Surgical stress creates a state of insulin resistance and hyperglycemia which has been related to increased postoperative morbidity and mortality.1 The degree of insulin resistance which develops is positively associated with inflammatory mediator release2 and hospital length of stay (LOS).3 Elective surgery usually involves an 8- to 12-hour fast to reduce the risk of pulmonary aspiration of gastric contents. However, fasting induces a catabolic state4 that contributes to the development of insulin resistance,5,6 leading to questions about the scientific basis of “nil per os” practices.
Investigations comparing fasting with preoperative glucose infusions revealed that patients in a fed state had better postoperative outcomes, including less protein breakdown7 and reduced postoperative insulin resistance.8 Consuming a carbohydrate supplement before surgery appears to have the same metabolic benefits as glucose infusions.9–11 Although physiologically important, these studies failed to examine whether reduced postoperative insulin resistance was related to improved clinical outcomes. Since the degree of postoperative insulin resistance is directly related to the magnitude of surgery,3 patients undergoing major cardiac and spinal surgery may serve as a better model to study the effects of preoperative carbohydrate loading after major surgical stress. Furthermore, patients undergoing these procedures could potentially benefit from preoperative carbohydrate supplementation.
Therefore, the primary objective of this study was to determine whether preoperative oral carbohydrate loading would attenuate postoperative insulin resistance in patients undergoing coronary artery bypass graft (CABG) or spinal decompression and fusion surgery. As secondary objectives, we investigated whether oral carbohydrate supplementation influenced the inflammatory response and clinical outcomes. We hypothesized that an oral preoperative carbohydrate load would reduce postoperative insulin resistance and inflammation and improve clinical outcomes in comparison with standard preoperative fasting.
Individuals undergoing elective CABG surgery or multilevel (>1 interspace) spinal decompression and fusion surgery were eligible to participate in this randomized, controlled trial. Subjects were ineligible if they had gastrointestinal reflux, diabetes, body mass index >40 kg/m2, were unable to speak English, were undergoing urgent/emergency surgery, or entered surgery >5 hours after ingestion of the morning carbohydrate supplement. This study was approved by St. Michael’s Hospital Research Ethics Board, and written informed consent was obtained from all subjects (ClinicalTrials.gov Identifier: NCT00618592, February 8, 2008).
Baseline information was collected before surgery at which time patients were randomized to either receive preoperative carbohydrate supplementation (CHO) or to fast preoperatively (FAST). Patients randomized to the CHO group consumed 800 mL of an isomolar preoperative supplement (12.5 g/100 mL CHO, PreOp®, Nutricia, Zoetermeer, The Netherlands) between 9:00 pm and 11:00 pm the evening before surgery and another 400 mL of the supplement 2 hours before their scheduled operation. The FAST group consumed no food or drink after 8:00 pm the evening before their surgery. Randomization was conducted in permuted blocks of 6, stratified by procedure, using computer-generated random numbers and sequentially numbered opaque envelopes. The surgeon, nursing staff, and anesthesiologist were blinded to the preoperative treatment.
Surgery and Anesthesia
Choice of general anesthetics was at the discretion of the anesthesiologist and consisted of a combination of midazolam (0.1–0.3 mg/kg), fentanyl (10–20 µg/kg), sufentanil citrate (2–8 µg/kg), an inhaled anesthetic (isoflurane, desflurane, or sevoflurane), and pancuronium (0.1–0.2 mg/kg) or rocuronium (1–2 mg/kg).
IV fluids were administered to maintain central venous pressure >12 mm Hg. Inotropes were administered to maintain cardiac index >2 L/min/m2. Red blood cells were transfused for hemoglobin <75 g/L and fresh frozen plasma given for nonsurgical bleeding if International Normalized Ratio was >1.4. CABG surgery was performed using cardiopulmonary bypass with nonpulsatile flow, mild hypothermia (33°–35°), blood crystalloid cardioplegia (Fremes solution 8:1 or 16:1), and standard institutional operating procedures as previously described.12 Nonglucose-containing IV solutions were administered in the operating room (OR) and cardiovascular intensive care unit including for measurement of cardiac index.
Posterior spinal surgery of the thoracic, lumbar, and/or sacral spine was conducted in the prone position. Fusion was performed with autogenous, morselized bone grafts from localized bone and instrumentation used interbody cage, pedicle screws, and precontoured lordosis rods. In most patients, tracheal extubation was performed before transfer to the medical-surgical intensive care unit or the postanesthetic care unit (PACU) after surgery. Nonglucose-containing fluids were administered in the OR, medical-surgical intensive care unit, or PACU.
Insulin sensitivity was measured at baseline after a 12-hour fast and in the immediate postoperative period using the short insulin tolerance test. Blood samples from an arterialized, cannulated vein or indwelling arterial cannula were collected before and 3, 5, 7, 9, 11, 13, and 15 minutes after the administration of a bolus of human insulin (0.05 U/kg, Humulin R®, Eli Lilly, Indianapolis, IN). Postoperatively, the short insulin tolerance test was performed immediately on stabilization in the intensive care unit or PACU, usually within an hour after surgery.
The slope of the decline in blood glucose from 3 to 15 minutes was determined using linear regression by plotting log (plasma glucose) concentrations against time. Insulin sensitivity was taken to be the rate constant for the disappearance of blood glucose (KITT) calculated as the slope of glucose disappearance multiplied by 100. Results >2%/min are considered normal, and KITT values <1.5%/min are abnormal or insulin resistant.13 The short insulin tolerance test is reproducible14 and correlates well with the euglycemic clamp.15,16 The relative reduction in insulin sensitivity was determined using the calculation: postoperative KITT/preoperative KITT × 100 and presented as a percentage based on preoperative levels. Serum insulin and glucose, measured by the hospital laboratory using a standard radioimmunoassay (detection limit: 0.21 pmol/L) and the glucose oxidase method (detection limit: 0.2 mmol/L) (Beckman-Coulter LX-20, Fullerton, CA), were determined at baseline and in the immediate postoperative period and used in the homeostasis model assessment (HOMA) to determine insulin resistance (HOMA-IR) and β-cell function (HOMA-β).17 HOMA is a mathematical model that reflects the balance between hepatic glucose output and insulin secretion and has been found to be correlated with other insulin sensitivity measures, including the euglycemic clamp.17,18 HOMA-IR was calculated using the equation: (fasting plasma insulin [mU/L] × fasting plasma glucose [mmol/L])/22.5. Results are unitless with normal insulin sensitivity valued at 1, and higher values indicating increased insulin resistance. HOMA-β was calculated using the equation: (20 × fasting plasma insulin [mU/L])/(fasting plasma glucose [mmol/L] − 3.5) with results in percentages. Normal β-cell function is indicated at 100%, with lower values indicating impaired or diminished β-cell function.
Blood samples for analysis of free fatty acid (FFA), interleukin-6 (IL-6), and high-sensitivity C-reactive protein (CRP) concentrations were collected at baseline, immediately after surgery and 24, 48, and 72 hours after surgery. Plasma aliquots were stored at −70°C for batch analysis. FFA was measured using an enzymatic colorimetric assay (detection limit: 0.0014 mEq/L; Wako Chemicals, Richmond, VA), IL-6 using a commercial ELISA kit (detection limit: 0.039 pg/mL; R&D Systems, Minneapolis, MN), and CRP using end-point nephelometry (detection limit: 0.16 mg/L; BN ProSpec System, Siemens, Deerfield, IL). Plasma adiponectin, a protein hormone released by adipose tissue that has been shown to improve insulin sensitivity,19 was measured at baseline using a commercial ELISA kit (detection limit: 0.78 ng/mL; Millipore, Billerica, MA) to determine its relationship with pre- and postoperative insulin sensitivity in our study population.
Participants completed 100-mm visual analog scales (VASs) to measure subjective well-being at baseline and before entering the OR. The variables examined were measured in a previous study20 and included: anxiety, depression, hunger, malaise, inability to concentrate, nausea, pain, thirst, tiredness, feeling unfit, and weakness. Each scale consisted of horizontal lines anchored at 2 predefined ends, with the left anchor representing “not at all” (score: 0) and the right anchor representing “extremely” (score: 100). Patients completed each scale by marking an X somewhere along the horizontal line. For this scale, the median of the difference between 2 scorings 5 minutes apart has been found to vary from −2 to 0 mm.20 A previous investigation found relatively homogenous VAS scores when results of patients undergoing laparoscopic cholecystectomy and major colorectal surgery were compared.20
Intra- and postoperative events were documented on OR/intensive care unit records or nurses’ notes. Blood glucose was monitored at least every 30 minutes during cardiopulmonary bypass, and insulin was administered in the OR if glucose levels were >10 mmol/L. Left ventricular function was defined as follows: left ventricular grade I ≥50% left ventricular ejection fraction (LVEF), grade II = LVEF 35% to 49%, grade III = LVEF 20% to 34%, grade IV = LVEF <20%. A complication was defined as any one of the following: significant perioperative bleeding (requiring reoperation or transfusion); perioperative inotrope requirement (administration of dobutamine [>5 µg/kg/min], epinephrine [>0.05 µg/kg/min], dopamine [>5 µg/kg/min], or levophed [>0.05 µg/kg/min] for >30 minutes in the OR or ≥6 hours postoperatively to maintain adequate arterial blood pressure or cardiac output); hyperglycemia (serum glucose >8 mmol/L); infection (clinical signs, positive culture, and new treatment); myocardial infarction (clinical diagnosis based on electrocardiogram and cardiac enzymes); atrial fibrillation, pleural effusion (clinical/radiological diagnosis); or pulmonary embolism/deep vein thrombosis. The number of patients who experienced a complication and the total number of complications were determined.
The sample size was estimated based on previous data suggesting a significant decrease in relative insulin sensitivity of approximately 75% after bypass surgery together with an anticipated 40% improvement in those who had received carbohydrate supplementation with a power of 80% and an α of P = 0.05. A previous meta-analysis found that an approximate 40% improvement in insulin sensitivity was associated with a reduction in LOS of 1.2 days.21 Continuous data, including LOS, were analyzed using the Student t test for independent or paired samples as appropriate to determine between or within-group differences, respectively, and presented as mean ± SD with the mean difference (99% confidence interval [CI]). The Levine test for equality of variances was used with the Student t test. Equal variances were assumed if P ≥ 0.01. The Levine test was significant (P < 0.01) for postoperative HOMA-IR and insulin, and the t statistic and significance level for unequal variances were used with these 2 variables. Secondary outcome variables are presented as median (25th, 75th percentile). Categorical data were analyzed using the χ2 test, or Fisher exact test when the number in any cell was <5, and described as counts (percentage). Analysis of covariance was used to compare postoperative KITT, HOMA-IR, HOMA-β as well as circulating levels of glucose and insulin while controlling for baseline levels. An analysis evaluating the homogeneity-of-regression assumption was completed. The relationship between the covariate and the dependent variable did not differ significantly as a function of the independent variable and the data were close to normally distributed except postoperative HOMA-IR and insulin levels were not normally distributed, so the data were log-transformed resulting in data that were close to normally distributed. Data were considered significant at P < 0.01.
Analysis of covariance was applied to preoperative VAS scores with baseline VAS scores added as a covariate in the model to adjust for baseline differences. Mixed model statistics using an autoregressive assumption were used for outcomes with repeated measures to determine the effect of time, treatment, and interaction. The random effects assumptions used in the mixed model analysis (autoregressive, unstructured, and compound symmetry) did not affect data interpretation as all results had nonsignificant P-values that were identical to 2 decimal places. IL-6 and CRP were log-transformed before analysis. Baseline FFA values were added as a covariate in the model. Generalized linear model with Poisson distribution was used to compare the total number of complications. Spearman rank correlation coefficient was applied to determine associations between variables.
Characteristics of the 26 CABG and 12 spinal surgical patients recruited for this study are summarized in Table 1. CABG patients in the FAST group had more prior myocardial infarctions than those in the CHO group (P = 0.02); otherwise the 2 groups were similar.
Serum glucose and insulin were not different between groups at baseline or postoperatively (Table 2). After surgery, both groups had an increase in blood glucose (P < 0.001). The CHO group tended to have had a lower serum glucose concentration postoperatively than the FAST group (6.2 ± 0.9 vs 6.9 ± 1.2 mmol/L [mean ± SD]), but the difference was not significant (99% CI for difference, −1.7 to 0.25, P = 0.05).
One patient in the FAST group was unable to complete the baseline short insulin tolerance test due to a vasovagal response. Twenty-four patients were insulin resistant at baseline (KITT <1.5%/min) and 38% of these patients were found in the FAST group (P = 0.09). Immediately after surgery, both groups experienced a significant decrease in insulin sensitivity compared with baseline (P < 0.001) but the relative reduction in insulin sensitivity between the 2 groups was not different (Table 2).
HOMA-IR scores were not different between groups at baseline or postoperatively (Table 2). HOMA-β revealed no differences at baseline between the 2 groups (Table 2). After surgery, β-cell function decreased in both groups, however, was not significantly different from baseline. Postoperative β-cell function was 87% ± 12% in the CHO group compared with 47.5% ± 12% in the FAST group (99% CI for difference, −9.4 to 88.4).
Baseline plasma FFA levels were 0.56 [0.34, 0.68] mEq/L (median [25th, 75th percentile]) in the FAST group compared with 0.32 [0.19, 0.56] mEq/L (median [25th, 75th percentile], P = 0.03) in the CHO group. Postoperatively, FFA levels in both groups were not significantly different compared with baseline and no time or treatment effect was found. Log IL-6 and log CRP levels were similar between groups at baseline (Figs. 1 and 2, respectively). Postoperatively, IL-6 and CRP levels increased and there was a significant effect of time (P < 0.001) but not treatment on the 2 inflammatory markers.
Adiponectin levels were similar between the FAST and CHO group at baseline (9.01 [5.75, 17.16] vs 9.95 [6.33, 13.49] µg/mL, (median [25th, 75th percentile], P = 0.85). Bivariate analysis revealed no relationship between adiponectin and baseline KITT (rs = −0.06, P = 0.76) or baseline HOMA-IR (rs = −0.08, P = 0.72) or between adiponectin and postoperative KITT (rs = −0.03, P = 0.90) or postoperative HOMA-IR (rs = 0.25, P = 0.24).
The FAST group reported a higher anxiety score: 62 [38, 72] vs 34 [18, 48], (median [25th, 75th percentile], P = 0.010) and thirst score: 50 [24, 70] vs 10 [7, 34], (median [25th, 75th percentile], P = 0.005) before surgery compared with the CHO group (Fig. 3). No differences were found between groups for any other measures of subjective well-being (Table 3).
Perioperative outcomes were similar between groups (Table 4). There were no differences between the FAST and CHO group in the duration of operation (240 [210, 265] vs 230 [205, 305] minutes, (median [25th, 75th percentile], P = 0.84) or total dose of fentanyl (624 ± 901 vs 366 ± 523 µg [mean ± SD], P = 0.77), sufentanil (131 ± 227 vs 126 ± 172 µg [mean ± SD], P = 0.76) or morphine (7 ± 12 vs 13 ± 15 mg [mean ± SD], P = 0.08) administered. The volume of cardioplegia (152 ± 50 vs 157 ± 55 mL [mean ± SD], P = 0.84) or amount of glucose received (7.6 ± 2.5 vs 7.8 ± 2.8 g [mean ± SD], P = 0.84) was not different between groups.
The total number of complications in the FAST group was 64 (mean 3) compared with 44 (mean 2) in the CHO group (P = 0.60). The number of complications weakly correlated with postoperative glucose levels (Table 5).
The hospital LOS was 4.8 ± 1.2 days in the CHO group and 6.8 ± 4.2 days in the FAST group (99% CI for difference, −0.66 to 4.74; Table 4). A weak inverse relationship was found between LOS in a recovery unit and postoperative HOMA-β scores (Table 5). No relationship was found between hospital LOS and postoperative glucose levels (Table 5). Bivariate analysis revealed a correlation between hospital LOS and reported preoperative anxiety (rs = 0.66, P < 0.001). No differences were noted between groups in glucose and insulin outcomes (Table 5).
In this study, preoperative carbohydrate loading did not reduce the development of postoperative insulin resistance in patients undergoing CABG or multilevel spinal decompression surgery compared with preoperative fasting. However, reduced patient discomfort in the preoperative period combined with the observed postoperative blood glucose levels and β-cell function support a potential beneficial role of preoperative carbohydrate loading.
The relative reduction in insulin sensitivity in the FAST and CHO group postoperatively was 74% and 71%, respectively, more than previously reported after open cholecystectomy (58%)22 or hernia repair (32%).23 This is likely due to the fact that both CABG and spinal decompression and fusion surgery are more invasive procedures of longer duration and result in more blood loss than cholecystectomy or hernia repair operations. The degree of postoperative insulin resistance has been found to be proportional to the magnitude of the surgical trauma and related to the degree of perioperative blood loss.3
In contrast to our findings, previous work with patients undergoing elective gastrointestinal surgeries and hip replacement procedures found reductions in postoperative insulin resistance with preoperative carbohydrate loading.9,11 Several studies investigating carbohydrate supplementation in CABG patients found no improvement in insulin sensitivity postoperatively.24,25 However, they were limited as no direct measurement of insulin sensitivity was used. Although not examined in this study, there is also some evidence that preoperative carbohydrate supplementation may assist in earlier return to normal gut function postoperatively.26,27
Postoperatively, insulin levels in the FAST group appeared to be blunted in response to increasing blood glucose levels. Postoperative HOMA-β scores confirm this observation in the FAST group as β-cell function was less than half compared with that of the CHO group. Improved β-cell function may be an important factor in postoperative recovery because a correlation was found between postoperative HOMA-β scores and LOS in a recovery unit. Nevertheless, HOMA scores are based on fasting glucose and insulin levels17 whereas the postoperative situation may reflect supraphysiological levels of these blood markers.
A previous meta-analysis reported that patients who received preoperative carbohydrate loading had a shorter LOS in the hospital compared with those who fasted.21 High blood glucose levels, or hyperglycemia, have been shown to be related to the development of postoperative complications.28,29 Our LOS findings in the CHO group compared with the FAST group are not inconsistent with previous findings; however, our study design was too small to detect the effect of preoperative carbohydrate supplementation on reduction in LOS. There was also a weak relationship found between postoperative glucose levels and total number of complications in our study.
A substantial increase in IL-6 and CRP was observed in both groups, consistent with the inflammatory reaction seen in response to surgical stress.30,31 Inflammation has been shown to be reduced after treatment with intensive insulin therapy to normalize postoperative blood glucose levels.32 However, preoperative carbohydrate supplementation may not exert a strong enough effect physiologically to blunt the postoperative inflammatory response.
A lesser degree of anxiety and thirst immediately before surgery in patients who have received oral preoperative carbohydrate supplementation has been previously reported.20 We also found a relationship between preoperative anxiety scores and hospital stay. Previous studies suggest that preoperative anxiety is related to the degree of pain experienced postoperatively.33 Greater postoperative pain can result in decreased mobility, increased analgesic requirements, and ultimately a longer hospital LOS.34 Therefore, the reported reduced anxiety in the CHO group may provide an additional explanation for the reduction in LOS.
Several limitations to this study are acknowledged. The CIs around the point estimate of the difference in postoperative insulin sensitivity suggest that a larger sample size may have been needed to identify differences in the short insulin tolerance test. Also, more than half of our patients were insulin resistant at baseline and chronic insulin resistance may have been a factor preventing improvement in postoperative insulin sensitivity. Previous studies examining carbohydrate supplementation used the euglycemic clamp technique to measure insulin sensitivity. Although the short insulin tolerance test directly measures insulin sensitivity, it may not have been sensitive enough to detect differences in insulin sensitivity when compared with the gold standard clamp technique.
Some patients received blood transfusions in our study. Unfortunately, the glucose concentration of the blood products patients received was not measured, so we were unable to incorporate this into our analysis. In addition, patients in the FAST group were aware that the CHO group received an oral carbohydrate supplement before surgery and this may have influenced their VAS scores. The composition of our study population which included patients undergoing CABG or spine surgery may have been another limitation due to differences in the surgical procedures. Our analysis indicated that inclusion of 2 surgical procedures (rather than 1) in the study did not change the results.
We conclude that postoperative insulin resistance developed in our patients undergoing major elective cardiac or spinal surgery. Although we were unable to detect any statistically significant effect of preoperative carbohydrate supplementation on postoperative insulin sensitivity, the results of our study support other research findings examining preoperative carbohydrate loading. Patients who received preoperative carbohydrate in our study reported less anxiety and thirst in the preoperative period. This suggests that the potential benefits of a preoperative carbohydrate supplement include enhanced patient satisfaction as well as important cost savings in clinical institutions. Thus, further investigation into the physiological and clinical effects of preoperative carbohydrate loading is warranted.
Name: Susan Tran, MSc.
Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.
Attestation: Susan Tran has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.
Name: Thomas M. S. Wolever, MD.
Contribution: This author helped design the study, conduct the study, and write the manuscript.
Attestation: Thomas M. S. Wolever approved the final manuscript.
Name: Lee E. Errett, MD.
Contribution: This author helped conduct the study.
Attestation: Lee E. Errett approved the final manuscript.
Name: Henry Ahn, MD.
Contribution: This author helped conduct the study.
Attestation: Henry Ahn approved the final manuscript.
Name: C. David Mazer, MD.
Contribution: This author helped design the study, conduct the study, analyze the data and write the manuscript.
Attestation: C. David Mazer reviewed the analysis of the data and approved the final manuscript.
Name: Mary Keith, PhD.
Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.
Attestation: Mary Keith has seen the original study data, reviewed the analysis of the data, approved the final manuscript, and is the author responsible for archiving the study files.
This manuscript was handled by: Charles W. Hogue, Jr., MD.
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© 2013 International Anesthesia Research Society
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