Abstract
Objective
To investigate whether preoperative corticosteroid administration plays a role in attenuating postoperative morbidity.
Summary Background Data
There is as yet no consensus on the beneficial effects of steroids in alleviating surgical stress.
Methods
A total of 66 patients undergoing surgery for thoracic esophageal cancer were randomly categorized preoperatively into two groups of 33 patients each. One group was administered an intravenous infusion of methylprednisolone (10 mg/kg body weight) 30 minutes before the surgery (MP group), while the other group received a placebo infusion (control group). The primary endpoint was organ system failure during the first 7 days after surgery. Comparisons of surgery-related complications, cytokine responses, and blood counts were also made between the two groups.
Results
The percentage of patients in the MP group who had one or more organ system failures was 33%, significantly lower than the corresponding percentage of 61% in the control group. The surgery-related complication rate and long-term survival rate were similar in the two groups. The peak plasma levels of interleukin (IL)-1 receptor antagonist, IL-6, and IL-8 were significantly lower in the MP group than in the control group. Changes in the plasma levels of IL-10 were significantly larger in the MP group. No significant differences in the circulating lymphocyte and neutrophil counts were observed between the groups.
Conclusions
The results suggest that prophylactic administration of corticosteroids is associated with a decrease in postoperative morbidity in patients undergoing invasive surgery. The laboratory data suggest that corticosteroids may attenuate surgical stress-induced inflammatory responses both directly by suppressing the release of proinflammatory cytokines and via inducing IL-10 synthesis.
Stress-induced organ dysfunction states are thought to be provoked by an uncontrolled inflammatory response due to the overproduction of proinflammatory mediators. 1–3 However, the results of clinical studies on the usefulness of recombinant interleukin (IL)-1 receptor antagonist (IL-1ra) and antitumor necrosis factor antibodies have so far been unsatisfactory. 4,5 The plausible reasons for this could be that when a specific cytokine is suppressed, the inflammatory reactions that result from the activity of various cytokine networks may not be suppressed; or, in the face of uncontrolled inflammatory reactions progressing locally, stimulation of the general antiinflammatory activity in the entire body may not be of much avail if the timing of administration and pharmacokinetics of the administered drugs do not match the clinical course. 6,7 Therefore, it would be important to administer agents that modulate the actions of the cytokine network nonspecifically just before or after the induction of stress.
With regard to corticosteroids, large-scale multicenter have studies concluded that the drugs are ineffective in the treatment of sepsis. 8,9 Nonetheless, as the mechanisms of actions of corticosteroids are being clarified in detail, including from molecular-biologic aspects, 10,11 the clinical benefits of corticosteroids are being reevaluated, taking into account the timing of drug administration.
Based on the above, this prospective randomized controlled study was conducted to investigate the clinical benefits on surgical stress-induced organ failure and cytokine modulating-effects of preoperatively administered corticosteroids.
PATIENTS AND METHODS
The protocol of the study was approved by the institutional review board. The study began in June 1996 and continued for 4 years, ending in June 1999; however, the patients continued to be followed up until January 2001.
Protocol
The subjects of the study were patients with esophageal squamous cell carcinoma who were scheduled to undergo esophageal resection. Patients who met one or more of the following criteria were excluded from the study: 1) preoperative chemotherapy, radiation therapy, or immunotherapy, 2) older than 76 years, 3) preoperative complications, such as liver cirrhosis or diabetes mellitus (insulin therapy), creatinine clearance of less than 60 mL/min, vital capacity of less than 80%, or forced expiratory volume in 1 second of less than 70%, 4) HBs-antigen positive or HCV-antibody positive, 5) multiple cancer, or 6) old tuberculous lesions.
Written informed consent was obtained from each of the patients enrolled in the study. Randomization was conducted by the research fellow using a computer-generated randomization table based on blocks of four to assign the patients into the preoperative methylprednisolone (Pharmacia Corp., Peapack, NJ) administration group (MP group, n = 33) and the control group (n = 33). Patients in the MP group received methylprednisolone diluted in 100 mL physiologic saline, at a dosage of 10 mg/kg body weight, within 30 minutes of the start of surgery. Patients in the control group received a corresponding placebo infusion. The surgeons, anesthesiologists, and intensive care staff remained unaware of the patients’ group allocation.
The primary endpoint of the study was the development of medical complications during the first 7 days after surgery. The secondary parameters assessed included the development of postoperative surgical complications, the plasma concentrations of IL-6, IL-8, IL-10, IL-1ra, and cortisol, the duration of mechanical ventilation, and the long-term survival rate.
Surgical Procedure
The right pleural cavity was entered through a posterolateral incision along the fifth intercostal space. Radical esophagectomy was commenced with thorough dissection of the supradiaphragmatic, paraesophageal, bilateral pulmonary hilar, and some of the paratracheal nodes along the recurrent laryngeal nerves on both sides. After closure of the pleural cavity, the abdomen was entered through an upper midline incision. Proximal gastrectomy and radical dissection of the lymph nodes along the common hepatic artery, left gastric artery, lesser curvature, and the cardia were performed. Then, a U-shaped incision was made in the neck, and the cervical paraesophageal nodes, deep cervical nodes, and supraclavicular lymph nodes were dissected. For reconstruction, the gastric tube was pulled up to the neck through the posterior mediastinum, and gastroesophagostomy was performed.
Postoperative Management
At the end of the operation, all patients were immediately placed on prophylactic mechanical ventilation. The criteria for the commencement of weaning from mechanical ventilation included: 1) [Fio2 × (760 - 47) - Paco2/0.8]/Pao2 less than 2.0; 2) urine output less than 2.0 mL/kg per hour; 3) heart rate less than 120 beats/min; 4) fully conscious and well-oriented condition. Patients able to breathe spontaneously for 6 hours with a PEEP of 5 cm H2O and pressure support of 5 cm H2O, not fulfilling the following weaning failure criteria, were extubated: 1) respiratory rate more than 25/min, 2) heart rate more than 120/min, 3) arterial oxygen saturation less than 95%, 4) increase in sputum volume, 5) blunting of the cough reflex, and 6) restlessness.
For nutritional support, enteral nutrition was provided via the jejunostomy from postoperative day 3, and the dose was increased stepwise to 30 kcal/kg by postoperative day 7. No intravenous total parenteral nutrition or lipids were provided.
Definition of Postoperative Complications
Postoperative organ system failures were defined as shown in Table 1. We adopted abnormal values leading to the mortality rate of 10% or more for each organ from the MOF scores obtained by Marshall et al. 12 As to renal function, the N-acetyl-β-d-glucosamidase (NAG) index was adopted as an indicator of renal tubular dysfunction. 13,14 Infectious complications were defined as positive culture of blood, sputum, or other body fluids in the presence of clinical evidence of infection. 15,16
Table 1. DEFINITION OF ORGAN SYSTEM FAILURE WITHIN POSTOPERATIVE DAY 7
* Pressure-adjusted heart rate (PAR) = heart rate × central venous pressure/mean blood pressure.
† Respiratory index (RI) = [FIo2 × (760 − 47) − Paco2/0.8]/Pao2.
‡N-acetyl-β-d-glucosamidase index (NAGI) = urinary NAG/urinary creatinine.
§ Aspartate aminotransferase or alanine aminotransferase.
Blood Sampling and Assay
EDTA-blood samples were collected before surgery, at the end of the intrathoracic surgical procedures, 1 hour after the end of surgery, and at 7 am on postoperative days 1, 3, 5, and 7. The plasma was stored at −80°C until the assay. The plasma levels of the cytokines were measured using an enzyme-linked immunosorbent assay kit (R&D Systems, Inc., Minneapolis, MN). The plasma levels of cortisol were measured by radioimmunoassay (SRL, Tokyo, Japan); in this system of measurement, MP shows 43% cross-reactivity with cortisol. Other laboratory tests were conducted at the hospital’s central laboratory. The respiratory index (RI) and NAG index were calculated using the following formulas: RI = [Fio2 × (760 - 47) - Paco2/0.8]/Pao2; NAG index = urinary NAG/urinary creatinine.
Statistical Analysis
As reported previously, the most common complications and their frequencies following esophageal cancer surgery are as follows 17–19: respiratory failure, 20% to 30%; arrhythmia, 30% to 40%; cardiovascular failure, 10% to 15%; hyperbilirubinemia, 20% to 30%. Overall, almost 60% of the patients have been reported to have one or more postoperative organ system failures. In our preliminary study, 20 we found an overall complication rate of 30% in the patients receiving preoperative MP. In the current study, we estimated a complication rate of 60% in the control group and 30% in the MP group. The required sample size was 66 patients (33 per group) for a one-tailed hypothesis with alpha set at 0.05 and 80% power. 21
The differences in clinical characteristics and postoperative complication rates between the two groups were analyzed by the chi-square or Fisher exact test. Chronological changes in the laboratory data were analyzed by analysis of variance for repeated measures. When a significant difference was found by analysis of variance, differences at several time points were checked by Student t test. Time-to-event data were analyzed by the Kaplan-Meier survival analysis and compared by the log-rank test. P < .05 was considered to indicate statistical significance. All statistical analyses were performed on a personal computer with the statistical package SPSS for Windows, Advanced Statistics 7.5J (SPSS, Chicago, IL).
RESULTS
Patient Characteristics
A total of 66 patients were enrolled in the study. None of the patients withdrew from the study. There were no statistically significant differences in the pathologic cancer staging according to the International Union against Cancer Classification 22 or the clinical characteristics between the two groups (Table 2).
Table 2. CLINICAL CHARACTERISTICS OF PATIENTS
Postoperative Complications
The postoperative complications are summarized in Table 3. Overall, 33% of the patients in the MP group had one or more postoperative organ system complications within 7 days after surgery, which was significantly (P < .05) lower than the corresponding percentage of 61% in the control group. Significantly fewer patients in the MP group had cardiovascular failure (P < .05) and respiratory failure (P < .05) than in the control group. Figure 1 shows the Kaplan-Meier plots for the rate of weaning from mechanical ventilation. The median duration (with 95% confidence interval [CI]) of mechanical ventilation was 3 days (95% CI 2.4–3.6) in the MP group as compared with 5 days (95% CI 4.1–5.9) in the control group (P = .0009, log-rank test).
Table 3. POSTOPERATIVE COMPLICATIONS AND OUTCOMES
* Fisher exact test (one-tailed test).
Figure 1. Kaplan-Meier curves for the duration of mechanical ventilation in the methylprednisolone group (solid line) and the control group (dashed line). The median duration (with 95% confidence interval [CI]) of mechanical ventilation was 3 days (95% CI 2.4–3.6) in the methylprednisolone group as compared with 5 days (95% CI 4.1–5.9) in the control group (P = .0009, log-rank test).
The surgery-related complication rates were similar in the two groups. There was no case requiring reoperation and no death within 30 days of surgery in either group.
Long-Term Survival
Figure 2 shows the Kaplan-Meier survival curves for the long-term survival rate. No statistically significant difference in the overall survival rate was found between the two groups. No significant differences were observed between the two groups with respect to the survival rates examined by stage (data not shown).
Figure 2. Kaplan-Meier curves for long-term survival in the methylprednisolone group (solid line) and the control group (dashed line). No statistically significant differences in the overall survival rates were found between the two groups (P = .4465, log-rank test). The 1- and 3-year survival rates were 82% and 62% in the methylprednisolone group and 85% and 65% in the control group, respectively.
Laboratory Tests
In the MP group, the degree of postoperative increase in the plasma levels of IL-6, IL-8, and IL-1ra was significantly lower than in the control group (Fig. 3).
Figure 3. Postoperative changes in the plasma levels of interleukin (IL)-8 (top), IL-6 (middle), and IL-1ra (bottom) in the methylprednisolone group (○ and the control group (▪). The postoperative increases in the plasma levels of IL-8, IL-6, and IL-1ra were significantly suppressed in the methylprednisolone group (P < .01, analysis of variance, respectively). **P < .01, *P < .05, methylprednisolone group versus control group (paired t test).
The maximum plasma level of IL-10 was significantly higher in the MP group than in the control group. The plasma level of cortisol during surgery was significantly higher in the MP group than the control group, since MP shows 43% cross-reactivity with cortisol. After that point, there were no significant differences in the cortisol levels between the two groups (Fig. 4).
Figure 4. Postoperative changes in the plasma levels of cortisol (left) and interleukin (IL)-10 (right) in the methylprednisolone group (○ and the control group (▪). Since methylprednisolone shows 43% cross-reactivity with cortisol, the levels of cortisol during the operation were higher in the methylprednisolone group than in the control group (P < .01, analysis of variance), but after that point there were no differences in the cortisol levels between the two groups. The plasma levels of IL-10 were higher in the methylprednisolone group than in the control group (P < .01, analysis of variance). **P < .01, methylprednisolone group versus control group (paired t test).
There were no significant differences between the two groups in the postoperative circulating lymphocyte count and neutrophil count (Fig. 5).
Figure 5. Postoperative changes in the circulating lymphocyte counts (left) and neutrophil counts (right) in the methylprednisolone group (○ and the control group (▪). There were no marked differences in lymphocyte and neutrophil counts between the two groups.
DISCUSSION
We made two important clinical observations in this study. First, prophylactic administration of MP reduced the incidence of postoperative pulmonary failure and instability of cardiac function as well as the overall morbidity rate in patients undergoing esophageal cancer surgery. While the morbidity rate of 61% in the control group patients in our study was similar to that reported in other studies of patients undergoing esophageal cancer surgery, 17–19 the rate was as low as 33% in the MP group. In particular, improvement of respiratory function was related to the shorter duration of mechanical ventilation. Second, no clinical adverse effects of MP administered at the dose of 10 mg/kg body weight were observed. Preoperative administration of MP did not significantly affect the circulating lymphocyte and neutrophil counts in this study setting. Furthermore, no cases of clinically significant postoperative infectious complications or suture failures were confirmed. The survival rates in none of the categories of patients who underwent resection presented in our present study were significantly different from those reported in other recent studies. 23,24 These results suggest that preoperative MP administration may be useful for alleviating surgical stress.
Several trials have investigated the benefits of administering corticosteroids as a modulator of the cytokine responses in patients undergoing elective thoracic surgery, gastrointestinal surgery, or cardiac surgery, as well as in cases of septic shock. 25 However, there is as yet no agreement on the beneficial effects of corticosteroids in alleviating surgical stress. This disagreement probably stems from the variability in the drugs used, their dosage and administration schedule, and in the nature of the surgical procedure in different studies. The benefits of cytokine response-modulating therapy may become blunted in the presence of complications such as surgery-related organ failure or basic cardiopulmonary management. After perusal of the literature, we planned the optimal subject and administration schedule of corticosteroids in the clinical setting.
In this study, patients with esophageal cancer scheduled for surgery were selected for the following reasons. Surgical treatment of thoracic esophageal cancer is one of the most stressful surgical procedures, and the frequency of postoperative organ failure remains very high. 17–19 On the other hand, cases with poor surgical technique that could affect the cytokine responses have recently became rare at our institute (anastomotic leakage, 1.5%; intraoperative massive hemorrhage >1,500 mL, 5%; postoperative hemorrhage, 1%, between 1990 and 1995, n = 250). Esophageal cancer surgery was therefore selected as one of the most suitable procedures for evaluating the effects of steroids on surgical stress. At the time of planning this study, previous studies had yielded conflicting information on the influence of neoadjuvant chemotherapy on the risk of postoperative morbidity, 26,27 and we believed it appropriate to exclude the patients given neoadjuvant chemotherapy to simplify the patients’ background factors. On the basis of our results, the effects of preoperative steroid administration need to be examined in the future in the population, including patients who received neoadjuvant therapy.
Since corticosteroids primarily inhibit transcriptional factors such as nuclear factor-κB and AP-1, once transcription has begun, corticosteroids would probably be rendered ineffective. 10,11 Furthermore, modification of the inflammatory response at an early stage would seem to be very important because compensatory antiinflammatory responses occur in very quick succession after the inflammatory response. 6,7 In this study, therefore, corticosteroids were administered just before the surgery.
While the antiinflammatory actions of MP are five times as strong as those of cortisol, the actions on electrolyte metabolism are less than half as strong. 28 Also, the half-life of MP in the blood is 2.8 hours. 28,29 When MP is administered intravenously at the dose of 1,000 mg/body, its maximum blood concentration in healthy adults is about 10 μg/mL, and more than 10 μg/mL MP can significantly suppress lymphocyte blastoid transformation, immunoglobulin production, and NK cell activity. 28–30 Since we considered that less than 1,000 mg/d would be sufficient as a prophylactic dose, the dose of the drug in the present study was set at 10 mg/kg body weight.
The present study also showed that preoperative MP administration suppressed postoperative increases in the plasma levels of IL-6 and IL-8. Of the various endogenous antiinflammatory mediators, while the postoperative plasma levels of IL-10 were high in the MP group, the levels of IL-1ra were low. Differences in the sensitivity to corticosteroids according to the cytokine type suggest the presence of transcription factors for IL-10 other than AP-1 or nuclear factor-κB that are not influenced or activated by corticosteroids. 31,32 According to recent research, the production of IL-1ra was stimulated by IL-1β, and the genes encoding IL-1β and IL-1ra are located close to each other on 22q12-21. 33,34 It is possible that corticosteroid pretreatment suppressed the production of IL-1ra by suppressing IL-β production and the inhibitory effect of the transcription factors similar to the other proinflammatory cytokines. The preoperative administration of corticosteroids, while directly suppressing proinflammatory cytokine production, also simultaneously induces the synthesis of Th2 cytokines, thus modulating the surgical stress-induced inflammatory responses.
In conclusion, we have shown that the prophylactic administration of corticosteroids decreased postoperative morbidity following the highly invasive esophageal cancer surgery. However, since cytokine responses constitute an early protective response to stress, careful investigation as to which type of surgery would constitute an indication for prophylactic administration of corticosteroids, and to what extent these responses should be suppressed, is warranted.
Footnotes
Correspondence: Nobuhiro Sato, MD, Department of Critical Care and Emergency Medicine, Iwate Medical University, School of Medicine, 19-1 Uchimaru, Morioka, 020-8505, Japan.
E-mail: satonobu@iwate-med.ac.jp
Supported in part by a grant-in-aid for cancer research (S8-1 and S8-13) from the Ministry of Health and Welfare, Japan.
Accepted for publication December 10, 2001.
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