Effect of prostaglandin E1 on inflammatory responses and gas exchange in patients undergoing surgery for oesophageal cancer

K. Nakazawa1,*, Y. Narumi1, S. Ishikawa1, K. Yokoyama1, T. Nishikage2, K. Nagai2, T. Kawano2 and K. Makita1

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.


    Abstract
 Top
 Abstract
 Introduction
 Method
 Results
 Discussion
 References
 
Background. Oesophageal surgery causes morbidity and mortality from respiratory complications. We tested the possibility that prostaglandin E1 (PGE1) could reduce inflammatory cytokine responses and improve gas exchange after oesophagectomy.

Methods. We randomized 14 patients into two groups. One group received PGE1 20 ng kg–1 min–1 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


    Introduction
 Top
 Abstract
 Introduction
 Method
 Results
 Discussion
 References
 
Morbidity after oesophagectomy has decreased over the last few decades owing to technical modifications and improvements in perioperative care.13 However, the mortality of the transthoracic approach remains at 5–12%.46 Postoperative pulmonary complications such as pneumonia, acute lung injury and acute respiratory distress syndrome prolong the duration of mechanical ventilation and are strongly associated with morbidity and mortality.6 7 Generally, proinflammatory cytokines are important in the progression of lung injury. Increased serum IL-6 and IL-8 concentrations are found after oesophageal surgery,811 and these increases could lead to acute lung injury.1214

Prostaglandin E1 (PGE1) is a pulmonary and systemic vasodilator with anti-inflammatory properties.15 A low dose of PGE1 (20 ng kg–1 min–1) 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.


    Method
 Top
 Abstract
 Introduction
 Method
 Results
 Discussion
 References
 
This study was approved by the Ethical Committee on Human Research at Tokyo Medical and Dental University and was performed between March 2001 and July 2002. Written informed consent was obtained from patients about to have right-sided transthoracic oesophagectomy with three-field lymph node dissection for thoracic oesophageal cancer. Reconstruction using stomach and cervical oesophagogastrostomy was performed. Exclusion criteria were: trans-hiatal oesophagectomy, minimal invasive techniques using thoracoscopy or laparoscopy, reconstruction using a segment of colon or jejunum, preoperative steroid administration, and age greater than 75 yr.

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 kg–1 min–1 (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 2–8 µg kg–1 min–1 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 kg–1 min–1, administration of PGE1 would be stopped.

Anaesthesia was induced with propofol 2–2.5 mg kg–1 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 kg–1 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 0.5–1.0, using oxygen and air mixture to keep . Tidal volume was maintained at 10 ml kg–1. 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 kg–1 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 0.2–0.3 mg day–1. 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 kg–1, 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 Kruskal–Wallis test followed by the Mann–Whitney 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.


    Results
 Top
 Abstract
 Introduction
 Method
 Results
 Discussion
 References
 
Fourteen patients were studied. The patients' characteristics are shown in Table 1. The operative time, duration of anaesthesia, duration of thoracotomy and the volumes of intraoperative fluid administration and blood loss were similar between the two groups. One patient in each group developed pneumonia. In one patient in the control group, extubation was delayed for 9 days because of pneumonia and acute respiratory distress syndrome, and in the PGE1 group one patient developed pneumonia after discharge from the intensive care unit. No patients died after surgery. Time to extubation and discharge from the intensive care unit were very similar in the two groups.


View this table:
[in this window]
[in a new window]
 
Table 1 Patient details (median, interquartile values)

 
There were no differences in systolic blood pressure, arterial blood pH and during and after surgery between the two groups (Table 2). In no case did PGE1 infusion have to be stopped because of hypotension. The ratio during surgery was similar for the two groups (Table 2), but the values were greater in the PGE1 group 2 h after surgery and significantly greater on the first day after surgery.


View this table:
[in this window]
[in a new window]
 
Table 2 Blood gas and cardiovascular values (median, interquartile values) during and after oesophagectomy.

 
Serum IL-6 increased after surgery in both groups, but the increase was less after PGE1 administration (Table 3). The IL-6 values in the PGE1 group were significantly less at the end of the operation and 2 h after surgery in comparison with the control group. IL-8 values did not differ between the control group and the PGE1 group. There was a significant correlation between IL-6 and the ratio on the first day after surgery (r=–0.724, P<0.01) (Fig. 1).


View this table:
[in this window]
[in a new window]
 
Table 3 Values of cytokines (median, interquartile values) during and after oesophagectomy.

 


View larger version (24K):
[in this window]
[in a new window]
 
Fig 1 Relationship between serum IL-6 concentration and the ratio on the first day after surgery. There was a significant correlation between these values (r=–0.724, P<0.01).

 

    Discussion
 Top
 Abstract
 Introduction
 Method
 Results
 Discussion
 References
 
We found that serum IL-6 increased after oesophagectomy and that PGE1 attenuated this increase and oxygenation was better in the early postoperative period.

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 kg–1 min–1 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 20–50 ng kg–1 min–1 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 ischaemia–reperfusion 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.


    References
 Top
 Abstract
 Introduction
 Method
 Results
 Discussion
 References
 
1 Ando N, Ozawa S, Kitagawa Y, et al. Improvement in the results of surgical treatment of advanced squamous esophageal carcinoma during 15 consecutive years. Ann Surg 2000; 232: 225–32[CrossRef][ISI][Medline]

2 Swisher SG, Hunt KK, Holmes EC, et al. Changes in the surgical management of esophageal cancer from 1970 to 1993. Am J Surg 1995; 169: 609–14[CrossRef][ISI][Medline]

3 Bartels H, Stein HJ, Siewert JR. Preoperative risk analysis and postoperative mortality of oesophagectomy for resectable oesophageal cancer. Br J Surg 1998; 85: 840–4[CrossRef][ISI][Medline]

4 Altorki N, Kent M, Ferrara C, et al. Three field lymph node dissection for squamous cell and adenocarcinoma of the esophagus. Ann Surg 2002; 236: 177–83[CrossRef][ISI][Medline]

5 Tandon S, Batchelor A, Bullock R, et al. Peri-operative risk factors for acute lung injury following elective oesophagectomy. Br J Anaesth 2001; 86: 633–8[Abstract/Free Full Text]

6 Millikan KW, Silverstein J, Hart V, et al. A 15-year review of esophagectomy for carcinoma of the esophagus and cardia. Arch Surg 1995; 130: 617–24[Abstract]

7 Ferguson MK, Martin TR, Reeder LB, et al. Mortality after esophagectomy: risk factor analysis. World J Surg 1997; 21: 599–603[CrossRef][ISI][Medline]

8 Abe T, Oka M, Tangoku A, et al. Interleukin-6 production in lung tissue after transthoracic esophagectomy. J Am Coll Surg 2001; 192: 322–9[CrossRef][ISI][Medline]

9 Kooguchi K, Kobayashi A, Kitamura Y, et al. Elevated expression of inducible nitric oxide synthase and inflammatory cytokines in the alveolar macrophages after esophagectomy. Crit Care Med 2002; 30: 71–6[ISI][Medline]

10 Ono S, Aosasa S, Mochizuki H. Effects of a protease inhibitor on reduction of surgical stress in esophagectomy. Am J Surg 1999; 177: 78–82[CrossRef][ISI][Medline]

11 Nakanishi K, Takeda S, Terajima K, et al. Myocardial dysfunction associated with proinflammatory cytokines after esophageal resection. Anesth Analg 2000 91: 270–5[Abstract/Free Full Text]

12 Pittet JF, Mackersie RC, Martin TR, et al. Biological markers of acute lung injury: prognostic and pathogenetic significance. Am J Respir Crit Care Med 1997; 155: 1187–205[ISI][Medline]

13 Reid PT, Donnelly SC, Haslett C. Inflammatory predictors for the development of the adult respiratory distress syndrome. Thorax 1995; 50: 1023–6[ISI][Medline]

14 Fujishima S, Sasaki J, Shinozawa Y, et al. Interleukin 8 in ARDS. Lancet 1993; 342: 237–8[ISI][Medline]

15 Haynes DR, Whitehouse MW, Vernon-Roberts B. The prostaglandin E1 analogue, misoprostol, regulates inflammatory cytokines and immune functions in vitro like the natural prostaglandins E1, E2 and E3. Immunology 1992; 76: 251–7[ISI][Medline]

16 Kawamura T, Nara N, Kadosaki M, et al. Prostaglandin E1 reduces myocardial reperfusion injury by inhibiting proinflammatory cytokines production during cardiac surgery. Crit Care Med 2000; 28: 2201–8[ISI][Medline]

17 Sugawara Y, Kubota K, Ogura T, et al. Protective effect of prostaglandin E1 against ischemia/reperfusion-induced liver injury: results of a prospective, randomized study in cirrhotic patients undergoing subsegmentectomy. J Hepatol 1998; 29: 969–76[CrossRef][ISI][Medline]

18 Nagawa H, Kobori O, Muto T. Prediction of pulmonary complications after transthoracic oesophagectomy. Br J Surg 1994; 81:860–2[ISI][Medline]

19 Teng S, Karl R. Surgical approaches to esophageal cancer. Cancer Control 1999; 6: 36–42[Medline]

20 Swisher SG, Deford L, Merriman KW, et al. Effects of operative volume on morbidity, mortality and hospital use after esophagectomy for cancer. J Thorac Cardiovasc Surg 2000; 119: 1126–32[Abstract/Free Full Text]

21 Reid PT, Donnelly SC, MacGregor IR, et al. Pulmonary endothelial permeability and circulating neutrophil-endothelial markers in patients undergoing esophagogastrectomy. Crit Care Med 2000; 28: 3161–5[CrossRef][ISI][Medline]

22 Gee MH, Tahamont MV, Flynn JT, et al. Prostaglandin E1 prevents increased lung microvascular permeability during intravascular complement activation in sheep. Circ Res 1987; 61: 420–8[Abstract]

23 Tsukada K, Hasegawa T, Miyazaki T, et al. Predictive value of interleukin-8 and granulocyte elastase in pulmonary complication after esophagectomy. Am J Surg 2001; 181: 167–71[CrossRef][ISI][Medline]

24 Luketich JD, Alvelo-Rivera M, Buenaventura PO, et al. Minimally invasive esophagectomy: outcomes in 222 patients. Ann Surg 2003; 238: 486–94[CrossRef][ISI][Medline]

25 Kawano T, Iwai T. Hand-assisted thoracoscopic esophagectomy using a new supportive approach. Surg Endosc 2001; 15: 330[CrossRef][ISI][Medline]

26 Lanefelt F, Ullberg M, Jondal M, et al. PGE1 and prostacyclin suppression of NK-cell mediated cytotoxicity and its relation to cyclic AMP. Med Biol 1983; 61: 324–30[ISI][Medline]

27 Mokuno Y, Takano M, Matsuguchi T, et al. Prostaglandin E1 protects against liver injury induced by Escherichia coli infection via a dominant Th2-like response of liver T cells in mice. Hepatology 1999; 30: 1464–72[ISI][Medline]

28 Ben-Eliyahu S, Page GG, Yirmiya R, et al. Evidence that stress and surgical interventions promote tumor development by suppressing natural killer cell activity. Int J Cancer 1999; 80: 880–8[CrossRef][ISI][Medline]

29 Melamed R, Bar-Yosef S, Shakhar G, et al. Suppression of natural killer cell activity and promotion of tumor metastasis by ketamine, thiopental, and halothane, but not by propofol: mediating mechanisms and prophylactic measures. Anesth Analg 2003; 97: 1331–9[Abstract/Free Full Text]





This Article
Abstract
Full Text (PDF)
All Versions of this Article:
93/2/199    most recent
aeh184v1
E-Letters: Submit a response to the article
Alert me when this article is cited
Alert me when E-letters are posted
Alert me if a correction is posted
Services
Email this article to a friend
Similar articles in this journal
Similar articles in ISI Web of Science
Similar articles in PubMed
Alert me to new issues of the journal
Add to My Personal Archive
Download to citation manager
Disclaimer
Request Permissions
Google Scholar
Articles by Nakazawa, K.
Articles by Makita, K.
PubMed
PubMed Citation
Articles by Nakazawa, K.
Articles by Makita, K.