Department of Obstetrics and Gynaecology, Jichi Medical School, Minamikawachi-machi, Tochigi, 32904 Japan
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Abstract |
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Key words: albumin/assisted reproductive technologies/ovarian hyperstimulation syndrome/peritoneovenous shunt
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Introduction |
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In patients with cirrhosis and tense ascites, several modalities have been used including paracentesis (Salerno et al., 1987; Arroyo et al., 1988
), peritoneovenous shunting (Gines et al., 1991
), reinfusion of concentrated ascites (Parbhoo et al., 1974
; Landini et al., 1985
; Bruno et al., 1992
), and transjugular intrahepatic portosystemic shunts (Ferral et al., 1993
; Ochs et al., 1995
). In patients with OHSS, recirculation of ascites (i.e. reinfusion of ascites without concentration by ultrafiltration) has also been performed (Aboulghar et al., 1992
) although the clinical usefulness was equivocal. Peritoneovenous shunting has been reported only in one patient with severe OHSS (Beck et al., 1995
). The clinical efficacy of shunting has not been established.
Accordingly, we developed a continuous autotransfusion system of ascites (CATSA) with a peritoneoantecubital vein shunt for the treatment of severe OHSS. The preliminary findings were reported previously (Koike et al., 1998). We also reported that the intravenous protein supplement and restriction of water intake were effective for management of OHSS (Manaka et al., 1995
). Here, the preliminary findings of a study that compared the clinical effectiveness of CATSA with that of intravenous albumin supplement in treating OHSS patients with tense ascites are reported.
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Materials and methods |
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Continuous autotransfusion system of ascites (CATSA group) (Figure 1)
A 16-gauge Teflon catheter was placed, under ultrasonic guidance, into the peritoneal cavity, and was connected via a peristaltic pump (PRS-20, Nikkiso, Tokyo, Japan) and a micro-filter (diameter of the pore, 10 µm) (Imugard III-PL, Terumo, Tokyo, Japan) to an 18-gauge Teflon catheter inserted into the antecubital vein (total line length, 200 cm; an internal diameter, 3 mm). Continuous transfusion was performed once a day for 5 h at a rate of 100200 ml/h.
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Randomization of patients
All patients gave informed consent to participate in this study, which was approved by the local ethics committee. The 54 patients were initially randomly divided into two groups; 27 patients in the CATSA group and the remaining 27 in the albumin group. However, because nine of 27 patients who were allocated to the CATSA group rejected the treatment, a problem with counselling was suspected. These nine received protein supplementation and henceforward the study was considered to be prospective rather than randomized. Thus, 18 patients belonged to the CATSA group and the remaining 36 patients belonged to the albumin group. Patients in both groups were weighed and had blood samples taken to measure complete blood count, serum protein, creatinine, electrolytes and coagulation parameters before initiation of the treatment. Oral intake of water was restricted (<500 ml/day).
Additional treatment
In every patient, diuretics (frusemide 20 mg/day and 15% mannitol solution 300 ml/day) were used when Ht value reached <40%. Diuretics were continued until evidence of spontaneous diuresis (urine volume >1200 ml/day irrespective of the use of diuretics) was obtained. In patients with Ht 50%, fluid replacement (1000 ml/day), using a solution without potassium, was added to decrease blood viscosity. When a patient exhibited a shortened activated partial thromboplastin time (aPTT) >20% (approximately <23 s), heparin sulphate (10 000 units/day) was administered i.v. continuously. If a patient became oliguric (<500 ml/day) or hyperkalaemic (K
5.0 mEq/l), diuretics (dopamine 3 µg/min/kg of body weight and furosemide 20 to ~40 mg/day) were administered i.v. The response to each treatment (CATSA/albumin) was judged 24 and 48 h after treatment. Responders were defined as those who exhibited a decrease of haematocrit by 5% or a urine output >1000 ml in 24 h. Non-responders to initial treatment within 48 h received integral treatment (protein supplementation plus ascites recirculation, albumin plus CATSA).
Data are reported as means ± 1 SD. Student's paired t-test, Student's unpaired t-test, the MannWhitney U-test and the 2 test with Yates' correction were used for statistical analysis of findings as appropriate. A P-value < 0.05 was accepted as significant.
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Results |
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A significantly larger (P = 0.024) number of patients required heparin in the CATSA group (9/18) than in the albumin group (6/36). Four of nine patients who required heparin in the CATSA group exhibited an activated partial thromboplastin time (aPTT) of 22.7 ± 1.0 s on admission and required heparin before the CATSA procedure. The remaining five had an aPTT of 25.2 ± 1.1 s on admission and exhibited shortening of aPTT (22.8 ± 1.5 s) after the CATSA, and subsequently required heparin following the CATSA procedure. All six patients with an aPTT of 22.7 ± 1.3 s on admission in the albumin group required heparin before the albumin supplementation.
All patients in both groups recovered favourably without proceeding to critical condition. No adverse effects were observed except in one patient who experienced low-grade fever (37.5°C) after the CATSA.
Clinical, biochemical and haematological data on admission and 24 h after the initial treatment in the 54 patients are shown in Table II. On admission, a relatively higher concentration of haemoglobin, lower sodium serum concentration, smaller volume of urine output and smaller pulse pressure were observed in the CATSA group than in the albumin group, suggesting that patients in the CATSA group suffered from severer OHSS than patients in the albumin group. The leukocyte count and Ht decreased significantly in both groups. Haemoconcentration improved in the CATSA group, whereas it did not in the albumin group. Oliguria in the CATSA group was rapidly normalized. While pulse pressure increased significantly, body weight decreased significantly in the CATSA group, suggesting that fluid volume in the third space shrank, moved into the general circulation and was excreted as urine. In several parameters such as serum sodium, urinary output, body weight and pulse pressure, the degree of improvement after the initial treatment was significantly larger in the CATSA group than in the albumin group (Table II
).
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The CATSA procedure was performed 51 times in 29 patients (18 and 11 patients from the CATSA and the albumin groups respectively). The volume of reinfused ascites per procedure was 833 ± 167 ml. The ascites at the first sampling contained 4.5 ± 0.3 g/dl of total protein, 135.1 ± 1.6 mEq/l of sodium, 4.1 ± 0.5 mEq/l of potassium and 279 ± 46 µg/ml of fibrin/fibrinogen degradation products (FDP). Thus, FDP was abundant in the ascites. However, recirculation of the ascites did not cause a significant rise in the serum concentration of FDP.
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Discussion |
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An acute shift of intravascular fluid into the third space occurs in patients with OHSS, causing severe dehydration and abnormal coagulability (Pride et al., 1990). The chemical mediators that are considered to cause and/or prolong clinical conditions of OHSS may be numerous in the ascitic fluid, and accumulate without being metabolized in the liver, lungs or kidneys. The several chemical mediators are found in large amounts in the ascites (Revel et al., 1996
). The CATSA has a theoretical risk of the substances responsible for the syndrome, e.g. cytokines, re-entering the general circulation, leading to exacerbation of OHSS. However, after recirculation of ascites, mediators such as renin, angiotensin I, angiotensin II and vascular endothelial growth factor were decreased in concentration in the serum and ascites in patients with severe OHSS (T.K., unpublished data). Therefore, we performed the CATSA procedure in treating severe OHSS on the assumption that recirculating the ascitic fluid to the general circulation may facilitate degradation of possible agents causing the OHSS and resultant revision of the fluid imbalance may lead to shortening of the clinical course of OHSS. FDP, a bioactive substance that inhibits coagulation (Bithell, 1993
) and was abundant in the ascites, was metabolized once it entered general circulation in the present study. However, because a control was not used, in which standard treatment for severe OHSS could be performed, i.e. simple ascites drainage and albumin infusion (Borenstein et al., 1989
; Jenkins et al., 1995
), the factor responsible for recirculation or reduction of ascites, which played an important role in the present favourable results for the CATSA procedure was not determined. It remained unanswered whether simple ascites drainage and albumin infusion shorten the clinical course of severe OHSS.
The CATSA procedure avoided the use of exogenous albumin in the present study. Serum total protein in the CATSA group was maintained without exogenous albumin except in two patients, whereas its concentration in the albumin group did not increase despite daily supplementation with 37.5 g albumin. This may indicate that 37.5 g albumin moved into the third space daily in the albumin group patients. Protein at a concentration of 4.5 ± 0.3 g/dl was present in the ascitic fluid. The mean volume of ascites recirculated per procedure, 833 ± 167 ml, contained 37.4 g protein. Thus, the recirculation of ascites corresponded to the 37.5 g albumin supplementation used in the present study. CATSA is thus a viable method of maintaining the serum protein concentration. Blood products, such as a commercially available protein, potentially contain transmissible agents. Parvovirus B19, which can cause hydrops fetalis (Brown et al., 1984; Anand et al., 1987
), cannot yet be excluded from human blood products (Satagostino et al., 1994
; Yee et al., 1996
). The use of blood products should be avoided if possible. In this respect, recirculation of ascites in patients with OHSS may have advantages over simple ascites drainage and exogenous albumin infusion.
Paracentesis for severe OHSS was initially introduced by Thaler et al. (Thaler et al., 1981), and supportive studies have subsequently been reported (Borenstein et al., 1989
; Aboulghar et al., 1990
). Several authors have reported favourable effects of reinfusion of ascites on OHSS (Aboulghar et al., 1992
; Fukaya et al., 1994
). However, this has the risk of an abrupt decrease of intra-abdominal pressure caused by total paracentesis, which may facilitate shifting of fluid from the intravascular compartment to the peritoneal cavity, with a rapid re-accumulation of ascites and a decrease of the effective intravascular volume. Those sequelae have been expected through experience in patients with cirrhosis and tense ascites (Nelson et al., 1951
; Liebowitz et al., 1962). The CATSA procedure is expected to overcome these problems and proved useful in this respect in the present study. The discomfort due to massive ascites diminished promptly and it did not recur in most patients treated with the CATSA.
Coagulation abnormalities after peritoneovenous shunting have been reported in patients with liver cirrhosis (Stein et al., 1978). Underlying liver disease per se and/or reinfused activated factor X in the ascitic fluid are considered responsible for coagulation abnormalities (Grieg et al., 1980
). In the present study, heparin was used more frequently in patients in the CATSA than the albumin group. After excluding four and six patients respectively who required heparin before the CATSA and the albumin treatment, 36% (5/14) of the CATSA patients compared with 0.0% (0/30) of the albumin patients developed shortening of aPTT and required heparin following treatment. However, these five patients in the CATSA group already had a marginal level of aPTT of 25.2 ± 1.1 s on admission. The mean values of aPTT, prothrombin time, FDP and antithrombin III activity in the serum did not change significantly after the CATSA procedure. Since this study did not lead to conclusive findings concerning the effects of the CATSA on the coagulationfibrinolysis system, further monitoring of these indices is required.
In conclusion, the newly developed continuous autotransfusion system with a peritoneo-antecubital vein shunt appeared to lead to prompt recovery from severe OHSS. Recirculation of ascites makes it possible to maintain serum protein concentration without supplementation of exogenous albumin. Possible adverse effects of this technique on the coagulationfibrinolysis system should be monitored.
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Notes |
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References |
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Submitted on July 12, 1999; accepted on October 11, 1999.