Intraoperative Tight Glucose Control Using Hyperinsulinemic Normoglycemia Increases Delirium after Cardiac Surgery

POSTOPERATIVE delirium is common in patients recovering from cardiac surgery. It is a disturbing complication that is associated with prolonged duration of hospitalization, increased costs, mortality, and long-term neurocognitive impairment.^1–8  The causes of postoperative delirium remain unclear, but are thought to include pain, sleep deprivation, anesthetic and narcotic effects, concomitant medications, surgical stress, and the inflammatory response to surgery.^2,9–19 

Hyperglycemia is both a consequence and a cause of perioperative inflammation. The surgical stress response and concomitant inflammation augment perioperative blood glucose concentrations.²⁰  Thus, hyperglycemia is particularly common in patients undergoing cardiac surgery. “Stress hyperglycemia” is exacerbated by factors specific to cardiopulmonary bypass including heparin administration, hypothermia, and administration of glucose-containing cardioplegic solutions.^21–23  Other factors that worsen hyperglycemia during cardiac surgery include increased renal absorption of glucose, increased substrate availability in the form of lactate, and decreased exogenous insulin activity.²⁴  Hyperglycemia itself also induces inflammation and expression of proinflammatory cytokines.²⁵  Consequently, tight perioperative glucose control with intensive insulin therapy decreases perioperative inflammation.^26,27  Insulin per se also decreases concentrations of proinflammatory cytokines, adhesion molecules, chemokines, acute phase proteins, and C-reactive protein.²⁶ 

Thus, it seems likely that tight glucose control and reduced inflammation will also decrease the risk of postoperative delirium. Consistent with this theory, a retrospective analysis suggests an association between hyperglycemia and delirium in patients undergoing abdominal surgery.²⁸  To the extent that tight glucose control reduces the risk of delirium, using a hyperinsulinemic–normoglycemic clamp may be especially helpful because insulin per se is antiinflammatory. Therefore, first, we tested the primary hypothesis that tight glucose control using a hyperinsulinemic–normoglycemic clamp approach decreases the incidence of postoperative delirium as assessed by the Confusion Assessment Method (CAM) in patients recovering from cardiac surgery. Second, we tested the hypothesis that normoglycemic clamp reduces the severity of delirium as assessed by the Memorial Delirium Assessment Scale (MDAS).

With the approval of Cleveland Clinic Institutional Review Board, 203 consenting adults undergoing cardiac surgery with cardiopulmonary bypass between March 2008 and January 2010 were randomly assigned to tight intraoperative glucose control with a hyperinsulinemic–normoglycemic clamp or standard therapy. Randomization was based on a computer-generated sequence in random-sized permuted blocks of 4 to 16 patients. Assignments were stratified by procedure (coronary artery bypass, valve, or both) and history of diabetes (none vs. any of the following: diet controlled, type I or type II diabetes). Allocation was concealed until just before surgery by a web-based system. These patients were part of a large multicenter study evaluating the effect of tight glucose control on postoperative morbidity and mortality in patients undergoing cardiac surgery (ClinicalTrials.gov identifier: NCT00524472).

Patients randomized to tight intraoperative glucose control received a hyperinsulinemic–normoglycemic clamp. A constant infusion of insulin (5 mU·kg⁻¹·min⁻¹) was given with a concomitant variable infusion of 20% dextrose titrated to target blood glucose concentrations from 80 to 110 mg/dl. The standard therapy group received standard insulin infusion as per the Cleveland Clinic insulin treatment protocol, which targets blood glucose concentrations less than 150 mg/dl.

We recorded blood glucose concentrations preoperatively, before anesthetic induction, beginning of cardiopulmonary bypass, end of cardiopulmonary bypass, after weaning from cardiopulmonary bypass, arrival in the intensive care unit (ICU), and 12, 24, and 48 h after arrival in ICU. In addition, frequent blood glucose concentrations were evaluated during the intraoperative period (every 5 to 10 min in the treatment group; every 30 to 60 min in the control group) and every 30 to 60 min during the first 2 h in ICU.

The designated treatment with either hyperinsulinemic–normoglycemic clamp or standard therapy began after induction of anesthesia and continued until sternal closure. Thereafter, the hyperinsulinemic–normoglycemic clamp infusion was reduced to 1 mU·kg⁻¹·min⁻¹. On arrival in the ICU, both groups received standard glucose control therapy as per our ICU protocol that aimed for blood glucose concentrations between 80 and 150 mg/dl on day of surgery and between 80 and 120 mg/dl on subsequent postoperative days.

We attempted delirium assessments the evening of surgery and then twice daily (morning and evening) for five postoperative days while patients remained hospitalized (a maximum of 11 assessments per patient). Reasons for nonassessments include patient refusal, intubation, sedation, ventilation, or undergoing another procedure. Delirium was assessed using a comprehensive delirium battery consisting of Richmond Agitation and Sedation Scale (RASS), CAM, Memorial Delirium Assessment Scale, and digit span test. In the previous studies, by using this delirium battery, trained research personnel was nearly as accurate in identifying delirium as psychiatrists using Diagnostic and Statistical Manual of Mental Disorders criteria.²⁹ 

Delirium was assessed by trained investigators who were blinded to intraoperative glucose management. Each investigator underwent a series of mock assessments and required certification before performing assessments on study patients. Monthly meetings and feedback sessions with case discussions ensured quality and consistency of the assessments. We considered patients to have experienced postoperative delirium when CAM testing was positive at any assessment.³⁰  CAM evaluates four features: (1) acute onset and fluctuating course, (2) inattention, (3) disorganized thinking, and (4) altered consciousness. A positive CAM test was defined by the presence of features 1 and 2 and either 3 or 4.

Sedation level was evaluated in every patient at the beginning of an assessment using the RASS.³¹  Patients with the RASS score of −4 or −5 were excluded from further evaluations. The digit span test evaluates working memory and consists of repeating back a series of numbers in the correct order.^32,33  Patients were further evaluated with the MDAS, which measures 10 items related to the severity of delirium. Disturbances in arousal, level of consciousness, memory, attention, orientation, and disturbances of thinking are rated on a four-point scale (0 to 3).^34,35 

The two randomized groups were compared for balance on demographics and baseline characteristics using standard summary statistics and the absolute standardized difference (ASD), defined as the absolute difference in means or proportions divided by the pooled SD. Any variable with an ASD greater than 0.2 was considered to be imbalanced.

The hyperinsulinemic–normoglycemic clamp group and standard therapy group were compared on postoperative delirium using chi-square test and generalized regression model with log link with adjustment for any imbalanced covariables. The relative risk (RR) was estimated along with the CI. We also conducted a sensitivity analysis to evaluate the treatment effect on postoperative delirium, where we assumed that all missing CAM assessments (due to refusal) were assigned to be positive delirium.

Second, we evaluated the difference between the two randomized groups on the average digit span score and average and maximum MDAS scores (a total of three analyses), using the independent Student t test and the Wilcoxon rank sum test as appropriate. The significance criterion for the three secondary analyses was P < 0.017 (i.e., 0.05/3, Bonferroni correction).

This is a sub study of a prospective, randomized, double-blind, single-center trial. All the available data were used to examine the focused aims and hypotheses. SAS software version 9.3 (SAS Institute, USA) was used for all statistical analyses.

Among 203 participating patients, 5 patients did not have any postoperative CAM assessments and were excluded; thus, we included a total of 198 patients each with at least one postoperative CAM assessment (fig. 1). On average, patients in each group had 8 ± 2 CAM assessments of the 11 possible measurements. Overall, 19% of the patients had assessments twice daily for 5 days, and 28, 26, 14, and 10% patients had assessments twice daily for 4, 3, 2, and 1 days, respectively. Among patients who were available for assessment (in hospital, awake, and unintubated), 94% of the evaluations were completed.

Demographics and baseline variables were well balanced between the hyperinsulinemic–normoglycemic clamp and the standard therapy groups (ASD <0.2, except for preoperative usage of calcium channel blocker and American Society of Anesthesiologist [ASA] physical status, table 1). Thus, we adjusted for these two variables when we compared the two randomized groups on the postoperative delirium. Intraoperative transfusions, fluids, opioids, medications (except insulin), total clamp and bypass times, and duration of surgery were also similar in each group (table 2).

The median intraoperative insulin dose was 126 (interquartile range, 94 to 184) and 18 (interquartile range, 11 to 27) units for patients in the hyperinsulinemic–normoglycemic clamp group and the standard therapy group, respectively. There were three patients in the standard therapy group who did not require insulin. Time-weighted average intraoperative glucose was 119 ± 18 and 171 ± 29 mg/dl in the hyperinsulinemic–normoglycemic clamp group and standard therapy group, respectively (fig. 2). No glucose assessments showed hypoglycemia (i.e., <40 mg/dl).

The average RASS was comparable in the clamp (−0.22 ± 0.4) and routine (−0.22 ± 0.5) glucose management groups (P > 0.99). Twenty-one percent (41 of 198) patients screened positive for delirium on at least one assessment. The incidence of delirium was 28% (26 of 93) and 14% (15 of 105) in the hyperinsulinemic–normoglycemic clamp group and the standard therapy group, respectively; unadjusted RR was 1.96 (95% CI, 1.11 to 3.46), P = 0.02. After adjusting for preoperative usage of calcium channel blockers and ASA physical status (ASD >0.20), the estimated RR was 1.89 (95% CI, 1.06 to 3.37), P = 0.03. Thus, patients randomized to tight glucose control had a higher probability of being diagnosed as delirious than those assigned to standard glucose control. Time-weighted average intraoperative glucose concentrations were 138 ± 31 and 149 ± 37 mg/dl in patients with and without delirium, respectively (P = 0.14, fig. 3). For a decrease of 10 mg/dl in minimum of intraoperative glucose, the estimated odds ratio of experiencing delirium was 1.15 (0.99 to 1.34; P = 0.06, post hoc analysis). For information purpose, baseline characteristics were summarized for patients with and without delirium (appendix).

Five percent of planned CAM assessments could not be done in the hyperinsulinemic–normoglycemic clamp patients because they refused evaluation; 3% of the assessments in the standard therapy group could not be completed for the same reason (table 3). Refusal may have been nonrandom as delirium per se often reduces cooperation. Therefore, we performed a sensitivity analysis in which all missing (due to refusal) CAM assessments were assigned to be positive. Under this assumption, the incidence of delirium in the hyperinsulinemic–normoglycemic clamp group (49%, 46 of 93) was again higher than the standard therapy group (32%, 34 of 105). These results were consistent with our original analysis indicating that the hyperinsulinemic–normoglycemic clamp causes delirium (RR, 1.60; 95% CI, 1.13 to 2.27; P = 0.01), after adjusting for preoperative usage of calcium channel blockers and ASA status.

In addition, we compared the incidence of delirium in patients who refused one or more delirium assessment (34%, 20 of 59) versus patients who never refused any assessment (including patients missed evaluations due to unavailability) (15%, 21 of 139). Patients refusing a delirium assessment were 2.2 times (95% CI, 1.3 to 3.8) more likely to develop delirium at a later point in time (P = 0.003, univariably).

We found that the average digit span was lower (worse) in hyperinsulinemic–normoglycemic clamp group (4.2 ± 0.7) than in the standard therapy group (4.5 ± 0.6). The estimated mean difference in the average digit span score was −0.32 (98.3% CI, −0.57 to −0.08; P = 0.002), after adjusting for usage of calcium channel blocker.

Among the 41 delirious patients, median MDAS scores did not differ significantly in patients assigned to the hyperinsulinemic–normoglycemic clamp (4.9 [2.7 to 8.3]) than for patients assigned to standard glucose control (4.1 [3.3 to 6.2], P = 0.43). The estimated median difference in the average MDAS score was 0.6 (98.3% CI, −1.6 to 3.4). Likewise, maximum MDAS score was not different in the hyperinsulinemic–normoglycemic group (11 [8 to 17]) than in the standard therapy group (9 [7 to 13]) with an estimated median difference of 2 (98.3% CI, −2 to 7), P = 0.29 (fig. 4).

The pathophysiology of delirium is multifactorial and remains poorly understood. However, delirium seems to result from reversible impairment of cerebral oxidative metabolism and multiple neurotransmitter abnormalities. Surgical stress up-regulates sympathetic tone and down-regulates parasympathetic tone, impairing cholinergic function and thus contributing to delirium. Another theory is that cytokine activation and alteration of growth factors are causes of postoperative delirium.³⁶ 

Hyperglycemia is both a response to inflammation and itself inflammatory, whereas insulin is antiinflammatory.^37,38  Thus, we expected tight glucose control with a hyperinsulinemic strategy to reduce the risk of postoperative delirium. In distinct contrast to our hypothesis, we found that tight intraoperative glucose control using hyperinsulinemic–normoglycemic clamp significantly increased the incidence of delirium in patients recovering from cardiac surgery.

Although tight intraoperative glucose control using a hyperinsulinemic–normoglycemic clamp increased the incidence of delirium, it did not alter its severity. (Digit span was significantly reduced in the clamp patients, and the difference was not clinically important.) Maximum MDAS scores were elevated in both glucose management groups, but did not differ significantly between the groups, with the maximum scores in the delirious patients being about 10 points. Typically a score of 13 has been associated with delirium diagnosis. Our maximum MDAS scores are slightly lower, but show a great variability. This variability in combination with low overall average MDAS scores (fig. 4) could indicate the fluctuating nature of delirium or the effects of medical interventions to improve delirium symptoms.

Observational studies report that hyperglycemia worsens delirium risk.^28,39,40  The difficulty with these analyses is that hyperglycemia is a response to inflammation, as well as potentially causing inflammation. Thus, patients with hyperglycemia are likely to have baseline inflammatory conditions and have experienced greater surgical stress—both of which likely provoke delirium independent of glycemic status. Thus, it is difficult to convincingly attribute delirium to hyperglycemia in observational studies because of potential confounding. Randomization eliminates selection bias and confounding, thus providing more reliable results. Our randomized results show just the opposite effect: Tight glucose control worsened delirium risk.

Our results are based on controlling glucose with a hyperinsulinemic strategy, which we expected to enhance protection because insulin is antiinflammatory. Although it remains possible that worsened delirium was specific to our hyperinsulinemic strategy, it seems unlikely that insulin per se caused delirium. Consistent with this theory, there was no association between insulin concentration and delirium in patients having hip surgery.⁴¹  However, we did not measure insulin concentrations in our patients and therefore cannot directly address this issue.

A consequence of tight glucose control is the occasional episode of severe hypoglycemia (i.e., ≤40 mg/dl), although none was observed in our patients. Thus, there is little reason to believe that severe hypoglycemia contributed to postoperative delirium. In contrast, it is worth considering that hyperglycemia is the normal physiological response to stress—cardiac surgery is an enormous stress. In fact, blood glucose concentrations in the routine management group averaged about 170 mg/dl, which is consistent with the Society of Thoracic Surgeons recommendation to keep glucose level less than 180 mg/dl in adults undergoing cardiac surgery.⁴²  Recommendations of American Diabetes Association⁴³  and the American Association of Clinical Endocrinologists⁴⁴  are similar. It may be that various organs benefit from generous glucose availability during periods of stress and that the brain is among them.

A difficulty with delirium assessments is that they are facilitated by a degree of patient cooperation. (Cooperation is more important for hypoactive delirium than for hyperactive delirium that is usually readily apparent.) A small fraction of the patients refused one or more assessments. The concern is that refusal may be nonrandom in that patients who suspect a cognitive problem may avoid confirmatory testing. Consistent with this theory, patients who refused a delirium assessment were twice as likely to subsequently have a positive CAM test. However, several sensitivity analyses to evaluate attrition bias did not materially alter the results, which is unsurprising because attrition was small and comparable in each group (3% in the routine management patients and 5% in the clamp patients).

Our study was restricted to patients recovering from cardiac surgery, a particularly stressful procedure and one that is frequently accompanied by delirium.^45–50  The extent to which our results generalize to other populations remains to be determined. We included patients with and without diabetes, but did not attempt a subanalysis because only about 30 patients in each group were diabetic. A final and important limitation of our study is that it is relatively small. Thus, although the incidence of delirium was significantly reduced in patients assigned to hyperinsulinemic–normoglycemic clamp management, this result is fragile and should be confirmed in a much larger trial.

In summary, our present results suggest that delirium incidence is higher in patients treated with intraoperative insulin therapy administered to achieve tight glucose control. These findings provide basis for reevaluation of beneficial effects of tight intraoperative control in patients undergoing cardiac surgery on outcome with specific aim to assess delirium.

This study was supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health, Bethesda, Maryland, under award number HL093065 (to Dr. Duncan) and the Department of Outcomes Research, Cleveland Clinic, Cleveland, Ohio. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

The authors declare no competing interests.