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Anesth Analg 2002;95:9-18
© 2002 International Anesthesia Research Society

CARDIOVASCULAR ANESTHESIA

Myocardial Ischemia and Cytokine Response Are Associated with Subsequent Onset of Infections After Noncardiac Surgery

Claudia D. Spies, MD*, Hartmut Kern, MD*, Torsten Schröder, MD*, Michael Sander, MD*, Henning Sepold, MD*, Philip Lang, MD*, Karl Stangl, MD{dagger}, Steffen Behrens, MD{ddagger}, Pranav Sinha, MD§, Walter Schaffartzik, MD||, Klaus-Dieter Wernecke, PhD, Wolfgang J. Kox, MD, PhD*, and Uday Jain, MSIT, PhD, MD#

Departments of *Anesthesiology and Intensive Care Medicine and {dagger}Cardiology and §Institute of Clinical Chemistry and Pathological Biochemistry, University Hospital Charité, Campus Charité Mitte, Humboldt-University, Berlin, Germany; {ddagger}Department of Cardiology, University Hospital Benjamin Franklin, Free University, Berlin, Germany; ||Department of Anesthesiology and Intensive Care Medicine, Unfallkrankenhaus Berlin-Marzahn, Berlin, Germany; ¶Department of Medical Biometry, Humboldt University Berlin, Germany; and #Department of Anesthesiology, Stanford University School of Medicine Partner, SFA Medical Group, Hillsborough, California

Address correspondence and reprint requests to Prof. Dr. med. Claudia D. Spies, Klinik für Anaesthesiologie und Operative Intensivmedizin, Universitätsklinik Charité, Campus Charité Mitte, Humboldt-Universität zu Berlin, Schumannstr. 20/21, 10117 Berlin, Germany. Address e-mail to claudia.spies{at}charite.de


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Postoperative myocardial ischemia (POMI) is prevalent among patients after major noncardiac surgery. Surgery, as well as POMI, may modulate the immune system, potentially worsening patient outcome. We sought to investigate the modulation of soluble interleukin (IL)-6 and IL-10 by POMI and its association with increased postoperative infection rates. Two-hundred-three patients undergoing elective major abdominal, vascular, and orthopedic surgery participated in this prospective observational study. Perioperative management was standardized. Hemodynamic variables were kept within 20% of baseline. POMI was assessed by Holter electrocardiography starting at least 8 h before the induction of anesthesia and continued until 96 h after surgery. Twelve-lead electrocardiograms, cardiac enzymes, and immune variables were obtained at the time of admission to the hospital, before surgery, before the induction of anesthesia, after surgery, at the time of admission to the intensive care unit, and 6, 12, 18, 24, 36, 48, 72, 96, 120, 144, and 168 h after surgery. Infections were diagnosed according to the Centers for Disease Control criteria. The incidence of POMI was 27%, and the majority of cases (76%) occurred within the first 24 h after surgery. IL-6 and IL-10 levels significantly increased during surgery but did not differ between the POMI and Non-POMI groups. However, in the subset of patients who developed severe infections or sepsis (n = 47) a median of 3 days (range, 1–8 days) after surgery, the intraoperative increases of IL-6 and IL-10 in the POMI group were, respectively, 3 and 10 times higher compared with the increase in the Non-POMI group. By using a multifactorial analysis in these patients with severe infections, the type of surgical trauma was associated with an increased IL-6 response, whereas the increase in IL-10 was attributed to POMI. These findings suggest that immediate cytokine responses due to POMI and type of surgery might be relevant for the later onset of severe infections and sepsis.

IMPLICATIONS: Postoperative myocardial ischemia (POMI) occurred in 27% of patients after major noncardiac surgery. This was associated with an immediate augmented cytokine response in the first 12 h after surgery in patients who developed severe infections or sepsis 3 days later. POMI was associated with an increased interleukin (IL)-10 response, whereas IL-6 was associated with the type of surgery.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Perioperative immune responses to surgical trauma and other stressors are reported to be associated with proinflammatory cytokines and the induction of antiinflammatory reactions. Interleukin (IL)-6 plays an important role in host inflamma- tory responses, whereas IL-10 is linked to the suppression of cellular immunity. An increase in IL-6 and IL-10 has been reported after different types of surgery, including major orthopedic, thoracoabdominal, and abdominal procedures (1–3). IL-6 was reported early after surgery, whereas IL-10 has been reported in the later course (2). An IL-6 increase after injury is reportedly associated with more severe trauma (4). After abdominal surgery (5) and in major vascular surgery, immediate postoperative IL-6 increases were reported (6,7). Immediate increases of IL-10 levels were reported in the context of intraoperative blood loss after abdominal surgery (3), whereas in patients after cholecystectomy, IL-10 increases were not observed (5).

Some of the cytokine responses observed during surgery are very similar to changes observed with myocardial ischemia. The association of perioperative cytokine changes with myocardial ischemia has not been investigated. Increases in IL-6 and IL-10 are reported in patients with variant angina and acute myocardial infarction (MI) and in patients at risk of MI (8–13). The degree of IL-6 release depends on the severity of angina (14,15). In patients with unstable angina, the frequency of detectable levels of IL-6 was 61%, whereas it was only 21% in patients with stable angina (14). Plasma IL-6 concentrations were significantly larger in patients with unstable angina and acute MI compared with those in patients with stable angina. The levels were higher in patients with acute MI than in patients with unstable angina (15). IL-10 levels were closely correlated with the severity of hemodynamic derangement in acute MI (13). Endogenous IL-10 was reported to decrease the production of nitric oxide (NO), which may decrease the perfusion of the coronary arteries and may increase the risk of developing postoperative myocardial ischemia (POMI) (16).

In a previous study, an early postoperative increase in IL-6 levels due to abdominal sepsis was reported after surgery. Because this increase occurred before the development of hypotension, a relationship between the kinetics of this cytokine and the observed hemodynamic instability was proposed (17). Different early proinflammatory cytokine responses, as well as exaggerated increases in IL-10, are associated with later onset of infections (18–21). In a previous study, second to the Acute Physiology and Chronic Health Evaluation II score, either IL-6 or IL-10 concentration was considered the most reliable variable for stratification of patients in future studies of severe Gram-negative sepsis (22). The aim of this study was to investigate perioperative soluble IL-6 and IL-10 changes and their association with perioperative myocardial ischemia and postoperative infection.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
After institutional approval and written informed consent of the patients, a prospective observational study of 203 consecutive patients undergoing major elective noncardiac surgery was performed. Prerequisites for a patient’s inclusion in the study were a minimum age of 18 yr and major intraabdominal, vascular, or orthopedic surgery requiring general anesthesia and scheduled for at least 2 h. Coronary artery disease (CAD) was confirmed by the existence of any of the following conditions: 1) a history either of typical angina (as defined by the Canadian Heart Classification system) or atypical angina with an ischemic (electrocardiographic [ECG] or echocardiographic) response to exercise testing, or with scintigraphic evidence of myocardial perfusion defect; 2) a history of MI; 3) new Q wave on ECG typical of MI, with no history of MI; or 4) angiographic evidence of CAD. Patients at risk for CAD did not fulfill these criteria for CAD but had at least three of the following: 1) treated hypertension, 2) hypercholesterinemia (either treated or at least two increased levels >260 mg/dL within the last year), 3) diabetes mellitus, 4) peripheral vascular disease, 5) current smoking, or 6) age >65 yr. Patients who did not fulfill the criteria for CAD or had only two or fewer of the risk factors were considered to be without increased risk and served as controls (23). Patients were excluded from the study if they had conduction defects that precluded ECG analysis of the ST segment or signs of preoperative infection identified by the criteria of the Centers for Disease Control (24).

Demographic data and clinical data were gathered before surgery. Hemodynamic variables, ambulatory (Holter) and 12-lead ECG, cardiac enzymes, and immune variables were recorded. Preoperative cardiac medications were continued until the day of surgery. Premedication consisted of midazolam 0.1–0.15 mg/kg given orally on the day of surgery.

Anesthesia was induced by IV administration of sodium thiopental 3–5 mg/kg and fentanyl 2–4 µg/kg. Anesthesia was maintained by continuous in-fusion of fentanyl 1–2 µg · kg-1 · h-1, nitrous oxide (minimal inspiratory oxygen fraction, 0.3), and isoflurane (end-tidal concentration of up to 1.5%). Vecuronium provided muscle relaxation.

Before the induction of anesthesia, hemodynamic monitoring was established with a radial artery catheter for invasive blood pressure monitoring, arterial blood gas sampling, and hemoglobin determinations. After the induction of anesthesia, a central venous catheter was inserted into the right jugular or right subclavian vein. Heart rate (HR), arterial blood pressure (systolic and diastolic), and central venous pressure were continuously monitored and recorded (Solar 8000; Marquette Hellige, Freiburg, Germany). Arterial oxygen saturation was continuously monitored by pulse oximetry. Inspired oxygen fraction and end-tidal isoflurane concentration, as well as end-tidal CO2, were measured (Solar 8000). Additional monitoring in all patients included esophageal temperature and tidal volume measurements.

Mean arterial blood pressure (MAP) and HR were kept within 20% of preoperative baseline values, which were taken out of the medical record, on admission to the hospital and measured on inclusion in the study, by the prespecified use of cardiovascular drugs and prespecified changes in anesthetic management. The first step to treat hemodynamic abnormalities was to alter anesthetic concentrations. After this, tachycardia with concomitant hypertension was treated with a ß-blocker, hypertension with urapidil, and bradycardia with atropine or, when necessary, orciprenaline. Hypotension was treated first with IV fluids as necessary to keep central venous pressure within a normovolemic range and subsequently, if needed, with dopamine or norepinephrine. Prophylactic use of nitrates and other drugs to prevent ischemia was prohibited. Nitroglycerine was used only to treat myocardial ischemia documented by ST segment changes on the monitor. The ST segment was observed continuously with ECG monitoring, which was routinely used during surgery (Solar 8000).

After surgery, clinical data (APACHE II score and infections, including pneumonia) were documented. Infections were diagnosed according to Centers for Disease Control criteria (24). For the diagnosis of pneumonia, a radiomorphological infiltrate was mandatory. Hemodynamic, ECG, and laboratory measurements were taken on admission to the hospital; at the time of patient screening; before the induction of anesthesia; on admission to the intensive care unit (ICU); at 6, 12, 18, and 24 h after surgery; at 36 and 48 h after surgery; and 3, 4, 5, 6, and 7 days after surgery.

Patients were monitored with a three-channel Holter echocardiograph (Cardio Corder; Medratec Inc., Ludwigsburg, Germany) beginning at least 8 h before the induction of anesthesia and continuing up to 96 h after surgery. After 96 h, only serial measurements at the previously mentioned times were taken. The mean time that Holter monitoring began before surgery was 7.2 h (range, 6–8 h). The monitoring was continued after surgery for a mean time of 91 h (range, 81–96 h) after surgery. Bipolar leads (CC5, CM5, ML) were used. Recordings were evaluated by using a commercial analysis system (Strata Scan Model 563; Medratec Inc.). A blinded cardiologist and a trained anesthesiologist verified any episode identified by the computer algorithm.

Episodes of POMI were defined as 1) horizontal or downsloping ST segment depression from baseline of >=1 mm, lasting at least 1 min, and separated from other episodes by >=1 min; or 2) ST segment increase from baseline >=2 mm, measured 60 ms after the J point, lasting at least 1 min, and separated from other episodes by >=1 min. The 12-lead ECG taken at each serial measurement was used to detect ischemia if Holter monitoring was not available.

MI was diagnosed if any of the following three conditions occurred: 1) new Q wave on a postoperative 12-lead ECG, as determined by application of the Minnesota Code criteria (25) (1-1 to 1-3) and analysis by a cardiologist; 2) myocardial bands (CK-MB) >10% creatine kinase (CK) if CK exceeded 80 U/L ("cardiac index") (26), or troponin T >0.2 µg/L (26) plus clinical or ECG signs of acute MI at any time after surgery; or 3) acute MI diagnosed on autopsy.

Troponin T was analyzed by the enzyme-linked immunosorbent assay technique (Enzymun-TestTM, batch ELISA ES 300 analyzer; Boehringer Mannheim Inc., N-acetylcysteine [NAC] Mannheim, Germany). CK and CK-MB were determined with an assay for enzyme activity (CK NAC-activated, CK-MB NAC-activated after immunoinhibition; BM/Hitachi 717 analyzer; Boeh- ringer Mannheim Inc.).

All mediators were analyzed at a room temperature of 23°C. The cytokine IL-6 was analyzed by a sandwich enzyme-linked immunosorbent assay by using a commercially available kit (QuantikineTM Immunoassay Kit; R&D Systems, Minneapolis, MN). The detection limit for IL-6 was 0.7 pg/mL. IL-10 was analyzed with a commercially available enzyme immunoassay (TiterZyme® IL-10 enzyme immunoassay kit; PerSeptive Diagnostic, Cambridge, MA). The detection limit for IL-10 was 1.0 pg/mL (microtiterplate reader MR 7000; Dynatech, Inc., Frankenthal, Germany GmbH; standard washer, 812 S W1; SLT Lab Instruments, Inc., Pforzheim, Germany GmbH).

Data are expressed as median and interquartile range. Statistical analysis was performed with the nonparametric analysis of variance (ANOVA)-type rank variance analysis for longitudinal data and small sample sizes (SAS version 8 macros F1_LD_F1 and F2_LD_F1; SAS Institute, Cary, NC) in two- and three-factorial designs, respectively (27). A multivariate logistic regression analysis was performed to identify independent variables associated with perioperative myocardial ischemia. Differences between independent groups were tested by the Kruskal-Wallis test and the Mann-Whitney U-test. Dichotomous variables were analyzed by the exact {chi}2 test. Diagnostic test performance was evaluated by receiver operating characteristic (ROC) analysis. P < 0.05 was considered significant.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Two-hundred-three patients were included in this study. Eighty-two patients (40%) had CAD, and 72 (36%) were at risk for it. One hundred-twenty-four patients (61%) had abdominal surgery, 49 patients (24%) had orthopedic surgery, and 30 patients (15%) had vascular surgery. The median duration of surgery was 180 min (range, 120–285 min).

POMI was detected in 55 patients (27%) during the study period. Weight and alcohol intake were the only characteristics that were different between patients with and without POMI (Table 1). Preoperative nitrate therapy was applied in 41 patients (50%) from the CAD group. Type of surgery significantly differed between groups (Table 2). Duration of surgery was significantly prolonged in patients with POMI (Table 2).


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  		Table 1. Demographic Data and Preoperative Existing Diseases
 

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  		Table 2. Surgery and POMI
 
POMI was not detected before surgery. During surgery, 12 patients (6%) had signs of POMI. On admission to the ICU, POMI was diagnosed in 30 (15%) patients. In the first 24 h after surgery, 42 patients (21%) developed POMI. A total of 261 ischemic episodes were observed (96 h of postoperative Holter monitoring and then serial measurements). For the ischemic episodes, the median ST segment change was -1.9 mm, the median duration was 78 min, and the median ischemic burden was 2.3 min/h. Indeterminate signs, however, were seen in 20 patients (10%) in the preoperative Holter, in 23 patients (11%) in the intraoperative Holter, and in 57 patients (28%) in the postoperative Holter.

Cardiac enzymes were increased after surgery in all patients (all intragroup PANOVA-type statistic < 0.01). Troponin T concentrations of >0.2 µg/L were found in 51 patients, and 156 patients had a CK-MB/CK ratio of >10%. Troponin T was significantly increased in the POMI group (between-group PANOVA-type statistic = 0.03), whereas CK-MB/CK index did not reach statistical significance (between-group PANOVA-type statistic = 0.32). In the POMI group, the mean maximum troponin T value was 0.02 µg/L (range, 0.01–3.29 µg/L), and the mean maximum CK-MB/CK index was 6% (range, 4%–20%). In the patients without POMI, the mean maximum troponin T value was 0.01 µg/L (range, 0.01–0.78 µg/L), and the mean maximum CK-MB/CK index was 4% (range, 1%–8%).

HR remained stable during surgery and was increased at 12, 48, and 72 h after surgery (maximum increase, 20%; intragroup PANOVA-type statistic < 0.01), but it did not differ between patients with and without POMI (between-group PANOVA-type statistic = 0.32). Blood pressures decreased significantly in both groups after the induction of anesthesia and increased again after surgery (maximum decrease, 20%; intragroup PANOVA-type statistic < 0.01). Blood pressures did not differ between groups (between-group PANOVA-type statistic = 0.29).

IL-6 and IL-10 significantly increased during surgery but did not significantly differ between the POMI and Non-POMI groups after all measurements were compared up to the seventh postoperative day (Fig. 1). Among the patients who had severe infection or sepsis, IL-6 and IL-10 were significantly increased in the group with POMI, comparing all measurements up to the seventh postoperative day (Fig. 1). However, in our study, in the first 24 h after surgery, IL-6 was significantly increased in different types of surgery (vascular > abdominal > orthopedic), whereas IL-10 did not differ among these different surgical procedures (Fig. 2). Taking all patients into account, vascular surgery led to the most pronounced increase in IL-6 (P < 0.01) (Fig. 2). Also in patients with vascular surgery, the duration of surgery was significantly prolonged (Table 2). Multifactorial statistical analysis revealed that in patients with severe infections, the surgical trauma influenced the IL-6 level (type of surgery significant [P = 0.03], but not POMI [P = 0.12]), whereas the increase in IL-10 (POMI significant [P < 0.01], but not type of surgery [P = 0.23]) was attributed to POMI. Furthermore, the influence of surgical trauma for IL-6 was enhanced in patients with POMI (interactions significant [P < 0.01]), whereas POMI influenced the IL-10 level, which was most aggravated in patients with vascular surgery (interactions significant [P < 0.01]). The areas under the ROC curve (AUC) showed that the IL-6 (AUC = 0.73) and IL-10 (AUC = 0.60) increases cannot be considered predictive for subsequent severe infections or sepsis among all patients.



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  		Figure 1. Interleukin (IL)-6 and IL-10 in all patients (left) and only in patients with severe infections (right), with and without postoperative myocardial ischemia (POMI). Data are on admission to the hospital, before surgery, and after surgery (6, 12, 18, 24, 36, 48, 72, 96, 120, 144, and 168 h after surgery). Data are median and interquartile range with multivariate analysis of variance (ANOVA)-type statistics.

 


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  		Figure 2. Interleukin (IL)-6 and IL-10 in all patients (left) and only in patients with severe infections (right) with different types of surgery. Data are on admission to the hospital, before surgery, and after surgery (6, 12, 18, 24, 36, 48, 72, 96, 120, 144, and 168 h after surgery). Data are median and interquartile range with multivariate analysis of variance (ANOVA)-type statistics.

 
Patients with POMI had a prolonged ICU and hospital stay (Table 3). Their postoperative morbidity was increased. Four patients in the CAD group with POMI developed MI, compared with zero patients at risk for CAD or controls (P = 0.01). Congestive heart failure was seen in only two patients in the POMI group. Arrhythmias did not differ between groups (9 of 55 vs 24 of 148; P = 0.40). In the POMI group, 22 of 55 patients (40%) and, in the Non-POMI group, 25 of 148 (17%) patients had severe infections (pneumonia and peritonitis, respectively) or sepsis (P < 0.001). Infections or sepsis occurred on a median Day 3 after surgery in both groups (range, 1–6 days in the POMI group; range, 1–8 days in the Non-POMI group; P = 0.36). The incidence of infection or sepsis did not differ among different types of surgery (patients with infection or sepsis in abdominal/orthopedic/vascular surgery versus patients without infection or sepsis in abdominal/orthopedic/vascular surgery, 43/12/11 vs 81/37/19; P = 0.38). In patients with severe infections, there were no differences in the IL-6 levels (PANOVA-type statistic = 0.41) or the IL-10 levels (PANOVA-type statistic = 0.29) among different types of surgery.


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  		Table 3. ICU Admission and Outcome
 
Regression analysis showed that vascular surgery (odds ratio, 6.2; 95% confidence interval, 2.5–15.5) was most predictive for POMI. Age, gender, body mass index, and preoperative diagnosis of CAD were not found to be predictive.

Because the study was conducted in two centers, the distribution of potential confounding factors was compared, with no significant differences identified between centers (Table 4).


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  		Table 4. Comparison of Patient Characteristics Between Study Centers
 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
Among patients who had postoperative severe infection or sepsis, the IL-6 and IL-10 values were, respectively, 3 and 10 times higher in patients who had POMI compared with those who did not have POMI during and in the first 24 hours after surgery. Also, the cytokine response among different types of surgery was significantly enhanced for IL-6. Multifactorial analysis (27) revealed that in patients with severe infections, the type of surgical trauma influenced the IL-6 level, whereas the increase in IL-10 was attributed to POMI. Considering further interactions, the influence of surgical trauma for IL-6 was particularly characteristic in patients with POMI, whereas POMI influenced the IL-10 level particularly in patients with vascular surgery. Thus, the more enhanced cytokine response may increase risk if both vascular surgery and POMI occur (18–22).

POMI occurred in 27% of patients in the postoperative period. This is consistent with the current literature reporting an incidence of POMI from 30% to 60% in CAD patients and patients at risk (28). Intraoperative ischemia was seen in only 6% of patients, whereas immediately after surgery an incidence of 15% was observed. This is supported by previous studies (28,29). Regression analysis in our patients found that vascular surgery was the only independent predictor of POMI. Bleeding complications are independently associated with a worse cardiac outcome (29). This association was not validated by regression analysis in our study. The hemoglobin level may be difficult to interpret because all patients with a hemoglobin value of <8 mg/dL received packed red blood cells to achieve a hemoglobin level of 10 mg/dL. This is considered without increased risk (30). In our study we did not find any other variable, such as sex, increased age, or current smoking, to be predictive for POMI. This finding might be due to the insufficient power of our study for the evaluation of these variables.

Cytokine response did not significantly differ between patients with and without POMI. IL-6 immediately increased after surgery and remained increased in the first 24 hours. It decreased in the following 72 hours. In the first 24 hours after surgery, IL-6 was significantly increased in different types of surgery (vascular > abdominal > orthopedic). Surgical trauma is reported to increase IL-6 early after surgery (1–3,5–7). The maximum release is reported in the first 24 hours (1–3,5–7). The significantly increased levels of IL-6 might point to an increased surgical trauma in these patients (4). This is in accordance with our study and previous studies (6,7), because the type, i.e., vascular surgery, was relevant, and the duration of surgery was prolonged in vascular surgery. Therefore, one can consider vascular surgery as the most relevant trauma for enhanced IL-6 release.

In our study, IL-10 did not differ between patients with and without POMI, considering all patients. In addition, it did not differ among surgical procedures. However, IL-10 peaked immediately after surgery in patients with severe infections and POMI. A multivariate approach revealed that IL-10 was associated with POMI in patients with severe infections. Because the interaction between POMI and vascular surgery for the IL-10 response in patients with severe infections was also highly statistically significant, an increased IL-10 response in patients with POMI may be an indicator of a worse outcome, because this response occurred before the onset of infection. Immediate increases of IL-10 levels were reported in the context of intraoperative blood loss after abdominal surgery (3). However, blood transfusions were required in only 53 of 203 patients, and the transfusion requirements did not differ between patients with and without POMI. IL-10 levels were closely correlated with the severity of hemodynamic derangement in acute MI (13). Because MAP and HR were kept within 20% of preoperative baseline values and because MAP and HR did not differ between groups, we do not consider this IL-10 response to be related to hemodynamic instability. Therefore, POMI might indicate a second immunological insult in addition to surgery. It is possible that POMI per se does not affect measurable differences in levels of IL-6 or IL-10 due to the postoperative increase of these cytokines (1–3). However, in the context of a beginning infection, or in patients at risk of developing an infection (e.g., because of perioperative immune suppression), POMI might trigger a measurable cytokine response in these patients.

Proinflammatory release has been reported during myocardial ischemia unrelated to surgery (8–13). The degree of IL-6 release was considered to be dependent on the severity of angina (14,15). However, the postoperative IL-6 increase shown in patients with POMI and severe infection was not seen in the multivariate analysis. This may be because the proinflammatory response to surgery per se (1–3,5–7) may hide the proinflammatory response to POMI (8–13).

All MIs occurred in CAD patients who were not treated with nitrates before surgery. Comparing patients with (n = 41) and without (n = 162) preoperative nitrates, IL-6 did not differ between groups (P = 0.25). However, IL-10 was significantly decreased in patients without nitrates from 6 until 48 hours after surgery (P = 0.02). Endogenous IL-10 inhibits the production of NO and serves to protects the ischemic and reperfused myocardium through the suppression of neutrophil recruitment (16), but it may also decrease perfusion in relevant areas. Of 92 studies that have examined the role of NO in modulating the severity of ischemia/reperfusion injury in nonpreconditioned myocardium, the majority (67; 73%) have concluded that NO (either endogenous or exogenous) has a protective effect, and only 11 (12%) found a detrimental effect. The proportion of studies supporting a cytoprotective role of NO is similar in vivo (35 of 49 [71%]) and in vitro (32 of 43 [74%]). With regard to the delayed acquisition of tolerance to ischemia (late preconditioning), overwhelming evidence indicates a critical role of NO in this phenomenon. A decade of research demonstrates that NO plays a fundamental biological role in protecting the heart against ischemia/reperfusion injury (31). In perfused guinea-pig Langendorff hearts subjected to ischemia and reperfusion, NO exogenously supplied by a specific NO donor, FK409, was responsible for the cardioprotective action (32).

Despite the fact that ROC curves were not sufficiently predictive for severe infections or sepsis 12 hours after surgery (in a study not designed to detect such a difference), the cytokine responses may be much more relevant for postoperative infections than expected, in case of IL-6 with respect to the type of surgery and in case of IL-10 due to POMI. Different early proinflammatory cytokine responses, as well as exaggerated increases in IL-10, are associated with later onset of infections (18–22).

Patients who developed POMI had a more frequent postoperative morbidity and mortality. Four patients developed MIs in the POMI group. This is in the range of the 1.8% reported in patients with and without CAD (33). However, rates up to 15% were observed in patients undergoing vascular surgery (34). Because all events in this study (4 of 30; 13%) occurred in vascular surgery patients, this is also consistent with the current literature (34).

In a retrospective study involving 8700 patients undergoing general surgery (35), the main cause of death in cardiac risk patients was infection. In our study, 7 of 9 patients (78%) died in the POMI group because of severe infections or sepsis, and 5 of 10 patients (50%) in the group without POMI (P = 0.32) died. However, the incidence of severe infections or sepsis was significantly increased in the POMI group. The incidence of pneumonia was 13 of 55 (24%) in the POMI group, whereas it was 15 of 148 (10%) in the patients without POMI (P < 0.01). The overall pneumonia rate (28 of 203; 14%) was in the range reported previously in intubated and ventilated ICU patients (36). The incidence of peritonitis was nine in each group; however, only five proceeded to septic shock in the Non-POMI group, compared with eight patients in the POMI group. The incidence of peritonitis (18 of 154; 12%) due to abdominal and vascular surgery was in the range published in the literature (37). The different intraoperative cytokine liberation in the POMI group may have been related to endotoxin liberation due to ischemic episodes (38). However, it cannot be excluded that the increased incidence of severe infections and sepsis in the POMI group was also related to preoperative alcohol abuse. Preoperative alcoholism increases the risk for severe infections three- to fourfold and the risk for POMI threefold (39).

Holter monitoring was performed only in the first 96 hours. Therefore, we may have missed relevant ischemic episodes after 96 hours. Previous studies show that mass concentrations of soluble CK-MB have both higher sensitivity and specificity than catalytic measurements (40). This may account for lower MB fractions in this study. Concentrations of the cardiac-specific proteins troponin T and troponin I in blood increase only from four to six hours after the onset of chest pain. Therefore, rapid increases may have been missed in the investigated patients.

There were 47 patients with severe infections. Therefore, studies with a larger number of patients and interventions are needed to elucidate the clinical importance of cytokine responses in POMI and subsequent infection and to develop strategies to treat patients at risk.

In conclusion, among patients with postoperative severe infections or sepsis on a median of 3 days after surgery, IL-6 and IL-10 responses were significantly higher in patients with POMI compared with those without POMI during surgery and in the first 24 hours after surgery. The type of surgical trauma influenced the IL-6 level in patients with severe infections, whereas the increase in IL-10 was attributed to POMI. Furthermore, the influence of surgical trauma for IL-6 was particularly characteristic in patients with POMI, whereas POMI influenced the IL-10 level particularly in patients with vascular surgery. Therefore, the more enhanced cytokine response may increase risk if vascular surgery and POMI occur, and this suggests that ischemic episodes in the immediate perioperative period might be clinically relevant for the development of these postoperative complications.


   Acknowledgments
 
Supported by departmental funding and institutional research grants of the Benjamin Franklin and Charité Medical Schools.

We thank Andreas Lorenz, MD, Department of Gynecology and Obstetrics, and Simone Hilscher, MD, Department of Anesthesiology and Intensive Care, Ernst-von-Bergmann Medical Center, Potsdam, Germany; and Jonas Teubner, MD, Department of Neurology, Medical Academy, Erfurt, Germany, who performed the pilot study to this investigation in the form of their doctoral thesis in our department, as well as Isabel Hass, MD, Department of Anesthesiology and Intensive Care Medicine, Unfallkrankenhaus-Berlin Marzahn, Berlin, Germany, for her clinical support with the pilot study. Also we thank Tanja Schink, Dipl.-Stat., Department of Medical Biometry, Humboldt University Berlin, Germany, for the multivariate analysis of the data and the detailed statistical advice for analyzing the data.


   Footnotes
 
Presented in part at the annual meeting of the American Society of Anesthesiologists, San Francisco, CA, October 14–18, 2000.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication February 28, 2002.




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