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Penetration of intravenous antibiotics from the lung into the pleural space after pulmonary resection*

1994; Elsevier BV; Volume: 107; Issue: 3 Linguagem: Inglês

10.1016/s0022-5223(94)70365-5

1097-685X

T. Sakuma, Hiroshi Kubo, Tatsuo Tanita, Kazuhiko Koike, S Fujimura,

Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis

Little information concerning penetration of antibiotics into the pleural space after pulmonary resection is available. If there are differences among the methods of lung resection in the penetration of antibiotics into the pleural space, different doses of antibiotics should be administered accordingto the method used. To determine the penetration of intravenous antibiotics into the pleural space, we administered Flomoxef sodium (Shionogi & Co. Ltd., Oskaka, Japan) intravenously. We then measured the concentration of Flomoxef sodium sequentially in pleural effusion of patients who underwent lobectomy or pneumonectomy. Flomoxef sodium is an injectable oxacepham antibiotic tha possesses a broad antibacterial spectrum effect against gram-positive and gram-negative bacteria.1Tsuji T Satoh H Narisada M Hamashima Y Yoshida T. Synthesis and antibacterial activity of 6315-S, a new member of the oxacephem antibiotic.J Antibiot. 1985; 38: 466-476Crossref PubMed Scopus (66) Google Scholar The lung remains after lobectomy but does not remain after pneumonectomy. The concentration of Flomoxef sodium in pleural effusion thus indicates the penetration of antibiotics occurs from both the lung and the parietal pleura in a patient who undergoes lobectomy but from only the parietal pleura in a patient who undergoes pneumonectomy. The concentration of Flomoxef sodium in pleural effusions were measured in the lobectomy group(five patients [66 ± 13 years] who underwent lobectomies for malignant tumors of the lung [two for adenocarcinoma, one for small-cell carcinoma, one for alveolar cell carcinoma, and one formetastatic lung tumor from osteosarcoma]) and in the pneumonectomy group (five patients [61± 2 years] who underwent pneumonectomies for bronchogenic carcinomas [two forsquamous cell carcinoma, two for small-cell carcinoma, and one for adenocarcinoma). Informedconsent was obtained from each patient before the operation. We maintained general anesthesia with halothane (1% to 3%), nitrous oxide, and oxygen. There was no difference between the period needed for lobectomy (190 ± 51 minutes) and that needed for pneumonectomy (260 ± 71 minutes). At the end of the operation, we rinsed the pleural space with 1500 to 2000 ml of normal saline solution and wiped it up. Then two 28F trocar replacement catheters (Argyle, Sherwood Medical Company, St. Louis, Mo.) with an end hole and a side hole were placed in the pleural cavity. Pleural effusion was drained through the catheters and continuous suction with negative pressures of 10 cm H2O or 5 cm H2O, in the lobectomy and pneumonectomy groups, respectively. We administered 2 gm Flomoxef sodium dissolved in 100 ml normal saline solution intravenously during 1 hour at 3 hours after lung resection. Pleural effusion and arterial blood were collected before the injection and at 0.5, 1, 2, 3, 4, and 6 hours after the beginning of intravenous administration. Collected samples were centrifuged at 3000 rpm for 15 minutes. Supernatant was stored at -80° C. Several days later, 0.5 ml supernatant mixed with 0.5 ml ethanol and 1.0 ml chloroform was centrifuged at 4000 rpm for 10 minutes. Concentrations of Flomoxef sodium in supernatantwere then measured with high-performance liquid chlomatography. A Nucleosil 10 C18 (Chemcho Co. Ltd., Tokyo, Japan) (4 × 300 mm; particle 5μm) was used with ultraviolet detection 268 nm and a tracer phase of 0.5 mol/L phosphate-buffered water and acetonitrile. To determine the permeability of pleural effusion, we measured total protein concentration in pleural effusion and plasma by the Biuret method just before administration of Flomoxef sodium. The ratio of pleural effusion to plasma total protein concentration was calculated. To detect hemorrhage in thepleural space, hemoglobin concentrations in pleural effusion and plasma were measured by the oxyhemoglobin method just before administration of Flomoxef sodium. Data are expressed as mean ± standard deviation. We used two-way analyses of variance and then the SheffeFtest to compare the data between groups. We also used Student’s pairedttest to compare the data within groups. Significance was set atp < 0.05. The studies showed that in pleural effusion, the concentration of Flomoxef sodium increased during the 6 hours after intravenous administration in both groups. The maximum concentration of Flomoxef sodium increased significantly more in the lobectomy group (37.4 ± 8.3 ng/ml)than in the pneumonectomy group (14.0 ± 2.6 ng/ml,Fig. 1). In plasma, the concentration of Flomoxef sodium increased during intravenous administration andthen diminished gradually. There was no difference between the concentration of Flomoxef sodium in the lobectomy group and that in the pneumonectomy group. Mean volume of pleural effusion was greater in the lobectomy group (178 ± 47 ml) than in the pneumonectomy group (130± 85 ml). There was, however, no significant difference between the groups. Total protein concentrations in pleural effusion (4.1 ± 1.2 and 4.0 ± 0.6 gm/dl in the lobectomy and pneumonectomy groups, respectively) were higher than those in our previous study.2Sakuma T Kubo H Tanita T Koike K Fujimura S. Migration of neutrophils from the lung into the pleural space after lung resection in human and in rabbit.Chest. 1983; 102: 812-818Abstract Full Text Full Text PDF Scopus (7) Google Scholar There were no differences between the total protein concentrations or between the ratios of pleural effusion to plasma total protein concentration(0.6 ± 0.1 in both groups). There was no difference between the hemoglobin concentration of pleural effusion in the lobectomy group (3.7 ± 1.4 gm/dl) and that in the pneumonectomy group (4.6 ± 3.2 gm/dl). In the patients after lobectomy, the penetration of Flomoxef sodium into the pleural space was greater from the lung than from the parietal pleura. The evidence is that the concentration of Flomoxef sodium in pleural effusion was greater in the lobectomy group than in the pneumonectomy group. The difference between the route of penetration of antibiotics after lobectomy and after pneumonectomy was that the penetration occurred from the lung and the parietal pleura in the lobectomy group, whereas it occurred only from the parietal pleura in the pneumonectomy group. If the penetration of Flomoxef sodium was not greater from the lung than from the parietal pleura in the lobectomy group, the concentration of Flomoxef sodium in the lobectomy group would be similar tothat in the pneumonectomy group. Recently, with the technique of enclosing a lung in a bag, pleural fluid was demonstrated to arise directly from the edematous lung into the pleural space.3Wiener-Kronish JP Broaddus VC Albertine KH Gropper MA Matthay MA Staub NC. The relationship of pleural effusions to increased permeability pulmonary edema in anesthetized sheep.J Clin Invest. 1988; 82: 1422-1429Crossref PubMed Scopus (69) Google Scholar, 4Broaddus VC Wiener-Kronish JP Staub NC. Clearance of lung edema into the pleural space of volume-loaded anesthetized sheep.J Appl Physiol. 1990; 68: 2623-2630PubMed Google Scholar Similar to the movement of pleural fluid collected using the enclosing bag, antibiotics probably moved primarily from the lung into the pleural space after lung resection. Several factors have been implicated in the penetration of antibiotics from the circulation into the pleural space.5Thys JP Vanderhoeft P Herchulz A Bergmann P Yourassowsky E. Penetration of aminoglycosides in uninfected pleural exudates and in pleural empyemas.Chest. 1988; 93: 530-533Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar, 6Bergogne-Berezin E. Pharmacokinetics of antibiotics in respiratory secretions.in: 2nd ed. Respiratory infections: diagnosis and management. Raven Press, New York1988: 608-631Google Scholar First, the surface area has been reported to play a role on the penetration and absorption of antibiotics in the pleural space when pleural effusion persists.7Van Etta LL Peterson LR Fasching CE Gerding DN. Effect of the ratio of surface area to volume on the penetration of antibiotics into extravascular spaces in an in vitro model.J Infect Dis. 1982; 146: 423-428Crossref PubMed Scopus (52) Google Scholar, 8Shohet I Yellin A Meyerovitch J Rubinstein E. Pharmacokinetics and therapeutic efficacy ofgentamicin in an experimental pleural empyema rabbit model.Antimicrob Agents Chemother. 1987; 31: 982-985Crossref PubMed Scopus (28) Google Scholar In our study, however, it is unlikely that surface area contributed to the difference in the concentration of antibiotics after lung resection. If the concentration of penetrated antibiotics from the lung is similar to that from the parietal pleura, there would be no difference in the concentration of Flomoxef sodium between the lobectomy group and the pneumonectomy group. Although the volume of penetrated antibiotics would be influenced by the surface area, the concentration of antibiotics would not be influenced. Second, the concentration of the antibiotics in plasma has been reported to influence the concentration of the pleural space.9Saito H Kimura T Takeda T Kishimoto S Oguma T Shimamura K. Pharmacokinetics of Flomoxefin mucosal tissue of the middle ear and mastoid following intravenous administration in humans.Chemotherapy. 1990; 36: 193-199Crossref PubMed Scopus (3) Google Scholar, 10Craig WA Kunin CM. Distribution of trimethoprim-sulfamethoxazole in tissues of rhesus monkeys.J Infect Dis. 1973; 128: S575-S579Crossref PubMed Scopus (37) Google Scholar In our study, however, the concentration of antibiotics in plasma had little effect on the difference of Flomoxef sodium concentration between the groups, because there was no difference between the concentrations of antibiotics in the plasma of the groups. Third, the limited usefulness of antibiotics was not caused by the depot effect11Wise R. Methods for evaluating the penetration of β-lactam antibiotics into tissues.Rev Infect Dis. 1986; 8: S325-S332Crossref PubMed Scopus (36) Google Scholar (that the moved antibiotics fail to increase the concentration because the antibiotics are diluted by pleural effusion pooled before the movement of antibiotics). In our study, there was no depot effect of pleural effusion because pleural effusion was drained out of the pleural space continuously through a tube placed at the lowest position in the pleural cavity. Chest radiography proved little pooling of pleural effusion. Fourth, the difference of the concentration of Flomoxef sodium was not caused by the hemorrhage in the pleural space after lung resection. There was no difference between hemoglobin concentrations in the pleural effusions of the groups. If the volume of pleural effusion was greater in the pneumonectomy group than in the lobectomy group, total amount of penetration of Flomoxef sodium would not differ between the groups. However, there was no difference between the volumes of pleural effusion in the two groups. Total amount of Flomoxef sodium thus penetrated more in the lobectomy group than in the pneumonectomy group. Would there be a difference between the inflammatory disorders in the lobectomy group and those in the pneumonectomy group? The answer is no. First, there was no difference between the groups in age, disease, or the period needed for operation. Second, there was no difference in the ratios of pleural effusion to plasma protein concentration, although the ratios were greater than 0.41± 0.04 in patients without inflammation.2Sakuma T Kubo H Tanita T Koike K Fujimura S. Migration of neutrophils from the lung into the pleural space after lung resection in human and in rabbit.Chest. 1983; 102: 812-818Abstract Full Text Full Text PDF Scopus (7) Google Scholar This study suggests that the patient who undergoes pneumonectomy should receive a higher dose of antibiotics than one who undergoes lobectomy to obtain similar net dosage effects. Empyema after pneumonectomy is a serious complication.12Pairolero PC Arnold PG Trastek VF Meland NB Kay PP. Postpneumonectomy empyema: therole of intrathoracic muscle transposition.J THORAC CARDIOVASC SURG. 1990; 99: 958-968PubMed Google Scholar A lower concentration of antibiotics in patients after pneumonectomy may result in lessened bactericidal effect in the pleural space. This study also suggests that a different penetration of antibiotics would be measured at a period later than that used in this study. This is difficult to study, however, because of little pleural effusion.