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Therapeutic effects of diuretics and paracentesis on lung function in patients with non-alcoholic cirrhosis and tense ascites
Journal of Hepatology 1997; 26:833-838 Printed in Denmark • All rights reserved Munksgaard. Copenhagen
Copyright © European Association for the Study of the Liver 1997 Journal of Hepatology ISSN 0168-8278
Therapeutic effects of diuretics and paracentesis on lung function in patients with non-alcoholic cirrhosis and tense ascites Shi-Chuan Chang 1, Huei-Ing Chang l, Funn-Juh Chen l, Guang-Ming Shiao l, Sun-Sang Wang 2 and Shou-Dong Lee 2 1Chest Department and 2Division of Gastroenterology, Department of Medicine, Veterans General Hospital-Taipei; and Department of lnternal Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan, ROC
Background~Aims: Ascites may cause or aggravate pulmonary dysfunction in patients with fiver cirrhosis. Diuretics and paracentesis are the main therapies for ascites. The aim of the present study was to evaluate and compare the therapeutic effects of diuretics and large-volume paracentesis on lung function in 26 male patients with non-alcoholic cirrhosis and tense ascites. Methods: The patients were divided into two groups. Group A was composed of 13 subjects who were treated with diuretics including spironolactone (100400 mg/day) and furosemide (80-320 mg/day). In group B, 13 subjects received large-volume paracentesis plus intravenous albumin (6-8 g/l ascites removed). Pulmonary function tests including spirometry, plethysmography, single-breath carbon-monoxide diffusing capacity (DLco) and arterial blood gases, were done 1 day before diuretic treatment and 1 day after termination of the study in group A patients, and 1 day before and after large-volume paracentesis in group B subjects. Results: Before treatment, the clinical and laboratory data were comparable between the two groups. After
treatment, ventilatory function as evidenced by forced expiratory volume in 1 S, forced vital capacity, total lung capacity, functional residual capacity and expiratory reserve volume, and DLco increased significantly in both groups. Arterial PO2 and PCO2 increased significantly and AaPO2 (alveolar-arterial PO2 difference) decreased significantly in the subjects treated with diuretics. Nevertheless, paracentesis did not improve arterial blood gases. The changes in lung volumes, DLco and PaO2 after treatment (the data after minus those before treatment) were comparable, except that a significant decrease in AaPO2 was observed in the diuretic groulx Conclusions: Both diuretic therapy and large-volume paracentesis significantly improved the ventilatory function in patients with tense cirrhotic ascites. In terms of oxygenation improvement as evaluated by AaPO2, diuretic treatment may be superior to largevolume paracentesis.
SCITES is a common complication in patients with cirrhosis. Large-volume paracentesis (LVP) was employed for a long time to remove ascitic fluid in patients with cirrhosis (1), but was abandoned as the treatment of choice for ascites after the introduction of effective diuretic therapy because of the hazards of LVE including orthostatic hypotension, renal failure, symptomatic hyponatremia, hepatic enc6]ghalopathy,
infection, and protein depletion (2-7). Recent studies have shown that 5-1 and 6.3- to 22.5-1 LVP in patients with cirrhosis and tense ascites is safe and without significantly deleterious effects on serum sodium, blood urea nitrogen, hematocrit, blood pressure or plasma volume (8,9). However, increased serum creatinine levels and a progressive decline in renal function were observed when decreased plasma volume was not restored (10). Further reports indicated that intravenous albumin infusion could prevent these complications in patients with cirrhosis and tense ascites, particularly in those who received repeated LVP (11,12). Ascites is known to result in dyspnea and to affect pulmonary function in patients with liver cirrhosis
Received 21 June; revised 7 October; accepted 21 October 1996
Correspondence: Shi-Chuan Chang, Chest Department, Veterans General Hospital-Taipei, Shih-Pai, Taipei, Taiwan 11217, ROC. Tel: 866-2-875-7564; 866-2-875-7034. Fax: 866-2-875-2380.
Key words: Ascites; Diuretics; Gas exchange; Liver cirrhosis; Paracentesis; Pulmonary function.
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S-C. Chang et aL TABLE 1
of cardiopulmonary disorders and no evidence of abnormal findings on chest radiographs and electrocardiograms; (4) stable hemodynamic state without evidence of gastrointestinal bleeding, encephalopathy, acute pancreatitis, bloody ascites, peritoneal carcinomatosis, or spontaneous bacterial peritonitis; (5) serum bilirubin< 10 mg/dl; (6) prothrombin time (INR)< 1.6; (7) peripheral platelet count >40000/ mm3; and (8) serum creatinine< 3.5 mg/dl. The study was approved by the local ethics committee, and all patients gave informed consent to participate in the study. After admission, diuretic treatment was withdrawn and the patients were given a 2-g sodium diet with fluid intake restricted to 1500 ml/day for 3 days. Patients were then randomly allocated to two groups (random number table). Group A subjects were treated with diuretics including spironolactone (100400 mg/day) and furosemide (80-240 mg/day). The dosages were adjusted in an attempt to achieve a weight loss of 1-1.5 kg/day (20). The end-point of the study was determined by whichever of the following occurred: (1) absence of ascites as evidenced by sonography; (2) poor response to the highest scheduled doses of diuretics; or (3) progressive increase of serum creatinine. The group B subjects were treated with LVR Paracentesis was performed using a standard peritoneal dialysis kit with a flexible sheath introducer. The needle was inserted in the midline, 2 cm below the umbilicus under sterile conditions and after local anesthesia. Once the needle entered the peritoneal cavity, the inner part was removed and the ascitic fluid was mobilized by static pressure. When the fluid stopped flowing, a 500-ml blood bottle with negative pressure was used to remove more ascitic fluid. The physician stayed at the patient's bedside during the entire procedure. Intravenous infusion of albumin with 6-8 g per liter of ascitic fluid removed was given after paracentesis. The dur-
Hepatic functional characteristics*
Pedal edema, Yes/No Albumin, g/dl Bilirubin, mg/dl AST, I.U./1 ALT, I.U./1 Alkaline phosphatase, U/1 Prothrombin time, INR Pugh's classification
Diuretic group (n=13)
Paracentesis group (n=13)
10/3 2.48-+0.46 2.42-+0.78 87-+33 55-+15 137-+40 1.36__.0.15 10.7-+0.4
11/2 2.45-+0.46 2.67-+0.81 86_+31 50+--14 133-+39 1.32-+0.11 10.8-+0.5
* Values of mean and SD are given. No statistical difference between the two groups.
(13,14). However, recent studies indicated that LVP could improve dyspnea, lung volume and respiratory reserve of patients with cirrhosis and ascites, but did not improve gas exchange, as evidenced by pulmonary diffusing capacity or arterial oxygen tension (PaO2) (15-17). Diuretic therapy has been thought as the treatment of choice for ascites, although paracentesis can shorten the duration of hospital stay. To the best of our knowledge, however, little attention has been paid to the effect of diuretic therapy on gas exchange in patients with cirrhosis and tense ascites. Thus, in this study, we intended to evaluate and compare the therapeutic effects of diuretic treatment and LVP on lung function in patients with cirrhosis and tense ascites.
Patients and Methods Patients with cirrhosis hospitalized for the treatment of tense ascites were considered for this study. The criteria for inclusion were as follows: (1) a positive HBsAg test in peripheral blood; (2) cirrhosis based on a histopathologic diagnosis or compatible laboratory data and sonographic findings (18,19); (3) no history
TABLE 2 Clinical and laboratory data of patients with tense cirrhotic ascites treated with diuretics and paracentesis* Paracentesis group (n= 13)
Diuretic group (n= 13)
Body weight, kg MBP, mmHg HR, beats/min Urea nitrogen, mg/dl Creatinine, mg/dt Sodium, mmoLq Potassium, mmol/l Hemoglobin, g/dt Hematocrit, %
Before
After
P
Before
After
P
73.2_+12.0 89.2_+5.3 87.5-+7.4 23.5_+6.3 1.25_+0.35 136.9+_4.2 4.15+_0.36 10.38-+1.26 30.3-+2.5
66.2-+11.0 90.3-+7.7 89.5-+6.7 22.3-+7.5 1.23_+0.43 135.7_+4.1 4.10-+0.29 11.1-+1.34 31.1_3,7
<0.001 NS NS NS NS NS NS NS NS
69.1-+8.2 88.7__-6.5 90.2-+8.3 22.6-+8.3 1.26-+0.37 137.1-+4.8 4.12+0.31 10.42-+0.89 30.7-+2.2
62.2_+8.1 89.3_+8.1 88.7_+7.8 23.6_+7.1 1.29-+0.4I 136.4___3.7 4.15-+0.40 10.31-+t.42 30.4-+3.9
<0.001 NS NS NS NS NS NS NS NS
* Values of mean and SD are given. The data obtained before and after treatment between the two groups show no statistical difference. MBP= mean blood pressure; HR=heart rate; NS=not significant.
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Lung function in patients with cirrhosis and ascites TABLE 3
Pulmonary function tests including spirometry, plethysmography, single-breath carbon monoxide diffusing capacity (DLco), and arterial blood gases were performed in all subjects. Spirometry was done in the standard sitting position at least three times (using CPI 5000 IV, Gould, Houston, Texas, USA) in accordance with American Thoracic Society recommendations (21). The best values of forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1) were selected for analysis. Total lung capacity (TLC) was measured with a body plethysmograph (model 2000 TB, Gould, Houston, Texas, USA). The diffusing capacity of the lung for carbon monoxide (DLco) was measured in the sitting position by the single-breath method, with minor modification (22,23). The exchange time, t, is the sum of the breathholding time plus two-thirds of the inspiratory time and one-half of the collecting time of the expired samples (24). The breath-holding time was 10 s. Alveolar volume (VA) was measured using the singlebreath helium (He) technique while DLco was measured. Arterial blood samples were taken anaerobically in the sitting position before the test of DLco. Blood samples for pH, PaO2 (arterial PO2) and PaCO2 (arterial PCO2) values were analyzed immediately using ABL III (Radiometer, Copenhagen, Denmark). PAO2 (alveolar oxygen tension) is calculated by the following equation. PAOE=(barometric pressure 47)×FIO2-PaCO2/R. R, an exchange ratio, is assumed to be 0.8 in this study. The alveolar-arterial PO2 difference (AaPO2) is calculated by subtracting PaO2 from PAO2. Pulmonary function tests were performed 1 day be-
Physical and pulmonary functional characteristics*
Age, year Height, cm Body weight, kg FEVI, % pred. FVC, % pred. FEV1/FVC, % TLC, % pred. FRC, % pred. ERV, % pred. RV, % pred. DLco, % pred. Kco, % pred. PaO2, mmHg PaCO2, mmHg AaPO2, mmHg pH
Diuretic group (n = 13)
Paracentesis group (n = 13)
59_+11 165.9-+3.8 73.2-+ 12.0 70.5_+13.6 65.2_+ 14.2 82.0-+7.3 84.7-+17.8 95.1 -+19.3 39.6---21.2 101.3_+18.2 48.1-+14.0 59.5-+ 15.7 72.4-+8.7 28.4-+ 1.3 41.9_+9.3 7.468-+0.017
58-+12 165.0-+5.4 69.1 -+8.2 71.8-+11.1 67.1 -+ 12.0 81.6-+8.3 81.4-+12.0 104.9-+ 19.6 44.5-+20.6 101.8-+24.0 53.2-+16.1 62.8_+ 15.5 72.3-+8.1 29.6-+ 3.3 40.4-+9.8 7.472-+0.026
* Values of mean and SD are given. No statistical difference between the two groups. FEVI = forced expiratory volume in 1 s; FVC= forced vital capacity; TLC= total lung capacity; FRC= functional residual capacity; ERV= expiratory reserve volume; RV= residual volume; DLco= diffusing capacity of lung; Kco = DLco corrected by alveolar volume; PaO2 = arterial PO2; PaCO2 = arterial PCO2; AaPO2 = alveolar-arterial PO2 difference.
ation of the peritoneal taps ranged from 45 to 120 min. Body weight, blood pressure, heart rate and urine amount were measured daily. Blood samples were taken for standard liver and renal tests, and hemoglobin, hematocrit as well as blood cell counts were also measured 1 day before, twice a week during diuretic treatment, and 1 day after termination of the study in group A subjects, and 1 day before and after paracentesis in group B subjects.
TABLE 4 Comparison of the effects of diuretics and paracentesis on lung function in patients with tense cirrhotic ascites* Paracentesis group (n= 13)
Diuretic group (n= 13)
FEVb % pred. FVC, % pred. FEVt/FVC, % TLC, % pred. FRC, % pred. ERV, % pred. RV, % pred. DLco; % pred. Kco, % pred. PaO2, mmHg PaCO2, mmHg AaPO2, mmHg pH
Before
After
p
Before
After
p
70.5--- 13.6 65.2--- 14.2 82.0-+7.3 76.9-+ 11.9 87.7+--15.4 39.6-+21.2 101.3-+ 18.2 48.1_+14.0 59.9-+ 15.7 72.4-+8.7 28.4-+ 1.3 41.9_+9.3 7.468-+0.017
82.1 _+16.8 75.2+ 17.8 82.5-+7.4 85.1 - 15.1 95.1-4-19.3 67.3-+33.1 94.9-+ 17.0 54.6-+ 14.8 58.0-+ 12.0 79.3-+8.2 30.3-+2.4 31.8-+9.4 7.464-+0.010
<0.001 <0.001 NS <0.05 <0.05 <0.001 NS <0.01 NS <0.005 <0.01 <0.005 NS
71.8-+ 11.1 67.1 -+12.0 81.6-+8.3 79.8-11.1 93.8--- 19.7 44.5-+20.6 101.8-+24.0 53.2_+16.1 62.8-+ 15.5 72.3_+8.1 29.6-+3.3 40.4-+9.8 7.472-+0.026
89.6 + 13.2 83.4-+ 13.9 81.8-+8.2 89.8-10.5 104.9+ 19.6 75.7-+22.2 98.6-+22.9 56.8_+14.0 62.8-+ 15.5 74.9-+ 11.0 28.8-+3.2 38.8+ 12.5 7.469-+0.027
<0.001 <0.001 NS <0.002 <0.01 <0.002 NS <0.02 NS NS NS NS NS
* Values of mean and SD are given. Data obtained before and after treatment between the two groups show no statistical difference. FEV1 = forced expiratory volume in 1 s; FVC= forced vital capacity; TLC= total lung capacity; FRC= functional residual capacity; ERV= expiratory reserve volume; RV= residual volume; DLco= diffusing capacity of lung; Kco= DLeo corrected by alveolar volume; PaO2 = arterial PO2; PaCO2 = arterial PCO2; AaPO2= alveolar-arterial PO2 difference; NS= not significant.
835
S-C Chang et al. TABLE 5 Changes of pulmonary functions before and after treatment in patients with tense cirrhotic ascites*
Body weight, kg FEVb I FVC, 1 TLC, 1 FRC, 1 ERV, 1 RV, 1 DLco, mI. min- I • mmHg- l Kco, ml. rain -1 • mmHg -1 • 1-1 PaO2, mmHg PaCO2, mmHg AaPO2, mmHg pH
Diuretic group (n= 13)
Paracentesis group (n= 13)
P value
-7.0+-2.1 0.32_.+0.28 0.37_+0.34 0.44_+.0.75 0.27+__0.41 0.38_+0.30 -0.10_+0.26 1.78 +_2.10 -0.07-+0.36 7.0_.+7.1 1.8+_2.3 - 10.2---5.0 -0.005+_.0.017
-6.9+-3.0 0.39+--0.28 0.47+--0.33 0.49_+0.66 0.34+_0.37 0.41+-0.36 -0.06+_0.31 0.94-+ 1.42 -0.22+-0.26 2.6+_7.6 -0.8-+2.2 - 1.6+-7.4 -0.005+_0.017
NS NS NS NS NS NS NS NS NS NS <0.005 <0.002 NS
* Values of mean and SD are given. FEVI= forced expiratory volume in 1 s; FVC= forced vital capacity; TLC= total lung capacity; FRC= functional residual capacity; ERV= expiratory reserve volume; RV= residual volume; DLco= diffusing capacity fo lung; Kco= DLco corrected by alveolar volume; PaOz = arterial PO2; PaCO2= arterial PCOz; AaPO2= alveolar-arterial PO2 difference; NS= not significant.
fore diuretic treatment and 1 day after termination of the study in group A subjects. In group B patients, the tests were done 1 day before and after LVR Statistical comparison of the data between the two groups was carried out using the unpaired Student's ttest or Mann-Whitney U test. The effect of diuretics or paracentesis on lung function was examined using paired Student's t-test or Wilcoxon's signed-rank test. A p-value less than 0.05 was considered statistically significant.
Results One patient treated with diuretics was not included because a progressive decline in renal function was found, as evidenced by increased serum levels of urea nitrogen and creatinine. Another patient who received LVP was excluded because upper gastrointestinal hemorrhage occurred after paracentesis. Finally, this series included 26 male patients with non-alcoholic cirrhosis and tense ascites. Thirteen patients received diuretic therapy. The duration o f treatment ranged from 4 to 9 days (mean+_SD, 5.7 + _ 1.7 days). Another 13 patients underwent LVP. The amount of ascitic fluid removed ranged from 4.5 to 12.5 1 (mean+-SD, 8.2+-3.1 1). The clinical characteristics and laboratory data of the patients studied are summarized in Tables 1-3. They show that before treatment the two groups of patients with cirrhosis studied were homogeneous for a wide variety of clinical and laboratory parameters. After treatment, the body weight of the patients in both groups decreased significantly but the reduction of body weight (diuretic vs paracentesis group, 7.0+-2.1 kg vs 6.9+-3.0 kg) was comparable (Table 4). The data for mean blood pressure, heart rate, serum levels of creatinine, urea nitrogen, sodium and potassium,
836
hemoglobin and hematocrit showed no significant changes after treatment (Table 2). The results of pulmonary function tests before and after treatment in these two groups are summarized in Table 4. After treatment, significant improvement of ventilatory function, as evidenced by FEVb FVC, TLC, functional residual capacity (FRC) and expiratory reserve volume (ERV) was found in both groups. The DLco also increased significantly in both groups. Nevertheless, Kco (DLco corrected by VA) showed no significant improvement in either group. LVP did not improve arterial blood gases. In contrast, significant improvement of arterial blood gases, as evidenced by an increase of PaO2 and PaCO2, and a decrease in AaPO2 was observed in the diuretic group (Table 4). Comparison of the changes in lung function (data after minus those before treatment) between the two groups is shown in Table 5. The changes in body weight, FEVb FVC, TLC, FRC, ERV, RV, DLco, Kco, PaO2 and pH were comparable in both groups. However, the reduction in AaPOz between the two groups showed a significant difference. A greater reduction in AaPO2 was found in the diuretic group.
Discussion Impairment of gas exchange (arterial hypoxemia or decreased DLco and/or Kco) of varying severity is common in patients with liver cirrhosis, even in the absence of any apparent lung or heart disease. A variety of mechanisms may explain this condition, and possible contributing factors include an increase in Ps0, intrapulmonary and extrapulmonary shunting, alveolarcapillary diffusing limitation and ventilation-perfusion (V/Q) mismatch (25-29). Based on the published data,
Lung function in patients with cirrhosis and itscites
a V/Q mismatch appears to be the main cause for this hypoxemia (29-33). At baseline, the results of pulmonary function tests showed various degrees of restrictive ventilatory impairment and the mean DLco of the patients in the present study were reduced disproportionately more than the reduction in lung volumes. This finding suggested that decreased lung volumes alone could not explain the reduction of DLco. After treatment with diuretics or LVP, the mean DLco remained moderately reduced, although ventilatory function returned to normal in most patients (Table 4). These findings confirmed that impairment of gas exchange is quite common in patients with cirrhosis. Ascites is considered to play a role in worsening gas exchange in patients with liver cirrhosis (34,35). The effect of ascites on the respiratory system may be mediated by hydrostatic pressure exerted on the diaphragm from within the peritoneal cavity. By and large, ascites restricts full inflation of the respiratory system, immobilizes the diaphragm, diminishes lung volume, and thus, decreases ventilation to the basal lung zones. It may relatively increase closing volume due to a decrease in ERV. All these effects may lower the overall V/Q ratios in basal lung zones and worsen gas exchange in patients with cirrhosis. It may thus be anticipated that paracentesis will improve ventilatory function and gas exchange in patients with cirrhosis and tense ascites. Nevertheless, previous studies demonstrated that LVP did not alter gas exchange, as evaluated by DLco, Kco or PaO2, although lung volumes increased significantly (15-17). In agreement with these reports, our results showed that LVP significantly improved ventilatory function, as evidenced by FEV1, FVC, TLC, F R C and ERV, but did not significantly improve gas exchange, as evidenced by Kco, PaO2 and AaPO2. These results imply that the functional impairment of gas exchange found in patients with liver cirrhosis and tense ascites may not be due simply to the presence of ascites. The different mechanisms underlying the impairment of gas exchange associated with liver cirrhosis, the varying amounts of ascites and differential effects of ascites on pulmonary ventilation and perfusion in patients with cirrhosis may explain why Kco, PaO2 and AaPO2 values, in the present study, did not improve consistently after paracentesis. The current study demonstrated that the changes in lung volumes, DLco and Kco in patients treated with diuretics were quite similar to those in patients undergoing LVP (Table 4). Compared to LVP, diuretic treatment significantly improved arterial blood gases, as evidenced by increases in PaO2 and PaCO2 and a de-
crease in AaPO2. In addition, a greater reduction in AaPO2 after treatment was found in the diuretic than in the paracentesis group (Table 5). This further supported the superiority of diuretic treatment compared to paracentesis in terms of oxygenation improvement in patients with cirrhosis and tense ascites. Because the patients included in the two groups were similar as regards clinical features, liver, renal and pulmonary function before treatment, and reduction in body weight, as well as improvement in ventilatory function after treatment, the difference in the improvement of arterial blood gases is likely to be related to different treatment modalities (Tables 2-5). The additional factors contributing to the impairment of gas exchange in patients with cirrhosis and tense ascites are still unknown. One probable explanation is that interstitial pulmonary edema, as fluid retention, may occur as ascites in patients with liver cirrhosis (14). This may, in part, explain why diuretic therapy improved the oxygenation of the patients studied but paracentesis did not. Further controlled studies are needed to verify this point. The flaw of the present study is that we did not measure respiratory rate, tidal volume and minute ventilation, which might influence the values of PaO2 and PaCO2. Measuring these respiratory parameters may be of value in observing changes in respiratory pattern and in shedding light on the mechanisms underlying the change of gas exchange in patients with cirrhosis and tense ascites after diuretic treatment or LVP. However, the value of AaPO2 is relatively unaffected by the level of ventilation. In addition, the improvement in gas exchange, as evidenced by AaPO2 (from 41.9_+9.3 mmHg to 31.8_+9.4 mmHg), is of clinical significance in patients treated with diuretics because a mean PaO2 of 72.4-+ 8.7 mmHg in association with a mean PaCO2 of 28.4-+ 1.3 mmHg represented a substantial oxygenation problem in the patients, particularly in those with low values of PaO2 or high values of AaPO2. In summary, the results of the present study indicated that both diuretic therapy and LVP treatment significantly improved the ventilatory function in patients with cirrhosis and tense ascites. In terms of oxygenation improvement, diuretic treatment may be superior to LVP. However, paracentesis may serve as an alternative treatment for rapid relief of abdominal tension, or when diuretics are ineffective or poorly tolerated.
Acknowledgements This work was supported by a grant from the National Science Council of the Republic of China (NSC842331-B075-005). 837
S-C. Chang et al.
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Copyright © European Association for the Study of the Liver 1997 Journal of Hepatology ISSN 0168-8278
Therapeutic effects of diuretics and paracentesis on lung function in patients with non-alcoholic cirrhosis and tense ascites Shi-Chuan Chang 1, Huei-Ing Chang l, Funn-Juh Chen l, Guang-Ming Shiao l, Sun-Sang Wang 2 and Shou-Dong Lee 2 1Chest Department and 2Division of Gastroenterology, Department of Medicine, Veterans General Hospital-Taipei; and Department of lnternal Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan, ROC
Background~Aims: Ascites may cause or aggravate pulmonary dysfunction in patients with fiver cirrhosis. Diuretics and paracentesis are the main therapies for ascites. The aim of the present study was to evaluate and compare the therapeutic effects of diuretics and large-volume paracentesis on lung function in 26 male patients with non-alcoholic cirrhosis and tense ascites. Methods: The patients were divided into two groups. Group A was composed of 13 subjects who were treated with diuretics including spironolactone (100400 mg/day) and furosemide (80-320 mg/day). In group B, 13 subjects received large-volume paracentesis plus intravenous albumin (6-8 g/l ascites removed). Pulmonary function tests including spirometry, plethysmography, single-breath carbon-monoxide diffusing capacity (DLco) and arterial blood gases, were done 1 day before diuretic treatment and 1 day after termination of the study in group A patients, and 1 day before and after large-volume paracentesis in group B subjects. Results: Before treatment, the clinical and laboratory data were comparable between the two groups. After
treatment, ventilatory function as evidenced by forced expiratory volume in 1 S, forced vital capacity, total lung capacity, functional residual capacity and expiratory reserve volume, and DLco increased significantly in both groups. Arterial PO2 and PCO2 increased significantly and AaPO2 (alveolar-arterial PO2 difference) decreased significantly in the subjects treated with diuretics. Nevertheless, paracentesis did not improve arterial blood gases. The changes in lung volumes, DLco and PaO2 after treatment (the data after minus those before treatment) were comparable, except that a significant decrease in AaPO2 was observed in the diuretic groulx Conclusions: Both diuretic therapy and large-volume paracentesis significantly improved the ventilatory function in patients with tense cirrhotic ascites. In terms of oxygenation improvement as evaluated by AaPO2, diuretic treatment may be superior to largevolume paracentesis.
SCITES is a common complication in patients with cirrhosis. Large-volume paracentesis (LVP) was employed for a long time to remove ascitic fluid in patients with cirrhosis (1), but was abandoned as the treatment of choice for ascites after the introduction of effective diuretic therapy because of the hazards of LVE including orthostatic hypotension, renal failure, symptomatic hyponatremia, hepatic enc6]ghalopathy,
infection, and protein depletion (2-7). Recent studies have shown that 5-1 and 6.3- to 22.5-1 LVP in patients with cirrhosis and tense ascites is safe and without significantly deleterious effects on serum sodium, blood urea nitrogen, hematocrit, blood pressure or plasma volume (8,9). However, increased serum creatinine levels and a progressive decline in renal function were observed when decreased plasma volume was not restored (10). Further reports indicated that intravenous albumin infusion could prevent these complications in patients with cirrhosis and tense ascites, particularly in those who received repeated LVP (11,12). Ascites is known to result in dyspnea and to affect pulmonary function in patients with liver cirrhosis
Received 21 June; revised 7 October; accepted 21 October 1996
Correspondence: Shi-Chuan Chang, Chest Department, Veterans General Hospital-Taipei, Shih-Pai, Taipei, Taiwan 11217, ROC. Tel: 866-2-875-7564; 866-2-875-7034. Fax: 866-2-875-2380.
Key words: Ascites; Diuretics; Gas exchange; Liver cirrhosis; Paracentesis; Pulmonary function.
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S-C. Chang et aL TABLE 1
of cardiopulmonary disorders and no evidence of abnormal findings on chest radiographs and electrocardiograms; (4) stable hemodynamic state without evidence of gastrointestinal bleeding, encephalopathy, acute pancreatitis, bloody ascites, peritoneal carcinomatosis, or spontaneous bacterial peritonitis; (5) serum bilirubin< 10 mg/dl; (6) prothrombin time (INR)< 1.6; (7) peripheral platelet count >40000/ mm3; and (8) serum creatinine< 3.5 mg/dl. The study was approved by the local ethics committee, and all patients gave informed consent to participate in the study. After admission, diuretic treatment was withdrawn and the patients were given a 2-g sodium diet with fluid intake restricted to 1500 ml/day for 3 days. Patients were then randomly allocated to two groups (random number table). Group A subjects were treated with diuretics including spironolactone (100400 mg/day) and furosemide (80-240 mg/day). The dosages were adjusted in an attempt to achieve a weight loss of 1-1.5 kg/day (20). The end-point of the study was determined by whichever of the following occurred: (1) absence of ascites as evidenced by sonography; (2) poor response to the highest scheduled doses of diuretics; or (3) progressive increase of serum creatinine. The group B subjects were treated with LVR Paracentesis was performed using a standard peritoneal dialysis kit with a flexible sheath introducer. The needle was inserted in the midline, 2 cm below the umbilicus under sterile conditions and after local anesthesia. Once the needle entered the peritoneal cavity, the inner part was removed and the ascitic fluid was mobilized by static pressure. When the fluid stopped flowing, a 500-ml blood bottle with negative pressure was used to remove more ascitic fluid. The physician stayed at the patient's bedside during the entire procedure. Intravenous infusion of albumin with 6-8 g per liter of ascitic fluid removed was given after paracentesis. The dur-
Hepatic functional characteristics*
Pedal edema, Yes/No Albumin, g/dl Bilirubin, mg/dl AST, I.U./1 ALT, I.U./1 Alkaline phosphatase, U/1 Prothrombin time, INR Pugh's classification
Diuretic group (n=13)
Paracentesis group (n=13)
10/3 2.48-+0.46 2.42-+0.78 87-+33 55-+15 137-+40 1.36__.0.15 10.7-+0.4
11/2 2.45-+0.46 2.67-+0.81 86_+31 50+--14 133-+39 1.32-+0.11 10.8-+0.5
* Values of mean and SD are given. No statistical difference between the two groups.
(13,14). However, recent studies indicated that LVP could improve dyspnea, lung volume and respiratory reserve of patients with cirrhosis and ascites, but did not improve gas exchange, as evidenced by pulmonary diffusing capacity or arterial oxygen tension (PaO2) (15-17). Diuretic therapy has been thought as the treatment of choice for ascites, although paracentesis can shorten the duration of hospital stay. To the best of our knowledge, however, little attention has been paid to the effect of diuretic therapy on gas exchange in patients with cirrhosis and tense ascites. Thus, in this study, we intended to evaluate and compare the therapeutic effects of diuretic treatment and LVP on lung function in patients with cirrhosis and tense ascites.
Patients and Methods Patients with cirrhosis hospitalized for the treatment of tense ascites were considered for this study. The criteria for inclusion were as follows: (1) a positive HBsAg test in peripheral blood; (2) cirrhosis based on a histopathologic diagnosis or compatible laboratory data and sonographic findings (18,19); (3) no history
TABLE 2 Clinical and laboratory data of patients with tense cirrhotic ascites treated with diuretics and paracentesis* Paracentesis group (n= 13)
Diuretic group (n= 13)
Body weight, kg MBP, mmHg HR, beats/min Urea nitrogen, mg/dl Creatinine, mg/dt Sodium, mmoLq Potassium, mmol/l Hemoglobin, g/dt Hematocrit, %
Before
After
P
Before
After
P
73.2_+12.0 89.2_+5.3 87.5-+7.4 23.5_+6.3 1.25_+0.35 136.9+_4.2 4.15+_0.36 10.38-+1.26 30.3-+2.5
66.2-+11.0 90.3-+7.7 89.5-+6.7 22.3-+7.5 1.23_+0.43 135.7_+4.1 4.10-+0.29 11.1-+1.34 31.1_3,7
<0.001 NS NS NS NS NS NS NS NS
69.1-+8.2 88.7__-6.5 90.2-+8.3 22.6-+8.3 1.26-+0.37 137.1-+4.8 4.12+0.31 10.42-+0.89 30.7-+2.2
62.2_+8.1 89.3_+8.1 88.7_+7.8 23.6_+7.1 1.29-+0.4I 136.4___3.7 4.15-+0.40 10.31-+t.42 30.4-+3.9
<0.001 NS NS NS NS NS NS NS NS
* Values of mean and SD are given. The data obtained before and after treatment between the two groups show no statistical difference. MBP= mean blood pressure; HR=heart rate; NS=not significant.
834
Lung function in patients with cirrhosis and ascites TABLE 3
Pulmonary function tests including spirometry, plethysmography, single-breath carbon monoxide diffusing capacity (DLco), and arterial blood gases were performed in all subjects. Spirometry was done in the standard sitting position at least three times (using CPI 5000 IV, Gould, Houston, Texas, USA) in accordance with American Thoracic Society recommendations (21). The best values of forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1) were selected for analysis. Total lung capacity (TLC) was measured with a body plethysmograph (model 2000 TB, Gould, Houston, Texas, USA). The diffusing capacity of the lung for carbon monoxide (DLco) was measured in the sitting position by the single-breath method, with minor modification (22,23). The exchange time, t, is the sum of the breathholding time plus two-thirds of the inspiratory time and one-half of the collecting time of the expired samples (24). The breath-holding time was 10 s. Alveolar volume (VA) was measured using the singlebreath helium (He) technique while DLco was measured. Arterial blood samples were taken anaerobically in the sitting position before the test of DLco. Blood samples for pH, PaO2 (arterial PO2) and PaCO2 (arterial PCO2) values were analyzed immediately using ABL III (Radiometer, Copenhagen, Denmark). PAO2 (alveolar oxygen tension) is calculated by the following equation. PAOE=(barometric pressure 47)×FIO2-PaCO2/R. R, an exchange ratio, is assumed to be 0.8 in this study. The alveolar-arterial PO2 difference (AaPO2) is calculated by subtracting PaO2 from PAO2. Pulmonary function tests were performed 1 day be-
Physical and pulmonary functional characteristics*
Age, year Height, cm Body weight, kg FEVI, % pred. FVC, % pred. FEV1/FVC, % TLC, % pred. FRC, % pred. ERV, % pred. RV, % pred. DLco, % pred. Kco, % pred. PaO2, mmHg PaCO2, mmHg AaPO2, mmHg pH
Diuretic group (n = 13)
Paracentesis group (n = 13)
59_+11 165.9-+3.8 73.2-+ 12.0 70.5_+13.6 65.2_+ 14.2 82.0-+7.3 84.7-+17.8 95.1 -+19.3 39.6---21.2 101.3_+18.2 48.1-+14.0 59.5-+ 15.7 72.4-+8.7 28.4-+ 1.3 41.9_+9.3 7.468-+0.017
58-+12 165.0-+5.4 69.1 -+8.2 71.8-+11.1 67.1 -+ 12.0 81.6-+8.3 81.4-+12.0 104.9-+ 19.6 44.5-+20.6 101.8-+24.0 53.2-+16.1 62.8_+ 15.5 72.3-+8.1 29.6-+ 3.3 40.4-+9.8 7.472-+0.026
* Values of mean and SD are given. No statistical difference between the two groups. FEVI = forced expiratory volume in 1 s; FVC= forced vital capacity; TLC= total lung capacity; FRC= functional residual capacity; ERV= expiratory reserve volume; RV= residual volume; DLco= diffusing capacity of lung; Kco = DLco corrected by alveolar volume; PaO2 = arterial PO2; PaCO2 = arterial PCO2; AaPO2 = alveolar-arterial PO2 difference.
ation of the peritoneal taps ranged from 45 to 120 min. Body weight, blood pressure, heart rate and urine amount were measured daily. Blood samples were taken for standard liver and renal tests, and hemoglobin, hematocrit as well as blood cell counts were also measured 1 day before, twice a week during diuretic treatment, and 1 day after termination of the study in group A subjects, and 1 day before and after paracentesis in group B subjects.
TABLE 4 Comparison of the effects of diuretics and paracentesis on lung function in patients with tense cirrhotic ascites* Paracentesis group (n= 13)
Diuretic group (n= 13)
FEVb % pred. FVC, % pred. FEVt/FVC, % TLC, % pred. FRC, % pred. ERV, % pred. RV, % pred. DLco; % pred. Kco, % pred. PaO2, mmHg PaCO2, mmHg AaPO2, mmHg pH
Before
After
p
Before
After
p
70.5--- 13.6 65.2--- 14.2 82.0-+7.3 76.9-+ 11.9 87.7+--15.4 39.6-+21.2 101.3-+ 18.2 48.1_+14.0 59.9-+ 15.7 72.4-+8.7 28.4-+ 1.3 41.9_+9.3 7.468-+0.017
82.1 _+16.8 75.2+ 17.8 82.5-+7.4 85.1 - 15.1 95.1-4-19.3 67.3-+33.1 94.9-+ 17.0 54.6-+ 14.8 58.0-+ 12.0 79.3-+8.2 30.3-+2.4 31.8-+9.4 7.464-+0.010
<0.001 <0.001 NS <0.05 <0.05 <0.001 NS <0.01 NS <0.005 <0.01 <0.005 NS
71.8-+ 11.1 67.1 -+12.0 81.6-+8.3 79.8-11.1 93.8--- 19.7 44.5-+20.6 101.8-+24.0 53.2_+16.1 62.8-+ 15.5 72.3_+8.1 29.6-+3.3 40.4-+9.8 7.472-+0.026
89.6 + 13.2 83.4-+ 13.9 81.8-+8.2 89.8-10.5 104.9+ 19.6 75.7-+22.2 98.6-+22.9 56.8_+14.0 62.8-+ 15.5 74.9-+ 11.0 28.8-+3.2 38.8+ 12.5 7.469-+0.027
<0.001 <0.001 NS <0.002 <0.01 <0.002 NS <0.02 NS NS NS NS NS
* Values of mean and SD are given. Data obtained before and after treatment between the two groups show no statistical difference. FEV1 = forced expiratory volume in 1 s; FVC= forced vital capacity; TLC= total lung capacity; FRC= functional residual capacity; ERV= expiratory reserve volume; RV= residual volume; DLco= diffusing capacity of lung; Kco= DLeo corrected by alveolar volume; PaO2 = arterial PO2; PaCO2 = arterial PCO2; AaPO2= alveolar-arterial PO2 difference; NS= not significant.
835
S-C Chang et al. TABLE 5 Changes of pulmonary functions before and after treatment in patients with tense cirrhotic ascites*
Body weight, kg FEVb I FVC, 1 TLC, 1 FRC, 1 ERV, 1 RV, 1 DLco, mI. min- I • mmHg- l Kco, ml. rain -1 • mmHg -1 • 1-1 PaO2, mmHg PaCO2, mmHg AaPO2, mmHg pH
Diuretic group (n= 13)
Paracentesis group (n= 13)
P value
-7.0+-2.1 0.32_.+0.28 0.37_+0.34 0.44_+.0.75 0.27+__0.41 0.38_+0.30 -0.10_+0.26 1.78 +_2.10 -0.07-+0.36 7.0_.+7.1 1.8+_2.3 - 10.2---5.0 -0.005+_.0.017
-6.9+-3.0 0.39+--0.28 0.47+--0.33 0.49_+0.66 0.34+_0.37 0.41+-0.36 -0.06+_0.31 0.94-+ 1.42 -0.22+-0.26 2.6+_7.6 -0.8-+2.2 - 1.6+-7.4 -0.005+_0.017
NS NS NS NS NS NS NS NS NS NS <0.005 <0.002 NS
* Values of mean and SD are given. FEVI= forced expiratory volume in 1 s; FVC= forced vital capacity; TLC= total lung capacity; FRC= functional residual capacity; ERV= expiratory reserve volume; RV= residual volume; DLco= diffusing capacity fo lung; Kco= DLco corrected by alveolar volume; PaOz = arterial PO2; PaCO2= arterial PCOz; AaPO2= alveolar-arterial PO2 difference; NS= not significant.
fore diuretic treatment and 1 day after termination of the study in group A subjects. In group B patients, the tests were done 1 day before and after LVR Statistical comparison of the data between the two groups was carried out using the unpaired Student's ttest or Mann-Whitney U test. The effect of diuretics or paracentesis on lung function was examined using paired Student's t-test or Wilcoxon's signed-rank test. A p-value less than 0.05 was considered statistically significant.
Results One patient treated with diuretics was not included because a progressive decline in renal function was found, as evidenced by increased serum levels of urea nitrogen and creatinine. Another patient who received LVP was excluded because upper gastrointestinal hemorrhage occurred after paracentesis. Finally, this series included 26 male patients with non-alcoholic cirrhosis and tense ascites. Thirteen patients received diuretic therapy. The duration o f treatment ranged from 4 to 9 days (mean+_SD, 5.7 + _ 1.7 days). Another 13 patients underwent LVP. The amount of ascitic fluid removed ranged from 4.5 to 12.5 1 (mean+-SD, 8.2+-3.1 1). The clinical characteristics and laboratory data of the patients studied are summarized in Tables 1-3. They show that before treatment the two groups of patients with cirrhosis studied were homogeneous for a wide variety of clinical and laboratory parameters. After treatment, the body weight of the patients in both groups decreased significantly but the reduction of body weight (diuretic vs paracentesis group, 7.0+-2.1 kg vs 6.9+-3.0 kg) was comparable (Table 4). The data for mean blood pressure, heart rate, serum levels of creatinine, urea nitrogen, sodium and potassium,
836
hemoglobin and hematocrit showed no significant changes after treatment (Table 2). The results of pulmonary function tests before and after treatment in these two groups are summarized in Table 4. After treatment, significant improvement of ventilatory function, as evidenced by FEVb FVC, TLC, functional residual capacity (FRC) and expiratory reserve volume (ERV) was found in both groups. The DLco also increased significantly in both groups. Nevertheless, Kco (DLco corrected by VA) showed no significant improvement in either group. LVP did not improve arterial blood gases. In contrast, significant improvement of arterial blood gases, as evidenced by an increase of PaO2 and PaCO2, and a decrease in AaPO2 was observed in the diuretic group (Table 4). Comparison of the changes in lung function (data after minus those before treatment) between the two groups is shown in Table 5. The changes in body weight, FEVb FVC, TLC, FRC, ERV, RV, DLco, Kco, PaO2 and pH were comparable in both groups. However, the reduction in AaPOz between the two groups showed a significant difference. A greater reduction in AaPO2 was found in the diuretic group.
Discussion Impairment of gas exchange (arterial hypoxemia or decreased DLco and/or Kco) of varying severity is common in patients with liver cirrhosis, even in the absence of any apparent lung or heart disease. A variety of mechanisms may explain this condition, and possible contributing factors include an increase in Ps0, intrapulmonary and extrapulmonary shunting, alveolarcapillary diffusing limitation and ventilation-perfusion (V/Q) mismatch (25-29). Based on the published data,
Lung function in patients with cirrhosis and itscites
a V/Q mismatch appears to be the main cause for this hypoxemia (29-33). At baseline, the results of pulmonary function tests showed various degrees of restrictive ventilatory impairment and the mean DLco of the patients in the present study were reduced disproportionately more than the reduction in lung volumes. This finding suggested that decreased lung volumes alone could not explain the reduction of DLco. After treatment with diuretics or LVP, the mean DLco remained moderately reduced, although ventilatory function returned to normal in most patients (Table 4). These findings confirmed that impairment of gas exchange is quite common in patients with cirrhosis. Ascites is considered to play a role in worsening gas exchange in patients with liver cirrhosis (34,35). The effect of ascites on the respiratory system may be mediated by hydrostatic pressure exerted on the diaphragm from within the peritoneal cavity. By and large, ascites restricts full inflation of the respiratory system, immobilizes the diaphragm, diminishes lung volume, and thus, decreases ventilation to the basal lung zones. It may relatively increase closing volume due to a decrease in ERV. All these effects may lower the overall V/Q ratios in basal lung zones and worsen gas exchange in patients with cirrhosis. It may thus be anticipated that paracentesis will improve ventilatory function and gas exchange in patients with cirrhosis and tense ascites. Nevertheless, previous studies demonstrated that LVP did not alter gas exchange, as evaluated by DLco, Kco or PaO2, although lung volumes increased significantly (15-17). In agreement with these reports, our results showed that LVP significantly improved ventilatory function, as evidenced by FEV1, FVC, TLC, F R C and ERV, but did not significantly improve gas exchange, as evidenced by Kco, PaO2 and AaPO2. These results imply that the functional impairment of gas exchange found in patients with liver cirrhosis and tense ascites may not be due simply to the presence of ascites. The different mechanisms underlying the impairment of gas exchange associated with liver cirrhosis, the varying amounts of ascites and differential effects of ascites on pulmonary ventilation and perfusion in patients with cirrhosis may explain why Kco, PaO2 and AaPO2 values, in the present study, did not improve consistently after paracentesis. The current study demonstrated that the changes in lung volumes, DLco and Kco in patients treated with diuretics were quite similar to those in patients undergoing LVP (Table 4). Compared to LVP, diuretic treatment significantly improved arterial blood gases, as evidenced by increases in PaO2 and PaCO2 and a de-
crease in AaPO2. In addition, a greater reduction in AaPO2 after treatment was found in the diuretic than in the paracentesis group (Table 5). This further supported the superiority of diuretic treatment compared to paracentesis in terms of oxygenation improvement in patients with cirrhosis and tense ascites. Because the patients included in the two groups were similar as regards clinical features, liver, renal and pulmonary function before treatment, and reduction in body weight, as well as improvement in ventilatory function after treatment, the difference in the improvement of arterial blood gases is likely to be related to different treatment modalities (Tables 2-5). The additional factors contributing to the impairment of gas exchange in patients with cirrhosis and tense ascites are still unknown. One probable explanation is that interstitial pulmonary edema, as fluid retention, may occur as ascites in patients with liver cirrhosis (14). This may, in part, explain why diuretic therapy improved the oxygenation of the patients studied but paracentesis did not. Further controlled studies are needed to verify this point. The flaw of the present study is that we did not measure respiratory rate, tidal volume and minute ventilation, which might influence the values of PaO2 and PaCO2. Measuring these respiratory parameters may be of value in observing changes in respiratory pattern and in shedding light on the mechanisms underlying the change of gas exchange in patients with cirrhosis and tense ascites after diuretic treatment or LVP. However, the value of AaPO2 is relatively unaffected by the level of ventilation. In addition, the improvement in gas exchange, as evidenced by AaPO2 (from 41.9_+9.3 mmHg to 31.8_+9.4 mmHg), is of clinical significance in patients treated with diuretics because a mean PaO2 of 72.4-+ 8.7 mmHg in association with a mean PaCO2 of 28.4-+ 1.3 mmHg represented a substantial oxygenation problem in the patients, particularly in those with low values of PaO2 or high values of AaPO2. In summary, the results of the present study indicated that both diuretic therapy and LVP treatment significantly improved the ventilatory function in patients with cirrhosis and tense ascites. In terms of oxygenation improvement, diuretic treatment may be superior to LVP. However, paracentesis may serve as an alternative treatment for rapid relief of abdominal tension, or when diuretics are ineffective or poorly tolerated.
Acknowledgements This work was supported by a grant from the National Science Council of the Republic of China (NSC842331-B075-005). 837
S-C. Chang et al.
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