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© 2002 International Anesthesia Research Society
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Abstract |
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We previously reported that a continuous insulin infusion improves neutrophil phagocytic function after cardiac surgery in diabetic patients. These data suggested that hyperglycemia impairs neutrophil function, and because nondiabetic patients also experience hyperglycemia during cardiac surgery, we hypothesized that a continuous insulin infusion would improve glucose control and neutrophil function in nondiabetic cardiac surgical patients. Patients were randomized to receive either no insulin (Control group) or a continuous insulin infusion (Insulin group), with glucose measurements every 10 min during cardiopulmonary bypass (CPB). Blood glucose was significantly lower in the Insulin group immediately after surgery but not during surgery. When assessed as the percentage of phagocytic cells, neutrophil function was similar in the Control and Insulin groups at baseline (55% and 57%, respectively) and after CPB (38% and 43%, respectively). However, a quantitative determination of neutrophil phagocytic activity showed that whole blood neutrophil phagocytic capacity increased significantly in both groups at 60 min after CPB when compared with their respective baseline values and that the increase in total neutrophil phagocytic capacity was significantly more in the Insulin group compared with the Control group (P = 0.036). This observation was primarily due to a larger increase in the peripheral blood neutrophil count and not to increased activation of neutrophils.
IMPLICATIONS: IV insulin, as used in this study, had effects on blood glucose only after cardiac surgery, when it was associated with an increased neutrophil count and a greater total capacity of peripheral blood neutrophils to ingest foreign particles.
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Introduction |
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Diabetic patients who undergo major surgery are at increased risk for postoperative infections compared with nondiabetic patients (1–3). Several factors may contribute to the increased incidence of infection in diabetic patients, including impairment of the innate immune response, especially the response of neutrophils. Neutrophils isolated from diabetic patients demonstrate impairment of several important functions, including chemotaxis, oxidative burst, and phagocytosis (4,5). The hallmark of diabetes, hyperglycemia, appears to contribute substantially to impaired neutrophil reactivity. In vitro, hyperglycemia inhibits the oxidative burst response of neutrophils (6), whereas in vivo, even short-term increases in blood glucose, as experienced daily by many diabetic patients, can cause a significant decrement in leukocyte phagocytic activity (7). In contrast to neutrophil bactericidal functions, neutrophil adherence appears to be increased in diabetics. Even when diabetic patients are free of infection, their neutrophils have an increased expression of adhesion molecules CD11b and CD11c; this is associated with spontaneous adherence in in vitro assays (4). Similarly, diabetic rats demonstrate increased levels of neutrophil CD11b, CD11c, and CD18, and these are associated with increased neutrophil microvascular adherence (8). Hyperglycemia also appears to be a factor in the increased adherence of diabetic neutrophils. Morigi et al. (9) showed that hyperglycemia or hyperglycemic sera from diabetic patients increased endothelial cell expression of E selectin and of intercellular adhesion molecules (ICAM) and vascular cell adhesion molecules, resulting in increased leukocyte adhesion to endothelial cells.
We previously reported that an intraoperative insulin infusion improved glucose control and neutrophil phagocytic function in diabetic cardiac surgical patients when compared with glucose treatment with intermittent IV insulin (10). Hyperglycemia is also a common accompaniment to CPB in nondiabetic cardiac surgical patients, despite increases in plasma insulin (11,12). On the basis of data showing that hyperglycemia per se, in the absence of diabetes, contributes to altered neutrophil functions in vivo (6,7,9,13), we hypothesized that a continuous insulin infusion would improve glucose control and neutrophil phagocytic function in nondiabetic patients undergoing cardiac surgery. The results suggest that insulin may act to increase peripheral blood neutrophil counts and thereby increase total phagocytic capacity in the peripheral blood of nondiabetic cardiac surgical patients.
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Methods |
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This study was approved by the Dartmouth College Committee for the Protection of Human Subjects (IRB), and written informed consent was obtained from all participants. Patients scheduled for elective cardiac surgery with cardiopulmonary bypass (CPB) who had no history of diabetes were considered eligible for inclusion in the study. Specific exclusion criteria included recent infection, use of oral hypoglycemic medications or medications that alter immune function (glucocorticoids or immunosuppressants), or a body mass index (weight/height) of more than 37 kg/m2 (to exclude patients with undiagnosed Type II diabetes).
After discussion of the study objectives and interventions, participants were randomized by using a computerized random number generator to a treatment group that received an insulin infusion (Insulin group) or to a Control group (Appendix). All patients were scheduled as the first surgical case on the operative day. The anesthetic technique included premedication with a histamine type 2-receptor antagonist for those patients with a history of gastroesophageal reflux and titrated doses of midazolam (1–5 mg) and fentanyl (50–200 µg). General anesthesia consisted of fentanyl 20–50 µg/kg, midazolam 2–10 mg, pancuronium 0.1–0.2 mg/kg, and isoflurane 0.2%–1.5% in an oxygen/air mixture. Vasoactive medications and blood product transfusions were administered at the discretion of the anesthesiologist. All patients received prophylactic perioperative antibiotics. 
-Aminocaproic acid was used in all cases except for those judged to be at increased risk for inadequate hemostasis; to these, aprotinin was administered. CPB was conducted at normothermia (37°C) with a membrane oxygenator (CML Duo®; Cobe Cardiovascular, Arvada, CO). A centrifugal blood pump was used (BioPump®; Medtronic, Minneapolis, MN). The pump prime consisted of a mixture of Plasmalyte® (Baxter Healthcare Corporation, Deerfield, IL) and mannitol, with or without 6% hetastarch or 25% albumin. Intraoperative red cell scavenging and processing for transfusion was also used (Brat2TM; Cobe Laboratories). All surgical procedures were performed via a median sternotomy. Separation from CPB was attempted without the use of inotropes, although, if necessary, epinephrine or dopamine was used. Whole blood glucose (Accu-Chek; Roche Diagnostics, Basel, Switzerland) was measured at baseline (before anesthesia induction), 10 min before CPB, every 10 min while on CPB, at 30 and 60 min after CPB, and upon arrival in the postoperative intensive care unit (ICU).
Peripheral blood (1 mL) for neutrophil phagocytic studies was withdrawn from the arterial catheter before anesthesia induction (baseline), immediately before surgical incision, immediately before CPB, approximately 10 min after the initiation of CPB, and 60 min after termination of CPB. Heparinized whole blood samples were incubated with 18 µL of a 1.5% vol/vol solution of 2.0-µm fluorescent microspheres (FluoSpheres®; Molecular Probes, Eugene, OR) and agitated at 1 Hz for 10 min in a 37°C water bath. Patients typically exhibit a decrease in the peripheral blood neutrophil count during CPB, and therefore the ratio of neutrophils to beads was kept constant in each assay by adjusting the quantity of whole blood to include the same number of neutrophils in each assay. To accomplish this, a 250-µL sample of whole blood from the sample with the smallest measured neutrophil count (Coulter JT; Beckman Coulter, Inc., Fullerton, CA) was used to define the number of neutrophils tested in all five assays, with the final volume of the other assays adjusted to 250 µL by adding phosphate-buffered saline. After incubation and red cell lysis with ammonium chloride, the sample was fixed in a 10% formaldehyde solution and stored at 4°C until analysis by flow cytometry (FACScan; Becton Dickinson, Franklin Lakes, NJ). Neutrophils were gated according to their forward and side scatter characteristics, and data for 5000 leukocytes were acquired from each sample. Neutrophils with green fluorescence greater than the background were classified as bead positive. Calculation of neutrophil phagocytic activity was determined as the number of bead-positive neutrophils (i.e., the number of neutrophils with positive fluorescence) divided by the total number of cells in the gated neutrophil region (expressed as a percentage). Fluorescence intensity distribution of the bead-positive cells demonstrated discrete peaks (Fig. 1), with intensities in approximately two-, three-, and fourfold increments relative to the intensity of the lowest positive peak. When cells were flow sorted (FACStar; Becton Dickinson) from each of the first four peaks, light microscopy of 200 sorted cells per peak confirmed that the first four peaks contained neutrophils with one, two, three, and four beads (with a population homogeneity of bead counts from 87% to 95%). In the fifth and final peak, 60% of the cells had ingested five beads by light microscopy, and 40% of cells had ingested more than five beads; this population was subsequently assigned a conservative value of five ingested beads per cell. Computerized analysis of data from each assay (CellQuest®; Becton Dickinson) determined the total number of cells in each fluorescence intensity region, and these data were used to calculate the total number of beads ingested by neutrophils in each sample of 5000 leukocytes. The total white blood cell (WBC) count of each sample was measured (Coulter JT), and the absolute neutrophil count (ANC) was then determined by multiplying the percentage of leukocytes that were in the neutrophil region in each sample by the total WBC count of the sample. The total phagocytic capacity in a cubic millimeter of peripheral blood was then determined as
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equation
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where total beads ingested is the total number of beads ingested in the gated sample of neutrophils, gated neutrophils is the total number of neutrophils counted in the gated region of the blood sample, and neutrophils/mm3 is the ANC per cubic millimeter of peripheral blood.
In a previous work (10), we demonstrated an approximately 50% difference in polymorphonuclear phagocytosis between groups of diabetic patients randomized to receive continuous versus intermittent insulin during cardiac surgery. By use of similar preliminary data with nondiabetic patients undergoing cardiac surgery (data not shown), we performed a power analysis that assumed a 20% difference between treatment and control groups at a 5% level of significance. Unadjusted intergroup comparisons for ordinal data were performed by the 
2 test with the continuity correction technique and, for continuous data, by one-way analysis of variance. When appropriate, repeated-measures analysis of related dependent variables was applied. This technique uses an analysis of variance that generalizes the paired-samples Students’ t-test to test sources of variation among a group of related dependent variables that represent different measurements of the same attribute (the same patient was observed on multiple occasions). Adjusted comparisons were modeled for possible confounders by using generalized estimating equations. Intragroup comparisons were performed with a paired Student’s t-test (to evaluate differences from baseline for each group), Wilcoxon’s ranked sum test, or the 2 test with continuity correction, when appropriate. A P value of <0.05 was considered significant. Statistical analysis was performed with SPSS 10.0 for Macintosh (SPSS, Inc., Chicago, IL).
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Results |
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Thirty patients (15 in each group) completed the study protocol. The patients were similar with regard to age, baseline glucose values, duration of surgery, duration of CPB, aprotinin and catecholamine use, and total fentanyl dose. The Control group had a significantly lower body mass index (P = 0.0043) (Table 1).
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Patients in the Insulin group received a mean insulin dose of 16.3 U of insulin during a mean CPB time of approximately 95 min (Table 1). Patients in the Insulin group had significantly lower blood glucose than did patients in the Control group upon arrival in the postoperative ICU (110 mg/dL [95% confidence interval ± 19] vs 148 mg/dL [95% confidence interval ± 17], respectively; P = 0.003) (Fig. 2). The difference in blood glucose concentrations measured at all other time points was not significantly different. One patient in the Insulin group was treated with IV dextrose upon arrival in the ICU because a blood glucose value of 44 mg/dL was considered to be low enough to warrant treatment. No patient in the Control group required insulin.
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The total WBC counts, ANCs, percentage phagocytic activity, and total phagocytic capacity were similar at baseline between the two groups (Table 2, Figs. 3 and 4). The total peripheral WBC count increased significantly after CPB compared with baseline levels in both groups (Table 2). Both WBC and ANC were significantly higher at 60 min after CPB in the Insulin group compared with respective values in the Control group (P = 0.034 and P = 0.02, respectively) (Table 2). The percentage phagocytic activity of neutrophils decreased significantly in both groups immediately before CPB and at 60 min after CPB (compared with respective baseline values in each group), with no significant differences observed between the groups at any time (Fig. 3). Although the percentage of phagocytic neutrophils decreased 60 min after CPB in both groups, the neutrophil phagocytic capacity in peripheral blood increased significantly compared with baseline values in both groups (P = 0.046 for the Control group; P = 0.0004 for the Insulin group) (Fig. 4). Increases in phagocytic capacity were significantly larger in the Insulin group compared with the Control group (P = 0.036). This increase in phagocytic capacity appeared to be due primarily to the increased peripheral neutrophil counts, because determination of the average number of beads ingested per neutrophil did not change significantly in either group from baseline to 60 min after CPB (2.3 to 1.9 beads per cell in the Control group and 2.6 to 2.2 beads per cell in the Insulin group).
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Discussion |
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Hyperglycemia is a common response to cardiac surgery with CPB. The induction of hyperglycemia in this setting is largely caused by a temporary state of insulin resistance that is part of a well defined generalized hormonal stress response (13). Although the hyperglycemia is often transient, arguments in favor of tight control of intraoperative glucose in cardiac surgical patients cite two potentially deleterious effects of hyperglycemia: worsening neurologic outcomes and an increased incidence of infections. Some centers have protocols for control of glucose during CPB in an attempt to limit neurological injury after cardiac surgery, but the possibility of a beneficial effect of tight glucose control on neurologic outcomes in this setting remains controversial. Studies also suggest that improved control of glucose during CPB may lead to a decrease in the incidence of infection after surgery (14).
In this study, glucose levels during CPB were, in fact, not decreased by an insulin infusion and were significantly decreased only after CPB in the early postoperative period. This finding is very similar to that reported by Chaney et al. (11), who also did not achieve improved glucose control with an insulin infusion in nondiabetic patients during hypothermic CPB. Despite using a protocol with a more aggressive dosing strategy for insulin than the protocol that we used, they observed increases in glucose during CPB very similar to those reported here, further documenting the severity of insulin resistance that occurs during CPB. Patients in our study, who would not be considered to be insulin resistant outside of the cardiac surgical setting, nonetheless received an insulin dose during CPB that was larger (average 
10 U/h) than doses generally recommended for glucose control in diabetic noncardiac surgery patients (15). Given our data and the results reported by Chaney et al., it is questionable whether larger doses of insulin would have normalized blood glucose during CPB without an unacceptable risk of postoperative hypoglycemia. Notably, our results were observed in the setting of endogenous glucose control and should be distinguished from results that might be observed with glucose/insulin/potassium infusions used as a metabolic substrate for myocardial preservation (16).
When we measured neutrophil function as percentage phagocytic activity, the decrease in the percentage of phagocytically active neutrophils was similar in both the Control group and the Insulin group and was also virtually identical to that which we reported in diabetic patients receiving an insulin infusion during cardiac surgery (10). Diabetic patients in the latter study who received intermittent glucose had higher glucose levels and a significantly larger percentage decline in the number of phagocytically active neutrophils. Taken together, these results suggest that diabetic patients may be more susceptible to the neutrophil-inhibiting effects of acute hyperglycemia during CPB, because control of postoperative hyperglycemia in the nondiabetic patients did not alter the observed changes in percentage phagocytic activity. Another important result from this study is the finding of an increased total peripheral blood neutrophil count after surgery and a consequent increase in the peripheral blood phagocytic capacity, with a significantly larger increase in the treatment group that received insulin. Most assays of neutrophil phagocytic activity report the percentage of cells that have ingested a foreign particle, even though many times an individual cell will ingest more than one particle. We attempted to overcome the imprecision of percentage measurements by using a quantitative assessment of phagocytic capacity to obtain information reflecting total neutrophil phagocytic activity in peripheral blood. Determination of phagocytic capacity takes into account both the number of circulating neutrophils present in peripheral blood at the time of the assay measurement and their phagocytic activity, as determined by the number of foreign particles ingested by each cell. Because the average number of beads ingested per cell was not different between the groups and did not increase over the course of the study, the greatest contribution to the larger increase in phagocytic capacity in the Insulin group appeared to be a consequence of a significantly larger increase in the number of circulating neutrophils after CPB.
The mechanism by which insulin might increase circulating neutrophils after cardiac surgery was not examined in this study. As an anabolic hormone, the administration of insulin to rats induces an increase in the number of erythroid progenitor cells, but this effect is observed over a much longer time period than the conditions of this study and has not been reported for myeloid progenitor populations (17). Therefore, it seems unlikely that the larger increase in the WBC and ANC in the Insulin group was a consequence of increased release of leukocytes from the marrow. There is, however, considerable evidence to suggest that hyperglycemia leads to increased endothelial adherence of neutrophils and may lead to a lower WBC in hyperglycemic patients. In vitro, exposure of human umbilical vein cells to hyperglycemic conditions for 24 hours increases expression of E selectin, ICAM, and vascular cell adhesion molecules, with a consequent increase in leukocyte adherence (9). Functional blocking of the adhesion molecules with murine monoclonal antibodies prevented leukocyte adherence (9). Diabetic rats also have a more marked increase in leukocyte adhesion molecule expression and mesenteric vein emigration after a 10-minute experimental ischemia-reperfusion injury (18). Increased adherence in this study was associated with an increase in leukocyte CD11 expression. In humans, the induction of acute hyperglycemia in both nondiabetic and recently diagnosed Type II diabetics resulted in an increase in circulating levels of soluble ICAM within one hour, an effect that was aggravated when octreotide was used to inhibit endogenous insulin release (19). Furthermore, overnight euglycemia in the diabetic patients normalized soluble ICAM levels. These studies document that hyperglycemia per se leads to an increase in leukocyte and endothelial cell adhesion molecule expression, that this effect can be observed in a matter of hours, and that it leads to increased in vivo adhesion of leukocytes to endothelial cells. These data suggest that one explanation for the difference in peripheral WBC counts that we observed could have been due to diminished in vivo leukocyte adherence, because the difference was observed only at the end of surgery, when the Insulin group had lower glucose values than the Control group. However, because we did not measure neutrophil adhesion in this study, such a conclusion remains entirely speculative.
Finally, the significance, if any, of an increase in blood phagocytic capacity after cardiac surgery is entirely unknown. There are data to support the use of granulocyte colony stimulating factor to stimulate neutrophilia in certain settings of nonneutropenic fever (20,21), with the implication that increases in neutrophil activity above the normal range are more effective in eliminating infection. Alternatively, if an increase in the number of circulating neutrophils indicates less endothelial cell adhesion, this could be associated with less organ damage caused by neutrophil oxidative injury within the microvasculature (22). Whether or not insulin-induced neutrophilia would affect either of these responses in the cardiac surgical population is simply not known.
In summary, continuous IV insulin therapy to treat the acute hyperglycemia associated with CPB was associated with greater neutrophil phagocytic capacity in the peripheral blood of nondiabetic cardiac surgical patients. Although the calculated difference in phagocytic activities was due to an increase in the ANC of the Insulin group, the possible mechanisms of this effect remain unknown.
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Appendix |
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Insulin group treatment protocol: An insulin infusion was started at the beginning of CPB and adjusted as follows at 10-min intervals after initiation of CPB.
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Acknowledgments |
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Supported by National Institutes of Health Grant DA-09162 (MPY).
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