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Journal of Parenteral and Enteral Nutrition
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Original Communications

Gastric Motility Function in Critically Ill Patients Tolerant vs Intolerant to Gastric Nutrition

James Landzinski, PharmD*, Tyree H. Kiser, PharmD{dagger}, Douglas N. Fish, PharmD, FCCM, FCCP{dagger}, Paul E. Wischmeyer, MD{ddagger} and Robert MacLaren, PharmD, FCCM, FCCP{dagger}

From the * Department of Pharmacy, Georgetown University Hospital, Washington, DC; and the{dagger} Department of Clinical Pharmacy, School of Pharmacy, and {ddagger} Department of Anesthesiology, School of Medicine, University of Colorado at Denver and Health Sciences Center, Denver, Colorado

Correspondence: Robert MacLaren, PharmD, FCCM, FCCP, School of Pharmacy, University of Colorado at Denver and Health Sciences Center, 4200 East Ninth Avenue, C238, Denver, CO 80262. Electronic mail may be sent to rob.maclaren{at}uchsc.edu.

Background: Administration of gastric enteral nutrition (EN) in the intensive care unit (ICU) is commonly impeded by high gastric residual volumes (GRV). This study evaluated gastric emptying in patients with limited GRV (tolerant group) vs volumes ≥150 mL (intolerant group) and whether prokinetic therapy improves gastric motility in intolerant patients. Methods: To assess gastric motility, mechanically ventilated patients received acetaminophen 975 mg, and peak plasma concentration (Cmax), concentration at 60 minutes (C60), time to Cmax (Tmax), and area under the concentration-time curve from 0 to 60 minutes (AUC0-60) were determined. This evaluation was repeated in intolerant patients after 24 hours of either erythromycin 250 mg or metoclopramide 10 mg therapy, both administered intravenously every 6 hours. Results: Ten tolerant and 20 intolerant patients were studied. Tolerant patients had significantly greater Cmax (14.12 ± 7.25 vs 9.28 ± 5.22 mg/L; p < .05), C60 (9.62 ± 4.65 vs 6.08 ± 4.00 mg/L; p < .001), and AUC0-60 (10.01 ± 5.97 vs 3.93 ± 2.84 mg/h/L; p < .01) and shortened Tmax (0.81 ± 0.61 vs 1.98 ± 1.26 hours; p < .001) compared with intolerant patients. After prokinetic therapy, Cmax (15.26 ± 8.85 mg/L), C60 (11.96 ± 5.99 mg/L), and AUC0-60 (10.90 ± 6.57 mg/h/L) increased and Tmax (1.07 ± 1.01 hours) decreased in the intolerant group to values similar to the tolerant group. Conclusions: ICU patients with elevated GRV during gastric EN have delayed gastric motility. Initiating prokinetic therapy accelerates gastric emptying to resemble that of ICU patients tolerating EN.

The initiation of early gastric enteral nutrition (EN) in critically ill patients increases secretion of mucosal immune factors and enhances the integrity of the gastrointestinal wall to limit septic complications and possibly decrease the overall cost and length of intensive care unit (ICU) and hospital stays.1–4 Consequently, expert opinions recommend initiating EN within 24 hours of ICU admission.5–7 Only 42%–76% of critically ill patients achieve goal caloric rate and 43%–63% of patients are unable to tolerate gastric EN.8–17 The development of high gastric residual volumes (GRV) impedes the delivery of gastric EN, occurring in 30%–51% of patients.8–17 Patients with high GRV are at increased risk of aspiration and have lengthened ICU stays and higher mortality rates.17

Gastrointestinal motility dysfunction is the primary reason for intolerance and is associated with several factors, including medications (opioid agonists, dopamine), hyperglycemia, electrolyte disturbances, ischemia/hypoxia, burns, trauma, surgery, sepsis, increased intracranial pressure, and the administration of calorically dense or hyperosmolar formulas.18–21 Impaired motility is attributed to alterations of the interstitial cells of Cajal, which are concentrated in the gastric antrum and act as the "pacemaker" of gastrointestinal motility and disturbances of the interdigestive motility pattern known as the migrating motor complex.22,23

Most experts recommend monitoring GRV as a method of assessing gastrointestinal motility and initiating therapy with a prokinetic agent (erythromycin or metoclopramide) when these volumes are elevated.4–7,20,21,24–27 Unfortunately, definitions of elevated GRV vary widely across recommendations and studies, likely because data in ICU patients relating gastrointestinal motility function to GRV are few. Studies have demonstrated that prokinetic agents enhance motility and reduce GRV in ICU patients with intolerance to facilitate EN administration, but other clinical outcomes, such as aspiration, have not been adequately studied.28–33 The purpose of this study was to comparatively evaluate gastric emptying function, using the acetaminophen absorption method34,35 in patients with limited GRV and in those with increased GRV, and to subsequently determine if prokinetic therapy improves gastric motility in patients with intolerance.


   MATERIALS AND METHODS
Top
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 
Patients
The study protocol was approved by the institutional review board of the University of Colorado at Denver and Health Sciences Center. Patients were enrolled from 1 of 3 ICUs at the University of Colorado Hospital (16-bed medical ICU, 16-bed surgical ICU, and 8-bed neurologic ICU), resulting in a heterogeneous study population. Written informed consent and authorization in compliance with the Health Insurance Portability and Accountability Act were obtained from the patient or next of kin/legal representative.

Critically ill, mechanically ventilated patients between the ages of 18 and 85 years were eligible for enrollment if they were receiving continuous naso- or orogastric administration of EN and were either tolerant or intolerant to EN. Tolerance was defined as the administration of EN at a feeding rate sufficient to supply at least 75% of the patient's daily energy requirements (as determined by an ICU dietitian) and a cumulative GRV ≤120 mL in the 24-hour period preceding enrollment, with each individually measured GRV ≤30 mL. Intolerance was defined as a single aspirated GRV ≥150 mL within the 24-hour period preceding enrollment, unless this volume was measured within 4 hours of enteral administration of contrast media, sterile water, or medications. GRVs were measured by a bedside nurse every 4 hours, using the aspiration-by-syringe technique through an 18-Fr large-diameter tube. EN was administered through this tube. As outlined by an institution-specific EN administration protocol that existed before this study was initiated, EN is started as early as possible, according to physician discretion and after consultation with an ICU dietitian. The protocol starts gastric EN at a rate of 20 mL/h with increases of 20 mL/h every 8 hours until the goal rate is achieved. For patients receiving continuous administration of vasopressor agents (see exclusion criteria for definitions) or neuromuscular blocking agents, the rate is started at 10 mL/h and increased by 10 mL/h every 12 hours. The protocol stipulates that EN be discontinued for 4 hours after the development of intolerance and then restarted at half the previous rate and increased by 10 mL/h every 8 hours as tolerated. Volumes <150 mL are returned, and half the volume is returned for GRVs ≥150 mL.

Patients were excluded from enrollment if any of the following were present: administration of erythromycin or metoclopramide within 24 hours of evaluation for study eligibility; known severe adverse event to acetaminophen; gastrointestinal hemorrhage or bowel surgery within 24 hours of evaluation of eligibility; malabsorptive gastrointestinal disease (obstruction, perforation, short bowel syndrome, or Crohn's disease); abnormal liver function as defined by liver transplantation or the presence of 2 of the following: transaminases or total bilirubin ≥3 times the upper limit of normal, or prothrombin time ≥2 times the upper limit of normal; renal dysfunction requiring active renal replacement therapy; hemodynamic instability defined by a mean arterial pressure (MAP) <65 mm Hg despite fluid resuscitation and the administration of IV infusions of dopamine >10 µg/kg/min, norepinephrine at any dose, epinephrine at any dose, or phenylephrine at any dose; blood depletion within 12 hours of evaluation for study eligibility, defined by the presence of a hemoglobin count <6.5 g/dL or hematocrit <0.22 and not replaced with packed red blood cells; pregnant women or women suspected of being pregnant; or severe obesity, defined by actual body weight ≥150% of ideal body weight.

Study Design
Consecutive ICU patients were screened daily by an investigator to determine study eligibility. Before enrollment, correct antral positioning of the gastric tube was determined by auscultating over the stomach after injecting air and confirmed radiographically when possible. After patient consent was obtained, Acute Physiology and Chronic Health Evaluation (APACHE) III score was assessed for the 24-hour period before enrollment. The use of agents affecting gastric motility (dopamine, opioids, cathartics) was recorded but not controlled for by the study protocol.

The acetaminophen absorption method was used to assess gastric emptying function. Studies in critically ill patients have demonstrated that acetaminophen absorption (plasma concentration at 60 minutes [C60] and area under the plasma concentration-time curve from 0 to 60 minutes [AUC0-60]) correlates significantly with gastric emptying.34,35 Both peak plasma concentration (Cmax) and time to peak concentration (Tmax) have been validated as markers of gastric emptying and have showed gastric motility dysfunction at baseline, with enhanced emptying after prokinetic therapy.28–32,36–41 Within 6 hours of study enrollment, all patients received 975 mg of enteral acetaminophen as 30 mL of undiluted syrup (32.5 mg/mL), followed by 20 mL of sterile water to flush the feeding tube (the tube was not flushed before acetaminophen administration). The exact time of administration was recorded by the bedside nurse and verified by a study investigator. All gastric contents were emptied and discarded immediately before acetaminophen administration, regardless of the volume. This GRV was included in the daily GRV calculations. EN was then temporarily discontinued during the 6-hour period of blood collection. Venous blood samples of 3 mL in volume were obtained from an indwelling catheter by a study investigator immediately before and 15, 30, 45, 60, 90, 120, 180, 240, and 360 minutes after acetaminophen administration. Blood samples were collected in test tubes without heparin and transported on ice. Plasma was separated from cellular components by centrifugation for 15 minutes at 3000 rpm. Plasma samples were placed in labeled polyethylene vials, frozen at –80°C immediately after processing, and kept frozen until assayed. Acetaminophen concentrations were determined in duplicate by a fluorescence polarization assay (TDx-FLx; Abbott Diagnostics, Chicago, IL), as described elsewhere,31 and the mean concentration at each time point was used for pharmacokinetic analysis. Noncompartmental analysis of acetaminophen concentrations with WinNonlin version 5.0.1 (Pharsight Corporation, Mountain View, CA) was used to determine Cmax, C60, Tmax, the area under the concentration-time curve from 0 to 360 minutes (AUC0-360), and AUC0-60. As per the institution-specific EN protocol, patients in the intolerant group received therapy with a prokinetic agent (either erythromycin 250 mg or metoclopramide 10 mg, each administered intravenously every 6 hours) that was initiated after all blood samples for acetaminophen pharmacokinetic analysis were collected. The acetaminophen absorption procedures were repeated 30 minutes after administration of the fourth dose of prokinetic agent to assess whether gastric emptying improved with prokinetic therapy. Other orders for acetaminophen-containing products were discontinued during the study, with the last dose administered at least 6 hours before gastric motility assessment.

Statistical Analyses
For a power of 0.8 and a significance level of .05, enrollment of 9 patients in the tolerant group and 18 patients in the intolerant group was required in order to show a difference of 4.6 mg/L in C60, assuming standard deviations of 3.5 mg/L and 5 mg/L, respectively.32 A previous, randomized, crossover study of single doses of erythromycin and metoclopramide showed erratic acetaminophen absorption for 2 (20%) of 10 patients.31 Therefore, 10 patients were enrolled in the tolerant group and 20 patients in the intolerant group. All statistical analyses used SAS (version 9.1; SAS Institute, Inc, Cary, NC). Statistical analysis of continuous variables between study groups used the t-test or Mann-Whitney U test for parametric data and nonparametric data, respectively. Statistical analysis of continuous variables before and after the administration of prokinetic agents used the paired t-test or the Wilcoxon matched pair test for parametric data and nonparametric data, respectively. Statistical significance was defined as p <.05. All data are reported as mean ± standard deviation (SD) unless stated otherwise.


   RESULTS
Top
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 
Ten and 20 patients were enrolled into the tolerant and intolerant groups, respectively. All patients were included in the final data analyses. Patient demographics and clinical characteristics were similar between study groups (Table I). Although not stipulated in the study protocol, all patients had the head of the bed elevated at least 30°. With respect to nutrition-related variables, the tolerant group had lower cumulative GRV for the 24-hour period before enrollment despite receiving EN at rates higher than the intolerant group (Table II). All patients in the tolerant group were receiving EN at rates sufficient to supply goal caloric intake (0% caloric deficit) and all patients in this group continued to receive EN at goal caloric intake for at least 72 hours after enrollment, with minimal GRV. Seventeen (85%) intolerant patients had at least 1 other GRV assessment ≥100 mL during the 24-hour period preceding enrollment. Patients tolerating EN had significantly greater Cmax, C60, AUC0-360, and AUC0-60 and shortened Tmax compared with patients intolerant to EN (Table III). All patients in the intolerant group received prokinetic therapy (n = 10 erythromycin and n = 10 metoclopramide). After 4 doses, Cmax, C60, AUC0-360, and AUC0-60 increased and Tmax shortened (Table III) with the magnitude of differences from baseline slightly greater with erythromycin. After administration of prokinetic therapy, all of these pharmacokinetic variables were similar to the values initially obtained in the tolerant group (Table III). Once adjusted for absorption rates, no differences existed between groups or within groups for any other pharmacokinetic parameter, including elimination rates. Active bowel sounds were evident in 9 (90%) tolerant patients and 3 (15%; p < .001) intolerant patients, which increased to 15 (75%; p < .01) patients with prokinetic therapy. The mean GRV after the fourth prokinetic dose was 28 ± 36.5 mL, which was significantly lower than the initial GRV of 208 ± 75.1 mL (p < .0001) that was required for study eligibility. The rate of gastric EN increased from 36.4 ± 18.9 mL/h (43.4% caloric deficit) at study enrollment to 44.2 ± 20.5 mL/h (31.3% caloric deficit; p = .22) after the fourth prokinetic dose, with 7 (35%) patients achieving goal caloric rate.


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  		Table I Patient demographics and clinical characteristics

 

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  		Table II Nutrition-related variables

 

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  		Table III Pharmacokinetic variables

 


   DISCUSSION
Top
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 
The key findings of this study are (1) patients with elevated GRV have impaired gastric emptying compared with patients with minimal GRV; and (2) initiating prokinetic therapy in patients with elevated GRV accelerates gastric motility to the extent that gastric emptying function resembles that of patients tolerating EN. Our results corroborate the results of other studies demonstrating that critically ill patients have impaired gastrointestinal motility22,23,35,42,43 and that prokinetic agents accelerate gastric emptying.28–33,36–41,44 However, this is the first study to compare gastric motility function in critically ill patients tolerant and intolerant to EN, and relate the affect of subsequent prokinetic therapy.

Most previous studies of gastrointestinal motility function have enrolled consecutive critically ill patients and used healthy volunteers as a control group. Using 3 different methods of assessment (manometry, noninvasive breath test, and radiography), several investigators have demonstrated that gastric emptying is delayed in mechanically ventilated patients when compared with healthy controls.22,42,43 However, only the study by McClave et al43 enrolled enough patients with feeding intolerance to assess whether a GRV of 200 mL represents hindered gastric emptying function. Heyland et al23 used the acetaminophen absorption method and found that critically ill patients have delayed gastric emptying vs healthy controls. The mean Tmax of 1.75 hours (SD not reported) obtained from ICU patients in that study resembles the Tmax of 1.98 ± 1.26 hours found among intolerant patients in the present study. However, the Cmax of 14.3 ± 11.4 mg/L in that study was similar to the Cmax of 14.12 ± 7.25 mg/L we observed in the tolerant group or the Cmax of 15.25 ± 8.85 mg/L observed after prokinetic therapy. The contrasting results may perhaps be explained by differences in subject recruitment between the two studies; Heyland et al23 recruited mostly surgery/trauma ICU subjects within 72 hours of ICU admission and before EN was initiated, whereas patients in the present study, on average, had been primarily in the medical ICU for 1 week and receiving EN for nearly 3 days before enrollment.

Cohen et al35 enrolled patients intolerant to gastric EN, defined as a GRV ≥150 mL, or twice the hourly feeding rate, and used the acetaminophen absorption method to assess gastric motility. The mean GRV for enrollment was 279.2 mL (SD not reported), similar to the 208 ± 75.1 mL observed in our intolerant group. The mean AUC0-60 reported in their study was 3.14 ± 2.78 mg/h/L, which is very similar to the AUC0-60 of 3.93 ± 2.84 mg/h/L obtained in our intolerant group. Cohen et al35 found that initiation of prokinetic therapy allowed EN to be initiated in 88% of their patients, whereas all patients in our intolerant group resumed EN with prokinetic therapy. Therefore, our results confirm those obtained by the previous study and suggest that a GRV of ≥150 mL is a marker of gastric hypomotility and warrants cautious EN progression. Cohen et al35 also suggested that an AUC0-60 <10 mg/h/L represents impaired motility. Although all intolerant patients in our study had an AUC0-60 <10 mg/h/L, 7 (70%) tolerant patients also had an AUC0-60 <10 mg/h/L. Moreover, only 7 intolerant patients reached an AUC0-60 >10 mg/h/L with prokinetic therapy. Therefore, we recommend monitoring of GRV rather than use of the acetaminophen absorption method as a means of assessing gastrointestinal motility among individual patients during routine clinical practice. Using aggregate data and various pharmacokinetic parameters, however, does provide a useful surrogate marker of gastric emptying function for the purpose of clinical research.

Patients with gastrointestinal dysfunction may be at increased risk of aspiration pneumonia, but the clinical application of elevated GRV as a marker of this increased risk remains controversial.4–7,20,21,24–27,45 Using yellow discoloration of tracheal aspirates under fluorometry after EN was marked with yellow microscopic beads as a definition of aspiration, McClave et al46 showed no association between GRV and the presence of aspiration in 40 critically ill patients. Unfortunately, only 6.8% of all GRV assessments were >150 mL, so statistical power may have been insufficient to determine the relationship between aspiration and elevated GRV. Similarly, Metheny et al47 found no association between aspiration, defined as the presence of pepsin in tracheal secretions, and GRV in 360 ICU patients. The management of high GRV, however, was not controlled for and resulted in inconsistent patterns of EN discontinuation and initiation of prokinetic therapy. In contrast to the 2 aforementioned studies, Mentec et al17 showed in a prospective observational study of 153 ICU patients that increased GRV, defined as a single residual >500 mL, or 2 consecutive GRVs of 150–500 mL or vomiting, was associated with more frequent pneumonia (43% vs 24%; p = .01), longer ICU stay (23 ± 21 vs 15 ± 16 days; p = .007), and increased ICU mortality (41% vs 25%; p = .03). Using the presence of conjugated bilirubin >10 mg/L in gastric aspirates as their definition of gastrointestinal motility dysfunction, Inglis et al48 found higher rates of Gram-negative bacilli in both gastric and tracheal aspirates when motility was impaired. In the present study we have shown that a GRV ≥150 mL represents impaired gastric emptying function. The volume(s) of residual that adequately defines intolerance needs further evaluation because many patients in our study had volumes exceeding the threshold value of 150 mL or had consistently elevated volumes. In addition, we did not enroll patients with GRV that were <150 mL but exceeded our definition of tolerance so we are unable to characterize the relationship between motility function and GRV beyond documenting that 150 mL represents impaired motility. Future studies are needed to define the relationship between residual volume and aspiration. These studies should control for the variability in assessment techniques; feeding characteristics such as body position, tube location, type of tube and EN product, and measurement of feeding volume vs gastric secretion; and therapeutic management of elevated GRV.

The clinical implications of elevated GRV are primarily limited to nutrition deficiencies as elevated GRV impede the provision of EN, frequently necessitating prokinetic therapy.20,21,26,27,45 Our results indicate that gastric emptying is impaired in patients intolerant to EN, but therapy with prokinetic agents improves motility function to the extent that gastric emptying resembles that of patients tolerating EN. Although several studies have demonstrated that both erythromycin and metoclopramide accelerate gastric motility in critically ill patients,28–33,36–41,44 only 6 of these studies enrolled patients with EN intolerance.28–33 Two studies investigated only IV erythromycin (either 250 mg every 6 hours administered indefinitely or a single dose of 200 mg)28,29 and 1 study investigated only IV metoclopramide (10 mg every 6 hours for 36 hours).30 Both studies of erythromycin found that GRVs were reduced and EN feeding rates increased when compared with placebo. The metoclopramide study did not demonstrate significant changes. Neither erythromycin study objectively measured gastric emptying, whereas metoclopramide showed a trend toward increased AUC0-60 using the acetaminophen absorption method. The other studies were comparative evaluations of prokinetic agents.31–33 Of these studies, 2 objectively measured gastric motility using the acetaminophen absorption method: the first concluded that either cisapride or metoclopramide accelerated gastric emptying to a greater extent than erythromycin or placebo after single enteral doses, and the second demonstrated enhanced motility with metoclopramide over cisapride after 7 enteral doses.31,32 The third comparative study did not objectively measure gastric motility but showed that multiple-dose erythromycin or metoclopramide significantly lowered GRVs, but that erythromycin appeared to be more effective for facilitating successful EN.33 In another study, the initiation of enteral metoclopramide at the time of nasogastric tube placement delayed the occurrence of pneumonia but not the overall rate.49 Future studies are needed to assess whether the administration of prokinetic agents to patients experiencing EN intolerance reduces aspiration and pneumonia while promoting EN tolerance.

In summary, this study demonstrates that ICU patients intolerant to gastric EN have delayed gastric motility but that initiation of prokinetic therapy with erythromycin or metoclopramide accelerates gastric emptying to the extent that it comes to resemble gastric motility found in patients initially tolerating EN. Additional studies are needed to further define the volume(s) of residual that represents intolerance, assess the relationship between GRV and other clinical outcomes such as aspiration, and determine the optimal role of prokinetic agents in patients experiencing intolerance.

The study was supported by a grant provided by the American Association of Colleges of Pharmacy. The results have been submitted for poster presentation at the Society of Critical Care Medicine 37th Critical Care Congress in Honolulu, HI, in February 2008.

Received for publication June 13, 2007. Accepted for publication August 29, 2007.

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Journal of Parenteral and Enteral Nutrition, Vol. 32, No. 1, 45-50 (2008)
DOI: 10.1177/014860710803200145
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