tan attila, m.d. and timothy r. koch, m.d. · physiological basis for gastric smooth-muscle ......

427

23 Pathophysiology and Management of Diabetic Gastropathy

Tan Attila, M.D. and Timothy R. Koch, M.D.

CONTENTS

I. Introduction................................................................................................428

II. Physiological Basis for Gastric Smooth-Muscle Activity ........................428

III. Pathophysiology of Diabetic Gastropathy.................................................429

IV. Symptoms of Diabetic Gastropathy ..........................................................431

V. Perspectives on Evaluation of Gastric Emptying......................................431

VI. Contemporary Methods for Evaluation of Gastric Emptying ..................432

A. Upper-Gastrointestinal X-Ray Series................................................433

B. Scintigraphic Assessment of Gastric Emptying ...............................433

C. Tracer Methods..................................................................................433

D. Ultrasonography ................................................................................434

E. Magnetic Resonance Imaging (MRI) ...............................................434

F. Electrogastrography (EGG)...............................................................434

VII. Evaluation of Patients with Suspected Diabetic Gastropathy ..................435

VIII. Treatment Strategies in Diabetic Gastropathy ..........................................436

A. Introduction .......................................................................................436

B. Dietary and Supportive Therapy .......................................................436

C. Optimizing Glycemic Control...........................................................436

D. Metoclopramide.................................................................................437

E. Erythromycin.....................................................................................437

F. Cisapride............................................................................................437

G. Domperidone .....................................................................................438

H. Tegaserod...........................................................................................438

I. Refractory Gastropathy .....................................................................438

IX. Future Studies ............................................................................................439

References..............................................................................................................439

428 Nutrition and Diabetes: Pathophysiology and Management

I. INTRODUCTION

Diabetes mellitus, with an estimated prevalence of 3 percent to 10 percent of the

population, is the fourth leading cause of death in the U.S. This disease complex

can affect almost every organ system, including the gastrointestinal tract. Patho-

physiologic changes involving the gut can be related to either acute hyperglycemia

or chronic changes resulting from neuropathic or myopathic processes. This chap-

ter will focus on the pathophysiology, diagnosis, and management of diabetic

gastropathy.

The clinical presentation of diabetic gastropathy is not specific and may overlap

with both structural disorders and functional dyspepsia. Nausea, vomiting, bloating,

early satiety, postprandial fullness, and upper-abdominal discomfort are the most

common presenting symptoms.1 Abdominal pain, which is likely due to gastric

distension or retension, may be an important component of the overall symptoma-

tology.2 Interestingly, symptoms do not correlate well with gastric-emptying rate;

therefore, an improvement in the gastric-emptying rate does not always result in

symptomatic improvement, or vice versa.

II. PHYSIOLOGICAL BASIS FOR GASTRIC SMOOTH-MUSCLE ACTIVITY

Gastrointestinal-contractile activity is regulated by smooth-muscle electromechani-

cal properties.3 Gastric smooth muscle, similar to other smooth muscle, is charac-

terized by a voltage-tension curve. In this relationship, depolarization of smooth-

muscle cell membrane results in increased smooth-muscle tonic contraction. Slow

waves, the basic gastric smooth-muscle electrical event, are periodic, regular depo-

larizations from the cell’s resting membrane potential.4 A slow wave follows a set

sequence during changes in resting membrane potential: initially, a rapid upstroke

depolarization, a partial repolarization, a sustained plateau potential, and then com-

plete repolarization to the resting membrane potential. This chain of events is largely

the result of activation and deactivation of calcium channels and calcium-dependent

potassium channels. Only slow waves exceeding a threshold depolarization will

result in an action potential leading to smooth-muscle contraction.

The basic rhythmic activity of gastric smooth-muscle cells is thought to originate

from the interstitial cells of Cajal, which are located in the greater curvature at the

junction of proximal and distal stomach.5–8 Interstitial cells of Cajal are found

throughout the gastrointestinal tract. Both extrinsic nerves innervating the stomach

and the intrinsic gastric nervous system are in constant interaction with the interstitial

cells of Cajal, and thus may modulate relaxation and contraction of gastric smooth

muscle. The regional variation of the relationship between electrical activity and

tension development is the result of a proximal-to-distal gradient in cell resting-

membrane potentials from –48 mV in the fundus to –75 mV in the pylorus.6,9 This

difference is likely related to differences in the density of calcium-dependent potas-

sium channels, since a chemical voltage clamp involving different concentrations of

potassium chloride can change both the resting-membrane potential and the tonic

contraction of smooth muscle obtained from different regions of the stomach.10 This

Pathophysiology and Management of Diabetic Gastropathy 429

relationship has been suggested to be the electrical basis for contraction and relax-

ation in canine gastric smooth muscle.10 This relationship may aid in understanding

the varying mechanical functions of different gastric compartments, as well as the

propagation of slow waves in an organized fashion from the proximal body to the

pylorus.

In human stomach, gastric pacemakers generate rhythmic depolarizations at a

frequency of three cycles per minute, resulting in circular muscle contractions.6,11

Abnormal rhythms of gastric myoelectrical activity, termed gastric dysrhythmias,

originate from abnormal or ectopic gastric pacemakers. A suggested classification

system includes a definition for tachygastria (> 6 cycles/min), bradygastria (< 3

cycles/min), bradytachyarrythmia, or absent activity.12, 13

III. PATHOPHYSIOLOGY OF DIABETIC GASTROPATHY

In this chapter, we will address the pathophysiology, symptoms, and treatment

options in patients with diabetic gastropathy. Potential pathophysiological abnor-

malities include: gastric dysrrhythmias,14–16 antral hypomotility,17 pylorospasm,18 and

gastroparesis.14,19

There are several potential mechanisms to explain altered gastric physiology in

patients with diabetes mellitus (Table 23.1). Almost 50 percent of diabetic patients

have some form of neuropathy, such as peripheral, autonomic, proximal, or focal

neuropathy, but gastrointestinal symptoms are not seen in all of these patients.20

Although the pathophysiology of diabetic neuropathy has not been clearly deter-

mined, the highest rates of diabetic neuropathy have been seen among patients with

long-standing disease, especially in those patients with poor glycemic control.20,21

Although autonomic dysfunction, particularly vagal neuropathy,17,22–23 has been tra-

ditionally regarded as the likely origin for diabetic gastropathy, morphologic abnor-

malities of the vagus nerve or gastric myenteric plexus in patients with diabetes

mellitus have not been routinely identified using conventional histology.24 Neurop-

athies, such as axonopathy in sympathetic nerves25 and ultrastructural and morpho-

metric changes in parasympathetic nerves,26 have been described in animal models

of diabetes mellitus.27,28 A decrease in the interstitial cells of Cajal, decreased

inhibitory neurotransmitter systems containing neuronal nitric-oxide synthase, vaso-

active intestinal peptide, or tyrosine hydroxylase immunopositive nerve fibers, and

TABLE 23.1Potential Pathophysiologic

Mechanisms for Diabetic

Gastropathy

1. Neuropathy

2. Myopathy

3. Glycemic Control

4. Impaired Antioxidant Capacity


increased levels of excitatory neurochemical and substance P have been observed

in the gut of long-standing diabetic patients.29 Further research examining the

neuropathic aspects of diabetic gastropathy is needed to better define this potential

pathophysiological feature.

There is a complex relationship between glycemic control and upper-gastrointes-

tinal function. Postprandial glucose levels both determine and are determined by the

delivery rate of nutrients from the stomach to the small intestine. Studies in both

healthy individuals and diabetic individuals have revealed that hyperglycemia can

affect gastrointestinal function (Table 23.2). It has been previously shown that

hyperglycemia can induce: 1) delayed gastric emptying;30–34 2) rapid gastric empty-

ing;35 3) gastric myoelectrical disturbances;36 4) inhibition of migrating motor com-

plexes; 5) inhibition of antral motility;37 6) pyloric contractions;38 7) inhibition of

gallbladder contractions and small-intestinal transit;39,40 8) altered esophageal motil-

ity; and 9) decreased lower esophageal sphincter pressure.41

Normalization of blood-glucose levels in diabetic patients has been shown to

improve gastric-emptying times.33 Previous studies have shown that secretion of the

pancreatic hormone, human Pancreatic Polypeptide (hPP), is regulated by vagal-

nerve input. Hyperglycemia can reduce hPP secretion, as well as gastric secretory

and plasma hPP responses to modified sham feeding in humans; these findings

support the notion of impaired vagal-cholinergic activity during hyperglycemia.42,43

Very low plasma levels of hPP have been reported in diabetic patients with cardiac

autonomic neuropathy and delayed gastric emptying.44 In support of this concept,

patients with poorly controlled diabetes mellitus have an increased perception of

upper-gastrointestinal symptoms, such as nausea, fullness, early satiety, and upper-

abdominal pain.45–47 The exact mechanisms by which hyperglycemia leads to dis-

turbances in gastric motility has not been fully delineated.

Unfortunately, much of the available information on the effects of blood-glucose

concentration on upper-gastrointestinal motor and sensory function has been obser-

vational. Available data on potential mechanisms that may mediate these effects are

sparse. Major neurochemicals involved in the regulation of gastrointestinal motor

TABLE 23.2Effects of Hyperglycemia on Upper

Gastrointestinal Function

1. Delayed Gastric Emptying

2. Accelerated Gastric Emptying

3. Gastric Myoelectrical Disturbances

4. Inhibition of Migrating Motor Complexes

5. Inhibition of Antral Motility

6. Pyloric Contractions

7. Inhibition of Gallbladder Contractions

8. Slowing of Small Intestinal Transit

9. Disturbances of Esophageal Motility

10. Decreased Lower Esophageal Sphincter Tonic Contraction


function include nitric oxide (NO),48–50 vagally mediated cholinergic input, and vaso-

vagal reflexes.51,52 In animal studies utilizing diabetic rats, there is evidence support-

ing the presence of impaired NO-synthase expression in the gastric myenteric

plexus.53 Delayed gastric emptying can be reversed by restoration of neuronal NO-

synthase expression through addition of insulin or addition of the phosphodiesterase

inhibitor sildenafil, which increases NO signaling.54

As an additional possible mechanism, impaired antioxidant status, which is

associated with accelerated liquid gastric emptying,55 has been noted in individuals

with impaired glucose tolerance and diabetes.56 However, a potential association

with delayed gastric emptying has not yet been delineated.

Defective cholinergic neuromuscular transmission in the myenteric plexus,57

impaired release of vasoactive intestinal polypepetide and calcitonin gene-related

peptide during stimulation of enteric nerves,58 and impaired NO-mediated relaxation

of the duodenum59 have been observed in diabetic rats. Indomethacin, a prostaglan-

din-synthesis inhibitor, reverses gastric dysrhythmia induced by hyperglycemia.60

Additional studies are needed to examine the effects of neurohumoral and cellular

mechanisms, and to elucidate the effects of abnormal glucose homeostasis on gas-

trointestinal motor and sensory function.

Although animal studies provide insight as to the mechanisms of diabetic gas-

tropathy, we should be very careful in extrapolating this information into human

disease. These observations suggest that the effect of glucose homeostasis on the

gastrointestinal system is multifactorial, and more work is required to explore the

pathophysiology of this common problem. In addition to the pathophysiological

effects of glucose homeostasis on gastrointestinal motility, factors that modulate the

rate of gastric emptying must be taken into consideration, such as volume, acidity,

osmolarity, nutrient density, fat content, ileal fat, colonic/rectal distention, and use

of medications.

IV. SYMPTOMS OF DIABETIC GASTROPATHY

Although gastrointestinal symptoms are common among diabetic patients seen in

diabetic clinics,62 the prevalence of most gastrointestinal-tract symptoms is similar

in persons in the community without diabetes mellitus.63 In subspecialty clinics, 76

percent of diabetic patients who participated in a survey had one or more gastrointes-

tinal symptoms (Table 23.3), including constipation, diarrhea, fecal incontinence,

and upper-abdominal symptoms, including nausea and vomiting.62 These patients

are not immune to the presence of functional gastrointestinal symptoms, perhaps

leading to an overestimation of symptom prevalence.

V. PERSPECTIVES ON EVALUATION OF GASTRIC EMPTYING

Beaumont made the earliest comments on the rates of gastric emptying in the early

19th century during his observations utilizing a patient with a traumatic gastric

fistula.63 Von Luebe performed the first definitive gastric-emptying study by a single


gastric aspiration seven hours after liquid-meal ingestion.64 Rehfuss introduced

repeated sampling of gastric contents at regular intervals.65 Hunt and Spurrell used

an aspiration technique to measure the volume of a residual test solution and the

concentration of a marker that was believed to estimate the amount emptied.66

To overcome the need for repeated gastric intubation, George described a method

using double-sampling of the stomach contents.67 A marker was administered fol-

lowing the initial sampling of a test meal. The marker concentration in the subsequent

sampling allowed calculation of the remaining gastric volume, and the chloride

concentration of the sample enabled determination of the rate of gastric secretion.

Recovery of a gastric marker from the duodenum, with the help of duodenal and

gastric intubation through a triple lumen assembly, allowed measurement of gastric

emptying. In addition, distal-duodenal sampling allowed measurement of pancreatic

and biliary secretions.68

The first gastric x-ray studies concentrated on gastric motility rather than eval-

uation of gastric-emptying time.69,70 Subsequent x-ray contrast studies examined the

emptying of liquid barium sulfate or a radiopaque meal. With these techniques, only

complete gastric-emptying time of radiopaque material could be calculated, because

the volume and density of gastric residual barium could not be determined radio-

graphically. Dissociation of barium into liquid phase allowed assessment of only

liquid emptying in tests using solid meals impregnated with barium granules.71

Comparison of a barium test meal with scintigraphic gastric emptying did not reveal

a correlation between the magnitude of retained barium at six hours and the half-

time, as well as percentage of gastric isotope remaining at six hours after ingestion

of a test meal.72 Therefore, results from these two tests are not comparable.

VI. CONTEMPORARY METHODS FOR EVALUATION OF GASTRIC EMPTYING

The presence of multiple methods to evaluate gastric emptying is an indication of

the absence of a precise and widely available technique (namely, a gold standard).

Different techniques have limitations that need to be overcome. The following

section critically analyzes and summarizes contemporary methods used for the

assessment of gastric emptying of solids.

TABLE 23.3Clinical Presentation

for Patients with

Diabetic Gastropathy

1. Abdominal Pain

2. Nausea

3. Emesis

4. Abdominal Bloating

5. Diarrhea

6. Constipation


A. UPPER-GASTROINTESTINAL X-RAY SERIES

Since radiocontrast material is not a physiological meal and residual gastric barium

can not be quantitatively measured, unless there is significant prolongation of gastric

emptying, an upper-gastrointestinal X-ray series is not sufficiently sensitive to com-

ment on gastric emptying. The primary role of these X-ray studies is to exclude a

significant mucosal abnormality or a gastric-outlet obstruction.

B. SCINTIGRAPHIC ASSESSMENT OF GASTRIC EMPTYING

This test is sensitive, quantitative, noninvasive, easy to perform, and a physiologic

method. Therefore, this test is currently considered to be the gold standard for the

assessment of gastric emptying in research and clinical practice. The technique is

based on the measurement of the disappearance of a radioisotope from the gastric

region during scintigraphic scanning. Evaluation of gastric emptying of solids is a

more sensitive technique, since gastric emptying of liquids is usually preserved even

in the presence of abnormal solid gastric emptying. Gastric emptying of liquids can

be clinically useful if the presence of rapid gastric emptying, termed dumping

syndrome, is suspected.

There are important, basic points that alter the sensitivity and specificity of

scintigraphic gastric-emptying studies.73 First, radioisotope marker should effec-

tively bind to substrate, be nonabsorbable, be resistant to a wide range of pH, and

be stable during the procedure. All studies should contain the same meal volume,

composition, and caloric content. A standard patient position should be preserved

to prevent variations due to the effect of posture. Appropriate corrections for radio-

isotope decay, three-dimensional motion of intragastric material, penetration, atten-

uation, and scattering must also be considered.

The use of a variety of radioisotopes, meals, and separate protocols by individual

hospital centers impede the comparison of gastric-emptying studies from different

institutions. Most major centers use either technetium99-labeled scrambled egg or

chicken liver. Simplified standardized scintigraphic gastric-emptying protocols have

been studied in order to establish normal gastric-emptying values, as well as to

screen patients with suspected gastric dysmotility.74,75 In these studies, one-half

emptying time of a gastric radioisotope (t1/2) is a commonly assessed parameter.

Unfortunately, scintigraphic gastric-emptying studies do not provide information

with regards to the etiology and pathophysiology of gastric dysmotility. There is

frequently no direct correlation between gastric-emptying time, patient symptoms,

and their response to therapy.76

C. TRACER METHODS

These methods are based on the assumption that measurement of the appearance of

a marker substance either in the blood or in expired air can serve as an indirect

estimation of gastric emptying. Gastric emptying should be the rate-limiting step in

the appearance of a marker substance either in the blood or in expired air. Specifi-

cally, the amount of gastric content that enters the duodenum should directly correlate

with the amount that is absorbed and appeared in the blood or expired air. It is


assumed that the absorption, transport, and metabolism of a marker are constant

both interindividually and intraindividually. Mucosal diseases that alter absorption,

pancreatic diseases, hepatic diseases, and pulmonary diseases, as well as hemody-

namic variations, can alter the accuracy of these studies.

Paracetamol,77 C13-octanoic acid,78–82 and C13-acetate have been used as markers

in these tracer studies.83 In contrast to scintigraphic studies, the absence of ionizing

radiation in C13 breath tests enables the safe evaluation of children and pregnant

women. Tracer methods can be used in centers without gamma camera, in physician’s

offices, or at a patient’s hospital bedside. These tests are considered as test choice

in certain centers in Europe, but are not widely used at this time in the U.S.

D. ULTRASONOGRAPHY

Real-time ultrasonographic evaluation of gastric emptying is based upon the mea-

surement of changes in the cross-sectional area of the antrum in response to a test

meal.84–86 The return of antral area and volume to the fasting baseline are considered

to mark the final emptying time. Gastric-contraction frequency can also be measured

by ultrasonography.87 Ultrasonography has been suggested to be equivalent to and

a valid alternative to the use of scintigraphy.88,89 The main advantages of this method

are that it is noninvasive, widely available, and there is absence of ionizing radiation.

This makes ultrasonography suitable for repeated examinations. However, it is time-

consuming, operator dependent, and difficult to perform in obese patients. It is also

difficult to perform this test in the presence of excessive abdominal gas, it generally

measures liquid gastric emptying, and it is not suitable for patients following partial

gastrectomy.

E. MAGNETIC RESONANCE IMAGING (MRI)

This noninvasive, radiation-free technique is very promising for providing informa-

tion on gastric emptying, anatomical morphology, and gastric secretion.90,91 Improve-

ments in MRI technology could allow the study of gastric motility.92,93 The cost and

availability of MRI presently limit its clinical utility.

F. ELECTROGASTROGRAPHY (EGG)

EGG is a noninvasive method for the recording of gastric myoelectrical activity by

placing electrodes on the anterior abdominal wall.95 The correlation between the

cutaneous EGG recordings and myoelectrical activity recorded from gastric serosal

electrodes has been previously validated.96–98 Important parameters that can be

obtained with the use of EGG include different frequency components and relative

power change.99 Normal gastric slow-wave frequency is considered to range between

two and four cycles per minute. Conditions below this range are termed bradygastria,

and above this range are termed tachygastria, or, as a general term, gastric arrhyth-

mia. The relative power change corresponds to the gastric-contractile strength. Since

gastric myoelectric activity is only one of many factors that alter gastric emptying,

the correlation between EGG and gastric emptying is variable.100–103 According to a

recent expert consensus opinion, the positive predictive value of an abnormal EGG


to predict delayed gastric emptying averages 65 percent, while the accuracy of a

normal EGG to predict normal gastric emptying averages 75 percent.104 Gastric

dysrhythmias rather than gastric retension may be a better prognosticator of upper-

gastrointestinal symptoms.105 Therefore, EGG may be a complementary study rather

than a replacement for standard gastric-emptying studies. Further studies are needed

to clarify the potential role for and indications for performance of EGG.

VII. EVALUATION OF PATIENTS WITH SUSPECTED DIABETIC GASTROPATHY

Suggestions for the potential evaluation of patients with suspected diabetic gastrop-

athy are outlined in Figure 23.1.

Major historical features can include a history of long-standing, insulin-dependent

diabetes mellitus or a prior history of peptic-ulcer disease. The patient may have known

diabetic nephropathy or diabetic retinopathy, which could support a diagnosis of gut

autonomic neuropathy. A history of migraine headaches could support the presence

of cyclical-vomiting syndrome. Suggestive gastrointestinal symptoms of diabetic gas-

tropathy may include nausea, emesis, weight loss, history of dehydration, or early

satiety. It is quite important to try to elicit the potential use of medications that can

alter gastric emptying, including use of over-the-counter, nonsteroidal, antiinflamma-

tory drugs or antihistamines, or prescription narcotics or anticholinergic compounds,

such as antispasmotics. Nonsteroidal, antiinflammatory drug use may be detected by

a serum platelet aggregation assay. Use of narcotics may be detected by urine screening.

In young individuals, bulimia must be considered.

FIGURE 23.1 Suggested evaluation of suspected diabetic gastropathya. Modified from sug-

gestions of Hasler, WL and Chey, WD, Gastroenterology, 125, 1860, 2003.

History and PhysicalExamination

Laboratory Tests (CBC, TSH,Electrolytes), Abdominal X-Ray

Upper Endoscopy+/–

Upper GI-Small Intestinal X-Ray

Mechanical Obstruction

Treatment

No Obstruction

Scintigraphy,Electrogastrography

Abnormal

Prokinetics, Antiemetics,Dietary Modification

Normal

Consider Etiologies,Symptomatic

Treatment


On physical examination, potential evidence for a peripheral neuropathy (stock-

ing, glove) should be sought. Examination of the extremities includes looking for

evidence of sclerodactyly. Upon examination of the abdomen, percussion in the

upper abdomen or shaking the upper abdomen may confirm the presence of a

succussion splash. It can be helpful to perform auscultation of the abdomen during

percussion of the upper abdomen, which is designed to elicit a splashing sound due

to the presence of air and fluid in the stomach. Normally, less than 200 ml of fluid

is present in the stomach following an overnight fast.

Laboratory testing should include examination for potential thyroid dysfunction,

hypokalemia, chronic renal failure, or hypercalcemia. Upper endoscopy is preferred

in order to exclude ulcer disease or an obstruction at the pylorus or proximal

duodenum. In the absence of obstruction, solid-meal gastric-emptying studies by

scintigraphy are more readily available to look for evidence of delayed gastric

emptying.

VIII. TREATMENT STRATEGIES IN DIABETIC GASTROPATHY

A. INTRODUCTION

The medical management of diabetic gastric disorders is challenging and may

become frustrating for both clinicians and their patients. Present management prin-

ciples include dietary and supportive care, optimizing care of an underlying etiology,

and symptomatic relief. Medicines that alter gastrointestinal motility, such as anti-

cholinergic medications and opiate agonists, should be avoided. Patients who do not

respond to dietary and lifestyle modifications, improved glycemic control, and phar-

macologic agents may be candidates for endoscopic or surgical intervention for

symptomatic and supportive management.

B. DIETARY AND SUPPORTIVE THERAPY

Dietary modifications, such as use of low-residue, low-lipid, high-liquid-content

meals in small but frequent portions may decrease bezoar formation, improve symp-

toms and prevent malnutrition, dehydration, and electrolyte imbalances. Some

patients may benefit from a gastroparesis diet.106 Enteral feeding can permit adequate

nutritional support and hydration in those patients who do not tolerate oral intake.

Parenteral nutrition is reserved for patients in whom enteral feeding is not possible.

C. OPTIMIZING GLYCEMIC CONTROL

Hyperglycemia may cause antral hypomotility and pyloric contractions,107 affect gastric

motility,108 and impair the efficacy of prokinetic agents.109,110 Gastric-emptying disor-

ders may result in erratic glycemic control due to variability of glucose availability or

absorption. Optimizing glycemic control may improve gastric dysmotility and patient

symptoms. It is not presently clear whether improved nutrition alters patient symptoms

via a mechanism that could include increased tissue levels of antioxidants.


D. METOCLOPRAMIDE

Metoclopromide, the only Food and Drug Administration-approved agent for the

treatment of gastroparesis, has both prokinetic and antiemetic effects through its

antidopaminergic, 5-HT3 antagonist, and 5-HT4 agonist properties.106 Its prokinetic

effects are limited to the upper-gastrointestinal tract. The usual oral dose ranges

from 5 mg to 20 mg before meals and at bedtime, and is best provided in syrup

form if gastroparesis is suspected. It can also be given to patients intravenously or

subcutaneously if there is intolerance to oral intake. Although metoclopramide

provides symptomatic relief and accelerates gastric emptying,111–113 its prokinetic

effects are not sustained over a long period of time.114 It appears that its symptomatic

relief may be due to its central antiemetic properties rather than being related to its

prokinetic effects. Contrary to early studies, a more recent publication did not show

any symptomatic, prokinetic benefit over use of a placebo.115

Numerous adverse events affect up to 20 percent of patients, including devel-

opment of acute dystonic reactions, extrapyramidal effects, drowsiness, fatigue,

lassitude, restlessness, akathisia, irritability, elevation of serum prolactin level, Par-

kinson-like symptom profile, and tardive dyskinesia (which may be irreversible after

the discontinuation of the drug).113,116–118 The poor side-effect profile and inconsistent

efficacy on gastric emptying may limit the long-term use of metoclopramide in

patients with diabetic gastropathy and gastric retention.

E. ERYTHROMYCIN

Erythromycin is a macrolide antibiotic that has prokinetic properties through its

presumed activation of motilin receptors.119 This agent may increase the amplitude

and frequency of antral contractions, as well as initiation of gastric phase three

contractions of the migrating motor complex.120–121 There is a motilin-receptor gra-

dient in mammalian gastrointestinal tract, with the highest concentrations identified

in the upper-gastrointestinal tract.122 Administration of erythromycin has been

reported to improve solid and liquid gastric emptying in diabetic, postvagotomy, and

idiopathic gastroparesis.123–127 Intravenous doses in acute treatment range between

1 to 3 mg/kg every eight hours. The commonly used oral doses are between 50 to

250 mg/kg every six to eight hours. Although the optimal dosing and route of

administration has not yet been resolved, oral regimen does not appear to be as

effective as intravenous administration.128 Unfortunately, the long-term efficacy of

erythromycin has been unsatisfactory and may include the risks of long-term anti-

biotic use.129 Adverse events induced by erythromycin include abdominal pain,

cramping, nausea, and vomiting.

F. CISAPRIDE

Cisapride, a prokinetic agent with a mixed 5-HT3 antagonist and 5-HT4 agonist

activity, has been extensively evaluated in those patients with gastrointestinal dys-

motility and gastroesophageal-reflux disease. Its effects on gastric emptying are

likely due to stimulation and coordination of antral-pyloro-duodenal motility and

possibly due to changes in gastric-outlet resistance.130–135 Although cisparide has


been shown to accelerate gastric emptying in multiple studies, the correlation

between improved gastric emptying and control of patient symptoms has remained

less convincing.136–139 Reports of arrythmias and sudden death related to prolongation

of the QT interval resulted in significant restrictions on the routine use of cisapride

in the United States.140–142 Most of these adverse events occurred in the context of

concomitant systemic diseases or drugs that could prolong cisapride metabolism.

G. DOMPERIDONE

Domperidone, similar to metoclopromide, is an agent with both prokinetic and

antiemetic properties related to its peripheral dopamine 2 receptor antagonist activ-

ity; this agent blocks dopamine’s inhibitory effects on smooth muscle.143 Domperi-

done is not available routinely in the United States, but it is available in Canada. Its

antiemetic property is due to its antidopaminergic action on the central chemore-

ceptor trigger zone. Unlike metoclopromide, this agent does not cross the

blood–brain barrier; therefore, adverse central nervous system side effects are less

likely.144,145 Domperidone has been shown to improve liquid and solid gastric

emptying and symptoms during the acute treatment of patients with diabetic gastro-

paresis.144,146 The long-term treatment effects on gastric emptying and symptoms

have been variable.146–148 Side effects of domperidone are related to elevated serum

prolactin levels, headache, diarrhea, somnolence, and abdominal pain.143

H. TEGASEROD

Tegaserod is a serotonergic (5-HT4) receptor partial agonist and has been approved

by the FDA for treatment of women with constipation-predominant irritable-bowel

syndrome.149 Although it increases orocecal transit time with preliminary promising

results on gastric emptying, further studies are needed to determine its role in the

management of gastroparesis.150–152 Use of tegaserod has been associated in routine

medical care with the development of diarrhea, and possibly ischemic colitis.

I. REFRACTORY GASTROPATHY

Some patients with refractory diabetic gastropathy undergo repeated hospitalizations

for dehydration, develop protein-calorie malnutrition, or require frequent outpatient

encounters. Frequent hospitalizations and outpatient encounters for refractory nausea,

vomiting, and dehydration can be major burdens to health-care costs, as well as to the

patient’s quality of life. Acceptable management of these difficult problems in refrac-

tory patients has been developed in medical centers that utilize a team approach.

Management decisions can include input from an endocrinologist, a gastroenterologist,

a nutritionist, a therapeutic radiologist, and a gastrointestinal surgeon.

Therapeutic options that utilize pharmacologic agents are limited for the treat-

ment of refractory gastroparesis. Surgically or endoscopically placed gastro-jejunal

or jejunal feeding tubes provide nutrition and rehydration by using a defined formula

diet or elemental diet, and permit delivery of medications in a patient with a poorly

emptying stomach. A gastrostomy or jejunostomy port allows simultaneous decom-

pression of a dilated stomach or small intestine.153,154 Unfortunately, it is extremely


difficult and time-consuming to maintain gastrojejunostomy tubes that have been

placed by therapeutic endoscopy. These devices are best managed in specialized

centers that have extensive experience in their utilization and limitations. The use

of total parenteral nutrition can be considered, especially in those patients with a

generalized gastrointestinal motility disorder. Total parenteral nutrition should be

reserved for those individuals who have not responded clinically during the use of

an elemental diet. Data on the long-term effects of parenteral and enteral nutrition

and micronutrients on diabetic gastroparesis is lacking.

Early data appears promising in specialty centers that have studied an external-

stimulation device with temporary electrodes to pace the stomach.155–157 These stud-

ies have shown improvement in symptoms and gastric emptying. Although these

devices are available in the United States, further controlled trials are needed to

define their role in the management of refractory diabetic gastroparesis.

Select patients with refractory diabetic gastroparesis have been referred to sur-

gery for total gastrectomy and formation of an esophago-jejunostomy. This extensive

procedure should be reserved for those medical centers in which there is experience

in the complex preoperative and postoperative evaluation and management of these

patients.

IX. FUTURE STUDIES

Diabetes mellitus is a common medical problem that can result in gastrointestinal

dysmotility secondary to acute hyperglycemic changes or chronic changes resulting

in neuropathic or myopathic disorders. The most common presenting symptoms of

patients with diabetic gastroparesis are nausea, vomiting, bloating, early satiety,

postprandial fullness, and upper-abdominal discomfort and pain. Available clinical

treatments are often unsatisfactory for refractory patients. Future research goals

could include studies of micronutrient supplementation or studies of improved gly-

cemic control by pancreas or islet-cell transplantation. It will be important to assess

their effects on clinical symptoms, gastric emptying, and myopathic and neuropathic

changes in the gut.

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