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Anesth Analg 2007;104:1334-1342
© 2007 International Anesthesia Research Society
doi: 10.1213/01.ane.0000264108.47280.f5

CARDIOVASCULAR ANESTHESIA

The Effects of Morphine and Fentanyl on the Inflammatory Response to Cardiopulmonary Bypass in Patients Undergoing Elective Coronary Artery Bypass Graft Surgery

Glenn S. Murphy, MD, Joseph W. Szokol, MD, Jesse H. Marymont, MD, Michael J. Avram, PhD, and Jeffery S. Vender, MD

From the Department of Anesthesiology, Evanston Northwestern Healthcare, Northwestern University Feinberg School of Medicine, Illinois.

Address correspondence and reprint requests to Glenn S. Murphy, MD, Department of Anesthesiology, Evanston Northwestern Healthcare, 2650 Ridge Ave., Evanston, Illinois 60201. Address e-mail to dgmurphy2{at}yahoo.com.


   Abstract
Top
 Abstract
Introduction
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
BACKGROUND: Experimental data suggest that morphine has unique antiinflammatory properties. We hypothesized that morphine, when compared with fentanyl, would attenuate the perioperative inflammatory response to cardiopulmonary bypass (CPB) when administered as part of a balanced anesthetic technique.

METHODS: Thirty patients undergoing elective coronary artery bypass graft surgery were randomized to receive, in a double-blind manner, either morphine (40 mg) or fentanyl (1000 µg) as part of a standardized opioid-isoflurane anesthetic. Serum concentrations of interleukin (IL)-6 and IL-8 and expression of neutrophil surface adhesion molecules (CD 11a, CD 11b, CD 11c, and CD 18) were measured perioperatively as indicators of the inflammatory response to surgery. Core temperatures were monitored in the intensive care unit to determine the incidence of postoperative hyperthermia (temperature >38.0°C).

RESULTS: IL-6 and IL-8 concentrations increased in all patients after CPB. The increase in serum IL-6 levels was significantly attenuated in the morphine group compared to the fentanyl group at 3 and 24 h post-CPB (P < 0.05). Reductions in expression of neutrophil adhesion molecules were observed in both groups 15 min and 3 h post-CPB; however, a significantly larger reduction in CD 11b and CD 18 expression was noted in patients receiving morphine (P < 0.05). The incidence of postoperative hyperthermia was more frequent in the fentanyl group (73%) compared to the morphine group (0%, P < 0.05).

CONCLUSIONS: Compared with fentanyl, the administration of morphine as part of balanced anesthetic technique suppressed several components the inflammatory response (IL-6, CD 11b, CD 18, postoperative hyperthermia) to cardiac surgery and CPB.


   Introduction
Top
 Abstract
 Introduction
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The initiation of cardiopulmonary bypass (CPB) results in the induction of a systemic inflammatory response that has been associated with postoperative organ dysfunction and injury (1–3). There is scant evidence from clinical trials that choice of anesthetic technique can influence the inflammatory response to cardiac surgery (3). Experimental data, however, suggest that morphine has potent immunoregulatory properties, and may attenuate inflammatory processes related to CPB (4). In cell culture models, morphine selectively inhibits inflammatory cell activation. The pretreatment of activated granulocytes and macrophages with morphine results in a significant reduction in phagocytosis, cytokine production (interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF)), and the expression of adhesion molecules (5–7). Pretreatment of monocytes and granulocytes with morphine significantly attenuated the hyperstimulation observed in these cells after exposure to plasma obtained from patients post-CPB (8). In a pig model of CPB, the administration of morphine significantly diminished activation levels of monocytes and granulocytes (9). The immunoregulatory properties of morphine appear to be mediated by the µ3 morphine-selective receptor (4). Fentanyl, a commonly used opioid in the perioperative setting, does not bind to the µ3 receptor, and does not appear to downregulate inflammatory cell function in cell models (10–12) or in humans after surgery (13).

On the basis of these laboratory studies, several reviews have suggested that morphine may modify inflammatory processes and may "be beneficial to patients undergoing cardiac surgery" (4,14). The impact of choice of opioid on perioperative inflammatory processes has not been assessed in the clinical setting. We hypothesized that the use of morphine as part of a balanced anesthetic technique would diminish the inflammatory reaction that occurs after CPB compared with fentanyl.


   METHODS
Top
 Abstract
 Introduction
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Subjects and Study Design
This study was approved by the IRB of Evanston Northwestern Healthcare and written informed consent was obtained from all subjects. Thirty patients presenting for elective primary coronary artery bypass graft surgery were eligible for enrollment. Exclusion criteria included: 1) reoperative procedures; 2) concurrent valvular surgery or the presence of valvular disease; 3) ejection fraction <40%; 4) the need for an intraaortic balloon pump or inotropic drugs preoperatively; 5) chronic renal insufficiency (creatinine >1.6 mg/dL) or chronic renal failure requiring dialysis; 6) preoperative use of steroids; 7) age <18 or >80 yr; and 8) weight 50% above or below ideal body weight. Patients were randomized to receive either morphine (morphine group) or fentanyl (fentanyl group) using a computer-generated randomization code. The operating room pharmacy was provided with the randomization assignment, and the study opioid was prepared in sequentially numbered, identical-appearing clear plastic bags. Either 40 mg of morphine or 1000 µg of fentanyl was added to 100-mL bags of normal saline (total volume 100 mL). All care providers were blinded to group assignment throughout the perioperative period.

All cardiac medications were continued until the morning of surgery. In both groups, premedication consisted of midazolam 1-3 mg. Peripheral IV and arterial access was established using local anesthesia. In addition to standard intraoperative monitoring, a pulmonary artery catheter and a transesophageal echocardiography probe were placed after tracheal intubation. Induction of anesthesia consisted of thiopental 2-4 mg/kg, midazolam 2-4 mg (total 5 mg before incision), and rocuronium 0.6-1.0 mg/kg. At anesthesia induction, one-half of the study opioid dose (20 mg of morphine or 500 µg of fentanyl) was administered over 5 min. The infusion pump was then programmed to deliver the study opioid at a rate of 8 mL/h (morphine 3.2 mg/h or fentanyl 80 µg/h), and the infusion continued until the total dose of opioid was administered. Anesthesia was maintained pre- and post-CPB using isoflurane 0.4%-3.0%, which was titrated to maintain bispectral index (BIS) values between 40 and 60 and systemic blood pressures within 25% of baseline values. End-tidal isoflurane concentrations were recorded at 10-min intervals. Neuromuscular blockade was maintained with rocuronium. Hypertension was treated by increasing the concentration of isoflurane or with nitroglycerine or nitroprusside, as appropriate. Hypotension was corrected with intravascular volume replacement or phenylepherine, as indicated.

All patients underwent a median sternotomy and CPB. Aminocaproic acid (5 g before skin incision, 5 g on initiation of CPB, and 1 g/h throughout the procedure) was administered to all subjects; no other antifibrinolytics were used. An initial dose of 300 U/kg of heparin was used to obtain an activated clotting time >400 s before CPB. The CPB circuit (Medtronic, Minneapolis, MN) consisted of a membrane oxygenator, a 40-µm arterial line filter, a centrifugal pump, and crystalloid prime. Moderate hypothermic CPB (28-32°C) was used in all patients. Cardiac arrest was achieved and maintained using cold antegrade/retrograde (4°C) blood cardioplegic solution. Mean blood pressures of 50-70 mm Hg and blood flows of 2.4-2.8 L · min–1 · m–2 were maintained during CPB. Isoflurane 0.5%-0.75% was administered during the entire period of CPB and was titrated to mean blood pressures (50-70 mm Hg) and BIS values of 40-60. Hematocrit was kept above 21% on CPB and above 27% postoperatively by transfusion of packed red blood cells. Cell salvage techniques were used in both groups. Insulin infusions were initiated for blood glucoses >150 mg/dL throughout the perioperative period. All patients were rewarmed to a bladder temperature of 37°C before separation from CPB. An additional 5 mg of midazolam was administered during rewarming. Inotropic drugs were used for a cardiac index <2.0 L · min–1 · m–2 or for clinical evidence of inadequate cardiac function. Propofol infusion (25-75 µg · kg–1 · min–1) was started during sternal closure and was continued until the time ventilatory weaning was initiated in the intensive care unit (ICU). Weaning of ventilatory support and tracheal extubation were performed using clinical criteria.

Hemodynamic data were collected at several times in the perioperative period: immediately preinduction; 10 and 30 min postinduction; 15, 30, and 60 min post-CPB; upon ICU admission; and 3 h after ICU admission. Hemodynamic data included heart rate, mean arterial blood pressure, mean pulmonary artery pressure, central venous pressure, cardiac index, and systemic vascular resistance index. Cardiac output was measured in triplicate by thermodilution and the mean value recorded. Temperature was measured from the pulmonary artery catheter at the conclusion of the surgical procedure, on arrival to the ICU, and every 2 h for the next 12 h in the ICU. Postoperative hyperthermia was defined as a core temperature >38.0°C. Other variables recorded included age, height, weight, preexisting medical conditions, preoperative medications, fluid and blood transfusion administration, duration of CPB, aortic cross-clamp, and surgical procedure, intraoperative arrhythmias and treatments, vasoactive drug administration, duration of tracheal intubation, and the duration of hospitalization in the ICU and on the postoperative ward. All postoperative complications were assessed and recorded by one of two nurse practitioners on the cardiac surgical service. Complications were defined as: respiratory (postoperative pneumonia or tracheal intubation >24 h); cardiac (atrial fibrillation on a postoperative electrocardiogram, heart failure (requirement for inotropic support >24 h or the need for an intraaortic balloon pump), or myocardial infarction (new Q-waves on a postoperative electrocardiogram); neurologic (new central neurologic deficit, postoperative delirium, or coma); renal (renal failure requiring dialysis or an increase in serum creatinine by more than 50% above baseline levels); and infection (wound infection requiring therapy or sepsis).

Inflammatory Markers
Blood samples for cytokines (IL-6 and IL-8) and adhesion molecules (CD 11a, CD 11b, CD 11c, CD 18) were drawn immediately after induction of anesthesia (baseline), 15 min post-CPB, 3 h post-CPB, and 24 h after baseline measurements. All samples were obtained from the arterial catheter and processed within 10 min to minimize ex vivo stimulation. Serum samples for IL-6 and IL-8 were collected into EDTA glass tubes and then centrifuged and stored at –20°C. IL-6 and IL-8 levels were measured using an enzyme-labeled sequential immunometric assay (chemiluminescent technique, DPC Immulite 1000, Diagnostic Products Corporation, Los Angeles, CA). The lower limit of detection for IL-6 and IL-8 was 2 pg/mL. Neutrophil adhesion molecule expression was determined by immunofluorescent staining of whole blood and flow cytometry. Samples were immediately placed into heparin-containing tubes. Duplicate aliquots of whole blood (100 µL) were incubated in the dark for 30 min with 20 µL of FITC- or PE-labeled monoclonal antibodies (IgG1 FITC, CD 11a FITC, CD 18, CD 11b PE, CD 11c PE, BD Biosciences). Red blood cells were lysed and leukocytes fixed using FACS Lysing Solution (Becton Dickinson). The sample was then centrifuged (400g for 5 min). The cell pellet was washed with a phosphate-buffer saline solution and resuspended in a 1% methanol-free formaldehyde solution. Neutrophil CD 11a, CD 11b, CD 11c, and CD 18 expression was measured using a FACScan flow cytometer (Becton Dickinson). Neutrophil cell populations were identified by their characteristic forward and side scatter profiles. Amplifier gains were calibrated with beads before each experiment. Five-thousand events were acquired for each sample. The neutrophils were analyzed for intensity of fluorescence by mathematically converting the logarithmic mean fluorescence values obtained from the histograms into relative mean fluorescence values. The values reported are as a percentage change from the observed baseline values.

Statistical Analysis
Sample size was based on previous studies examining the peak IL-6 response to cardiac surgery with CPB in subjects receiving fentanyl as a primary opioid (15,16). Two samples of 11 patients each would be required in order to detect a difference of 58 pg/mL between the null hypothesis that both group means are 232 pg/mL and the alternate hypothesis that the mean of the treatment (i.e., morphine) group is 174 pg/mL (i.e., a 25% reduction in peak IL-6 levels in the morphine group) with a known group standard deviation of 48 pg/mL (i.e., a 21% C.V.), a power of 81%, and a significance level ({alpha}) of 0.05 using a two-sided two-sample t-test.

Data are reported as the number of patients, median and range, or mean and standard deviation. Nominal patient data were compared between treatment groups using Fisher’s exact probability test. Ordinal patient data and non-normally distributed continuous data were compared using the Mann-Whitney rank sum test. Normally distributed continuous patient data were compared using the unpaired t-test.

Normally distributed continuous data were compared within groups across time and between groups using a two-factor analysis of variance with repeated measures on one factor. Post hoc pairwise multiple comparisons with baseline were made using the Tukey test.

The cytokine and integrin data were mostly not normally distributed based on the Kolmogorov-Smirnov test for normality of the underlying population. Therefore, these data are reported as median and range. They were compared within groups across time using the Friedman repeated measures analysis of variance on ranks and post hoc pairwise multiple comparisons with baseline were made using the Tukey test. Between group comparisons were made using the Mann-Whitney rank sum test, with the criterion for rejection of the null hypothesis corrected for multiple applications of the test to the same data.

The criterion for rejection of the null hypothesis was P < 0.05.


   RESULTS
Top
 Abstract
 Introduction
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
The two groups were similar in terms of demographic characteristics. There were no differences between groups in body weight, sex, preexisting medical conditions, preoperative ejection fraction, or preoperative medications (although height was greater in the morphine group) (Table 1). Intraoperative management was similar in the two groups, with no significant differences observed in the duration of aortic cross-clamping or CPB, the number of bypasses, the duration of surgery, the need for vasoactive medications, or the administration of crystalloids (Table 2). Mean end-tidal isoflurane concentrations were similar in the two groups from induction of anesthesia until initiation of CPB (0.78% ± 0.34% morphine group; 0.81% ± 0.45% fentanyl group) and from separation of CPB until end of procedure (0.54% ± 0.16% morphine group; 0.56% ± 0.19% fentanyl group). The length of postoperative intubation was similar in the morphine and fentanyl groups, as was the overall duration of the ICU and hospital admission (Table 2). The rate of postoperative complications was low in both groups, with a small incidence of atrial fibrillation (three patients in the morphine group, two patients in the fentanyl group), postoperative heart failure (one in each group), and stroke (one in the fentanyl group). All patients survived until hospital discharge.


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  		Table 1. Patient Characteristics

 

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  		Table 2. Patient Care Data

 

The percentage of patients receiving a red blood cell transfusion, a proinflammatory stimulus, was similar in the morphine (40.0%) and fentanyl (46.7%) groups, as was the median number of units transfused (0 U morphine group, 0 U fentanyl group) during the study period. Hemodynamic data are presented in Table 3. No significant differences between groups were observed in any measured variable during the intraoperative and early postoperative periods.


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  		Table 3. Hemodynamic Data

 

Changes in serum cytokines concentrations are presented in Figures 1 and 2. IL-6 levels increased significantly from baseline values in both groups, peaking at 3 h post-CPB. However, increases in IL-6 were significantly less in the morphine group compared with that in the fentanyl group 3 h post-CPB and at 24 h postinduction (P < 0.05). Serum IL-8 levels were significantly higher than baseline in both groups at all times measured but they did not differ between the groups at any time, perhaps because of our relatively small sample size and the high variability of the data. Changes in the expression of β2 integrins are shown in Figures 3–6. In both the morphine and fentanyl groups, reductions in the expression of the β-chain (CD 18) and all of the {alpha}-units (CD 11a, CD 11b, and CD 11c) from baseline values were observed 15 and 180 min after CPB. Mean fluorescence intensity returned towards baseline values 24 h postinduction. In the morphine group, however, the reduction in CD 11b and CD 18 expression was significantly greater than the values observed in the fentanyl group (P < 0.05), while the reduction in CD 11a was not.


Figure 14
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  		Figure 1. Interleukin-6 (IL-6) concentrations, expressed in pg/mL, for the 15 subjects in each group. The lower boundary of the box indicates the 25th percentile, the line within the box is the median, and the upper boundary of the box indicates the 75th percentile. Whiskers above and below the box indicate the 90th and 10th percentiles. Outlying points are graphed above and below the upper and lower whiskers, respectively. *P < 0.05 when compared with baseline and with 15 min post-CPB within treatment, **P < 0.05 when compared with baseline within treatment, ***P < 0.05 when compared with other treatment at the same time.

 

Figure 34
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  		Figure 3. CD 11a concentrations, expressed as percent change from baseline, for 11 of the subjects in each group. The lower boundary of the box indicates the 25th percentile, the line within the box is the median, and the upper boundary of the box indicates the 75th percentile. Whiskers above and below the box indicate the 90th and 10th percentiles. Outlying points are graphed above and below the upper and lower whiskers, respectively. *P < 0.05 when compared with baseline within treatment.

 


Figure 24
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  		Figure 2. Interleukin-8 (IL-8) concentrations, expressed in pg/mL, for the 15 subjects in each group. The lower boundary of the box indicates the 25th percentile, the line within the box is the median, and the upper boundary of the box indicates the 75th percentile. Whiskers above and below the box indicate the 90th and 10th percentiles. Outlying points are graphed above and below the upper and lower whiskers, respectively. *P < 0.05 when compared with baseline within treatment.

 


Figure 44
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  		Figure 4. CD 11b concentrations, expressed as percent change from baseline, for 11 of the subjects in each group. The lower boundary of the box indicates the 25th percentile, the line within the box is the median, and the upper boundary of the box indicates the 75th percentile. Whiskers above and below the box indicate the 90th and 10th percentiles. Outlying points are graphed above and below the upper and lower whiskers, respectively. *P < 0.05 when compared with baseline and with 24 h post-CPB within treatment, **P < 0.05 when compared with baseline within treatment, ***P < 0.05 when compared with other treatment at the same time.

 


Figure 54
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  		Figure 5. CD 11c concentrations, expressed as percent change from baseline, for 11 of the subjects in each group of the present study. The lower boundary of the box indicates the 25th percentile, the line within the box is the median, and the upper boundary of the box indicates the 75th percentile. Whiskers above and below the box indicate the 90th and 10th percentiles. Outlying points are graphed above and below the upper and lower whiskers, respectively. *P < 0.05 when compared with baseline and with 24 h post-CPB within treatment, **P < 0.05 when compared with baseline within treatment.

 


Figure 64
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  		Figure 6. CD 18 concentrations, expressed as percent change from baseline, for 11 of the subjects in each group of the present study. The lower boundary of the box indicates the 25th percentile, the line within the box is the median, and the upper boundary of the box indicates the 75th percentile. Whiskers above and below the box indicate the 90th and 10th percentiles. Outlying points are graphed above and below the upper and lower whiskers, respectively. *P < 0.05 when compared with baseline and with 24 h post-CPB within treatment, **P < 0.05 when compared with baseline within treatment, ***P < 0.05 when compared with other treatment at the same time.

 
The last core temperatures measured in the operating room (morphine group 36.1 ± 0.5°C, fentanyl group 36.4 ± 0.4°C, P = 0.124) and on ICU admission (morphine group 35.7 ± 0.3°C, fentanyl group 36.0 ± 0.6°C, P = 0.161) were similar between the two groups. The incidence of postoperative hyperthermia (core temperature >38.0°C) during the first 12 h in the ICU was significantly higher in the fentanyl group (73%, 11 of 15 subjects) compared with that in the morphine group (0%, 0 of 15 subjects, P < 0.05). Similarly, mean temperatures were higher in the fentanyl group compared with those in the morphine group at 8 and 10 h after ICU admission (P < 0.05), which was the time interval at which peak mean temperatures were recorded (Table 4).


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  		Table 4. Intensive Care Unit (ICU) Temperature Data

 


   DISCUSSION
Top
 Abstract
 Introduction
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The results from our pilot study demonstrate that the use of morphine, when compared to fentanyl, can attenuate the release of inflammatory cytokines (IL-6), produce a greater reduction in adhesion molecule expression (CD 11b/CD 18), and reduce the incidence of postoperative hyperthermia in patients undergoing CPB.

Pretreatment of inflammatory cells with morphine can decrease the responsiveness of these cells after stimulation and attenuate the release of humoral inflammatory mediators. Exposure of human monocytes and granulocytes to morphine results in significant reductions in chemotaxis, phagocytosis, oxidative burst activity, and the ability of the cells to respond to stimulatory molecules like TNF-{alpha} (5,17). Acute and chronic administration of morphine also attenuates cytokine production. The pretreatment of mice or human mononuclear cell cultures with morphine before lipopolysaccharide-induced cell stimulation resulted in significant inhibition of the production of TNF-{alpha}, IL-1, IL-2, and IL-6 compared to control groups (6,7,18). In addition, morphine may suppress expression of adhesion molecules on inflammatory cells and reduce binding of the cells to the endothelium. Incubation of human polymorphonuclear neutrophils with morphine for 10-150 min resulted in a significant decrease in the expression of surface receptors CD 11b/CD 18, CD 16, and CD 35 (5). The adherence of human granulocytes to the endothelium of the saphenous vein is reduced after a 30-min incubation of the preparation with morphine (10). CPB induces hyperstimulation of inflammatory cells. Plasma obtained from patients undergoing CPB can induce activation of naïve monocytes and granulocytes; pretreatment of these cells with morphine reduces spontaneous and induced activation (8,19). A similar reduction in leukocyte activity was observed in a porcine model of CPB when morphine was administered before surgery, compared to a control group receiving isoflurane (9).

In contrast to morphine, fentanyl appears to minimally affect inflammatory cell function. Treatment of leukocytes obtained from volunteers with clinically relevant concentrations of fentanyl did not influence chemotaxis, phagocytosis, or release of cytotoxic products (10–12). Unlike morphine, incubation of human polymorphonuclear neutrophils and monocytes with clinical and supraclinical concentrations of fentanyl produced no effect on expression of adhesion molecules on the surface of the cells (CD 11b/CD 18, CD 16, and CD 35) (5). In addition, two clinical studies in patients undergoing cardiac surgical procedures have demonstrated that supplementation of inhaled anesthesia with conventional doses of fentanyl does not modify the cytokine response (TNF-{alpha}, IL-6, IL-8) to surgery (13,20). The differences in activity between morphine and fentanyl on inflammatory cell function may be explained by fentanyl’s lack of affinity for the morphine-selective µ3 receptor, which has been identified on human granulocytes, monocytes, and endothelial cells (4,5,10). Stimulation of this receptor by morphine, but not opioid peptides, mediates the inhibitory effects on inflammatory cell activation, adhesion molecule expression, and adherence of granulocytes to the endothelium (5,10).

Of the cytokines measured in the inflammatory cascade in response to CPB, serum levels of IL-6 and IL-8 are the most consistently and significantly increased after CPB (5,21). In addition to its role in the regulation of acute-phase protein production and the growth and differentiation of B- and T-cells, IL-6 also acts as a pyrogen and a myocardial depressant (21). The production of IL-8 further results in neutrophil activation and degranulation and upregulation of adhesion molecules (CD 11/CD 18) (22). In our investigation, serum levels of IL-6 were significantly reduced in subjects administered morphine when compared to similarly managed patients receiving fentanyl. In contrast, serum IL-8 concentrations were not significantly different between groups, although it is possible the study was not adequately powered to detect differences in IL-8 production. Our findings support experimental data demonstrating that morphine administration can attenuate cytokine production.

The adhesion of activated neutrophils to endothelial cells and the subsequent release of cytotoxic products are largely responsible for mediating inflammatory damage to tissue after CPB (3,21). The enhanced expression of specific adhesion molecules on the surface of neutrophils is a critical primary step in this process. The β2 integrin complex has been the most studied group of neutrophil receptors. This complex consists of a constant β chain (CD 18) linked to variable {alpha} units; CD 11a/CD 18 (leukocyte function-associated antigen-1), CD 11b/CD 18 (Mac-1), and CD 11c/CD 18 (p150). The CD 11b molecule is the most important component of the β2-integrin family in mediating neutrophil-endothelial interactions (3). The {alpha} units CD 11a and CD 11c appear to play a more limited role in the adhesion of neutrophils to the endothelium. Since all members of the β2 integrin family share the β chain (CD 18), expression of the CD 18 molecule is thought to reflect changes across the entire group. Both increases and decreases in the expression of the various components of the β2 integrin complex have been observed (3,23,24). The variability in expression of adhesion molecules noted in previous investigations may have been due to differences in anesthetic or surgical management used in the perioperative period. In the present study, reductions in expression of all components of the β2 integrin complex were observed post-CPB, with a return to baseline levels 24 h post-CPB. These findings suggest that a balanced anesthetic technique using a moderate dose of an opioid can attenuate expression of adhesion molecules. However, a significantly larger reduction in the components of the Mac-1 complex (CD 11b and CD 18 expression) was observed in the morphine group. No significant differences between groups in CD 11a and CD 11c expression were observed throughout the study period. Our findings demonstrate that morphine may downregulate CD 11b/CD 18 expression on neutrophils to a greater degree than does fentanyl.

Postoperative hyperthermia is relatively common after cardiac surgery with CPB. Peak temperatures more than 38.0°C and 38.5°C have been observed in 89% and 38% of cardiac surgical patients, respectively, during the first 24 h in the ICU (25,26). Although the clinical relevance of early postoperative hyperthermia has not been clearly defined, data suggest that maximum temperature after coronary artery bypass graft surgery is associated with a greater amount of cognitive dysfunction 6 wk postoperatively (27). An association between increased IL-6 concentrations (a known pyrogen) and peak postoperative temperatures has been reported (28,29). In our investigation, we observed that significantly fewer patients in the morphine group (0 of 15) developed postoperative temperatures >38.0°C compared to the fentanyl group (11 of 15, P < 0.05). These observations suggest that the use of morphine intraoperatively may reduce the incidence of postoperative fever by attenuating the inflammatory response to surgery and CPB.

There are several potential limitations to our study. First, the dose of opioid required to influence the inflammatory response in humans has not been established. A dose of morphine was selected based on previous data demonstrating that 40 mg of morphine produced evidence of enhanced myocardial recovery in patients after CPB, and that doses in this range resulted in immune cell suppression in volunteers (30,31). Dosing of fentanyl (1000 µg) reflected both the lower range of equipotence of fentanyl to morphine (40-50:1) and is a dose that allows for early tracheal extubation (32,33). The use of fixed dosing may have resulted in higher or lower blood concentrations of opioids in patients at the extremes of body weight; however, patients 50% above or below ideal body weight were excluded from the investigation. Second, only a limited number of inflammatory markers were assessed in the study. The effect of opioids on other inflammatory cytokines (TNF-{alpha}, IL-1), antiinflammatory cytokines (IL-10), the complement system, oxygen-free radicals, and other inflammatory mediators was not assessed. Third, the dose of opioid and depth of anesthesia can affect the neuroendocrine response to surgery, which might subsequently influence perioperative inflammation (34,35). Although the neuroendocrine response was not assessed, depth of anesthesia was maintained at similar levels between groups using BIS monitoring, and isoflurane concentrations were comparable pre- and post-CPB. Fourth, only low-risk patients were enrolled in the investigation. It is possible that cardiac patients at a higher risk of adverse events (i.e., reoperative procedures) might derive greater benefit from morphine administration. Finally, this small pilot study was designed to assess the effect of choice of opioid on perioperative inflammation. Larger clinical trials are required to determine the influence of morphine on other clinical outcomes after cardiac surgery.

In conclusion, our findings demonstrate that morphine can attenuate the inflammatory response to CPB when used as part of a balanced anesthetic technique with isoflurane. When compared with patients receiving fentanyl, subjects in the morphine group exhibited a significant reduction in inflammatory cytokine release, a greater inhibition of adhesion molecule expression, and a lower incidence of postoperative hyperthermia. Further clinical trials are required to define the impact of choice of intraoperative opioid on major outcomes after surgery.


   Footnotes
 
Accepted for publication March 7, 2007.

Supported by the Department of Anesthesiology, Evanston Northwestern Healthcare, Evanston, Illinois.


   REFERENCES
Top
 Abstract
 Introduction
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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