- Email: [email protected]
Systemic inflammatory response syndrome and surgical stress in thoracic surgery
Journal of Critical Care (2006) 21, 48 – 55
Clinical Research—Adult
Systemic inflammatory response syndrome and surgical stress in thoracic surgery Kazumasa Takenakaa,*, Eiji Ogawaa, Hiromi Wadab, Toshiki Hirataa a
Department of Thoracic Surgery, Kishiwada City Hospital, Kishiwada 596-8501, Japan Department of Thoracic Surgery, Faculty of Medicine, Kyoto University, Kyoto 606-8507, Japan
b
Received 30 August 2004; revised 6 March 2005; accepted 12 July 2005
Keywords: Systemic inflammatory response syndrome; Surgical stress; Thoracic surgery
Abstract Purpose: To evaluate the clinical usefulness of postoperative systemic inflammatory response syndrome (SIRS) as an index of surgical stress in patients undergoing thoracic surgery. Methods: Forty-five consecutive patients who underwent thoracic surgery with thoracotomy were enrolled. The SIRS criteria were examined daily during the first 7 postoperative days. The serum interleukin-6 (IL-6) level, operation time, intraoperative blood loss, amount of thoracic drainage, and C-reactive protein levels were also measured. Results: Sixteen cases were categorized into the SIRS group, whereas 29 cases were categorized into the non-SIRS group. Among the patients who underwent thoracic surgery, the physiological responses of the patients to the surgery, such as serum IL-6 levels and C-reactive protein levels, were significantly higher in the SIRS group than in the non-SIRS group ( P = .002 and .024, respectively). The serum IL-6 level on the first postoperative day was an independent factor associated with SIRS (95% CI 1.0021.041; P = .030). Furthermore, there was a correlation between the number of SIRS days and the duration of the postoperative hospital stay (r = 0.379, P = .012). Conclusions: Our results demonstrated that SIRS reflected the degree of surgical stress, especially thoracotomic procedures, through the IL-6 levels, and affected the postoperative hospital stay. Systemic inflammatory response syndrome can be useful for the postoperative management of patients undergoing thoracic surgery. D 2006 Elsevier Inc. All rights reserved.
1. Introduction Excessive surgical stress results in a disruption of the homeostasis, and, as a result, various postoperative complications arise. Therefore, the objective evaluation of surgical * Corresponding author. Department of Thoracic Surgery, Kyoto University, Sakyo-ku, Kyoto 606-8507, Japan. Tel.: +81 75 751 4975; fax: +81 75 751 4974. E-mail address: [email protected] (K. Takenaka). 0883-9441/$ – see front matter D 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.jcrc.2005.07.001
stress is an important issue for postoperative management. The surgical method, operation time, and intraoperative blood loss have been used as surgical stress indices and are thought to be closely associated with the occurrence of postoperative complications [1-4]. However, the physiological responses vary even when these factors remain the same, suggesting that these factors are inadequate in predicting the occurrence of complications. Other studies have reported that changes in the neuroendocrine response such as cortisols and catecholamines, or immune responses such as cytokines,
Systemic inflammatory response syndrome and surgical stress in thoracic surgery reflect the degree of surgical stress [5-14]. However, none of these methods are used as a marker in a clinical setting. The development of clinically useful indices is needed for the prevention and early detection of complications, which are the most important goals of postoperative management. Proposed in 1992 by the American College of Chest Physicians–Society of Critical Care Medicine Consensus Conference Committee, SIRS is a concept that embodies the physiological responses against stress [15]. Systemic inflammatory response syndrome is a nonspecific systemic inflammatory response defined by abnormalities in more than 2 of the following 4 diagnostic criteria: temperature, heart rate, respiratory rate, and white blood cell count. It has been reported that SIRS is a preliminary stage in the development of more critical pathological states such as sepsis, multiple organ dysfunction syndrome, and multiple organ failure [16,17]. This pathology is caused by hypercytokinemia including IL-6, which is induced by cytokine network activation in response to primary stress to the body. Among the human body responses, cytokines have been frequently tested as an index to evaluate surgical stress. In particular, the serum IL-6 level has been reported to be a sensitive indicator of the physiological response that reflects the degree of surgical stress [5,10]. Thoracic surgeries are no exception: an increasing number of reports support the serum IL-6 level as an indicator of the degree of surgical stress, and it is becoming well established that thoracoscopic surgery is less stressful than a conventional thoracotomy [18,19]. The usefulness of IL-6 as a stress marker is almost clear, but there are few clinics that are equipped with facilities to measure cytokine levels, and thus this method cannot be fully exploited in a clinical setting. Haga et al [20], in their examination of gastrointestinal surgery, suggested that postoperative SIRS is potentially useful for the evaluation of the degree of surgical stress and for the detection of postoperative complications. Sakamoto et al [11] suggested that the thoracotomic procedure is a stress factor that is independent of the intraoperative blood loss and the operation time, and that is thought to be an important factor in evaluating surgical stress. However, there have been few studies reporting SIRS as an index to evaluate stress after thoracic surgery performed by the thoracotomic procedure. We hypothesized that SIRS may have a correlation with surgical stress in thoracic surgery and examined the clinical usefulness of postoperative SIRS in patients who underwent thoracic surgery.
2. Patients and methods 2.1. Patients The subjects consisted of 71 patients who underwent scheduled thoracic surgery with thoracotomic procedure under general anesthesia at the Department of Thoracic Surgery in Kishiwada City Hospital between October 2000
49
and February 2002. Informed consent was taken from all patients. The factors that were likely to interfere with our analysis were used as exclusion criteria such as: 1. 2.
Cases with preoperative SIRS. Non-SIRS cases in which the preoperative C-reactive protein (CRP) was high (N1.0 mg/dL) and inflammation was recognizable. 3. Cases in which the patients received radiation therapy or chemotherapy with anticancer drugs that could possibly affect the patients’ immune system. 4. Cases in which steroids were used preoperatively or postoperatively. As a result, 26 cases were excluded and 45 cases were processed for further analysis. Male and female patients represented 25 and 20 cases, respectively, and the average age was 62.8 years, ranging from 25 to 83 years old.
2.2. Definition of SIRS For the diagnosis of SIRS, the standards proposed in 1992 by the American College of Chest Physicians–Society of Critical Care Medicine Consensus Conference Committee were used [15]. Among the criteria used for the SIRS diagnosis, the patient’s temperature, heart rate, and respiratory rate were considered positive if critical values were reached at least once out of 3 vital sign checks (7:00 am, 2:00 pm, 8:00 pm) per day. Patients were categorized into the SIRS group if there was at least 1 day in the first 7 postoperative days where more than 2 criteria were found positive. If the diagnostic standard was not met in the first 7 days, then the patients were categorized into the nonSIRS group. The SIRS day number represents the number of days during the first 7 days in which the SIRS standards were met.
2.3. Sampling On the day of surgery, blood samples were collected at 8:40 am before surgery. Additional blood samples were collected at 10:00 am on the first and third postoperative days. Routine examinations during the first postoperative week included peripheral blood cell counts, and biochemical examinations were conducted on the day before the surgery and on the first, third, and seventh days after surgery. Furthermore, a chest x-ray was taken immediately after surgery and again at 1, 2, 3, 5, and 7 days after surgery. Postoperative vital sign examinations were conducted every 2 hours after surgery on the day of the surgery. During the first postoperative week, the vital signs were examined 3 times a day, but the schedule was modified according to the patient’s health condition. The volume of postoperative thoracic drainage (amount of postoperative pleural effusion) was measured at 10:00 am everyday as the volume of drainage fluid during the preceding 24-hour period (volume
50
K. Takenaka et al.
accumulated in the drainage bag). The volume was recorded everyday until the drain tubes were removed.
2.4. Cytokine assay Venous blood was centrifuged at 1700 rpm for 10 min immediately after collection, and cell-free serum was obtained from the supernatant. The supernatant was stored frozen at 808C until the assay was ready. The IL-6 concentration in the supernatant was measured by a commercially available CLEIA method (SRL Inc, Tokyo, Japan), which is a chemiluminescent enzyme immunoassay (2-step sandwich method) using recombinant human IL-6 and its antibody. Alkaline phosphatase was used as the labeling enzyme, and 3-(2V-spiroadamantane)-4-methoxy4-(3U-phosphoryloxy)phenyl-1,2-dioxetane disodium salt was used as the substrate.
2.5. Patient care One-lung ventilation was used in all patients. Epidural anesthetics were also administered in all cases. All patients received prophylactic cephem antibiotics during the first 4 to 7 postoperative days. Nonsteroidal anti-inflammatory drugs were given to the patients per os or per anum to treat postoperative spike fever and aches as required. Liver dysfunction was diagnosed if the glutamic-oxaloacetic transaminase or glutamic-pyruvic transaminase showed abnormal values at least once within the first postoperative week. In these cases where other complications were suspected, blood gas analysis, computed tomography, echography, a test of the sputum or pleural effusion for bacterial infection, and arterial blood culture analysis were performed. Prerequisites for discharge from the hospital were a generally favorable health status without any complications. The patients were discharged when the thoracic drain was removed, oral food intake was Table 1
Background data for cases with and without SIRS
Number of patients Age (y, mean F SD) Sex ratio (M/F) Disease Lung cancer Pneumothorax Metastatic lung tumor Organizing pneumonia Pulmonary tuberculosis Others Surgical method Partial resection Segmentectomy Lobectomy Others Complication Liver dysfunction Pulmonary embolism
Non-SIRS group
SIRS group
29 64.0 F 15.1 15/14
16 60.6 F 11.7 10/6
18 2 2 2 1 4
8 1 3 0 1 3
11 2 11 5
6 2 6 2
1 0
2 1
Table 2
Clinical outcome with SIRS and without SIRS
Operation time (min) Blood loss (g) Drainage fluid (mL) CRP 1POD (mg/dL) IL6 1POD (pg/mL) Hospital stay (d)
Non-SIRS group SIRS group
P
176.5 F 78.6 110.9 F 116.6 367.6 F 231.0 8.1 F 4.5 61.2 F 36.2 11 (5-24)*
.119 .176 .128 .024 .002 .015
217.9 F 91.9 161.9 F 123.7 505.9 F 368.1 11.7 F 5.6 111.5 F 64.6 15 (8-21)*
*Median value (range).
possible without the necessity of fluid replacement, and unaided walking became possible. The sutures were removed during a hospital visit after discharge.
2.6. Statistical analysis The StatView 5.0 statistical software package (SAS Institute, Cary, NC) was used for all statistical analyses. The proportions of the categorical variables were analyzed using the v 2 test. Comparisons between the 2 groups were performed using the Mann-Whitney U test or an unpaired Student t test. The correlations between interval and ordinal variables were analyzed by the Spearman rank correlation (r), the significance of which was determined by Spearman’s rank-sum test. A multiple logistic regression analysis was used to identify those variables independently associated with SIRS. A P value less than .05 was considered to be statistically significant.
3. Results 3.1. Systemic inflammatory response syndrome and clinical features Sixteen of 45 cases developed postoperative SIRS. As a result, 16 cases were categorized into the SIRS group, whereas 29 cases were categorized into the non-SIRS group. The patient’s background for each group is summarized in Table 1. The average age and sex ratio did not differ significantly between the 2 groups.
3.2. Relationship between SIRS and surgical stress parameters The surgical parameters from each group are shown in Table 2. The SIRS group seemed to have a longer operation time, a larger amount of blood loss, and a larger volume of postoperative drainage than the non-SIRS group, but no statistically significant differences were found.
3.3. Systemic inflammatory response syndrome and serum IL-6 There were no differences in the preoperative serum IL-6 levels between the SIRS group and the non-SIRS group ( P = .375) (Fig. 1). Compared with their preoper-
Systemic inflammatory response syndrome and surgical stress in thoracic surgery ative values, the serum IL-6 levels showed significantly higher values on the first postoperative day (Fig. 1). Furthermore, the serum IL-6 levels on the first postoperative day were significantly higher in the SIRS group than in the non-SIRS group ( P = .002) (Fig. 1). Moreover, we analyzed the correlation between the serum IL-6 levels on the first postoperative day and the number of SIRS days for the SIRS group; there was no correlation between the 2 parameters (r = 0.076, P = .828). For the SIRS group, there was no significant correlation either between the serum IL-6 levels on the first postoperative day and all other stress parameters in our study (data not shown). Finally, to test whether any of the parameters examined thus far were independent factors associated with SIRS manifestation, we conducted a logistic regression analysis using the following parameters: age, surgical method, operation time, intraoperative blood loss, amount of thoracic drainage, serum IL-6 level on the first postoperative day, and CRP. The results demonstrated that the serum IL-6 level on the first postoperative day was an independent factor associated with SIRS (95% CI 1.0021.041; P = .030).
3.4. Relationship between SIRS and surgical methods We examined the relationship between SIRS and the surgical methods, which have been considered as a cause of surgical stress. There was no significant correlation between the surgical methods and SIRS ( P = .916) as well as between the surgical methods and the serum IL-6 levels on the first postoperative day ( P = .646). Interestingly, there were no significant differences in both the number of SIRS days and the serum IL-6 levels on the first postoperative day
51
Fig. 2 Correlation between the number of SIRS days and the length of postoperative hospital stay. A statistically significant correlation was seen (r = 0.379, P = .012, n = 45).
between a lobectomy and partial resection (both of which are posterolateral incision), despite the impression that a lobectomy might cause greater surgical stress than a partial resection ( P = .809 and .932, respectively).
3.5. Systemic inflammatory response syndrome and postoperative complications Four of the 45 cases developed postoperative complications (Table 1). Three of these patients belonged to the SIRS group, whereas the remaining one belonged to the non-SIRS group. Two of the 3 SIRS patients had hepatic dysfunction, which had little effect on their postoperative recovery. The number of SIRS days was 2 for both patients. The one remaining patient had pulmonary embolism, which resulted in death. The number of SIRS days in this patient was 5. The patient without SIRS also had hepatic dysfunction, and there was no major effect of this complication during the postoperative recovery. There were no cases in which infection was apparent after surgery.
3.6. Systemic inflammatory response syndrome and the length of postoperative hospital stay The length of the hospital stay after surgery was significantly longer in the SIRS group than in the nonSIRS group ( P = .015) (Table 2). Furthermore, there was a correlation between the number of SIRS days and the length of the postoperative hospital stay (r = 0.379, P = .012) (Fig. 2). There was also a correlation between the serum IL-6 level on the first postoperative day and the length of the postoperative hospital stay (r = 0.438, P = .004). Fig. 1 Serum IL-6 profile in patients with or without SIRS. Compared with their preoperative values, the serum IL-6 levels showed significantly higher values on the first postoperative day (*P b .0001 in both the SIRS group and the non-SIRS group). Furthermore, the serum IL-6 level on the first postoperative day was significantly higher in the SIRS group than in the non-SIRS group (**P = .002). PRE indicates preoperative; POD, postoperative day.
4. Discussion In this study, we demonstrated that SIRS correlated with the physiological responses of the patient to the surgery, such as serum IL-6 and CRP levels. Moreover, SIRS was a predictive factor of the duration of the postoperative hospital
52 stay. These results demonstrated that SIRS might be useful for evaluating surgical stress in thoracic surgery. In this study, among the patients who underwent thoracic surgery, the postoperative serum IL-6 level was significantly higher in the SIRS group than in the non-SIRS group. However, only in the SIRS group did we fail to recognize any correlation between the number of SIRS days and the serum IL-6 level. In the SIRS group, there was no correlation either between surgical stress parameters and the serum IL-6 level as well as the number of SIRS. Therefore, whether the patient had SIRS or not after surgery may be critical. Unfortunately, we could not analyze the correlation between the number of SIRS criteria on the first postoperative day (degree of SIRS) and surgical stress parameters including the serum IL-6 level, because of the small number of patients with SIRS. A large-scale study should be conducted in the near future. Surgery is a stress on the body, and stress factors due directly to surgery include the thoracotomic procedure, intrathoracic procedure, intraoperative blood loss, operation time, and length of time under anesthetic. Among them, the thoracotomic procedure is thought to be one of the most serious stress factors on the body [11]. In support of this notion, there has been a study that compared thoracotomic chest surgeries with nonthoracotomic abdominal surgeries of similar severity [11]. The authors reported a difference in the serum IL-6 response, even when the 2 surgeries were not different in terms of factors such as the operation time and intraoperative blood loss. Furthermore, thoracoscopic surgery is known to result in lower postoperative serum IL-6 levels and fewer postoperative complications than a thoracotomy, although there are no differences between these 2 procedures in operation time or intraoperative blood loss [18,19]. Therefore, a thoracotomy is likely to be a stress factor that is independent of the intraoperative blood loss and operation time. We therefore considered the possibility that SIRS reflects the stress of thoracotomic surgery. Comparing those cases that underwent a thoracotomic lobectomy with those that underwent a thoracotomic partial resection of the lung, we found no difference in the number of SIRS days, although these 2 intrathoracic operations are thought to be different in stress level; these 2 procedures also differed in operation time and intraoperative blood loss. Furthermore, there were no differences in the serum IL-6 levels between these 2 procedures. Therefore, our results supported the contention that SIRS mainly reflects the stress of a thoracotomy that is not represented by parameters such as the operation time and intraoperative blood loss. We compared various parameters of surgical stress with the length of the postoperative hospital stay. If one quantifies the stress level by the serum IL-6 level as an indicator, then the postoperative hospital stay is shorter in surgeries that have low stress levels than in surgeries of relatively high stress levels, such as a thoracotomy [5,21,22]. There are few other studies reporting any relationship between SIRS and the postoperative hospital stay. Our analysis of SIRS and the
K. Takenaka et al. postoperative hospital stay demonstrated that there are differences in the postoperative hospital stay between the SIRS and the non-SIRS cases. Furthermore, the number of SIRS days correlated with the postoperative hospital stay. However, it should be noted that an analysis of the postoperative hospital stay is difficult because of the different institutional standards applied in different hospitals. Nevertheless, our results suggested a strong possibility of using SIRS in clinical research to predict the postoperative hospital stay. In the current study, because there were an insufficient number of cases with complications, we could not investigate whether SIRS can be used to predict the occurrence of surgical complications. Further study is needed to address this issue in the future. In conclusion, our results demonstrated that postoperative SIRS reflected the surgical stress, especially due to thoracotomic procedures, through IL-6 levels and affected the duration of the postoperative hospital stay in patients who underwent thoracic surgery. Therefore, SIRS is potentially useful as a simple evaluation system for surgical stress in the field of thoracic surgery.
References [1] Licker M, Spiliopoulos A, Frey JG, et al. Management and outcome of patients undergoing thoracic surgery in a regional chest medical enter. Eur J Anaesthesiol 2001;18:540 - 7. [2] Stephan F, Boucheseiche S, Hollande J, et al. Pulmonary complications following lung resection: a comprehensive analysis of incidence and possible risk factors. Chest 2000;118:1263 - 70. [3] Myrdal G, Gustafsson G, Lambe M, et al. Outcome after lung cancer surgery. Factors predicting early mortality and major morbidity. Eur J Cardiothorac Surg 2001;20:694 - 9. [4] Ruffini E, Parola A, Papalia E, et al. Frequency and mortality of acute lung injury and acute respiratory distress syndrome after pulmonary resection for bronchogenic carcinoma. Eur J Cardiothorac Surg 2001; 20:30 - 6. [5] Karayiannakis AJ, Makri GG, Mantzioka A, et al. Systemic stress response after laparoscopic or open cholecystectomy: a randomized trial. Br J Surg 1997;84:467 - 71. [6] Fukushima R, Kawamura YJ, Saito H, et al. Interleukin-6 and stress hormone responses after uncomplicated gasless laparoscopic-assisted and open sigmoid colectomy. Dis Colon Rectum 1996;39:S29 - S34. [7] Tschernko EM, Hofer S, Bieglmayer C, et al. Early postoperative stress: video-assisted wedge resection/lobectomy vs conventional axillary thoracotomy. Chest 1996;109:1636 - 42. [8] Baigrie RJ, Lamont PM, Kwiatkowski D, et al. Systemic cytokine response after major surgery. Br J Surg 1992;79:757 - 60. [9] Cruickshank AM, Fraser WD, Burns HJG, et al. Response of serum interleukin-6 in patients undergoing elective surgery of varying severity. Clin Sci 1990;79:161 - 5. [10] Oka Y, Murata A, Nishijima J, et al. Circulating interleukin 6 as a useful marker for predicting postoperative complications. Cytokine 1992;4:298 - 304. [11] Sakamoto K, Arakawa H, Mita S, et al. Elevation of circulating interleukin 6 after surgery: factors influencing the serum level. Cytokine 1994;6:181 - 6. [12] Pullicino EA, Carli F, Poole S, et al. The relationship between the circulating concentrations of interleukin 6 (IL-6), tumor necrosis factor (TNF) and the acute phase response to elective surgery and accidental injury. Lymphokine Res 1990;9:231 - 8.
Systemic inflammatory response syndrome and surgical stress in thoracic surgery [13] Leung KL, Lai PB, Ho RL, et al. Systemic cytokine response after laparoscopic-assisted resection of rectosigmoid carcinoma: a prospective randomized trial. Ann Surg 2000;231:506 - 11. [14] Nishiguchi K, Okuda J, Toyoda M, et al. Comparative evaluation of surgical stress of laparoscopic and open surgeries for colorectal carcinoma. Dis Colon Rectum 2001;44:223 - 30. [15] Members of the American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference: definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med 1992;20:864 - 74. [16] Pittet D, Rangel-Frausto S, Li N, et al. Systemic inflammatory response syndrome, sepsis, severe sepsis and septic shock: incidence, morbidities and outcomes in surgical ICU patients. Intensive Care Med 1995;21:302 - 9. [17] Smail N, Messiah A, Edouard A, et al. Role of systemic inflammatory response syndrome and infection in the occurrence of early multiple organ dysfunction syndrome following severe trauma. Intensive Care Med 1995;21:813 - 6. [18] Yim APC, Wan S, Lee TW, et al. VATS lobectomy reduces cytokine responses compared with conventional surgery. Ann Thorac Surg 2000;70:243 - 7. [19] Nagahiro I, Andou A, Aoe M, et al. Pulmonary function, postoperative pain, and serum cytokine level after lobectomy: a comparison of VATS and conventional procedure. Ann Thorac Surg 2001;72:362 - 5. [20] Haga Y, Beppu T, Doi K, et al. Systemic inflammatory response syndrome and organ dysfunction following gastrointestinal surgery. Crit Care Med 1997;25:1994 - 2000. [21] Harkki-Siren P, Sjoberg J, Toivonen J, et al. Clinical outcome and tissue trauma after laparoscopic and abdominal hysterectomy: a randomized controlled study. Acta Obstet Gynecol Scand 2000;79: 866 - 71. [22] Grande M, Tucci GF, Adorisio O, et al. Systemic acute-phase response after laparoscopic and open cholecystectomy. Surg Endosc 2002;16:313 - 6.
Commentary Systemic inflammatory response syndrome and complications after surgery In this edition of the Journal, Takenata and colleagues report data on the clinical usefulness of postoperative systemic inflammatory response syndrome (SIRS) as an index of surgical stress in patients undergoing thoracic surgery [1]. They conclude that (a) SIRS reflect the degree of surgical stress and (b) the SIRS criteria might be useful as an evaluation system to assess the severity of postoperative stress after thoracic surgery. Despite some problems with this study, evidence exists to support this notion. It is becoming apparent that cross talk occurs between the neuroendocrine and immune systems, and it is plausible that the postoperative stress response is a blow-levelQ clinical manifestation of SIRS. The response to surgical stress is mediated by a complex interaction between the nervous, endocrine, immune, and hematopoietic systems [2]. Tissue trauma, hypovolemia, and pain set off a neuroendocrine reflex characterized by the secretion of corticotropin, endorphins, growth hormones,
53
vasopressin, and prolactin [2,3]. Activation of the sympathetic system increases plasma levels of catecholamines, whereas increases in cortisol and aldosterone levels follow activation of the renin-angiotensin system [4-6]. These changes induce a state of catabolism, insulin resistance, increased metabolic rate, and sodium and water retention [5-7]. The intensity of the response varies with the severity of the insult and can be attenuated by various anesthetic and surgical techniques [5,8-12]. Adequate pain control seems to play an important role [13,14]. It has become clear that the postoperative stress response is related to neural input from surgical wounds and cytokines released during and after surgery [3,6]. Various cytokines have been implicated, but interleukin 6 appears to be the major mediator. Interleukin 6 levels correlate with numerous factors, including surgical issues (type of surgery, duration, volume of blood loss, complications), increases in metabolic rate, levels of stress hormones, and C-reactive protein concentration [6,9,11,15-17]. Other molecules such as p55, p75, and phospholipase A2 are further markers of the degree of surgical stress [18]. Fever due to a regulated elevation in core temperature set point also occurs after surgery [19]. Systemic inflammatory response syndrome is insult dependent and is common after surgery. The concept of SIRS was first explored in 1991 at a consensus conference of the American Society of Chest Physicians and the Society of Critical Care Medicine, where the similarities between the clinical and pathophysiological parameters of infectious and noninfectious etiologies were recognized [20]. The clinical manifestations of SIRS include abnormalities of temperature, heart and respiratory rate, and white blood cell count. Sepsis is defined as SIRS plus a documented infection, and severe sepsis as sepsis associated with organ dysfunction, hypoperfusion, or hypotension, whereas septic shock is sepsis-induced hypotension and hypoperfusion despite fluid resuscitation. The incidence of postoperative SIRS varies, but high rates have been reported. For example, Pittet and colleagues [21] reported a 93%, 49%, and 16% incidence of SIRS, sepsis, and severe sepsis, respectively, in patients admitted to a surgical intensive care unit (ICU). Interestingly, an increasing prevalence of organ dysfunction is seen with the fulfillment of increasing numbers of the SIRS criteria, whereas the presence of SIRS shows a positive association with mortality, organ failure, and Acute Physiology and Chronic Health Evaluation III [22,23]. Rangel-Frausto et al [22] prospectively defined the epidemiology of SIRS, sepsis, severe sepsis, and septic shock in 3708 medical, surgical, and cardiothoracic surgery patients. They also tested the hypothesis that the different stages (SIRS, sepsis, severe sepsis, and septic shock) represent an increasing level of severity of the systemic response to infection, rather than an increasing severity of infection. First, in the surgical, medical, and cardiovascular ICUs, the syndromes occurred at a rate of 857, 804, and
Clinical Research—Adult
Systemic inflammatory response syndrome and surgical stress in thoracic surgery Kazumasa Takenakaa,*, Eiji Ogawaa, Hiromi Wadab, Toshiki Hirataa a
Department of Thoracic Surgery, Kishiwada City Hospital, Kishiwada 596-8501, Japan Department of Thoracic Surgery, Faculty of Medicine, Kyoto University, Kyoto 606-8507, Japan
b
Received 30 August 2004; revised 6 March 2005; accepted 12 July 2005
Keywords: Systemic inflammatory response syndrome; Surgical stress; Thoracic surgery
Abstract Purpose: To evaluate the clinical usefulness of postoperative systemic inflammatory response syndrome (SIRS) as an index of surgical stress in patients undergoing thoracic surgery. Methods: Forty-five consecutive patients who underwent thoracic surgery with thoracotomy were enrolled. The SIRS criteria were examined daily during the first 7 postoperative days. The serum interleukin-6 (IL-6) level, operation time, intraoperative blood loss, amount of thoracic drainage, and C-reactive protein levels were also measured. Results: Sixteen cases were categorized into the SIRS group, whereas 29 cases were categorized into the non-SIRS group. Among the patients who underwent thoracic surgery, the physiological responses of the patients to the surgery, such as serum IL-6 levels and C-reactive protein levels, were significantly higher in the SIRS group than in the non-SIRS group ( P = .002 and .024, respectively). The serum IL-6 level on the first postoperative day was an independent factor associated with SIRS (95% CI 1.0021.041; P = .030). Furthermore, there was a correlation between the number of SIRS days and the duration of the postoperative hospital stay (r = 0.379, P = .012). Conclusions: Our results demonstrated that SIRS reflected the degree of surgical stress, especially thoracotomic procedures, through the IL-6 levels, and affected the postoperative hospital stay. Systemic inflammatory response syndrome can be useful for the postoperative management of patients undergoing thoracic surgery. D 2006 Elsevier Inc. All rights reserved.
1. Introduction Excessive surgical stress results in a disruption of the homeostasis, and, as a result, various postoperative complications arise. Therefore, the objective evaluation of surgical * Corresponding author. Department of Thoracic Surgery, Kyoto University, Sakyo-ku, Kyoto 606-8507, Japan. Tel.: +81 75 751 4975; fax: +81 75 751 4974. E-mail address: [email protected] (K. Takenaka). 0883-9441/$ – see front matter D 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.jcrc.2005.07.001
stress is an important issue for postoperative management. The surgical method, operation time, and intraoperative blood loss have been used as surgical stress indices and are thought to be closely associated with the occurrence of postoperative complications [1-4]. However, the physiological responses vary even when these factors remain the same, suggesting that these factors are inadequate in predicting the occurrence of complications. Other studies have reported that changes in the neuroendocrine response such as cortisols and catecholamines, or immune responses such as cytokines,
Systemic inflammatory response syndrome and surgical stress in thoracic surgery reflect the degree of surgical stress [5-14]. However, none of these methods are used as a marker in a clinical setting. The development of clinically useful indices is needed for the prevention and early detection of complications, which are the most important goals of postoperative management. Proposed in 1992 by the American College of Chest Physicians–Society of Critical Care Medicine Consensus Conference Committee, SIRS is a concept that embodies the physiological responses against stress [15]. Systemic inflammatory response syndrome is a nonspecific systemic inflammatory response defined by abnormalities in more than 2 of the following 4 diagnostic criteria: temperature, heart rate, respiratory rate, and white blood cell count. It has been reported that SIRS is a preliminary stage in the development of more critical pathological states such as sepsis, multiple organ dysfunction syndrome, and multiple organ failure [16,17]. This pathology is caused by hypercytokinemia including IL-6, which is induced by cytokine network activation in response to primary stress to the body. Among the human body responses, cytokines have been frequently tested as an index to evaluate surgical stress. In particular, the serum IL-6 level has been reported to be a sensitive indicator of the physiological response that reflects the degree of surgical stress [5,10]. Thoracic surgeries are no exception: an increasing number of reports support the serum IL-6 level as an indicator of the degree of surgical stress, and it is becoming well established that thoracoscopic surgery is less stressful than a conventional thoracotomy [18,19]. The usefulness of IL-6 as a stress marker is almost clear, but there are few clinics that are equipped with facilities to measure cytokine levels, and thus this method cannot be fully exploited in a clinical setting. Haga et al [20], in their examination of gastrointestinal surgery, suggested that postoperative SIRS is potentially useful for the evaluation of the degree of surgical stress and for the detection of postoperative complications. Sakamoto et al [11] suggested that the thoracotomic procedure is a stress factor that is independent of the intraoperative blood loss and the operation time, and that is thought to be an important factor in evaluating surgical stress. However, there have been few studies reporting SIRS as an index to evaluate stress after thoracic surgery performed by the thoracotomic procedure. We hypothesized that SIRS may have a correlation with surgical stress in thoracic surgery and examined the clinical usefulness of postoperative SIRS in patients who underwent thoracic surgery.
2. Patients and methods 2.1. Patients The subjects consisted of 71 patients who underwent scheduled thoracic surgery with thoracotomic procedure under general anesthesia at the Department of Thoracic Surgery in Kishiwada City Hospital between October 2000
49
and February 2002. Informed consent was taken from all patients. The factors that were likely to interfere with our analysis were used as exclusion criteria such as: 1. 2.
Cases with preoperative SIRS. Non-SIRS cases in which the preoperative C-reactive protein (CRP) was high (N1.0 mg/dL) and inflammation was recognizable. 3. Cases in which the patients received radiation therapy or chemotherapy with anticancer drugs that could possibly affect the patients’ immune system. 4. Cases in which steroids were used preoperatively or postoperatively. As a result, 26 cases were excluded and 45 cases were processed for further analysis. Male and female patients represented 25 and 20 cases, respectively, and the average age was 62.8 years, ranging from 25 to 83 years old.
2.2. Definition of SIRS For the diagnosis of SIRS, the standards proposed in 1992 by the American College of Chest Physicians–Society of Critical Care Medicine Consensus Conference Committee were used [15]. Among the criteria used for the SIRS diagnosis, the patient’s temperature, heart rate, and respiratory rate were considered positive if critical values were reached at least once out of 3 vital sign checks (7:00 am, 2:00 pm, 8:00 pm) per day. Patients were categorized into the SIRS group if there was at least 1 day in the first 7 postoperative days where more than 2 criteria were found positive. If the diagnostic standard was not met in the first 7 days, then the patients were categorized into the nonSIRS group. The SIRS day number represents the number of days during the first 7 days in which the SIRS standards were met.
2.3. Sampling On the day of surgery, blood samples were collected at 8:40 am before surgery. Additional blood samples were collected at 10:00 am on the first and third postoperative days. Routine examinations during the first postoperative week included peripheral blood cell counts, and biochemical examinations were conducted on the day before the surgery and on the first, third, and seventh days after surgery. Furthermore, a chest x-ray was taken immediately after surgery and again at 1, 2, 3, 5, and 7 days after surgery. Postoperative vital sign examinations were conducted every 2 hours after surgery on the day of the surgery. During the first postoperative week, the vital signs were examined 3 times a day, but the schedule was modified according to the patient’s health condition. The volume of postoperative thoracic drainage (amount of postoperative pleural effusion) was measured at 10:00 am everyday as the volume of drainage fluid during the preceding 24-hour period (volume
50
K. Takenaka et al.
accumulated in the drainage bag). The volume was recorded everyday until the drain tubes were removed.
2.4. Cytokine assay Venous blood was centrifuged at 1700 rpm for 10 min immediately after collection, and cell-free serum was obtained from the supernatant. The supernatant was stored frozen at 808C until the assay was ready. The IL-6 concentration in the supernatant was measured by a commercially available CLEIA method (SRL Inc, Tokyo, Japan), which is a chemiluminescent enzyme immunoassay (2-step sandwich method) using recombinant human IL-6 and its antibody. Alkaline phosphatase was used as the labeling enzyme, and 3-(2V-spiroadamantane)-4-methoxy4-(3U-phosphoryloxy)phenyl-1,2-dioxetane disodium salt was used as the substrate.
2.5. Patient care One-lung ventilation was used in all patients. Epidural anesthetics were also administered in all cases. All patients received prophylactic cephem antibiotics during the first 4 to 7 postoperative days. Nonsteroidal anti-inflammatory drugs were given to the patients per os or per anum to treat postoperative spike fever and aches as required. Liver dysfunction was diagnosed if the glutamic-oxaloacetic transaminase or glutamic-pyruvic transaminase showed abnormal values at least once within the first postoperative week. In these cases where other complications were suspected, blood gas analysis, computed tomography, echography, a test of the sputum or pleural effusion for bacterial infection, and arterial blood culture analysis were performed. Prerequisites for discharge from the hospital were a generally favorable health status without any complications. The patients were discharged when the thoracic drain was removed, oral food intake was Table 1
Background data for cases with and without SIRS
Number of patients Age (y, mean F SD) Sex ratio (M/F) Disease Lung cancer Pneumothorax Metastatic lung tumor Organizing pneumonia Pulmonary tuberculosis Others Surgical method Partial resection Segmentectomy Lobectomy Others Complication Liver dysfunction Pulmonary embolism
Non-SIRS group
SIRS group
29 64.0 F 15.1 15/14
16 60.6 F 11.7 10/6
18 2 2 2 1 4
8 1 3 0 1 3
11 2 11 5
6 2 6 2
1 0
2 1
Table 2
Clinical outcome with SIRS and without SIRS
Operation time (min) Blood loss (g) Drainage fluid (mL) CRP 1POD (mg/dL) IL6 1POD (pg/mL) Hospital stay (d)
Non-SIRS group SIRS group
P
176.5 F 78.6 110.9 F 116.6 367.6 F 231.0 8.1 F 4.5 61.2 F 36.2 11 (5-24)*
.119 .176 .128 .024 .002 .015
217.9 F 91.9 161.9 F 123.7 505.9 F 368.1 11.7 F 5.6 111.5 F 64.6 15 (8-21)*
*Median value (range).
possible without the necessity of fluid replacement, and unaided walking became possible. The sutures were removed during a hospital visit after discharge.
2.6. Statistical analysis The StatView 5.0 statistical software package (SAS Institute, Cary, NC) was used for all statistical analyses. The proportions of the categorical variables were analyzed using the v 2 test. Comparisons between the 2 groups were performed using the Mann-Whitney U test or an unpaired Student t test. The correlations between interval and ordinal variables were analyzed by the Spearman rank correlation (r), the significance of which was determined by Spearman’s rank-sum test. A multiple logistic regression analysis was used to identify those variables independently associated with SIRS. A P value less than .05 was considered to be statistically significant.
3. Results 3.1. Systemic inflammatory response syndrome and clinical features Sixteen of 45 cases developed postoperative SIRS. As a result, 16 cases were categorized into the SIRS group, whereas 29 cases were categorized into the non-SIRS group. The patient’s background for each group is summarized in Table 1. The average age and sex ratio did not differ significantly between the 2 groups.
3.2. Relationship between SIRS and surgical stress parameters The surgical parameters from each group are shown in Table 2. The SIRS group seemed to have a longer operation time, a larger amount of blood loss, and a larger volume of postoperative drainage than the non-SIRS group, but no statistically significant differences were found.
3.3. Systemic inflammatory response syndrome and serum IL-6 There were no differences in the preoperative serum IL-6 levels between the SIRS group and the non-SIRS group ( P = .375) (Fig. 1). Compared with their preoper-
Systemic inflammatory response syndrome and surgical stress in thoracic surgery ative values, the serum IL-6 levels showed significantly higher values on the first postoperative day (Fig. 1). Furthermore, the serum IL-6 levels on the first postoperative day were significantly higher in the SIRS group than in the non-SIRS group ( P = .002) (Fig. 1). Moreover, we analyzed the correlation between the serum IL-6 levels on the first postoperative day and the number of SIRS days for the SIRS group; there was no correlation between the 2 parameters (r = 0.076, P = .828). For the SIRS group, there was no significant correlation either between the serum IL-6 levels on the first postoperative day and all other stress parameters in our study (data not shown). Finally, to test whether any of the parameters examined thus far were independent factors associated with SIRS manifestation, we conducted a logistic regression analysis using the following parameters: age, surgical method, operation time, intraoperative blood loss, amount of thoracic drainage, serum IL-6 level on the first postoperative day, and CRP. The results demonstrated that the serum IL-6 level on the first postoperative day was an independent factor associated with SIRS (95% CI 1.0021.041; P = .030).
3.4. Relationship between SIRS and surgical methods We examined the relationship between SIRS and the surgical methods, which have been considered as a cause of surgical stress. There was no significant correlation between the surgical methods and SIRS ( P = .916) as well as between the surgical methods and the serum IL-6 levels on the first postoperative day ( P = .646). Interestingly, there were no significant differences in both the number of SIRS days and the serum IL-6 levels on the first postoperative day
51
Fig. 2 Correlation between the number of SIRS days and the length of postoperative hospital stay. A statistically significant correlation was seen (r = 0.379, P = .012, n = 45).
between a lobectomy and partial resection (both of which are posterolateral incision), despite the impression that a lobectomy might cause greater surgical stress than a partial resection ( P = .809 and .932, respectively).
3.5. Systemic inflammatory response syndrome and postoperative complications Four of the 45 cases developed postoperative complications (Table 1). Three of these patients belonged to the SIRS group, whereas the remaining one belonged to the non-SIRS group. Two of the 3 SIRS patients had hepatic dysfunction, which had little effect on their postoperative recovery. The number of SIRS days was 2 for both patients. The one remaining patient had pulmonary embolism, which resulted in death. The number of SIRS days in this patient was 5. The patient without SIRS also had hepatic dysfunction, and there was no major effect of this complication during the postoperative recovery. There were no cases in which infection was apparent after surgery.
3.6. Systemic inflammatory response syndrome and the length of postoperative hospital stay The length of the hospital stay after surgery was significantly longer in the SIRS group than in the nonSIRS group ( P = .015) (Table 2). Furthermore, there was a correlation between the number of SIRS days and the length of the postoperative hospital stay (r = 0.379, P = .012) (Fig. 2). There was also a correlation between the serum IL-6 level on the first postoperative day and the length of the postoperative hospital stay (r = 0.438, P = .004). Fig. 1 Serum IL-6 profile in patients with or without SIRS. Compared with their preoperative values, the serum IL-6 levels showed significantly higher values on the first postoperative day (*P b .0001 in both the SIRS group and the non-SIRS group). Furthermore, the serum IL-6 level on the first postoperative day was significantly higher in the SIRS group than in the non-SIRS group (**P = .002). PRE indicates preoperative; POD, postoperative day.
4. Discussion In this study, we demonstrated that SIRS correlated with the physiological responses of the patient to the surgery, such as serum IL-6 and CRP levels. Moreover, SIRS was a predictive factor of the duration of the postoperative hospital
52 stay. These results demonstrated that SIRS might be useful for evaluating surgical stress in thoracic surgery. In this study, among the patients who underwent thoracic surgery, the postoperative serum IL-6 level was significantly higher in the SIRS group than in the non-SIRS group. However, only in the SIRS group did we fail to recognize any correlation between the number of SIRS days and the serum IL-6 level. In the SIRS group, there was no correlation either between surgical stress parameters and the serum IL-6 level as well as the number of SIRS. Therefore, whether the patient had SIRS or not after surgery may be critical. Unfortunately, we could not analyze the correlation between the number of SIRS criteria on the first postoperative day (degree of SIRS) and surgical stress parameters including the serum IL-6 level, because of the small number of patients with SIRS. A large-scale study should be conducted in the near future. Surgery is a stress on the body, and stress factors due directly to surgery include the thoracotomic procedure, intrathoracic procedure, intraoperative blood loss, operation time, and length of time under anesthetic. Among them, the thoracotomic procedure is thought to be one of the most serious stress factors on the body [11]. In support of this notion, there has been a study that compared thoracotomic chest surgeries with nonthoracotomic abdominal surgeries of similar severity [11]. The authors reported a difference in the serum IL-6 response, even when the 2 surgeries were not different in terms of factors such as the operation time and intraoperative blood loss. Furthermore, thoracoscopic surgery is known to result in lower postoperative serum IL-6 levels and fewer postoperative complications than a thoracotomy, although there are no differences between these 2 procedures in operation time or intraoperative blood loss [18,19]. Therefore, a thoracotomy is likely to be a stress factor that is independent of the intraoperative blood loss and operation time. We therefore considered the possibility that SIRS reflects the stress of thoracotomic surgery. Comparing those cases that underwent a thoracotomic lobectomy with those that underwent a thoracotomic partial resection of the lung, we found no difference in the number of SIRS days, although these 2 intrathoracic operations are thought to be different in stress level; these 2 procedures also differed in operation time and intraoperative blood loss. Furthermore, there were no differences in the serum IL-6 levels between these 2 procedures. Therefore, our results supported the contention that SIRS mainly reflects the stress of a thoracotomy that is not represented by parameters such as the operation time and intraoperative blood loss. We compared various parameters of surgical stress with the length of the postoperative hospital stay. If one quantifies the stress level by the serum IL-6 level as an indicator, then the postoperative hospital stay is shorter in surgeries that have low stress levels than in surgeries of relatively high stress levels, such as a thoracotomy [5,21,22]. There are few other studies reporting any relationship between SIRS and the postoperative hospital stay. Our analysis of SIRS and the
K. Takenaka et al. postoperative hospital stay demonstrated that there are differences in the postoperative hospital stay between the SIRS and the non-SIRS cases. Furthermore, the number of SIRS days correlated with the postoperative hospital stay. However, it should be noted that an analysis of the postoperative hospital stay is difficult because of the different institutional standards applied in different hospitals. Nevertheless, our results suggested a strong possibility of using SIRS in clinical research to predict the postoperative hospital stay. In the current study, because there were an insufficient number of cases with complications, we could not investigate whether SIRS can be used to predict the occurrence of surgical complications. Further study is needed to address this issue in the future. In conclusion, our results demonstrated that postoperative SIRS reflected the surgical stress, especially due to thoracotomic procedures, through IL-6 levels and affected the duration of the postoperative hospital stay in patients who underwent thoracic surgery. Therefore, SIRS is potentially useful as a simple evaluation system for surgical stress in the field of thoracic surgery.
References [1] Licker M, Spiliopoulos A, Frey JG, et al. Management and outcome of patients undergoing thoracic surgery in a regional chest medical enter. Eur J Anaesthesiol 2001;18:540 - 7. [2] Stephan F, Boucheseiche S, Hollande J, et al. Pulmonary complications following lung resection: a comprehensive analysis of incidence and possible risk factors. Chest 2000;118:1263 - 70. [3] Myrdal G, Gustafsson G, Lambe M, et al. Outcome after lung cancer surgery. Factors predicting early mortality and major morbidity. Eur J Cardiothorac Surg 2001;20:694 - 9. [4] Ruffini E, Parola A, Papalia E, et al. Frequency and mortality of acute lung injury and acute respiratory distress syndrome after pulmonary resection for bronchogenic carcinoma. Eur J Cardiothorac Surg 2001; 20:30 - 6. [5] Karayiannakis AJ, Makri GG, Mantzioka A, et al. Systemic stress response after laparoscopic or open cholecystectomy: a randomized trial. Br J Surg 1997;84:467 - 71. [6] Fukushima R, Kawamura YJ, Saito H, et al. Interleukin-6 and stress hormone responses after uncomplicated gasless laparoscopic-assisted and open sigmoid colectomy. Dis Colon Rectum 1996;39:S29 - S34. [7] Tschernko EM, Hofer S, Bieglmayer C, et al. Early postoperative stress: video-assisted wedge resection/lobectomy vs conventional axillary thoracotomy. Chest 1996;109:1636 - 42. [8] Baigrie RJ, Lamont PM, Kwiatkowski D, et al. Systemic cytokine response after major surgery. Br J Surg 1992;79:757 - 60. [9] Cruickshank AM, Fraser WD, Burns HJG, et al. Response of serum interleukin-6 in patients undergoing elective surgery of varying severity. Clin Sci 1990;79:161 - 5. [10] Oka Y, Murata A, Nishijima J, et al. Circulating interleukin 6 as a useful marker for predicting postoperative complications. Cytokine 1992;4:298 - 304. [11] Sakamoto K, Arakawa H, Mita S, et al. Elevation of circulating interleukin 6 after surgery: factors influencing the serum level. Cytokine 1994;6:181 - 6. [12] Pullicino EA, Carli F, Poole S, et al. The relationship between the circulating concentrations of interleukin 6 (IL-6), tumor necrosis factor (TNF) and the acute phase response to elective surgery and accidental injury. Lymphokine Res 1990;9:231 - 8.
Systemic inflammatory response syndrome and surgical stress in thoracic surgery [13] Leung KL, Lai PB, Ho RL, et al. Systemic cytokine response after laparoscopic-assisted resection of rectosigmoid carcinoma: a prospective randomized trial. Ann Surg 2000;231:506 - 11. [14] Nishiguchi K, Okuda J, Toyoda M, et al. Comparative evaluation of surgical stress of laparoscopic and open surgeries for colorectal carcinoma. Dis Colon Rectum 2001;44:223 - 30. [15] Members of the American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference: definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med 1992;20:864 - 74. [16] Pittet D, Rangel-Frausto S, Li N, et al. Systemic inflammatory response syndrome, sepsis, severe sepsis and septic shock: incidence, morbidities and outcomes in surgical ICU patients. Intensive Care Med 1995;21:302 - 9. [17] Smail N, Messiah A, Edouard A, et al. Role of systemic inflammatory response syndrome and infection in the occurrence of early multiple organ dysfunction syndrome following severe trauma. Intensive Care Med 1995;21:813 - 6. [18] Yim APC, Wan S, Lee TW, et al. VATS lobectomy reduces cytokine responses compared with conventional surgery. Ann Thorac Surg 2000;70:243 - 7. [19] Nagahiro I, Andou A, Aoe M, et al. Pulmonary function, postoperative pain, and serum cytokine level after lobectomy: a comparison of VATS and conventional procedure. Ann Thorac Surg 2001;72:362 - 5. [20] Haga Y, Beppu T, Doi K, et al. Systemic inflammatory response syndrome and organ dysfunction following gastrointestinal surgery. Crit Care Med 1997;25:1994 - 2000. [21] Harkki-Siren P, Sjoberg J, Toivonen J, et al. Clinical outcome and tissue trauma after laparoscopic and abdominal hysterectomy: a randomized controlled study. Acta Obstet Gynecol Scand 2000;79: 866 - 71. [22] Grande M, Tucci GF, Adorisio O, et al. Systemic acute-phase response after laparoscopic and open cholecystectomy. Surg Endosc 2002;16:313 - 6.
Commentary Systemic inflammatory response syndrome and complications after surgery In this edition of the Journal, Takenata and colleagues report data on the clinical usefulness of postoperative systemic inflammatory response syndrome (SIRS) as an index of surgical stress in patients undergoing thoracic surgery [1]. They conclude that (a) SIRS reflect the degree of surgical stress and (b) the SIRS criteria might be useful as an evaluation system to assess the severity of postoperative stress after thoracic surgery. Despite some problems with this study, evidence exists to support this notion. It is becoming apparent that cross talk occurs between the neuroendocrine and immune systems, and it is plausible that the postoperative stress response is a blow-levelQ clinical manifestation of SIRS. The response to surgical stress is mediated by a complex interaction between the nervous, endocrine, immune, and hematopoietic systems [2]. Tissue trauma, hypovolemia, and pain set off a neuroendocrine reflex characterized by the secretion of corticotropin, endorphins, growth hormones,
53
vasopressin, and prolactin [2,3]. Activation of the sympathetic system increases plasma levels of catecholamines, whereas increases in cortisol and aldosterone levels follow activation of the renin-angiotensin system [4-6]. These changes induce a state of catabolism, insulin resistance, increased metabolic rate, and sodium and water retention [5-7]. The intensity of the response varies with the severity of the insult and can be attenuated by various anesthetic and surgical techniques [5,8-12]. Adequate pain control seems to play an important role [13,14]. It has become clear that the postoperative stress response is related to neural input from surgical wounds and cytokines released during and after surgery [3,6]. Various cytokines have been implicated, but interleukin 6 appears to be the major mediator. Interleukin 6 levels correlate with numerous factors, including surgical issues (type of surgery, duration, volume of blood loss, complications), increases in metabolic rate, levels of stress hormones, and C-reactive protein concentration [6,9,11,15-17]. Other molecules such as p55, p75, and phospholipase A2 are further markers of the degree of surgical stress [18]. Fever due to a regulated elevation in core temperature set point also occurs after surgery [19]. Systemic inflammatory response syndrome is insult dependent and is common after surgery. The concept of SIRS was first explored in 1991 at a consensus conference of the American Society of Chest Physicians and the Society of Critical Care Medicine, where the similarities between the clinical and pathophysiological parameters of infectious and noninfectious etiologies were recognized [20]. The clinical manifestations of SIRS include abnormalities of temperature, heart and respiratory rate, and white blood cell count. Sepsis is defined as SIRS plus a documented infection, and severe sepsis as sepsis associated with organ dysfunction, hypoperfusion, or hypotension, whereas septic shock is sepsis-induced hypotension and hypoperfusion despite fluid resuscitation. The incidence of postoperative SIRS varies, but high rates have been reported. For example, Pittet and colleagues [21] reported a 93%, 49%, and 16% incidence of SIRS, sepsis, and severe sepsis, respectively, in patients admitted to a surgical intensive care unit (ICU). Interestingly, an increasing prevalence of organ dysfunction is seen with the fulfillment of increasing numbers of the SIRS criteria, whereas the presence of SIRS shows a positive association with mortality, organ failure, and Acute Physiology and Chronic Health Evaluation III [22,23]. Rangel-Frausto et al [22] prospectively defined the epidemiology of SIRS, sepsis, severe sepsis, and septic shock in 3708 medical, surgical, and cardiothoracic surgery patients. They also tested the hypothesis that the different stages (SIRS, sepsis, severe sepsis, and septic shock) represent an increasing level of severity of the systemic response to infection, rather than an increasing severity of infection. First, in the surgical, medical, and cardiovascular ICUs, the syndromes occurred at a rate of 857, 804, and