1 Department of Anaesthesiology and Critical Care Medicine and 2 Department of Oesophagogastric Surgery, School of Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 1138519, Japan
* Corresponding author. E-mail: nakazawa.mane{at}tmd.ac.jp
Accepted for publication March 21, 2004.
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Abstract |
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Methods. We randomized 14 patients into two groups. One group received PGE1 20 ng kg1 min1 i.v. during anaesthesia (PGE1 group) and the other group did not (control group). Anaesthesia was maintained with sevoflurane and epidural anaesthesia. During oesophagectomy, ventilation of one lung was carried out with a double-lumen bronchial tube. The patients were extubated on or after the first postoperative day. Blood samples were taken at induction of anaesthesia, at the end of thoracotomy, at the end of the operation, 2 h after surgery and on the first day after surgery.
Results. The groups were similar for ASA physical status, age, FEV1%, operation time, duration of thoracotomy, intraoperative fluid volume and blood loss. The arterial blood gas and arterial pressure during surgery were also similar in the PGE1 and control groups. However, the ratio on the first day after surgery was significantly greater in the PGE1 group compared with the control group. Serum concentrations of IL-6 and IL-8 increased after surgery in both groups. IL-6 was significantly less in the PGE1 group at the end of the operation and 2 h after the operation.
Conclusions. Intraoperative PGE1 reduced IL-6 production in patients undergoing oesophagectomy and oxygenation was better in the postoperative period.
Keywords: blood, oxygenation ; hormones, prostaglandins ; polypeptides, cytokines, interleukins ; surgery, transthoracic oesophagectomy
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Introduction |
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Prostaglandin E1 (PGE1) is a pulmonary and systemic vasodilator with anti-inflammatory properties.15 A low dose of PGE1 (20 ng kg1 min1) reduced the increases of IL-6 and IL-8 caused by reperfusion injury in cardiopulmonary bypass without reducing blood pressure.16 Therefore, PGE1 might have beneficial effects on inflammatory responses in oesophageal surgery. We studied the effects of PGE1 on proinflammatory cytokine responses and gas exchange in patients undergoing oesophagectomy for oesophageal cancer. We studied patients having right-sided transthoracic oesophagectomy with cervical oesophagogastrostomy and three-field lymph node dissection, which is probably the most invasive procedure in oesophageal surgery.
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Method |
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The same experienced surgical team (25 or more transthoracic oesophagectomies performed every year) conducted each operation. Patients were allocated to one of two groups using closed envelopes: the PGE1 group and the control group. Patients in the PGE1 group received PGE1 20 ng kg1 min1 (Prostandin; Ono Pharmaceutical, Osaka, Japan) from induction of anaesthesia until the end of surgery. We did not give a placebo to the control group as it was very difficult to obtain patients' consent if the anaesthetists were not aware of the agents they were using during anaesthesia. However the anaesthetists and intensive care physicians who participated in anaesthetic management or postoperative cardiorespiratory care did not know the study objectives. All patients received dopamine 28 µg kg1 min1 during anaesthesia. If the mean blood pressure were to decrease to less than 80% of the preoperative value in spite of fluid administration and increasing dopamine to a dose of 10 µg kg1 min1, administration of PGE1 would be stopped.
Anaesthesia was induced with propofol 22.5 mg kg1 and a double-lumen bronchial tube was placed after giving vecuronium 10 mg i.v. Initial ventilation settings were a tidal volume of 10 ml kg1 based on ideal body weight, a respiratory rate of 10 /min, an inspiratory/expiratory ratio of 1:2 and an of 0.5. General anaesthesia was maintained with sevoflurane in combination with epidural anaesthesia using 0.25% bupivacaine. During oesophagectomy with right-sided thoracotomy in a left lateral decubitus position, one-lung ventilation was performed. The dependent lung was ventilated with
between 0.51.0, using oxygen and air mixture to keep
. Tidal volume was maintained at 10 ml kg1. If the peak inspiratory pressure exceeded 30 cm H2O, the position of the double lumen tube was confirmed with a fibre-optic bronchoscope and bronchial suction was also carried out. Tidal volume was also reduced to 8 ml kg1 if necessary. After removal of the thoracic oesophagus and dissection of the posterior mediastinal lymph nodes (around the recurrent nerve and oesophagus), the right lung was reinflated manually until collapse could not be seen and two-lung ventilation was resumed.
was decreased to <0.5 and 5 cm H2O PEEP was added, and other ventilation settings were left unchanged. After the thoracic procedures, the patients were placed supine and the bronchial tube was changed for a single-lumen orotracheal tube. At laparotomy, a gastric tube was constructed and cervical oesophagogastrostomy was done. After surgery, the patients were transferred to the intensive care unit, sedated with midazolam and buprenorphine i.v., and ventilated mechanically. Postoperative analgesia was provided with continuous epidural infusion of bupivacaine 0.25% in combination with buprenorphine 0.20.3 mg day1. The patients were weaned from mechanical ventilation and extubated on or after the first day after surgery if the
was <0.4,
was >33.3 kPa, the forced vital capacity was >15 ml kg1, and the circulation was stable. If the cough reflex was not present, percutaneous cricothyrotomy with a Minitrach II® (Sims Portex, Hythe, UK) was used for suctioning of tracheal sputum.
We took blood samples for blood gas analysis and interleukin (IL)-6 and IL-8 measurements at induction of anaesthesia, at the end of thoracotomy, at the end of the operation, 2 h after surgery, 12 h after the operation and before extubation. The ventilation settings were kept constant for at least 10 min before blood sampling, and blood pressure was recorded simultaneously with blood sampling. Arterial blood samples were collected into sterile 10 ml syringes and centrifuged at 1200 g for 10 min at 4°C. The serum was stored at 80°C until analysis. IL-6 and IL-8 were measured by enzyme-linked immunosorbent assay (Fujirebio, Tokyo, Japan) according to the instructions of the manufacturer.
The data are expressed as median (interquartile range). Non-parametric statistical analysis was applied. Statistical significance was determined by analysis of variance (ANOVA) with the KruskalWallis test followed by the MannWhitney U test. The Spearman rank test was used to test for a relationship between and serum IL-6. For statistical analyses we used the statistical software package StatView® (J 4.5; Abacus Concepts, Berkeley, CA, USA). A value of P<0.05 was considered statistically significant.
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Results |
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Discussion |
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The effect of PGE1 on proinflammatory cytokines seems to differ depending on the surgical site. Sugawara et al.17 reported that PGE1 given at 20 ng kg1 min1 increased plasma IL-6 concentrations after a Pringle manoeuvre in cirrhotic patients undergoing subsegmental hepatectomy. They concluded that PGE1 had cytoprotective effects, as IL-6 is a potent stimulator of acute-phase protein production by the liver and promotes repair and regeneration of liver tissues. On the other hand, Kawamura et al.16 gave PGE1 at 2050 ng kg1 min1 during cardiac surgery with cardiopulmonary bypass and reduced the increases of IL-6 and IL-8 after declamping the aorta. PGE1 also reduced the increases in serum troponin-T and an isozyme of creatine kinase with muscle and brain subunits.16 It was proposed that IL-6 and IL-8 production was involved in myocardial ischaemiareperfusion injury, and that PGE1 protected against myocardial injury by inhibiting proinflammatory cytokines.
In assessing the present study, the effects of conditions before and during surgery on postoperative pulmonary complications must be considered. Age, body mass index, vital capacity and smoking influence postoperative pulmonary function,3 5 18 but these did not differ between the groups. Surgical factors, such as approach, choice of conduit19 and skill of the operator,20 could also affect patient morbidity, but the surgical procedure in this study was uniform and done by the same surgical team. Intraoperative conditions such as operation time, thoracotomy time, blood loss and volume of fluid administration7 were also similar for the two groups.
We found that PGE1 did not cause systemic hypotension or impairment of gas exchange during surgery. Improvement of oxygenation, with a reduced increase of IL-6 in the PGE1 group, suggested that inflammatory responses in the lung might be reduced by PGE1, and impaired oxygenation was thus prevented. Reid et al.21 measured lung protein accumulation of radiolabelled transferrin using a double-isotope system in patients undergoing oesophagogastrectomy. Increased pulmonary endothelial permeability occurred after oesophagectomy, shown by increased protein accumulation. Gee et al.22 reported that PGE1 reduced the increase in lung vascular permeability in a model of lung vascular injury induced by complement in anaesthetized sheep. It is possible that the increase in extravascular lung water during surgery was reduced by PGE1, so that oxygenation was better after surgery.
We could not measure inflammatory cytokines in the bronchoalveolar lavage fluid, but Abe and colleagues8 found that increased concentrations of IL-6 come from alveolar and bronchial cells, not from alveolar macrophages. They showed that plasma concentrations of IL-6 reached a peak 12 h after transthoracic oesophagectomy, and this correlated with IL-6 production by cultivated lung tissue. A more recent study showed that alveolar macrophages also expressed IL-6 or IL-8 in oesophageal surgery9 and that expression was closely related to postoperative respiratory failure.
While reducing increases in serum IL-6, PGE1 did not affect IL-8 in the present study. Postoperative IL-8 did not increase in some cases and the increase in serum IL-8 was not so evident as that of IL-6. This might be related to the relatively low incidence of pulmonary complications in our patients. Tsukada et al.23 showed that the IL-8 concentration in bronchoalveolar lavage fluid did not change after oesophagectomy in patients without postoperative pneumonia, while it significantly increased after surgery in patients with postoperative pneumonia.
There are several limitations of the present study. First, although randomized, it was not masked or placebo-controlled. However, all of the patients in the present study were anaesthetized by one of several residents according to the protocol used during our routine practice for thoracic anaesthesia, and postoperative respiratory care and blood sampling and measurements were performed by personnel who were blinded to the treatment protocol. Secondly, although we found that the study demonstrated that intraoperative PGE1 maintained oxygenation postoperatively, the effect of PGE1 on morbidity and mortality remains to be tested because of the relatively small patient population in the study. Although further randomized trials of adequate sample size are anticipated, surgical approaches to oesophageal cancer have become diverse, depending on the patient's physical status and tumor stage. Less invasive procedures, such as thoracoscopic24 and hand-assisted thoracoscopic25 oesophagectomy, have now become popular. These approaches could reduce inflammatory responses and postoperative pulmonary complications, and this is worth investigating. Thirdly, PGE1 treatment has a theoretical risk of impaired tumour surveillance, especially during cancer surgery. PGE1 suppressed natural killer cell activity in in vitro26 and in vivo27 animal studies. Suppression of natural killer cells can increase susceptibility to tumour recurrence or metastasis.28 29 In our daily anaesthetic practice, PGE1 is one of the choices for the treatment of hypertension, but there are no reports of the danger of metastasis in cancer surgery. The effects of PGE1 on the spread of cancer cells, which could worsen disease prognosis, should be investigated. This may need to be considered when using PGE1 during surgery.
We conclude that intraoperative PGE1 reduced IL-6 production in patients undergoing transthoracic oesophagectomy, and maintained oxygenation in the postoperative period.
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References |
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