Invited Review

Nutrition in Clinical Practice

Volume 00 Number 0
Pathophysiology and Treatment of Gastrointestinal Motility September 2018 1–14

C 2018 American Society for

Disorders in the Acutely Ill Parenteral and Enteral Nutrition

DOI: 10.1002/ncp.10199
wileyonlinelibrary.com

Adam M. Deane, MBBS, PhD1 ; Marianne J. Chapman, BMBS, PhD2,3 ;

Annika Reintam Blaser, MD, PhD ; Stephen A. McClave, MD6 ;
4,5

and Anton Emmanuel, MD, PhD7

Abstract
Gastrointestinal dysmotility causes delayed gastric emptying, enteral feed intolerance, and functional obstruction of the small and
large intestine, the latter functional obstructions being frequently termed ileus and Ogilvie syndrome, respectively. In addition to
meticulous supportive care, drug therapy may be appropriate in certain situations. There is, however, considerable variation among
individuals regarding what gastric residual volume identifies gastric dysmotility and would encourage use of a promotility drug.
While the administration of either metoclopramide or erythromycin is supported by evidence it appears that, dual-drug therapy
(erythromycin and metoclopramide) reduces the rate of treatment failure. There is a lack of evidence to guide drug therapy of
ileus, but neither erythromycin nor metoclopramide appear to have a role. Several drugs, including ghrelin agonists, highly selective
5-hydroxytryptamine receptor agonists, and opiate antagonists are being studied in clinical trials. Neostigmine, when infused at a
relatively slow rate in patients receiving continuous hemodynamic monitoring, may alleviate the need for endoscopic decompression
in some patients. (Nutr Clin Pract. 2018;00:1–14)

Keywords
critical illness; enteral nutrition; gastrointestinal motility; gastroparesis; prescription drugs

Introduction Enteral nutrition is part of standard care provided to crit-

ically ill patients.1,2 Gastrointestinal motility is frequently
Gastrointestinal motility describes the process of smooth disordered in these patients.3-5 Not only does dysmotility
muscle contraction and relaxation within the gastrointesti- diminish the provision of enteral nutrition, it is also associ-
nal tract. Gastrointestinal motility regulates movement of ated with adverse, important patient-centered outcomes and
luminal contents, with the predominantly antegrade move- healthcare use, such as increased mortality and duration of
ment occurring because of coordination of peristaltic and intensive care unit (ICU) admission.6 While dysmotility per
non-peristaltic flow. This coordination of gastrointestinal se can result in a life-threatening condition due to intestinal
smooth muscle and the propagation of its contractions is ischemia and perforation,7 these associations are not proven
modulated by neural and humoral mechanisms.

From the 1 Intensive Care Unit, Royal Melbourne Hospital, University of Melbourne, Parkville, Australia; 2 Discipline of Acute Care Medicine,
University of Adelaide, Adelaide, Australia; 3 Department of Critical Care Services, Royal Adelaide Hospital, Adelaide, Australia 4 Department
of Anaesthesiology and Intensive Care, University of Tartu, Tartu, Estonia; 5 Center of Intensive Care Medicine, Lucerne Cantonal Hospital,
Lucerne, Switzerland; 6 Department of Medicine, University of Louisville, Louisville, Kentucky, USA; and the 7 Department of
Neuro-Gastroenterology, University College London, London, UK.
Financial disclosures: None declared.
Conflicts of interest: Adam M. Deane or his institution has received honoraria, travel grants, or project grant funding from Baxter, Fresenius
Kabi, GSK, Medtronic, and Takeda. Adam M. Deane has participated on advisory boards for Lyric Pharmaceuticals and Takeda. Marianne J.
Chapman or her institution has received honoraria, travel grants, or project grant funding from Nestlé, Baxter, Fresenius Kabi, GSK, Theravance,
and Takeda. Annika Reintam Blaser has received honoraria or project grant from Nestlé, Fresenius, and Nutricia. Stephen A. McClave is an
educational consultant for Nestlé, Abbott, Fresenius, Nutricia, and is on an advisory board for Lyrica Pharmaceuticals. Anton Emmanuel has
served on advisory boards for Allergan, Kyowa-Kirin, Shionogi, Shire, and Takeda.
This article originally appeared online on xxxx 0, 0000.
Corresponding Author: Dr. Adam M. Deane, MBBS, PhD, Intensive Care Unit, Level 6, Royal Melbourne Hospital, Grattan Street, Parkville,
3050, Victoria, Australia
Email: [email protected]
2 Nutrition in Clinical Practice 00(0)

Table 1. Summary of Dysmotility, Presentation, and Pharmacotherapy Used in Current Practice.

Region of Diagnosis of Interventions/Drugs

Gastrointestinal Motility During Dysmotility: Administered in
Tract Clinical Problem Motility in Health Critically Ill Clinical Research Clinical Practice

Stomach Delayed gastric Fasting pattern Gastric emptying Gastric residual Erythromycin
emptying (migrating motor frequently volume, vomiting (motilin agonist)
Enteral feed complex) delayed Breath test Metoclopramide
intolerance Fed pattern “Pump” via antral Acetaminophen
motility absorption
suppressed 3-O-methylglucose
“Brake” via pyloric scintigraphy
resistance Ultrasound
increased
Small bowel Substantial Fasting pattern Uncertain but Abdominal None routinely used
interpatient (migrating motor appears to not distension,
variability in complex) transition from increased gastric
transit times Fed pattern fasting motility residual volumes,
but in pattern to fed absent stool for ࣙ 3
proportion of pattern ± days, supported by
patients ileus retrograde ± confirmatory
is present disorganized radiology
motility Scintigraphy,
manometry, pill
cam, magnetic
resonance imaging
Large bowel Functional Large periodic Uncertain but Abdominal Neostigmine
obstruction propulsive clinical distension and
movements few appearance of absolute
times per day proportion of constipation,
patients with supported by
paralysis (too confirmatory
slow) and radiology
diarrhea (too Pill cam, magnetic
rapid) resonance imaging

causative relationships, as dysmotility is more prevalent as Clinical Presentation of Dysmotility

illness severity increases.8
Within this review we will summarize the gastrointestinal Differing clinical presentations may occur due to gastroin-
motility pattern that occurs in health, describe how this testinal dysmotility because of a pathophysiologic process
differs during critical illness, and outline the mechanisms in a defined region or a generalized dysmotility throughout
underlying these differences. We will emphasise conditions the entire gastrointestinal tract (Table 1). While retrograde
in the critically ill that relate to disordered gastrointestinal or excessively rapid movement of luminal contents oc-
motility, such as delayed gastric emptying, enteral feed in- cur as part of the spectrum of critical illness associated
tolerance, and intestinal functional obstruction (sometimes dysmotility,10,11 the more frequently observed phenomenon
termed pseudo-obstruction), describe the medications avail- is deceleration of antegrade movement,3 which reflects a
able, and summarize the best available evidence to inform decrease in propulsive force (peristaltic flow) and/or in-
clinical practice and the latest research using newer drugs. creased resistance to flow.4
In clinical practice, monitoring of dysmotility is chal- There is no agreed taxonomy to describe pathophysi-
lenging to identify and measure, with bedside techniques to ology associated with dysmotility in the critically ill. To
quantify dysmotility being imprecise.9 Nonetheless, aware- highlight this point, in a systematic review of enteral feed
ness and understanding of pathophysiologic mechanisms intolerance in the critically ill, there were 43 different def-
are important, so that clinicians can avoid or promptly initions for enteral feed intolerance used in the literature.6
treat conditions caused by dysmotility and prevent life- Trying to group these definitions, it seems that enteral
threatening complications, such as intestinal ischemia and feed intolerance is diagnosed using at least 1 of 3 cate-
perforation. gories: 1) presence of large gastric residual volumes (GRVs);
Deane et al 3

and/or 2) presence of gastrointestinal symptoms; and/or Stomach

3) inadequate delivery of enteral nutrition.6 According
to this systematic review, the prevalence of enteral feed Gastric Motility in Health
intolerance and the association between this condition and Gastric motor function has evolved to perform 3 ma-
mortality depended on the definition used, but the pres- jor physiologic functions: 1) a fasting motility pattern to
ence of large GRVs and other gastrointestinal symptoms intermittently expel ingested non-nutrient material which
(vomiting, abdominal distension, or diarrhea) provided the also avoids stagnation of content and subsequent bacterial
strongest relationship between the presence of enteral feed proliferation; 2) preparation of solid digestible nutrient for
intolerance and mortality.12 However, it has been recently the small intestine by reducing the size of the food particles
recommended by a group of experts, ie, The Working and mixing with gastric fluid to facilitate digestion. This
Group on Abdominal Problems of the European Society subsequent grinded matter is termed chyme; and 3) receiving
of Intensive Care Medicine, that enteral feed intolerance and storage of nutrient (chyme), and then regulating the
should be the general term for patients who cannot tolerate delivery of this matter, ideally to match the absorptive
enteral nutrition regardless of clinical reason or category capacity of the small intestine, via the rate of gastric
(large GRVs, vomiting, gastrointestinal bleeding, diarrhea, emptying.
etc.).13 Myogenic control of gut peristalsis is independent of the
Similarly, ileus is a term lacking an agreed definition in central nervous system.19 The frequency of myogenic initia-
the critically ill. It generally refers to hypomotility and a tion of peristalsis varies according to the region of the gut,
functional obstruction in the absence of a discreet luminal and has been variously named the basal electrical rhythm or
narrowing or stricture, usually including the small intes- gastric pacemaker. The interstitial cells of Cajal initiate this
tine, but any segment of the gastrointestinal tract can be electrical activity.20 Whether the electrical activity initiates
implicated.14 Given the lack of an agreed definition, it is mechanical contraction is determined by the influence of
not surprising that ileus can be challenging to identify in exogenous and endogenous factors.
clinical practice, with a range of possible signs, including The fasting motility pattern that commences in the stom-
abdominal distension, increased GRV, and absent bowel ach and progresses throughout the small intestine has been
sounds.7 Since many of these signs may be attenuated in arbitrarily divided into 3 phases, which have been termed
mechanically ventilated patients receiving sedation and/or the migrating motor complex.21 The housekeeping role, or
analgesia, the European Society of Intensive Care Medicine propulsion of luminal contents, occurs mainly during phase
Working Group recently suggested to use the term “paraly- III of the migrating motor complex.
sis of lower gastrointestinal tract,” defined as the absence To prepare solid digestible nutrient for the small intestine,
of stool for ࣙ3 consecutive days,13 but this definition is ingesta must be mixed with gastric fluid and processed
based solely on expert opinion and does not differentiate into particles of a sufficiently small size to pass through
between dysmotility in small bowel and large bowel. Clinical the pylorus. This occurs as antral contractions grind solid
relevance of such “paralysis” depends on presence of bowel food into particles because the contractions occur against a
dilatation and distension.15 closed pylorus or the particles are too large to pass through
When there is no physical obstruction, but functional an open pylorus.21
obstruction due to bowel paralysis in the large intestine, Finally, gastric emptying regulates movement of chyme
distension may be even more prominent.16 Acute functional into the duodenum. Nutrients interact with the small intesti-
obstruction of the large intestine is described using a variety nal mucosa, which induces the release of a number of neuro-
of terms, including acute colonic pseudo-obstruction and transmitters and hormones that modulate gastric emptying
the eponymous Olgilvie syndrome.17 This condition, which through feedback inhibition.21,22 Accordingly, gastric motil-
is diagnosed radiologically, is important because it is ity and emptying vary considerably depending on whether
more frequently associated with intestinal ischemia and the fasting or fed state is being evaluated.23 The rate of
perforation.7 While there are limited data regarding the gastric emptying of a meal is modified by its composition
prevalence and mortality rate of acute functional obstruc- and macronutrient content, with relatively little effect of
tion of the large intestine for patients already admitted meal volume.21,24 Liquid emptying by the stomach follows
to ICU, a study using a large United States hospital-wide an exponential pattern, whereas solid emptying, after an
database of >100,000 cases provided a mortality estimate initial lag phase, follows a linear phase.25
of 8%.18 It is important, however, to note that this is Gastric emptying is regulated by multiple neural and
all-cause mortality and is not attributable risk specifically hormonal pathways.21 The neural regulation of gastric
due to functional obstruction of the large intestine. emptying is mediated by extrinsic inputs from the central
We will consider each clinical scenario on an anatomic nervous system via the vagus nerve, and intrinsic modu-
basis, but it is important to recognize that these clinical– lation via enteric nerves. The extrinsic or parasympathetic
physiologic states may often overlap in an individual patient.
4 Nutrition in Clinical Practice 00(0)

input from the vagus nerve is particularly important in In the clinical setting, the rate of emptying is most
the upper gastrointestinal tract. The vagus nerve commu- frequently estimated using intermittent aspirates of the
nicates information using complex circuitry involving both gastric feeding tube, the so-called GRV.24,39 Using any
afferent and efferent components, by release of excitatory continuous variable to separate patients into binary cate-
neurotransmitters (eg, acetylcholine) and inhibitor neu- gories of either having or not having a disease has been
rotransmitters (eg, nitric oxide).23 The intrinsic pathway criticized in other areas of medicine.40 Consistent with the
mediates responses via ascending and descending enteric concept, aspirating the GRV and categorizing patients as
nerves and also by release of both excitatory and inhibitory having normal or delayed gastric emptying according to a
neurotransmitters. single volume is somewhat simplistic, eg, 2 patients with
Compared with these neutrally mediated effects, there aspirated GRVs of 249 and 251 mL will have similar, rather
may be more persistent endocrine-mediated mechanisms. than different, rates of gastric emptying. Moreover, GRVs
Hormonal pathways are also important and include may not be a specific marker for delayed gastric emptying,
hormones that slow gastric emptying, such as amylin, as many critically ill patients with slow gastric emptying
cholecystokinin, glucagon-like peptide-1, and peptide YY, will have GRVs <250 mL.41 Once GRVs are >250 mL,
and hormones that accelerate emptying rate, such as ghrelin the test is a relatively sensitive marker of delayed gastric
and motilin.26-29 Such endocrine targets may represent a emptying, having been measured against the gold standard
focus of future therapy, with the most likely candidates of scintigraphy.42 Accordingly, the greater the GRV, the
being ghrelin and motilin, discussed in detail under the more certain clinicians can be that a particular patient has
subheading drug therapies. disordered motility. While recent guidelines have included
Targeting amylin is unlikely to be a high priority. recommendations to use a threshold of 500 mL to identify
In an observational study of 26 critically ill patients patients who may require discontinuation or a reduction in
and 23 healthy participants as controls, fasting amylin feed rate,1,2 this value should not be interpreted as defining
concentrations were comparable between critical illness patients with gastric dysmotility. Using large cross-sectional
and health, and the rate of gastric emptying was not related datasets, it has been reported that ࣘone-third of all enterally
to fasting amylin concentrations,27 suggesting other targets fed, mechanically ventilated, critically ill patients experience
are more appealing. a moderate form of delayed gastric emptying presenting as
In the critically ill, pharmacologic administration of enteral feed intolerance.43 Many more patients may have
glucagon-like peptide-1 slows gastric emptying and lowers subclinical gastrointestinal dysmotility, with estimates of
blood glucose.30-32 In health, administration of an antago- the proportion of patients with disordered motility detected
nist to glucagon-like peptide-1 accelerates gastric emptying (if using more sophisticated research tools) being as high as
and increases blood glucose.33,34 Given the likely increase 80%.4,44-47 The variability in the literature of the proportion
in blood glucose that will occur with administration of of patients having gastrointestinal dysmotility is likely to
glucagon-like peptide-1 antagonists, such agents are un- reflect the precision of the research methodology to detect
likely to be a useful therapy. dysmotility and the factor that many of the studies are
Some, but not all, studies report that plasma cholecys- single-center studies with the risk of selection bias.
tokinin concentrations are increased in the critically ill,35,36
which raises the possibility that specific antagonists, such Mechanisms Underlying Critical
as loxiglumide, may be effective. However, in the critically
ill, small intestinal absorption of nutrient is substantially
Illness–Associated Gastric Dysmotility
impaired,11,28,37 and antagonism of cholecystokinin could To evaluate the mechanisms underlying disordered motil-
diminish pancreatic exocrine function. Any studies of chole- ity, researchers can undertake studies in patients or use
cystokinin antagonists like loxiglumide should, therefore, animal models of critical illness, both of which require
also measure the impact on nutrient absorption. sophisticated methodologies.48 To precisely determine the
effect of an endogenous neurotransmitter or hormone, the
researcher must then administer the specific antagonist
Gastric Motility During Critical Illness to the neurotransmitter or hormone.49 For example, the
Gastric emptying is delayed in a proportion of critically substantial slowing of gastric emptying that occurs with
ill patients, and the magnitude of delay is substantially endotoxin administration to rats is almost abolished with
more severe than in many other conditions, such as diabetic coadministration of capsaicin, which is used in neuroscience
gastroparesis, where gastric emptying of nutrient liquid laboratories to blunt vagal afferent responses.50,51 Assuming
may be abnormally slow, but usually occurs nevertheless.38 that the response in an animal model reflects the response
Precise quantification of gastric emptying is limited to the in a critically ill patient, these animal data are consistent
research setting; a summary of these techniques can be with the concept that the vagal afferent pathways are an
found elsewhere.24 important mediator of gastroparesis in the critically ill.
Deane et al 5

Table 2. Risk Factors for Gastrointestinal Dysmotility. fat or osmolarity more likely to slow gastric emptying.53,54
This hypersensitivity to the presence of nutrient in the
Factors on Preexisting medical problems (diabetes, small intestine is mediated via hormonal (and probably
admission Parkinson’s disease);
Presenting problem (spinal cord injury,
neurotransmitter) responses.22
burn injury, pancreatitis, Hormones are usually evaluated according to their en-
intra-abdominal surgery); docrine effect, ie, related to the concentration of hormone
Age in plasma. However, it is likely that most/all of the hormones
Dynamic Hyperglycemia; that regulate gastric emptying have additional paracrine ef-
endogenous Hypokalemia; fects that are mediated via vagal afferents or enteric nerves.55
factors Pain; Severity of illness; Consequently, the magnitude of hormone-mediated effects
Gastrointestinal hormone (excessive or
may be underestimated.49
suppressed secretion);
Inflammation
Dynamic Opiate analgesia; Small Intestine
exogenous Catecholamines/vasopressors;
factors Excessive volume resuscitation; Small Intestinal Motility in Health
Electrolyte disturbances;
Intraduodenal fat
As the predominant site for digestion and absorption of nu-
trient, small intestinal motility has 2 major motor functions,
mixing and propulsion of ingesta. Similar to the stomach,
Because of the challenges of conducting studies of intestinal motility also depends on presence of nutrient,
acute physiology in the critically ill, researchers may also with the fasting phase, the migrating motor complex (as
look for associations between physiologic variables, eg, described above), and a fed or postprandial phase.19 The
hyperglycemia, or administered therapies, eg, opiate drugs postprandial phase of intestinal motility facilitates mix-
and gastric dysmotility, and then extrapolate evidence from ing, aids digestion, and prolongs exposure of chyme to
health. Higher blood glucose concentrations, even minor absorptive epithelium.28 In the postprandial state, the speed
perturbations within normal physiologic range (gastric at which contents are propelled varies within the small
emptying is slower at 8 mmol/L than at 4 mmol/L)52 intestine, eg, transit is more rapid in the duodenum and
and opiate drugs, even modest doses, both impair motility jejunum and slower in the ileum, to allow for absorption of
patterns to identify risk factors for gastric dysmotility nutrient within the small intestine.11
(Table 2).19 Intrinsic pathways (ie, enteric nerves) are the major
One method that has been used to quantify mechanisms determinants of small intestinal motility, but additional
underlying dysmotility in the upper gastrointestinal tract in extrinsic parasympathetic pathways are also important.
the critically ill involves multilumen water-perfused mano- Extrinsic parasympathetic pathways, which to the upper
metric catheters. The recording of increased pressure will gastrointestinal tract are via the vagus nerve and to the
identify luminal occlusive contractions at various locations, lower tract via the sacral nerves, accelerate motility when
with organized and propagated luminal occlusive contrac- stimulated, whereas sympathetic activation, via thoracic
tions resulting in peristalsis. Certain motor patterns are splanchnic nerves, retard motility. Similar to the stomach,
known to slow transpyloric flow, eg, antral atony and/or the enteric nervous system contains a number of neuro-
isolated pyloric pressure waves.10 This technique allows re- transmitters that are responsible for stimulation of motility
searchers to study motility patterns while nutrient is infused (eg, acetylcholine) or relaxation (eg, nitric oxide).
directly into the small intestine and, thereby, to understand
feedback mechanisms.4
In the critically ill, this nutrient-stimulated feedback
Small Intestinal Motility During Critical Illness
mechanism is potentiated, so that after small intestinal Because of the difficulties with passing manometric
infusion of liquid nutrient (even at relatively low rates such catheters into the distal small intestine, there is a lack of
as 1 kcal/min), the frequency of antral waves is less than in granular detail regarding motility patterns distal to the
healthy subjects, with marked increases in pyloric tone and duodenum in critically ill humans. Even coarse information
in the number of isolated pyloric pressure waves (ie, strong related to small intestinal transit (duodenal-cecal) times are
contractions of the pyloric sphincter).4,10 These motility challenging to obtain, with only sparse data available. A
patterns retard further transpyloric flow (ie, slow gastric cohort of 8 critically ill mechanically ventilated patients
emptying).4,10 It is, therefore, clear that not only is gastroin- admitted following a traumatic brain injury were studied
testinal dysmotility present during fasting, but perhaps of using a wireless motility capsule.56 The capsule was placed
greater relevance to clinical care, this is exacerbated during in the stomach, and data were compared with a cohort of
the delivery of nutrition. The content of the liquid nutrient healthy volunteers who had participated in a separate trial.56
further influences gastric emptying, with formulae high in Enteral nutrition commenced at least 12 hours after the
6 Nutrition in Clinical Practice 00(0)

capsule was placed in the stomach. Small intestinal transit requires confirmatory evidence.62 There are μ-opioid re-
time was almost >2-fold in the critically ill.56 The same ceptors throughout the gastrointestinal tract. Activation of
investigators also studied 16 critically ill mechanically ven- μ-receptors delays gastric emptying, slows intestinal and
tilated patients with intracranial hemorrhage using a video colonic propulsion and coordination of peristalsis, increases
telemetry capsule placed directly into the small intestine and fluid absorption in the small and large intestine, and also
compared results with 16 healthy volunteers.57 This study increases anal sphincter tone. The net symptomatic result
was conducted in the fasted state, with data collected for of these pharmacologic effects is nausea, vomiting, loss of
8 hours. Transit times were not statistically different between appetite, abdominal pain, hard stool, and difficulty with
groups, but there was considerably greater variability in rectal evacuation. While opioid-induced constipation has
transit times in the critically ill.57 There was also a propor- recently been characterized by expert consensus (Rome IV),
tion (5/16) of the critically ill patients in whom the capsule reliance on subjective symptoms means that this definition
had not reached the cecum at the end of the study period, is less relevant to the critical care environment.13
whereas all healthy volunteers had, and a smaller proportion Additionally, fluid and electrolyte administration may
of critically ill patients who had very rapid transit.57 Using contribute to postoperative ileus. Excessive fluids lead to in-
a scintigraphic technique, we (AMD and MJC) measured testinal edema and intra-abdominal hypertension, whereas
duodenal-cecal transit time of radiolabelled nutrient over reduction of serum potassium concentrations affects the
a 4-hour period in 28 mechanically ventilated, critically ill opening of calcium channels, attenuating neuromuscular
patients and compared the results to healthy volunteers. function and, hence, slowing small intestinal transit.63 An-
Interpretation was limited by the fact that tracer had not other factor influencing gut motility in ICU patients is the
reached the cecum by the end of the study (240 minutes) in alteration of intestinal microbiota that occurs secondary to
12 of 28 patients and 6 of 16 healthy subjects.11 Similar to antibiotic use, leading to antibiotic-associated diarrhea or
the study by Rauch et al, we observed greater variability in even colitis due to Clostridium difficile.
transit times in the critically ill, but the median times were
not statistically different.11 Large Intestine
The motor functions of the large intestine are to provide
Mechanisms Underlying Critical conditions for fermentation of fiber and undigested nutrient
Illness–Associated Small Intestinal Dysmotility by microbes and, thereby, to produce feces and to absorb
The mechanisms underlying critical illness–associated small water from feces, which is then stored and finally excreted.
intestinal dysmotility are largely extrapolated from animal Unlike the gastric and small intestinal regions, there is
models and from humans suffering a discrete insult, such no clear separation between nutrient-stimulated and non-
as surgery. The pathogenesis of postoperative ileus occurs nutrient patterns; instead, periodic large propulsive contrac-
in 3 phases. First, a surgical stimulus causes activation tions sweep through the colon to move the contents into the
of inhibitory spinal reflex arcs, specifically those involving rectum and promote the urge to defecate.64
the prevertebral ganglia, and long reflexes involving the
spinal cord.58 Subsequently, endocrine and inflammatory Large Intestinal Motility in Health
cytokines augment inhibitory neurotransmitters and nitric In health, the motility patterns allow sufficient time for
oxide to paralyze gut peristalsis.59 The final phase involves resorption of luminal fluid that was secreted in the small
parasympathetic (vagal) activation, which mediates resolu- intestine. During mixing, short duration contractions move
tion of ileus via an anti-inflammatory mechanism.60 There is contents within haustra, and longer propagated contrac-
a complex interaction within the gut between inflammatory tions progress contents from 1 haustra to the next. A distinct
components of the mucosa (mast cells, neuroglial cells) pattern of high-amplitude propagating contractions causes
and submucosal tissue (enteric neurons, myocytes). This oc- aboral movement of feces longer distances to the rectum.
curs through Toll-like receptors and intracellular signalling
pathways involving neurotransmitters as diverse as nitric
oxide, cytokines, growth factors, proteases, prostaglandins,
Large Intestinal Motility During Critical Illness
and hormones. Furthermore, bidirectional signalling be- Colonic transit and/or large intestinal motility have rarely
tween enteric neurons and central nervous system neurons been quantified in the critically ill. In the wireless motility
cause systemic inflammation to have gastrointestinal conse- capsule study of 8 patients conducted by Rauch et al, the
quences, which in turn perpetuate the inflammation. excretion of the capsule was markedly slower in critically ill
Opioids and postoperative stress contribute to the symp- patients than in healthy controls (median [lower and upper
tom elaboration.61 It has been speculated that exogenous interquartile range, respectively], 10 [8.5–13] days vs 1.2
opioids have the capacity to promote virulence within the [0.0–1.9] days; P < .001),56 suggesting transit through the
microbiome of critically ill patients, but this hypothesis large intestine is delayed.
Deane et al 7

Given the lack of precise data, much of the current posthospital factors, such that even a well-designed trial
orthodoxy comes from clinical observations. Such observa- including a large number of participants is unlikely to detect
tional data are, however, imprecise, as there are no consensus a statistically significant difference for these outcomes when
definitions, or even consensus regarding the terminology evaluating a promotility drug.73,74
that should be used. Because patients are frequently un-
able to communicate their symptoms, several observational
studies have defined constipation as the failure to pass stool
Motilin Agonists
within 72 hours of admission to the ICU.65 Using this Motilin is secreted from the duodenum and the proxi-
definition to identify the proportion of patients who have mal small intestine during fasting, and the peak plasma
slow colonic transit, disordered motility may occur in ࣙ20% motilin concentration coincides with the onset of phase
and ࣘ60% of patients.5,66,67 However, given the frequent pe- III of the migrating motor complex.75-77 Receptors to
riods of inadequate delivery of enteral nutrition, prolonged motilin are found predominately in the smooth muscle in
immobility, sparse dietary fiber, and volume depletion, dis- the gastric antrum and proximal duodenum and, when
ordered large intestinal motility may be even more common. stimulated, induce isolated smooth muscle contractions.
The European Society of Intensive Care Medicine Working Exogenous motilin induces contractions in this region and,
Group on Abdominal Problems recommended avoiding the thereby, accelerates gastric emptying in healthy individuals
term constipation in the critically ill; instead, they advocated and patients with gastroparesis.38 When compared with
the term paralysis of lower gastrointestinal tract, which patients tolerating enteral nutrition, critically ill patients
they defined as the inability of the bowel to pass stool with enteral feed intolerance had similar plasma motilin
due to impaired peristalsis and an absence of stool for ࣙ3 concentrations.26
consecutive days without mechanical obstruction.13 Macrolide antibiotics, such as erythromycin, exert pro-
Similar to the variability in measured small intestinal motility effects via stimulation of motilin receptors.38 In
transit time, based on observational data alone, large intesti- the critically ill, erythromycin accelerates gastric emptying,
nal motility is likely to be variable, as both the infrequent reduces feed intolerance, and increases the delivery of calo-
passage of stool and the converse, diarrhea, are reported ries administered via the gastric route.78-83 The promotility
to occur frequently. Often, diarrhea reported in the ICU effects of erythromycin vary with dose, but even lesser doses
actually represents low-volume incontinence, and not true of erythromycin (eg, 40 mg IV) have promotility effects.19
diarrhea (defined by >200 g/d).68 Regardless of the defini- Measuring gastric emptying using an isotope breath test in
tion of diarrhea, regular passage of formed stools is less 35 critically ill patients, the use of erythromycin at 70 mg
common.69,70 did not appear to accelerate gastric emptying substantially
at <200 mg.84 While a lesser dose of erythromycin may
be used, it is our experience that the majority of clinicians
Mechanisms Underlying Critical
who prescribe intravenous (IV) erythromycin do so in the
Illness–Associated Large Intestinal Dysmotility range of 100–250 mg 2–3 times daily.85 Administration
The mechanisms underlying large intestinal dysmotility in of erythromycin may also increase small intestinal carbo-
the critically ill have been rarely studied but are likely to be hydrate absorption independent of the effect on gastric
complex and similar to those influencing gastric and small emptying, with the likely mechanism being minor variations
bowel motility as detailed earlier.71 in luminal flow, reducing the depth of the unstirred layer
within the small intestine.86 Motilin agonists have no role in
the treatment of ileus because erythromycin appears to slow,
Drug Therapies rather than accelerate, global small intestinal transit times.86
Promotility drugs are frequently administered to critically ill The use of erythromycin can prolong the QT interval and
patients and have an established role as effective treatment precipitate cardiac arrhythmias.38 In critically ill patients
to accelerate gastric emptying, improve feed tolerance, and who are continually monitored, the use of low doses (100–
increase the delivery of calories administered via the gastric 250 mg) infused over longer periods (eg, 20 minutes) rather
route.43,72 However, it should be noted that none of the than IV injection may reduce the risk of adverse outcomes.87
drugs described (Table 3) have been approved for the specific Nonetheless, it is prudent to avoid erythromycin in pa-
indication of treating critical illness– associated dysmotility, tients with established prolonged QT interval. As a potent
and their use remains off-label. Moreover, even when a inhibitor of CYP3A, there is the potential for drug–drug
promotility drug increases delivery of enteral nutrition or interactions when administering erythromycin.88 There is
reduces enteral feed intolerance, this has not been proven also concern that widespread use of erythromycin could
within a randomized clinical trial to reduce mortality promote the development of microbial resistance.38 Due to
and morbidity. This may be because these outcomes are concerns about side effects, we (AMD and MJC) recently
influenced by a variety of prehospital, inhospital, and completed 2 trials using a non-macrolide motilin receptor
8 Nutrition in Clinical Practice 00(0)

Table 3. Promotility Drugs Evaluated in Critically Ill Patients.

Drug Mechanism of Action Dose and Route Adverse Effects

Erythromycin Motilin agonist 100—250 mg IV, 2–3 QT prolongation; Cardiac

times daily dysrhythmia (at higher dose) and
potential for bacterial resistance
Camicinal Non-macrolide motilin 50 mg Insufficient numbers to accurately
agonist oral/nasogastric, once describe adverse effects in critically
daily ill
Ulimorelin Ghrelin agonist 600–1200 mcg/kg IV, 3 Insufficient numbers to accurately
times daily describe adverse effects in critically
ill
Metoclopramide Dopamine (D2) 10 mg IV, 3–4 times daily Dystonia;
antagonist, Tardive dyskinesis
5-hydroxytryptamine-3
antagonist,
5-hydroxytryptamine-4
agonist
Domperidone Dopamine agonist 10 mg, 3 times daily QT prolongation;
Extrapyramidal effects
Cisapride 5-hydroxytryptamine No longer available Cardiac dysrhythmia and removed
agonist (low from market
selectivity)
TAK-954 5-hydroxytryptamine 0.5 mg IV daily Insufficient numbers to accurately
agonist (high describe adverse effects in critically
selectivity) ill
Naloxone Opioid antagonist 8 mg oral/nasogastric, 4 Insufficient numbers to accurately
times daily describe adverse effects in critically
ill
Methylnatrexone Opioid antagonist 8–12 mg subcutaneous, Insufficient numbers to accurately
once daily describe adverse effects in critically
ill
Neostigmine Cholinesterase inhibitors 0.4–0.8 mg/h IV infusion Bradycardia; Hypotension and
cholinergic symptoms

agonist. In a single-center study of 23 critically ill patients Fasting plasma ghrelin concentrations have been reported
with established feed intolerance, a single dose of the motilin to be reduced by >50% in the early phase of critical illness,
receptor agonist, camicinal, when compared with placebo, with suppression continuing up to day 28 postadmission.91
appeared to accelerate gastric emptying and increase carbo- Moreover, a subsequent analyses of 2 studies that included
hydrate absorption.89 In a subsequent international multi- a total of 30 critically ill patients reported that when
center, parallel-group, blinded, randomized controlled trial compared with those tolerating enteral nutrition, those
of 84 critically ill patients, preemptive administration of with enteral feed intolerance had greater total ghrelin
enteral camicinal did not significantly augment the provi- concentrations, but that feed-intolerant patients had
sion of goal enteral nutrition.90 Based on these data, non- lesser acyl-ghrelin concentrations and acyl-ghrelin to
macrolide motilin receptor agonists, which are not currently non-acyl-ghrelin ratios.26 This is relevant as the acylation
available, may have a future role as treatment for patients process and subsequent transformation are required for
with established feed intolerance, but they do not appear ghrelin to have a physiologic effect. Ghrelin is a potent
effective as a preemptive strategy to prevent enteral feed acute stimulant of appetite; indeed, markedly increased
intolerance. ghrelin concentrations are likely to mediate the hyperphagia
observed in some patients with Prader-Willi syndrome.92
Ghrelin Agonists Ghrelin increases muscle mass as it is the natural ligand for
Ghrelin is a peptide that is structurally similar to motilin.49 the growth hormone secretagogue receptor, thereby stimu-
Ghrelin is secreted primarily by the stomach, with plasma lating growth hormone secretion.49 In addition, exogenous
concentrations greatest during fasting and suppressed by ghrelin accelerates gastric emptying in ambulant patients
nutrient.49 Receptors to ghrelin are distributed widely, with gastroparesis.93 A multicenter, blinded, randomized
including the hypothalamus, pituitary, and stomach.49 clinical trial is currently enrolling patients to evaluate the
Deane et al 9

use of an IV ghrelin agonist (ulimorelin) in patients with with functional transit problems, the drug is a pow-
enteral feed intolerance (clinicaltrials.gov NCT0278439). erful accelerator of transit and reduces symptoms of
constipation.106 There are highly selective IV 5-HT-4 recep-
Dopamine Antagonists tor agonists that have been studied in the critically ill. We
(AMD and MJC) were involved in a single-center pilot trial
Metoclopramide is a frequently prescribed prokinetic and
of 13 critically ill patients who were randomized to a highly
antiemetic drug with complex actions. It acts predomi-
selective 5-HT agonist, TAK-954, or metoclopramide, both
nantly as a dopamine (D2 receptor) antagonist with both
administered intravenously, in a blinded double-dummy
central and peripheral effects. The dominant mechanism
parallel-group fashion.107
underlying the prokinetic effect is via the dopamine re-
ceptor antagonism in the myenteric plexus.94 Metoclo-
pramide also has weak mixed serotonergic effects, partial
Opioid Antagonists
antagonism of 5-hydroxytryptamine (5-HT3 ), partial ag- Opioids are frequently prescribed in the critically ill to
onism of 5-HT4 receptors, and is a weak cholinesterase alleviate pain and are likely to cause gastrointestinal
inhibitor.38,94,95 dysmotility.62 Opioid antagonists, administered either en-
In the critically ill, IV metoclopramide accelerates gastric terally or parenterally, attenuate the effect of exogenous
emptying and is an effective treatment for enteral feed opioids on gastrointestinal motility. If they do not cross the
intolerance.96-99 In non-critically ill patients, adverse central blood–brain barrier, they will not interfere with analgesia.
nervous system effects are reported with some frequency.95 In health, coadministration of opioid antagonists with
The frequency of complications in the critically ill is un- opioids accelerates gastric emptying and small intestinal
known, but administration via infusion over longer time transit and is an effective treatment for constipation.108
periods and reduced frequency of dosing in renal failure are There is a lack of well-conducted clinical trials evaluating
likely to reduce the frequency of complications.95 the use of opioid antagonists in the critically ill.62 A single-
Domperidone is a more specific and peripherally act- center, parallel-group, blinded clinical trial randomized
ing dopamine receptor antagonist that does not cross the 84 critically ill patients who were receiving fentanyl to
blood–brain barrier; thus, central nervous system adverse receive either enteral naloxone or placebo. Patients re-
effects are rare.38 The antiemetic effects of domperidone ceiving naloxone had lower median daily GRV with no
occur via the area postrema chemoreceptor trigger zone difference in time to defecation.109 A placebo-controlled,
(ie, outside the blood–brain barrier).94 In ambulant patients parallel-group, blinded, randomized clinical trial to eval-
with delayed gastric emptying, domperidone is an effective uate the use methylnaltrexone was recently completed
therapy that is associated with fewer central nervous system (http://www.isrctn.com/ISRCTN75305839).110 When avail-
effects,100 but its use as a promotility drug in the critically ill able, the results are likely to inform further work in this field.
has not been evaluated.
Cholinesterase Inhibitors
Serotonin Agonists Cholinesterase inhibitors increase availability of
Serotonin, or 5-HT, is secreted from enterochromaffin cells acetylcholine at neuromuscular junctions, increasing
throughout the gut.94,101 Serotonin stimulates 5-HT re- contractility of the gastrointestinal tract and accelerating
ceptors, which modulate a number of neurotransmitters intestinal transit.38 Adverse effects include autonomic
including acetylcholine. cholinergic effects, such as bradycardia, bronchospasm,
Cisapride markedly accelerates gastric emptying in and salivation. Three trials have evaluated the use of
the critically ill.96,97,102,103 However, cisapride is not a the cholinesterase inhibitor neostigmine as a promotility
selective serotonin agonist and also stimulates the cardiac drug in the critically ill.111-114 In total, the effects of
ether a-go-go potassium channels, which prolong the QT neostigmine on gastric emptying appear modest. However,
interval leading to cardiac dysrhythmia.101 This effect neostigmine is an effective treatment for acute colonic
resulted in cisapride being withdrawn from the market. pseudo-obstruction,115,116 and a single-center, blinded,
The non-selective 5-HT Tegaserod was also evaluated randomized controlled trial of 30 critically ill patients with
in off-label audits and was reported to reduce GRVs in acute colonic ileus reported that continuous infusion of
the critically ill.104 However, it was withdrawn from the 0.4–0.8 mg/h of neostigmine markedly reduced time to defe-
market, also due to concerns about adverse cardiovascular cation and was well tolerated.117 The use of a continuous in-
effects.104 fusion at 0.4–0.8 mg/h appears to reduce the rate of adverse
Newer, highly selective 5-HT receptor agonists have effects, particularly bradycardia, when compared with bolus
recently become available, such as the highly selective dosing. The continuous monitoring and immediate avail-
5-HT4 receptor agonist, prucalopride.105 While prucalo- ability of resuscitation equipment, drugs, and personnel
pride is only available in enteral formulation, in patients that are standard for all ICUs provide a relatively controlled
10 Nutrition in Clinical Practice 00(0)

environment to implement this intervention. Accordingly, of a preemptive motilin agonist did not increase nutrient
cholinesterase inhibitors, when administered as an infusion, delivery. Given the risk of adverse events with any drug in
may be useful as a rescue therapy for functional obstruction the critically ill, our interpretation of the current literature
of the large intestine prior to more invasive therapies (eg, is that there is insufficient evidence to support the use
colonoscopy). of preemptive promotility drugs. While either metoclo-
pramide or erythromycin are supported by evidence as
first-line treatment, based on a trial that reported fewer
Recommendations treatment failures with dual-drug therapy (erythromycin
We are of the opinion that attention to general care of the and metoclopramide) when compared with erythromycin
patient, such as avoiding or treating marked hyperglycemia, alone,122 we favor initiating both drugs. On the available
prolonged starvation, excessive IV volume administration, evidence, there is currently no second-line drug that can
electrolyte disturbances, and excessive opiate drugs, will be recommended for patients who remain enteral feed–
reduce the frequency and severity of gastrointestinal dys- intolerant on dual-drug therapy, and we favor alternative
motility. approaches to gastric feeding, ie, small intestinal feeding or
Recent American Society for Parenteral and Enteral parenteral nutrition as determined by availability at individ-
Nutrition/Society of Critical Care Medicine guidelines rec- ual institutions.123-126 The effect of drugs on gastrointestinal
ommend that in patients with observed upper gastroin- motility is substantially modified by glycemia127 such that
testinal dysmotility, promotility drugs should be initiated.1 promotility drugs are less effective at higher blood glucose
However, these guidelines provided no recommendation concentrations.128 Accordingly, minimizing other systemic
about which drug should be used. factors that contribute to gastrointestinal dysmotility, such
In trials of critically ill patients, albeit small in number, as excessive exogenous opiates and hyperglycaemia, may im-
erythromycin appears to be a more potent promotility drug prove response to drugs. Given that all drugs have potential
than metoclopramide and leads to more frequent resolution side effects and the issue of tolerance, it seems sensible to
of enteral feed intolerance.82,83 However, erythromycin use discontinue promotility drugs once patients are tolerating
is associated with rapid tolerance to its effect, which may enteral feeds for at least 24 hours and limit duration of
explain why administration of both drugs (erythromycin therapy to ࣘ7 days.
and metoclopramide) appears to be more effective than There is a lack of evidence to guide drug therapy of
erythromycin alone.99,118,119 ileus. Erythromycin does not accelerate small intestinal
There is considerable variation between individuals as motility and may even exacerbate ileus.86 Based on studies
to what GRV defines gastric dysmotility that warrants in other patient settings, highly selective 5-HT receptor
administration of a promotility drug. Even among experts, agonists may be of use for ileus in the critically ill, but they
there is considerable variation with the threshold value that need to be studied before they can be recommended. There
represents large GRVs, ranging from 200–500 mL.1,13 As are inadequate data to provide strong recommendations
a group of authors who work in a variety of settings, to guide treatment for functional obstruction of the large
there are differences in our practices, but, in general, we intestine. However, neostigmine, when infused in an ICU
are of the opinion that for the majority of patients and in environment for a short duration at a relatively slow rate,
the absence of symptoms, a single GRV <500 mL should may alleviate the need for endoscopic decompression in
not lead to a reduction in the rate of enteral nutrition. some patients and appears to be a reasonable strategy.
Rather, this identifies a patient who may benefit from
administration of a promotility drug. However, when a
large GRV is associated with other features of gastroin-
testinal dysmotility (vomiting, diarrhea, or abdominal dis-
Statement of Authorship
tension), or is excessively large (>500 mL), administration A. M. Deane, M. J. Chapman, A. R. Blaser, S. A. McClave,
of a promotility drug should be considered along with and A. Emmanuel contributed to conception/design of the
a temporary reduction in the rate of feed or stopping manuscript; A. M. Deane, M. J. Chapman, A. R. Blaser, S.
altogether. A. McClave, and A. Emmanuel contributed to acquisition,
When possible, avoidance of rapid bolus injections and analysis, or interpretation of the data; A. M. Deane, M. J.
dose reduction during renal failure (metoclopramide) are Chapman, A. R. Blaser, S. A. McClave, and A. Emmanuel
likely to reduce adverse effects and appear a prudent drafted the manuscript; A. M. Deane, M. J. Chapman, A. R.
strategy. In a prospective, cluster, randomized trial and a Blaser, S. A. McClave, and A. Emmanuel critically revised
subsequent multicenter quality improvement initiative, the the manuscript; and A. M. Deane, M. J. Chapman, A. R.
use of preemptive promotility drugs, when incorporated Blaser, S. A. McClave, and A. Emmanuel agree to be fully
into a bundle of care, increased nutrient delivery.120,121 accountable for ensuring the integrity and accuracy of the
However, in the blinded NUTRIATE trial, administration work. All authors read and approved the final manuscript.
Deane et al 11

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