Ultradian Variation of Blood Glucose in Intensive Care Unit Patients Receiving Insulin Infusions

In this prospective, single-center, observational study in the ICUs of a university tertiary care hospital, we recorded all glucose measurements in two cohorts of ICU patients receiving an IIP targeting blood glucose 80–110 mg/dl. Supplementary details are available in an online appendix (available at http://dx.doi.org/10.2337/dc07-0865.).

Between 20 May 2006 and 6 August 2006, 141 ICU patients were treated with IIP, 8 of whom received insulin for two periods, resulting in 149 patient episodes. The average duration of insulin use for an episode was 115 ± 9 h (range 5–604). Forty-one percent (n = 11,670) of glucose measurements during this period were in the target range (80–110 mg/dl) (Fig. 1A). In preliminary data acquired between May 2004 and June 2005, the proportion of measurements in the target range increased initially and then stabilized (Fig. 1). Twenty-six percent of patients experienced at least one glucose value <60 mg/dl, and 2.7% had a glucose value <40 mg/dl.

The IIP was designed to control glucose within 8 h (1), and slightly more glucose measurements beyond 8 h (42%, n = 10,766) were in range (P = 0.014) (Fig. 1B). The mean and median of this positively skewed, non-Gaussian distribution (P < 0.0001, Kolmogorov-Smirnov test) were 118.5 and 112 mg/dl, respectively. The 0600-h measurements were also positively skewed (Fig. 1B) (P < 0.0001, Kolmogorov-Smirnov test). At 0600 h, glucose was lower than at the remaining times (112 ± 1.4 [n = 477] vs. 119 ± 0.3 [n = 10,364] mg/dl; P < 0.0001), and more of the 0600-h values were in the target range (47%). The correlation between 0600-h glucose measurement and average glucose for the consecutive 23 h was weak (Fig. 1C) (r² = 0.07; P < 0.0001; n = 472).

A plot of average glucose with time of day from the 149 patient episodes revealed an ultradian pattern (Fig. 1D). Mean glucose was steady overnight with an 0700-h nadir after which glucose values rose, peaking at 1100 and again at 2200 h. Mean blood glucose values were described after 0800 h by a sine wave with a period of 10.6 h and amplitude of 3 mg/dl. A second independent cohort of glucose measurements (n = 12,922) made from 201 patient episodes between 30 August and 31 October 2006 confirmed the ultradian pattern (Fig. 1D). Insulin infusion rates were collected, with the second cohort showing a similar partially sinusoidal ultradian pattern (Fig. 1D) (hourly n = 647–731) that was phase shifted by 1.2 h. Median and mean blood glucose values of the combined data varied similarly (Fig. 1E).

Interest in blood glucose control in the critically ill increased following the demonstration that targeting normoglycemia in a surgical ICU improves outcome (1). However, debate continues over the optimal target glucose and how to best achieve it using IIP. Our major findings are that glucose is the lowest in the morning, glucose at 0600 h correlates poorly with daily glucose, and glucose fluctuates with an ultradian pattern in ICU patients on IIP. Furthermore, we report that only a minority of glucose values were in the target range despite established IIP use, that glucose values were not normally distributed, and that insulin use was also ultradian.

Our data illustrate complex variability in blood glucose, which may complicate achievement of optimal control. The single randomized trial in which IIP improved mortality only reported 0600-h glucose values (mean ± SD 103 ± 19 mg/dl) (1). Assuming a normal distribution, we calculate that 55% of all glucose values in that study would have been in the target range (1). We found 47% of glucose values in range at 0600 h but only 42% if all values were considered, similar to the 22–52% reported previously (6–8). Since glucose is lowest at ∼0600 h (Fig. 1B and C), it remains unclear what proportion of the day glucose must be in the target range to improve outcome (9,10).

Difficulty in achieving tight glucose control has been attributed to patient instability and variability of glucose intake (11); however, the ultradian pattern of blood glucose demonstrated here may also explain some of the difficulty. Because a mean glucose rise of 20 mg/dl increases mortality by 30% (12), even the modest peak-to-trough ultradian variation (∼12 mg/dl) (Fig. 1D) that we observed may significantly impact mortality and morbidity.

This study cannot determine the mechanism of the ultradian variation. The falls in glucose from peaks at ∼1100 and 2300 h despite no increase in insulin indicate a decreased insulin requirement, possibly reflecting increasing insulin sensitivity or decreased glucose load. Likewise, the rise in glucose at 0900 and 2100 h occurred with little change in insulin. Nursing shift changes (Fig. 1D), changes in nutritional support, and medication administration are factors that may influence these observations. Interestingly, patients with type 2 diabetes have a similar ultradian pattern of blood glucose (13). Recently, a circadian pattern of glucose values was observed in Australian ICU patients when glucose values were pooled over 4-h periods. The apparently lower frequency of glucose variation may reflect the lower sampling rate or the impact of low use of IIP in Australian ICUs (14).

While we included medical, cardiac, neurosurgical, trauma, and general surgical ICU patients, further studies are required to determine if the findings may be extended to other patient populations at other institutions.

In conclusion, glucose is lower in the morning than during the remainder of the day. Blood glucose varies during the day in ICU patients receiving insulin. Consideration of this ultradian variation when treating hyperglycemia may help reduce the frequency of hypo- and hyperglycemic episodes.

We thank the volunteers of the Critical Care Academic Associates Program and the nursing staff and physicians in the ICUs at the Oregon Health and Science University. This work has been presented in abstract form at the 27th International Symposium on Intensive Care and Emerging Medicine, Brussels, Belgium, 27 March 2007.