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The Relationship Between a Pentagastrin-Stimulated Gastric Luminal Acid Production Test (Gastrotest) and Enteral Feeding-Related Gastrointestinal Complications in Critically Ill Patients

Hamilton, Mark A. MRCP, FRCA*; Chapman, Miriam V. MRCP, FRCA*; Mutch, Maj RGN*; Bennett-Guerrero, Elliott MD; Mythen, Monty G. MD, FRCA*†

doi: 10.1213/01.ANE.0000148688.30121.C0
Critical Care and Trauma: Research Report

Gastrointestinal feeding-related complications (GICs) are common in critically ill patients. Unfortunately, patients at risk for GICs cannot be easily identified. Therefore, we performed a prospective study of 20 critically ill patients to determine the association between a pentagastrin-stimulated gastric acid production test and GICs. Before feeding, the change in the pH of gastric juice was measured in response to a subcutaneous injection of pentagastrin (Gastrotest). We recorded GICs and the feeding volume ratio during each patient’s intensive care unit (ICU) stay. Nineteen patients’ data were analyzed and 9 patients (47%) developed ≥1 GIC, including large gastric residuals, 26%; abdominal distension, 26%; and vomiting, 21%. Patients with GICs had a longer length of ICU stay (mean 21.3, range 5–45 versus 10.1, range 3–32; P < 0.05). The 9 patients (47%) who were Gastrotest responders before starting enteral feeding exhibited a significantly larger volume ratio (P = 0.01) and fewer GICs (1 [11%] versus 8 [80%]; P < 0.05). Abdominal distension was seen in only nonresponders. The positive and negative predictive values for this test’s ability to predict GICs were 80% and 88.9%, respectively. Responding to a pentagastrin-stimulated gastric luminal acid production test is associated with the administration of larger volumes of enteral feed and fewer GICs.

IMPLICATIONS: Gastrointestinal feeding-related complications are common in critically ill patients. Unfortunately, patients at risk for these complications cannot be easily identified. In a cohort study of 20 patients, we describe how a functional stress test of the gut using pentagastrin can help identify patients at higher risk for gastrointestinal complications.

*Centre for Anaesthesia, University College London; †Department of Anaesthesia and Critical Care, Institute of Child Health, University College London, London, United Kingdom; and ‡Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina

Accepted for publication October 8, 2004.

Address correspondence and reprint requests to Elliott Bennett-Guerrero, MD, Duke Clinical Research Institute, Duke University (Anesthesiology-Box 3094), Durham, NC 27710. Address e-mail to

Early enteral (as opposed to parenteral) feeding of critically ill patients may improve gastrointestinal (GI) tract perfusion, mucosal integrity, and production of gastric acid and pancreatic juice, and as a result may improve outcome (1–6). However, enteral feeding is not successful in many critically ill patients because GI complications (GICs) are a common problem (2,7,8). GICs such as abdominal distension, large gastric residuals, and vomiting may not become obvious until >72 h after the start of enteral feeding (5). In addition, premature enteral feeding can adversely increase GI tract metabolic demand in patients with borderline splanchnic oxygenation and may promote the development of the nonocclusive bowel necrosis syndrome (8–13). Furthermore, failure to feed successfully via the GI tract despite reasonable efforts has repeatedly been associated with a poor outcome in critically ill patients (2,7,8,14). Many authors have hypothesized that there may be increased harm caused by feeding patients with an injured or poorly perfused GI tract.

Gut function can be measured experimentally, but the clinical relevance of such measures remains uncertain. There is a need for a simple test that can help clinicians predict whether a patient’s GI tract is receptive to enteral feeding. We hypothesized that the response of gastric juice pH to a test dose of a pharmacological stimulant may serve as a simple bedside test of GI tract function and predict subsequent success or failure of early enteral nutrition. Therefore, we decided to conduct a study to determine the relationship, if any, between a pentagastrin-stimulated gastric luminal acid production test (Gastrotest), efficacy of enteral feeding, and the incidence of related GICs in critically ill patients.

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After local ethics committee approval and written informed assent, we enrolled 20 patients who had been admitted to the Intensive Care Unit (ICU) at University College London Hospitals and whose lungs were ventilated, who had an arterial line in situ, and were to be fed enterally for an anticipated period of >5 days. Patients were excluded if they were <18 yr of age, pregnant, had nasopharyngeal or esophageal obstruction or esophageal varices, were receiving terminal palliative care, and/or were taking part in other clinical trials.

The gastric intraluminal pH was measured using a GrapHprobe gastric pH catheter (Zinetics Medical, Utah), which was inserted orally in each patient and connected to a Zinetics pH monitor (Zinetics Medical). Correct placement was then confirmed by radiography. Before the initiation of feeding, a subcutaneous injection of 6 μg/kg pentagastrin was administered to each subject. In healthy subjects with an intact splanchnic circulation, a subcutaneous injection of 6 μg/kg pentagastrin produces a rapid outpouring of gastric acid and thus a marked, but transient, decrease in intraluminal pH (15). A priori, we defined a positive test as a decrease in gastric juice pH of ≥1 pH unit within 90 min of the pentagastrin administration.

At baseline (T), defined as 150 min before the initiation of enteral feeding, a feeding tube and pH probe were inserted. At T + 60 min, the gastric juice pH was recorded, pentagastrin was administered as described above, and the pH was measured every 15 min for 90 min. At T + 150 min, enteral feeding was started as per unit protocol as described below.

Before feeding was commenced, a fine-bore feeding tube was inserted via the nose and its position confirmed by radiography. Enteral feed was then delivered according to our institutional algorithm in conjunction with dietetic advice as follows. Enteral feeding was initiated at a rate of 30 mL/h for 4 h. After checking an aspirate and ensuring that it was <200 mL, the rate was increased to 60 mL/h for 4 h. Another aspirate was then checked and if <200 mL, the feeding rate was increased to 83 mL/h for another 4 h. An aspirate was checked again and if <200 mL, the rate was maintained at 83 mL/h (with aspirates checked every 8 h thereafter). All aspirates <200 mL were returned to the stomach via the feeding tube. All patients received Osmolite™ as their standard feed (institutional standard of care). Efficacy of the administration of enteral feed was assessed in four different ways:

  1. The ratio of delivered to prescribed feed
  2. Delivered feed minus aspirates
  3. The ratio of delivered feed minus aspirates to prescribed feed
  4. The ratio of delivered feed minus aspirates to 70% of our goal feed (1394 mL)

Aspirates were only recorded if ≥200 mL because, according to our institutional protocol, aspirates of <200 mL are returned to the stomach via the nasogastric tube. Our goal feed target was 83 mL/h for 24 h. This equates to a delivery of 1992 mL, of which we deemed achieving 70% (1394 mL) would provide basic sufficient caloric intake.

In addition, information was collected on specific GICs related to enteral feeding. The main GICs were defined a priori by consensus. The group was guided by the results of a multicenter observational cohort study of feeding-related GICs in 192 patients in 5 ICUs, including the study ICU (7). Of note, the most common route of feed administration in the multicenter study was into the stomach. It was decided that the main GICs collected would be: large gastric residuals (>200 mL after 4 h), abdominal distension (confirmed by girth measurement), and vomiting, because these were thought to be the most objective. In addition, all other GICs thought to be related to feeding were recorded, but these were not statistically analyzed. Study staff recording the GICs and enteral feed volumes were blinded to the results of the Gastrotest.

Demographic details, history, current diagnosis, and Acute Physiology, Age, and Chronic Health Evaluation II score on admission were recorded. At baseline, and at each subsequent study time point, routinely measured cardiovascular variables, prescribed medications, and therapeutic interventions were recorded as well as the study variables. Patients were followed until discharge from the ICU or death in the ICU.

For this preliminary study, we studied 20 patients because we expected 1 or more GICs to occur in approximately 50% of patients based on our own audit data and the published literature. Descriptive statistics of the whole group’s study variables were produced to allow comparison with relevant published literature. The patients were then stratified into groups according to a positive or negative response to the pentagastrin test (Gastrotest responder and Gastrotest negative, respectively) at baseline. On initial analysis, the feed volume data were not normally distributed, therefore the Mann-Whitney U-test was used for primary intergroup analysis. These data were presented as median and interquartile range. Otherwise, between-group comparisons of continuous variables were made using the unpaired Student’s t-test and categorical variables using Fisher’s exact test. A P value < 0.05 was considered significant. All statistical analyses were performed using StatView for Windows version 4.57.

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A total of 20 patients were enrolled in the study. Clinical data were not available for one patient because of a clerical error and loss of data. Demographics and primary outcome variables for the individual study patients ranked according to their Gastrotest results are shown in Table 1. Overall, 9 patients (47%) developed 1 or more GICs. The frequency of the most common GICs was as follows: large gastric residuals, 26%; abdominal distension, 26%; vomiting, 21%. Patients who developed GICs had a longer mean length of stay in the ICU (21.3 days, range 5–45 versus 10.1, range 3–32; P < 0.05). Nine patients (47%) were Gastrotest responders before starting enteral feeding. Only 1 (11%) Gastrotest responder experienced GICs compared with 8 (80%) Gastrotest nonresponders (P < 0.05). Of note, the Gastrotest responder who developed GICs (large residuals and vomiting) was successfully enterally fed (mean volume ratio 102%). Of the eight patients who were Gastrotest nonresponders, five developed abdominal distension with or without vomiting and exhibited complications included ileus, pancreatitis, and peritonitis. Those patients who were Gastotest nonresponders had a positive predictive value for GIC of 80% and a negative predictive value for GIC of 88.9%.

Table 1

Table 1

Table 2 illustrates demographics by groups stratified by the pentagastrin test. There were no significant differences between groups at baseline. The feeding outcome variables used to determine the efficacy of administration of gastric enteral feed are summarized in Table 3. There was a statistically significant larger volume of feed administered to those patients who were Gastrotest responders for all four of the feeding outcome variables.

Table 2

Table 2

Table 3

Table 3

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Consistent with previous studies, we found frequent enteral feeding-related GICs (47%), including abdominal distension, large gastric residuals, and vomiting (2,5,7,14). Approximately 20% of our patients received <50% of their prescribed feed, and patients who developed GICs had longer stays in the ICU.

For example, Adam and Batson (7) described the problems associated with enteral feeding in five ICUs in the United Kingdom. They studied 193 patients involving 1929 patient days. On average, they found that 76% of prescribed feed was delivered and 23% of patients failed because of “problems with gut function.” In a meta-analysis of total parenteral nutrition versus total enteral nutrition (total of 230 mainly United States [USA] patients) by Moore et al. (5), it was reported that 48% of patients developed abdominal distension, which was described as “moderate to severe” in 14% of the total group. A multicenter immunonutrition study by Bower et al. (2) in the USA (n = 279) reported “unsuccessful feeding” in 28% of patients, and these patients had an excess mortality. Montejo (14) reported the results of a multicenter study of 37 ICUs in Spain and 400 consecutive patients who were enterally fed. One or more GICs occurred in 62.8% of patients, including: large gastric residuals, 39%; abdominal distension, 13.2%; and vomiting, 12.2%. In the Montejo study, GICs were associated with a longer ICU stay and excess mortality. It is interesting to note that, in our study as well, there was an increased length of ICU stay for those with GICs. These results need to be interpreted with some caution, however, because our study was not powered for length of stay or mortality.

The Gastrotest has a sound physiological basis. Pentagastrin-stimulated gastric luminal acid production requires drug delivery, receptor function, and energy-demanding gastric acid production, which is proton pump dependent (15). In our study, patients who were Gastrotest responders at baseline were more likely to tolerate enteral feedings based on clinical signs and received statistically significantly larger volumes of feed than the patients who were Gastrotest negative.

Determining efficacy of the administration of enteral feed is notoriously difficult. We chose to use four separate measures of efficacy and the ratio of prescribed-to-delivered volumes of feed as our primary measure based on published studies. The statistically significant differences in volumes of feed administered are of doubtful clinical significance in terms of delivered calories. Furthermore, food administration is no guarantee of food absorption from the GI tract or subsequent substrate utilization. Patients with distended abdomens and large gastric residuals may well have the majority of administered feed lurking in dilated loops of stagnant bowel. These issues could be examined using a variety of techniques, such as paracetamol or differential sugar absorption techniques or determination of metabolic changes by indirect calorimetry. We decided to take a pragmatic approach in this pilot study and were more focused on GICs than volumes of feed administered, for reasons discussed above. The results may have been different in terms of volumes administered if feeding had been subpyloric or bolus rather than continuous. However, continuous gastric feeding is our standard of care, as it was in 2 large observational European cohorts [Adam and Batson (7), 193 United Kingdom patients, 99% gastric route; Montejo (14), 400 Spanish patients, 91% gastric route].

It remains unclear if the association between feeding-related GICs and a worse outcome is a cause-and-effect relationship. Failure to feed may just be a manifestation of an injured or underperfused gut. However, there are now a number of reports of feeding-related complications (1–14,16–21). Gut hypoperfusion is common in critically ill patients and is associated with a poor outcome (15,22). Feeding patients with known mesenteric vascular disease can cause mesenteric ischemia and abdominal pain (23,24). It has been demonstrated in an animal model that enteral feeding during a reduced blood flow can cause a steal of blood away from nonfed gut to fed gut and induce distal ischemia (25). There is also a worrying trend toward excess mortality in patients who are randomized to receive immunonutrients compared with standard feed (1,2,21). Immunonutrients are known to produce a greater hyperemic response in healthy gut and therefore may result in increased metabolic demand and greater steal effect in the injured or hypoperfused gut (21).

The recurring theme of enteral feeding studies of critically ill patients being negative on an intent-to-treat analysis but often showing subset benefit in those who are “successfully fed” (and thus subset harm in the nonsuccessfully fed) is also consistent with this theory (1,2,21). However, the putative link between enteral feeding and harm to some patients remains speculative. It would seem beneficial if patients who can be fed easily and successfully into the stomach could be identified, because there is good evidence to suggest that early feeding is associated with a more favorable outcome (26,27).

This study shows that a positive pentagastrin-stimulated gastric luminal acid production test (Gastrotest) is associated with the administration of larger volumes of enteral feed and fewer related GICs. This suggests that the Gastrotest may be useful in guiding the early enteral feeding of critically ill patients. The benefits of using such a test may be twofold. First, a large group of patients with a receptive GI tract may be fed larger volumes of food, earlier via the gastric route. Early successful enteral feeding has repeatedly been demonstrated to be beneficial in post hoc analysis of relevant large prospective randomized controlled trials. Second, patients with a nonreceptive gut may benefit from early identification and avoidance of subsequent feeding-related complications. This group may benefit from further resuscitation of the GI tract, small-dose gastric feeding, early total parenteral nutrition, or a combination of all three.

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