Introduction
Delayed gastric emptying (GE) occurs frequently in critically ill patients [
1] and is associated with impaired tolerance to naso-gastric feeding [
2]. By slowing the transfer of food from the stomach into the small intestine and, thereby, reducing or delaying exposure of nutrient to small bowel mucosa, gastric stasis has the potential to adversely affect both the rate and extent of nutrient absorption [
3]. Absorption may also be compromised by factors other than GE, including the rate of small intestinal transit, mucosal villous atrophy or oedema and reduced splanchnic perfusion. There is limited information about nutrient absorption in critically ill patients, and the relation between GE and absorption has hitherto not been evaluated.
Postprandial blood glucose concentrations are affected by many factors, including GE and small intestinal glucose absorption [
3,
4]. In health, the relation between GE and glycaemia is complex. Acute hyperglycaemia, including elevations in blood glucose that are within the normal postprandial range, has been shown to slow GE when compared with euglycaemia [
5]. However, a reduced rate of GE will also slow the rate of carbohydrate absorption [
6] and, thereby, attenuate the rise in blood glucose following a carbohydrate meal [
3,
7]. Thus, in health and in type 2 diabetes, the rate of GE is both a determinant of, as well as being determined by, blood glucose concentrations [
4]. The relation between glycaemia and GE in critically ill patients has hitherto not been evaluated. Hyperglycaemia is usually attributed to insulin resistance and elevated glucagon concentrations, which frequently occur even when there is no history of diabetes [
8]. This could contribute to the delayed GE observed in many critically ill patients. Conversely, delayed GE may potentially attenuate hyperglycaemia in patients fed by the naso-gastric route. There is evidence that maintenance of blood glucose concentrations in the euglycaemic range improves outcomes in critically ill patients [
9]. Hence, an improved understanding of the factors influencing glycaemia is important.
The aims of this study were to quantify glucose absorption and assess the relations between absorption and glycaemia with GE in critically ill patients.
Discussion
This study suggests that both the rate and extent of glucose absorption are markedly reduced in critically ill patients [
14‐
16], and demonstrates that there is a close relation between glucose absorption and GE in these patients, such that slow GE is associated with a reduced rate of absorption. An important new finding is that, even when GE is normal, glucose absorption is impaired. This indicates that there are additional causes to account for impaired absorption, other than delayed GE. A relation was also demonstrated between the increment in plasma glucose after the nutrient bolus and glucose absorption.
Two authors have previously reported reduced sugar absorption in critically ill patients. Singh and colleagues [
16] found that plasma xylose concentrations were markedly reduced one hour after administration in patients with severe sepsis and trauma [
16]. Similarly, measuring a single plasma level at 120 minutes, Chiolero and colleagues [
14] demonstrated reduced, or delayed, absorption of xylose in a mixed group of ICU patients [
14]. These studies did not attempt to differentiate between rate and total absorption. The rate of absorption is indicated by the time taken to reach maximum concentration in the blood [
17], the maximum concentration achieved after a dose of substrate reflects both of these factors. The total absorption is indicated by the AUC, which reflects the extent of substrate absorbed over that time period [
17].
Our study confirms that the rate of glucose absorption is reduced in critical illness. It also suggests that total absorption is reduced. This result needs further confirmation as 3-OMG concentrations had not returned to baseline at the end of the four-hour period. So it is possible that had the blood sampling continued, complete absorption may have eventually occurred; however, this appears unlikely. Hadfield and colleagues [
15] assessed total 3-OMG absorption in a critically ill cohort by measuring urinary concentrations and found it to be reduced to approximately 20% of normal [
15]. Accordingly, although we could only calculate AUC 0 to 240 minutes, it is likely that both rate and total glucose absorption are affected. However, when the rate of GE is normal the rate of glucose absorption also appears to be normal, even though total absorption may be reduced.
Glucose absorption across enterocytes takes place predominantly in the proximal small intestine, via the sodium-glucose cotransporter (SGLT 1) at the luminal membrane and the GLUT2 at the basolateral membrane [
18]. Increased blood glucose concentrations are associated with increased glucose absorption [
19]. In the rat, hyperglycaemia increases glucose uptake by increasing the activity of intestinal disaccharidases [
20] and the number or activity of carriers at the basolateral membrane [
21]. In the current study no relation was observed between baseline blood glucose concentrations and glucose absorption.
The rate and/or extent of glucose absorption is dependent on a number of factors that include GE, the presence of pancreatic enzymes, contact time with the small intestinal mucosa (transit), contact surface area (length of intestine, surface villi, enzyme content of brush border, and function of carrier molecules) and the depth of the diffusion barrier of the absorptive epithelium (unstirred layer) [
22]. The underlying causes of the probable reductions in total glucose absorption in critical illness are unclear. Although in this study there was a relation between the rate of glucose absorption and GE, this did not account for the reduction in total absorption. Small intestinal mucosal abnormalities are known to occur in critically ill patients and are likely to be an important cause of malabsorption. Villous height and crypt depth are known to be reduced, while permeability is increased following a period of fasting [
23]. Mucosal atrophy could also be associated with disruption in the amount, or function of, digestive enzymes. In addition, mucosal oedema and reduced splanchnic blood flow may contribute to reduced absorption. Abnormal small intestinal motility may also be important [
24] and accelerated transit would reduce the time for absorption. However, to date, small intestinal transit has not been formally examined in the critically ill population. It is possible that some critically ill patients have significant malabsorption and cannot be fed enterally. This needs further investigation and, if confirmed, methods to identify these patients clinically need to be developed.
In health and some disease states, GE is both determined by, and a determinant of, blood glucose concentrations [
4]. This study found that slower GE was associated with a smaller increment in blood glucose in the healthy subjects, consistent with previous observations [
25]. Although no relation between postprandial blood glucose concentrations and GE was demonstrated in the critically ill patients in this study, the postprandial increment in blood glucose was related to glucose absorption.
Hyperglycaemia occurs frequently in critical illness, has been attributed to insulin resistance, as well as abnormalities in the release and action of other regulatory hormones and the presence of inflammatory cytokines [
8], and is associated with a worse clinical outcome [
9,
26]. The close relation between GE and glucose absorption suggests that, if GE is accelerated by the use of prokinetics, or if the stomach is bypassed and nutrient is placed directly into the small intestine, the rate of glucose absorption may be increased. This could have the undesirable effect of increasing blood glucose concentrations. However, it is unclear how important this effect is in patients receiving continuous infusions of enteral feeding because in this study the nutrient was delivered as a single naso-gastric bolus, which is likely to cause a greater increment in blood glucose concentration. This warrants further investigation.
Acute elevations in blood glucose concentration slow GE in healthy humans and patients with type 1 diabetes. Hyperglycaemia (about 15 mMol/l) markedly slows GE [
5,
27,
28], but even changes in blood glucose concentrations within the normal postprandial range (4 to 8 mmol/l) can have a significant impact [
29‐
31]. Consistent with these findings, this study found an inverse relation between baseline blood glucose concentrations and subsequent GE in the patients, such that higher blood glucose was associated with slower GE. The absence of a relation in healthy subjects is not surprising given that blood glucose concentrations were much lower (maximum 6.4 mMol/l). Hence, it is possible that in ICU patients glycaemia influences GE. However, the causes of delayed GE are likely to be multifactorial and the relative importance of changes in blood glucose concentrations is as yet unclear. Hyperglycaemia may also reduce the effect of prokinetic drugs such as erythromycin [
32‐
35] and metoclopramide.
There are some limitations in this study which need to be considered when interpreting the results. The kinetics of 3-OMG absorption have never been validated in the critically ill population. It is possible that kinetic variables, such as the volume of distribution and renal clearance, may affect 3-OMG concentrations following ingestion. These effects are likely to vary between individuals and in the same individual over time. An increase in volume of distribution would reduce 3-OMG concentrations but it is unlikely that this could account for the marked reduction in 3-OMG concentrations observed in this study. Similarly, three patients in this study were receiving renal replacement therapy. It is not known how 3-OMG is cleared by dialysis and so the effect of this on the 3-OMG concentrations cannot be predicted.
Blood samples for the measurement of glucose and 3-OMG were taken from an arterial line in the patients and a venous line in healthy subjects. There is a difference in blood glucose concentrations between arterial and venous samples, but this difference is generally believed to be small [
36,
37]. As 3-OMG is not metabolised by tissues, there is unlikely to be a difference between arterial and venous samples, but this has not been documented.
The number of subjects recruited was relatively small. Nevertheless, highly significant differences were observed between healthy subjects and critically ill patients, suggesting that a study with greater numbers is unlikely to generate different results. However, there was a difference in the age and gender ratio between the two groups. In health, GE is probably slightly slower in pre-menopausal women than in age-matched men [
38‐
40]. Interestingly, the largest study to date examining GE in critically ill patients suggests that gender has the opposite effect, in that women had a faster emptying rate [
2], although this is not a consistent finding [
41,
42]. It is possible that normal hormonal effects are less evident in critically ill patients, because critical illness causes marked aberrations in hormonal activity so the gender effect on GE may be less important. It is also likely that other factors have a stronger influence on GE causing marked slowing in some cases and obscuring the more subtle hormonal effects. In this study, there was a greater proportion of women in the healthy group, which could have resulted in a slowing of GE in this cohort. However, the current study demonstrated slowed GE in critically ill patients compared with healthy controls. We may have shown a greater difference if we had included more males in the control group.
The effect of healthy ageing on GE is uncertain with inconsistent observations [
43‐
49]. Extreme ageing is thought to be associated with a slowing of GE, which may reflect an increase in small intestinal nutrient feedback [
50]. Studies on the elderly usually evaluate subjects in the age range 65 to 80 years. The age range of the critically ill patients recruited into this study was 28 to 79 years (median 63). Heyland and colleagues [
2] reported a small, but significant slowing of GE with increasing age in a mixed critically ill cohort [
2]. It is possible that age may have contributed to the delays in GE observed in this critically ill cohort; however, its importance is unclear and any effect is likely to be small. It should be noted that the effects of gender imbalance and age would have opposing effects on the GE in the two groups. It is also possible that the differences in age and gender balance may be the cause of reduced glucose absorption in the critically ill group, but this unlikely.
Competing interests
The authors declare that they have no competing interests.
Authors' contributions
MC, RF and MH were involved with study conception and design, data interpretation, statistical analysis and drafting of the manuscript. MB, KJ and BC were involved in study design and scintigraphic data acquisition and interpretation. AR provided technical support for studies and data acquisition. LB was involved in data acquisition, technical support, analysis and revision of the manuscript. GM and RB were involved in study design and performed the analysis of plasma 3-OMG using HPLC. All authors read and approved the final manuscript.