be emphasized as rather arbitrary especially because the estimation of the amount of ascites is often subjectively performed by the surgeon. In the present study, the calculation of ascites was based on the amount that was drained in the beginning of the surgery before mixing with blood or other fluids, so measurements were as accurate as possible.
Based on the shown consequences of the presence of ascites on the clinical course of the patients, it can be claimed that ascites is a major risk factor for hemodynamic instability, higher fluid as well as transfusion demands, and an increased number of surgical as well as medical complications. Therefore, the presence of ascites might help identify at the preoperative evaluation the patients with EOC that are candidates for more intensive treatment with highly specialized infrastructure for transfusion and trained staff in advanced hemodynamic monitoring,19 interdisciplinary ICU concepts, and a high implementation rate of optimized care according to the enhanced recovery after surgery pathway for abdominal surgery.20
These data verify for the first time the presence of ascites as a considerable risk factor for the surgical outcome and set the basis for further interventional studies focusing on the interdisciplinary optimization of the intraoperative and postoperative management of this special patient collective.
1. du Bois A, Quinn M, Thigpen T, et al. 2004 consensus statements on the management of ovarian cancer: final document of the 3rd International Gynecologic Cancer Intergroup Ovarian Cancer Consensus Conference (GCIG OCCC 2004). Ann Oncol
. 2005; 16(suppl 8): viii7–viii12.
2. Sehouli J, Senyuva F, Fotopoulou C, et al. Intra-abdominal tumor dissemination pattern and surgical outcome in 214 patients with primary ovarian cancer. J Surg Oncol
. 2009; 99: 424–427.
3. Chi DS, Palayekar MJ, Sonoda Y, et al. Nomogram for survival after primary surgery for bulky stage IIIC ovarian carcinoma. Gynecol Oncol
. 2008; 108: 191–194.
4. Fotopoulou C, Richter R, Braicu EI, et al. Can complete tumor resection be predicted in advanced primary epithelial ovarian cancer
? A systematic evaluation of 360 consecutive patients. Eur J Surg Oncol
. 2010; 36: 1202–1210.
5. Vanacker B. Anaesthetic issues in women undergoing gynaecological cytoreductive surgery. Curr Opin Anaesthesiol
. 2009; 22: 362–367.
6. Reich DL, Bodian CA, Krol M, et al. Intraoperative hemodynamic predictors of mortality, stroke, and myocardial infarction after coronary artery bypass surgery. Anesth Analg
. 1999; 89: 814–822.
7. Bijker JB, van Klei WA, Vergouwe Y, et al. Intraoperative hypotension and 1-year mortality after noncardiac surgery. Anesthesiology
. 2009; 111: 1217–1226.
8. Monk TG, Saini V, Weldon BC, et al. Anesthetic management and one-year mortality after noncardiac surgery. Anesth Analg
. 2005; 100: 4–10.
9. Brandstrup B, Tonnesen H, Beier-Holgersen R, et al. Effects of intravenous fluid restriction on postoperative complications: comparison of two perioperative fluid regimens: a randomized assessor-blinded multicenter trial. Ann Surg
. 2003; 238: 641–648.
10. Nisanevich V, Felsenstein I, Almogy G, et al. Effect of intraoperative fluid management on outcome after intraabdominal surgery. Anesthesiology
. 2005; 103: 25–32.
11. Garrison RN, Galloway RH, Heuser LS. Mechanisms of malignant ascites
production. J Surg Res
. 1987; 42: 126–132.
12. Nagy JA, Masse EM, Herzberg KT, et al. Pathogenesis of ascites
tumor growth: vascular permeability factor, vascular hyperpermeability, and ascites
fluid accumulation. Cancer Res
. 1995; 55: 360–368.
13. Cheng D, Liang B, Kong H. Clinical significance of vascular endothelial growth factor and endostatin levels in the differential diagnosis of malignant and benign ascites
. Med Oncol
. 2012; 29: 1397–1402.
14. Carmeliet P. Angiogenesis in health and disease. Nat Med
. 2003; 9: 653–660.
15. Jain RK. Molecular regulation of vessel maturation. Nat Med
. 2003; 9: 685–693.
16. Simmons DL, Botting RM, Hla T. Cyclooxygenase isozymes: the biology of prostaglandin synthesis and inhibition. Pharmacol Rev
. 2004; 56: 387–437.
17. Vorgias G, Iavazzo C, Mavromatis J, et al. Determination of the necessary total protein substitution requirements in patients with advanced stage ovarian cancer and ascites
, undergoing debulking surgery. Correlation with plasma proteins. Ann Surg Oncol
. 2007; 14: 1919–1923.
18. Khuri SF, Henderson WG, DePalma RG, et al. Determinants of long-term survival after major surgery and the adverse effect of postoperative complications. Ann Surg
. 2005; 242: 326–341; discussion 341–343.
19. Rahbari NN, Zimmermann JB, Schmidt T, et al. Meta-analysis of standard, restrictive and supplemental fluid administration in colorectal surgery. Br J Surg
. 2009; 96: 331–341.
20. Lassen K, Soop M, Nygren J, et al. Consensus review of optimal perioperative care in colorectal surgery: Enhanced Recovery After Surgery (ERAS) Group recommendations. Arch Surg
. 2009; 144: 961–969.
Keywords:© 2014 by the International Gynecologic Cancer Society and the European Society of Gynaecological Oncology.
Ascites; Epithelial ovarian cancer; Transfusion; Hemodynamic stability; Length of hospital stay