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10.1245/s10434-007-9404-x
Annals of Surgical Oncology 14:1919-1923 (2007)
© 2007 Society of Surgical Oncology
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Original Article

Determination of the Necessary Total Protein Substitution Requirements in Patients with Advanced Stage Ovarian Cancer and Ascites, Undergoing Debulking Surgery. Correlation with Plasma Proteins

George Vorgias, MD, PhD, Christos Iavazzo, MD, John Mavromatis, MD, Joanna Leontara, MD, Michael Katsoulis, MD, PhD, Nickolas Kalinoglou, MD and Thrassivoulos Akrivos, MD, PhD

Department of Gynecology, "Metaxa" Memorial Cancer Hospital, Piraeus, Greece

Correspondence: Address correspondence and reprint requests to: George Vorgias, MD, PhD; E-mail: vorgiasgeorge{at}yahoo.gr


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Ascites is common in patients with advanced ovarian carcinoma (AOC). Its drainage during surgery affects plasma proteins. We sought to correlate the volume of ascites with the oncological parameters of the disease, calculate its drainage effect on plasma proteins, and determine the necessary substitution requirements and a clinical way of achieving that.

Patients and Methods: We evaluated 138 patients with AOC and ascites who underwent primary cytoreductive surgery. Intraoperatively found ascites and its postoperative production were evaluated. Its drainage effect on plasma proteins and the substitution requirements were determined using a mathematic formula. Human albumin(HA) and fresh frozen plasma (FFP) were used to cover these requirements.

Results: The intraoperative ascites was found to correlate only with the stage of the disease, while its postoperative production correlated with the residual disease. Optimally debulked patients had a mean ascites production of 128 mL on postoperative day 1 compared with 668 mL of the suboptimally debulked. This production required 3 and 5–7 days, respectively, to drop <50 mL. Plasma proteins fell on their minimum level (88.9 versus 80.8%) on the second postoperative day. The protein deficit was calculated to be 379 and 691 g/day, respectively. This deficit was substituted by administering 2 HA and 2 FFP for 3–6 days.

Conclusions: Ascites drainage affects the postoperative homeostasis of plasma proteins. A mean acute drop of 12–20% is monitored on postoperative day 2. This deficit can be managed with HA and FFP for a minimum of 3 days.

Key Words: Advanced stage ovarian cancer • Ascites • Protein substitution requirements • Debulking surgery


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Ascites is present in the majority of advanced stage ovarian carcinoma cases. Its volume usually reflects the burden of the intraperitoneal tumor, especially that of the omentum, mesenterium, and splachnic peritoneum.

Damaged peritoneal surfaces, obstructed lymph vessels, vascular hyperpermeability, and decreased plasma osmotic pressure are some mechanisms that contribute to its formation.1–4

Ascitic fluid is rich in proteins (so called "exidroma"), with their concentrations varying from 0.5–4.2 g/100 mL. Of this amount, 50–70% is albumin, 30–45% globulins, and 0.3–4.5% fibrinogen. The last figure reflects the clinical importance of ascitic fluid in the coagulation mechanism.5

During debulking surgery this volume of ascites (which many times reaches 6–8 L) is drained and, hopefully, with optimal surgical results will not be formed again.

The means of replacement of this volume, both in terms of oncotic pressure and albumin repletion are either with crystalloids or with colloids. In the literature, there are controversial evaluations regarding a definite advantage of one regimen over the other, although most of the recent meta-analyses favor the use of colloids.6–10

The important consideration of postoperative protein homeostasis remains the cornerstone problem and requires appropriate management. In optimally debulked patients, this homeostasis is disrupted from the rapid intraoperative drainage of the ascites. In suboptimally debulked women, the gynecologist must not only balance the immediate protein loss from the preexisting ascitic fluid volume, but also take into account the continuing production of it, due to the residual tumor masses. Moreover, the protein homeostasis is affected in all cases by the redistribution between vascular and third space.

The goals of the present study were: 1) Correlate the intraoperatively found volume of ascites, as well as the postoperative ascitic fluid production with the disease parameters, 2) Evaluate the effect of ascites drainage on plasma proteins, and 3) Determine the necessary protein substitution requirements (quantity and duration) for the plasma proteins to return to preoperative levels.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Over the last 3 years 138 patients with epithelial ovarian carcinomas entered this study. We used two inclusion criteria: (i) Only patients undergoing primary cytoreductive surgery were considered eligible to exclude the effect of neoadjuvant chemotherapy on tumor masses and ascites and (ii) patients in whom the preoperative radiological evaluation (U/S and CT-scan) reported ascites, as a minimum cutoff limit for ascitic fluid volume of 100 mL.

Preoperative counting of total plasma proteins and albumins were taken in all patients. These measurements were repeated on a daily basis the first 3 postoperative days and every second day afterward until preoperative protein levels were restored or the patient was discharged from the hospital.

During surgery, we drained and recorded the existing ascitic fluid volume, and at the end of the operation we recorded the residual disease (RD <2 or >2 cm). At least one drainage tube (could be more if GI resection and anastomosis had been performed) was placed in the pouch of Douglas in all cases. The tube(s) were removed postoperatively when the drainage dropped at <50 mL/day.

For the substitution of proteins we used two products: Human Albumin 20%® (Biotest Pharma GmbH, Germany), which contains 200 g of proteins/ vial, 95% of which is albumin, and fresh frozen plasma (FFP), which contains 30–40 g of proteins/ 150–200 mL of every plasma unit, to give fibrinogen and other coagulation factors.

The necessary total protein substitution requirement was calculated according to the following mathematic formula, which is described in most textbooks of pathophysiology: [preoperative total protein (g/L) – postoperative total protein (g/L)] x plasma volume x 2. As for postoperative total protein we used its lowest values to optimally cover the deficit. The normal volume of blood plasma is approximately 40 mL/kg of body weight.

HA and FFP administration complications were recorded.

Statistical analysis was performed using SPSS 12.0 software for Windows. Multivariate analysis was used to correlate the disease parameters with intra-operatively and postoperatively ascites. P-value ≤ .05 was considered significant.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
The mean ascitic fluid volume that was found and drained intraoperatively was less than 500 mL in all cases with stage IIc–IIIb disease. On the contrary, macroscopic infiltration of the upper abdomen (stage ≥IIIc) and especially the presence of an omental cake, was leading in a significant increase of the volume of ascites. The mean stage IIIc ascites volume was 879 mL [range 250–6500 mL], while for stage IV patients that figure was quadrupled as shown in Fig. 1Go.


Figure 1
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  		FIG. 1. Intraoperative ascites volume with respect to the stage of disease.

 
The clinical characteristics of our patients are presented in Table 1Go. Except for the stage of the disease (P < .01), no other tumor characteristic (histological type, grade) or patient’s age was found to correlate with the volume of ascites.


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  		TABLE 1. Patients’ clinical characteristics
 
Optimal cytoreduction was achieved in 93 (67.4%) patients, while suboptimal in the remaining 45 (32.6%). As it was clinically expected, the postoperative production/drainage of ascites were directly influenced from the residual disease. The mean drainage of ascites in optimally debulked patients (RD < 2 cm) was 128 mL on postoperative day 1 and was dropping below 50 mL on postoperative day 3, thus permitting the removal of the drainage tube. On the contrary, in suboptimally debulked patients (RD > 2 cm) the mean ascitic fluid drainage was 668 mL on postoperative day 1, dropping to 375 mL on postoperative day 3, and requiring overall 5–7 days to cross down the limit for the drainage tube removal (50 mL) P = .015 (Fig. 2Go). Neither the volume of the preexisting ascites nor the stage of the disease was found to correlate with the postoperative ascitic fluid production/drainage or its duration.


Figure 2
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  		FIG. 2. Postoperative ascites production with respect to residual disease.

 
Total plasma proteins dropped to their lowest levels on postoperative day 2 in both groups (RD <2 and > 2 cm), while plasma albumins on postoperative days 2 and 3, respectively. Their mean minimum protein concentrations were 88.9% (range 69.8–97%) of the preoperative levels for optimally debulked patients and 80.8% (range 61–94) for suboptimally debulked, respectively (Fig. 3Go). Regarding albumin, their minimum levels were 83.9% and 76.7% of the preoperative levels for optimally and suboptimally debulked patients (Fig. 4Go).


Figure 3
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  		FIG. 3. Postoperative plasma proteins with respect to residual disease.

 

Figure 4
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  		FIG. 4. Postoperative plasma albumins with respect to residual disease.

 
By using the aforementioned mathematical formula for protein substitution and taking as postoperative total protein the lowest (2nd day) one, we calculated the daily necessary substitution requirements. The results were 379 and 691 g of proteins for optimally and suboptimally debulked patients, respectively.

Theoretically, these amounts could be effectively substituted by giving 2 HA and 2 FFP per day to optimally debulked patients and 4 HA and 4 FFP to suboptimal debulked patients.

In practice, the [4 + 4] substitution scenario for the suboptimal debulked patients proved unfeasible. In our study population we administered effectively and without any cardiopulmonary side effect 2 HA and 2 FFP per day, but in the patients for whom we tried to increase that dose, both subjective (headache, dyspnoia etc.) and objective (tachypnoia, increased blood pressure, increased central venous pressure) symptoms and signs occurred, with the most serious being two cases in whom acute pulmonary edema was installed.

The parameter that limited the above quantities is the increased colloid pressure of HA (fourfold that of plasma), which created significant risk of cardiopulmonary overloading. Consequently, we adopted the [2 + 2] dose of substitution in all further cases. The substitution was given the first 3 postoperative days, and consequently FFP was stopped, while HA was continued until per os high protein diet could initiate.

Overall, 3 days of [2 + 2] substitution were enough for the optimally debulked patients, while the suboptimally debulked patients required 5–6 days. This result is logical, since double days of protein administration were used instead of the required double protein quantity.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The word ascites is of Greek origin ("askos," which means bag or sac for fluid or gas). Ascites describes the pathologic fluid accumulation into the peritoneal cavity, due to various medical conditions. Advanced stage ovarian carcinoma is one of them, producing the so-called "malignant ascites."

Over the last 80 years, many suggestions have been written for the mechanisms that create ascites. Meigs and Cass11 suggested that irritation of the peritoneal surfaces by a hard, solid ovarian tumor stimulates the production of ascites. Samanth and Black12 concluded that tumors bigger than 10 cm, with myxoid component, favored the secretion of fluid into the peritoneal cavity. Our present knowledge is that ascites is formed by multiple mechanisms, such as mechanical damage of peritoneal surfaces, obstruction, and/or leakage of normal lymph vessels, tumor neo-angiogenesis, vascular hyperpermeability, and disturbance of the osmotic balance between veins and interstitial space.1–4

The fact that ascites is so rich in proteins, together with the considerable high volume that is accumulated and drained during debulking surgery for ovarian carcinoma, is the basis for the need for proper postoperative substitution. Furthermore, 40–55% of hospitalized patients with gynecological cancer are malnourished or at risk for malnutrition, thus giving low preoperative protein/albumin levels.13–15 Other conditions in which protein (especially albumin) substitution is well defined are large volume paracentesis in cirrhotic patients, acute nephrotic syndrome with diuretic resistance, plasmapheresis, and organ transplant.16

Although the advantage of albumin use in ovarian cancer patients with ascites has been debated, it seems that the main considerations are economic and transfusion-risk related. Moreover, the majority of the recent studies, including meta-analyses seem to favor its use because of multiple benefits gained. Haynes et al.6 in their review of randomized controlled trials found that "in ascites, albumin reduced haemodynamic derangements, morbidity and length of hospital stay and improved survival after spontaneous bacterial peritonitis." Although Mendez et al.7 outline the high cost of albumin use, which in some hospitals accounts for up to 30% of pharmacy budgets, they conclude its use offers significant advantages in patients with ascites. While Smorenburg et al.8 some 10 years ago strongly debated the use of albumin, they accepted its value in cirrhotic patients with ascites who undergo paracentesis to prevent renal insufficiency and hyponatraemia. Vincent et al.9 in their recent meta-analyses of randomized controlled trials found that albumin significantly reduced overall morbidity in acutely ill hospitalized patients, including cancer and ascites. On the other hand, Abu-Rustum et al.10 in their retrospective study documented a higher risk of venous thromboembolism in ovarian cancer patients who received FFP or packed red blood cells.

Thus, the purpose of this study was to provide a comprehensive clinical model for protein substitution and balance, using routine medical examinations and widely available commercial products.

A theoretically simple approach could be to measure the protein of the drained ascites and substitute accordingly. This hypothesis does not stand. The multiple formation mechanisms of ascites—as well as the fact that during the postoperative period plasma proteins’ homeostasis is protected to some degree by the redistribution between vascular and third space—limit in clinical reality the divergence of protein requirements between optimally and suboptimally debulked patients. This fact is clearly shown at Fig. 2Go–4GoGo. Although postoperative ascites volume significantly differed between the two groups, plasma protein and albumin curves presented a much more limited difference.

We found that there was an acute drop of plasma proteins postoperatively, which varied from 12–20% in all patients. This deficit not only affects plasma’s colloid-osmotic pressure, but also disturbs its binding capacity (for nutrients, metabolites, drugs), as well as platelet and coagulation cascade functions. This deficit of 379 and 691 g/day (in optimally and suboptimally debulked patients), which was calculated using the mathematical formula, can be effectively substituted with Human Albumin® (HA) and fresh frozen plasma.

The bias of our study is that we did not compare with a nonsubstituted group (control) since it was considered unethical. Therefore, we cannot present data for the time that would require for plasma proteins to return to preoperative levels, and furthermore we cannot present data for possible clinical consequences of such a prolonged protein deficit.

The important limitation that was found in this substitution regimen was that we cannot exceed the [2 + 2] quantities per day due to the quadruple colloid pressure of HA and the consequent risk for cardiopulmonary overloading. Increase of that quantity led two patients to acute pulmonary edema. Hence, in the suboptimally debulked patients the time required for normalization of proteins was approximately double (5–6 days). No other albumin-related complications (allergy, deep venous thrombosis, infections) were recorded.

In conclusion, we found that ascites is strongly related to the stage of disease (tumor burden), while its postoperative production (both in terms of quantity and duration) is related to the residual disease. The drainage of ascites creates an acute 12–20% drop of plasma proteins. Protein substitution can be effectively done by administrating 2 HA and 2 FFP per day for a minimum of 3 days.

Received for publication December 28, 2006. Accepted for publication February 23, 2007.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Garrison RN, Galloway RH, Heuser LS. Mechanisms of malignant ascites production. J Surg Res 1987; 42(2):126–32.[Medline]
  2. Heuser LS, Miller FN, Gilley-Pietsch C. Protein leak from normal vasculature due to the malignant ascites. Am J Surg 1988; 155(6):765–9.[CrossRef][Medline]
  3. Chu CS, Rubin SC. Management of intestinal obstruction in the terminal patient and management of ascites. In Gershenson D, Mc Guire W, Gore M, Quinn M, Thomas G (eds.) Gynecologic Cancer: Controversies in Management. Elsevier Ltd., 2004:736–7.
  4. Nagy JA, Masse EM, Herzberg KT, Meyers MS, Yeo KT, Yeo TK, Siousset TM, Dvorak HF. Pathogenesis of ascites tumor growth: vascular permeability factor, vascular hyperpermeability, and ascites fluid accumulation. Cancer Res 1995; 55(2):360–8.[Abstract/Free Full Text]
  5. Wallach J. Ascites. In: Interpretation of Diagnostic Tests. Boston: Little, Brown & Co., 1975:117.
  6. Haynes GR, Navickis RJ, Wilkes MM. Albumin administration—what is the evidence of clinical benefit? A systematic review of randomized controlled trial. Eur J Anaesthesiol 2003; 20(10):771–93.[CrossRef][Medline]
  7. Mendez CM, McClain CJ, Marsano LS. Albumin therapy in clinical practice. Nutr Clin Pract 2005; 20(3):314–20.[Abstract/Free Full Text]
  8. Smorenburg CH, ter Wee PM, Gans RO. Clinical application of albumin: a closer look at indications. Ned Tijdschr Geneeskd 1997; 141(15):719–23.[Medline]
  9. Vincent JL, Navickis RJ, Wilkes MM. Morbidity in hospitalized patients receiving albumin: a meta-analysis of randomized controlled trials. Crit Care Med 2004; 32(10):2029–38.[CrossRef][Medline]
  10. Abu-Rustum NR, Richard S, Wilton A, et al. Transfusion utilization during adnexal or peritoneal cancer surgery: effects on symptomatic venous thromboembolism and survival. Gynecol Oncol 2005; 99(2):320–6.[CrossRef][Medline]
  11. Meigs JV, Cass JW. Fibroma of the ovary with ascites and hydrothorax: report of seven cases. Am J Obstet Gynecol 1937; 33:249–67.
  12. Samanth KK, Black WC. Benign ovarian stromal tumors associated with free peritoneal fluid. Am J Obstet Gynecol 1970; 107(4):538–45.[Medline]
  13. Gallagher-Allred CR, Voss AC, Finn SC, McCamish MA. Malnutrition and clinical outcomes: the case for medically nutrition therapy. J AM Diet Assoc 1996; 96:361–6.[CrossRef][Medline]
  14. Naber TH, Schermer T, de Bree A, et al. Prevalence of malnutrition in nonsurgical hospitalized patients and its association with disease complications. Am J Clin Nutr 1997; 66:1063–4.[Free Full Text]
  15. Santoso JT, Canada T, Latson B, Aaaadi K, Lucci JA III, Coleman RL. Prognostic nutritional index in relation to hospital stay in women with gynecological cancer. Obstet Gynecol 2000; 95:844–6.[CrossRef][Medline]
  16. Hastings GE, Wolf PG. The therapeutic use of albumin. Arch Fam Med 1992; 1(2):281–7.[Abstract/Free Full Text]




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