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Nmo_760 263.283

Neurogastroenterol Motil (2006) 18, 263–283 Treatment of gastroparesis: a multidisciplinary clinicalreview The American Motility Society Task Force on Gastroparesis (members in alphabetical order) T. L. ABELL,* R. K. BERNSTEIN,  T. CUTTS,à G. FARRUGIA,§ J. FORSTER,– W. L. HASLER,** R. W. MCCALLUM,– K. W. OLDEN,   H. P. PARKMAN,àà C. R. PARRISH,§§ P. J. PASRICHA,–– C. M. PRATHER,*** E. E. SOFFER,    R. TWILLMAN– & *University of Mississippi Medical Center, Jackson, MS, USA Diabetes Center, Mamaroneck, NY, USAàUniversity of Tennessee Health Science Center, Memphis, TN, USA§Mayo Clinic College of Medicine, Rochester, MN, USA–University of Kansas Medical Center, Kansas City, KS, USA**University of Michigan Medical Center, Ann Arbor, MI, USA  University of South Alabama, Mobile, AL, USAààTemple University School of Medicine, Philadelphia, PA, USA§§University of Virginia Health System, Charlottesville, VA, USA––University of Texas Medical Branch, Galveston, TX, USA***Saint Louis University, St Louis, MO, USA   Cedars-Sinai Medical Center, Los Angeles, CA, USAàààEastern Virginia Medical School, Norfolk, VA, USA Abstract This clinical review on the treatment of Keywords gastroparesis, gastric emptying, prokinetic patients with gastroparesis is a consensus document agents, antiemetic agents, botulinum toxin.
developed by the American Motility Society TaskForce on Gastroparesis. It is a multidisciplinary effort with input from gastroenterologists and otherspecialists who are involved in the care of patients This consensus document reviews the current treat- with gastroparesis. To provide practical guidelines ment options for management of gastroparesis. The for treatment, this document covers results of paper was conceived by gastroenterologists with input published research studies in the literature and from nutrition, diabetology, surgery, pain management areas developed by consensus agreement where and psychology specialists who are involved in the care clinical research trials remain lacking in the field of of patients with gastroparesis. To provide practical therapeutic guidelines, the authors reviewed researchstudies published in the literature from 1966 to 2005.
Abstract data presented at meetings of national and Address for correspondenceHenry P. Parkman MD, Gastroenterology Section, Parkinson international societies of gastroenterology and gastro- Pavilion, 8th Floor, Temple University School of Medicine, intestinal (GI) motility where appropriate are discussed 3401 North Broad Street, Philadelphia, PA 19140, USA.
to complement the published findings. Finally, in areas where clinical trials have not been performed, consen- sus opinions were formulated by the authors to Received: 29 August 2005Accepted for publication: 14 December 2005 Ó 2006 The AuthorsJournal compilation Ó 2006 Blackwell Publishing Ltd exclude luminal blockage have been performed.1 It has been a common assumption that the GI symptoms canbe attributed to delays in gastric emptying; however, most investigations have observed only weak correla- Gastroparesis is a disorder characterized by symptoms tions between symptom severity and the degree of of and evidence for gastric retention in the absence of gastric stasis. In diabetics, the correlation between mechanical obstruction.1 Gastroparesis typically af- global gastric symptoms and rates of gastric emptying fects patients, mostly women, and has significant is poor.7 When individual symptoms have been exam- impact on quality of life.2–4 The true prevalence of ined, only postprandial fullness appears to associated gastroparesis is not known; however, it has been with delayed emptying of solid food.8 In functional estimated that up to 4% of the population experiences dyspepsia, symptoms of early satiety, postprandial symptomatic manifestations of this condition. Diabetes fullness, nausea and vomiting are more prevalent in mellitus is the most common systemic disease associ- individuals with delayed gastric emptying than those ated with gastroparesis. A similar number of patients with normal emptying.9,10 However, in this condition, present with gastroparesis of an idiopathic nature.
these symptoms exhibit a relatively poor accuracy in Postsurgical gastroparesis, often with vagotomy or predicting the rate of gastric emptying. More recent damage to the vagus nerve, represents the third most studies confirm an association of delayed gastric common aetiology of gastroparesis. The most fre- emptying with postprandial symptoms in functional quently reported symptoms of gastroparesis include dyspepsia; however, some symptomatic patients can nausea, vomiting, early satiety and postprandial full- exhibit accelerated rather than delayed emptying in the ness.2 Abdominal discomfort and pain also are noted by early postprandial period.11 These observations suggest many affected patients and represent challenging symp- that, while delayed gastric emptying of triturated food toms to treat.5 Weight loss, malnutrition and dehydra- may participate in the genesis of symptoms in patients tion may be prominent in severe cases. In diabetics, with gastroparesis, other factors likely to have import- gastroparesis may adversely affect glycaemic control.
ant roles as well. This conclusion factors into the Gastroparesis may also be part of a larger problem of approach to the management of gastroparesis, which motor function in generalized dysmotility syndromes should not only include therapies, which promote such as chronic intestinal pseudo-obstruction. There is gastric emptying but also therapies that act through some overlap between gastroparesis and functional dyspepsia as both symptoms and gastric emptying testresults may meet definitions for both in a subset of patients.1,6 As a consequence, some patients with mildabdominal pain, nausea, vomiting and evidence of delayed emptying are considered to have functionaldyspepsia by some clinicians and gastroparesis by For rational therapy of gastroparesis, it is important to others. Patients with marked delay in gastric emptying attempt to understand the pathogenesis of the disorder.
should be diagnosed with gastroparesis not functional Delays in gastric emptying may result from a variety of dyspepsia. In general, predominant abdominal pain with deficits of neuromuscular function. Distinct regional lesser degrees of nausea is more consistent with a motor abnormalities of the stomach may have select- diagnosis of functional dyspepsia, whereas predominant ive effects on global emptying and symptoms. Further- nausea and vomiting with lesser degrees of abdominal more, symptomatic manifestations of gastroparesis pain is more characteristic of gastroparesis.
require the involvement of the peripheral and thecentral nervous systems. Indeed, the act of emesis withgastroparesis mandates participation of a number of linked brainstem nuclei. Effective management of A variety of methods have been advocated for the gastroparesis relies on the design of therapies that act measurement of gastric emptying of nutritive and inert meals. The best accepted technique is scintigraphy The different symptoms of gastroparesis may have involving ingestion of an egg meal cooked with a their basis from regional abnormalities within the technetium radiolabel. The diagnosis of gastroparesis is stomach. Manometric studies have characterized made when a delay in gastric emptying is present and increases in tonic and phasic motor activity of the laboratory studies to rule out metabolic causes of pylorus in subsets of gastroparesis patients.12 This, symptoms and endoscopic and radiographic testing to along with antral hypomotility, may be the cause of Journal compilation Ó 2006 Blackwell Publishing Ltd delays in gastric emptying in individuals with gastrop- symptoms and (iii) identify and rectify the underlying aresis.13 Alterations in compliance and accommodation cause of gastroparesis, if possible.1 Care of patients of the proximal stomach may explain symptoms such generally relies on dietary modification, medications as early satiety and postprandial fullness and discom- that stimulate gastric motor activity and antiemetic fort.14–16 Heightened perception of gastric distention drug therapy. Although in most cases, rigorous inves- has been described in diabetic patients with upper GI tigations have not assessed therapeutic responses as a symptoms suggesting a possible contribution from function of symptom severity, a number of basic visceral afferent hypersensitivity to symptoms such as recommendations can be made. For mild symptoms nausea and pain. Further, many patients have associ- (grade 1), dietary modifications should be tried. When ated dysmotility of the small bowel whose contribution possible, patients should avoid the use of medications to the clinical syndrome has not been well-defined.13 that delay gastric emptying. If needed, low doses of Potentially, each of these regional abnormalities repre- antiemetic or prokinetic medications can be taken on sents a distinct and useful therapeutic target.
an as needed basis. Diabetic patients should strive foroptimal glycaemic control to minimize effects ofhyperglycaemia on gastric function. For individuals with compensated gastroparesis (grade 2), treatment Many therapies of gastroparesis relieve symptoms only recommendations commonly involve a combination of in subsets of gastroparesis patients or are associated antiemetic and prokinetic medications given at regu- with significant side-effects. Recent investigations larly scheduled intervals to relieve more chronic have focused on the quantification of disease severity symptoms of nausea, vomiting, fullness and bloating.
both for research purposes and to assist in the delin- These agents frequently have no effect on the pain and eation of which patients are likely to benefit from the discomfort that may be associated with gastroparesis.
different modes of treating gastroparesis. A symptom In these patients, measures which are directed to pain questionnaire, the Gastroparesis Cardinal Symptom control but which do not exacerbate the other mani- Index (GCSI), has been developed and validated in festations of gastroparesis must be designed. For university-based clinical practices for quantifying patients with severe gastroparesis (grade 3), more symptoms in gastroparesis.17 The GCSI is based on aggressive treatments including hospitalization for three subscales (postprandial fullness/early satiety, i.v. hydration, insulin administration and i.v. admin- nausea/vomiting and bloating) and represents a subset istration of antiemetic and prokinetic agents are con- of the longer Patient Assessment of Upper Gastroin- sidered. Chronic care of these individuals may include testinal Disorders-Symptoms (PAGI-SYM). In addition, enteral or parenteral nutritional support with endo- a simple clinical severity grading scale was proposed in scopic and/or surgical intervention.
2003 but has yet to validated (Table 1). Future inves-tigations will determine if the use of such scoring systems for patient stratification will improve care.
The general principles for treating symptomatic gastroparesis are to: (i) correct and prevent fluid, There have been no published controlled trials exam- electrolyte and nutritional deficiencies; (ii) reduce ining the effects of dietary interventions on clinicaloutcomes in patients with gastroparesis. Nevertheless, Table 1 Proposed classification of gastroparesis severity a number of dietary recommendations can be madebased on our understanding of the physiology of gastric emptying of foods of different physical properties and Able to maintain weight and nutrition on a regular diet different nutrient classes.18 Such dietary recommenda- tions are likely to be of greatest benefit to those with mild disease (grade 1), but should also be offered to Moderate symptoms with partial control with patients with more severe gastroparesis (grades 2 and 3) Able to maintain nutrition with dietary and lifestyle to complement pharmaceutical and non-pharmaceuti- A careful patient history can identify intolerances to Grade 3: Gastroparesis with gastric failure specific foods, such as dairy products or red meats, Refractory symptoms despite medical therapy which can be addressed during design of a diet Inability to maintain nutrition via oral routeFrequent emergency room visits or hospitalizations programme for the patient with gastroparesis. Thephysical examination should include attention to Ó 2006 The AuthorsJournal compilation Ó 2006 Blackwell Publishing Ltd dentition. Impaired mastication resulting in consump- in 36 clinical trials reported that the macrolide antibi- tion of poorly chewed food could compound the defect otic erythromycin is the most potent stimulant of in antral trituration. Reducing meal size and increasing gastric emptying, while erythromycin and the dopam- the number of meals to 4–6 per day are reasonable ine receptor antagonist domperidone are best at redu- initial recommendations to minimize postprandial cing symptoms of gastroparesis.20 However, as for all gastric distention. Patients are instructed to chew food meta-analyses, concerns can be raised regarding publi- well, to avoid foods that cannot be chewed easily, to cation bias in which negative studies are not reported take fluids throughout the course of the meal and to sit and marked differences in study design that can inval- or walk for 1–2 h after meals. A diet low in indigest- idate comparisons of the different drugs. Thus, several ible, insoluble fibre is advocated as fibre delays gastric factors must be considered when choosing a prokinetic emptying and can contribute to bezoar formation in drug for the patient with gastroparesis including effic- those with profound gastric stasis.19 Likewise, fibre acy, toxicity, regional availability and cost.
supplements for treatment of constipation should bediscontinued if possible. Fatty foods should be restric- ted as lipids delay emptying. However, fat-containingliquids may be tolerated and provide needed calories. A Dopamine is an inhibitor of motor activity of the daily multivitamin/mineral supplement can be taken stomach. Two agents, which act as dopamine receptor antagonists, metoclopramide and domperidone, are If these measures are ineffective, the patient may be commonly used in patients with gastroparesis. Both advised to consume the bulk of their calories as liquid agents act to counteract the inhibitory effects of because gastric emptying of liquids often is preserved endogenous dopamine on gastric emptying. They fur- in gastroparesis. To meet the nutritional needs of the ther act as antiemetic agents by virtue of their patient, it may be necessary to supplement the diet blockade of dopamine receptor-mediated pathways in with a commercially available liquid nutrient prepar- the brainstem. Metoclopramide also acts as a serotonin ation that is low in fat and fibre. Homogenized solid 5-HT4-receptor agonist to stimulate cholinergic neural meal supplements such as blenderized foods may be pathways in the stomach and a weak 5-HT3-receptor used as a liquid nutrient source. Poor tolerance of a liquid diet is predictive of a future poor success with Metoclopramide has been approved for short-term use (4–12 weeks) since 1979. Several studies haveevaluated the efficacy of metoclopramide for thetreatment of gastroparesis. In one 3 week double-blind trial, metoclopramide produced greater symptom Prokinetic medications enhance contractility of the GI improvement and acceleration of gastric emptying tract and promote the movement of luminal contents in than placebo.21 Similar results were observed in other an antegrade direction (Table 2). There has been little in placebo-controlled crossover studies; however, individ- the way of controlled investigations directly comparing ual improvements in gastric emptying correlated the different prokinetic medications. A meta-analysis poorly with reductions in nausea and vomiting empha- assessing benefits of four different drugs in 514 patients sizing that symptom benefits may not result from the Table 2 Prokinetic medication classes for treatment of gastroparesis *Via FDA IND and IRB approval.
 Under strict compassionate use protocol approved by pharmaceutical company and IRB.
FDA, Food and Drug Administration; IND, investigational new drug; IRB, Institutional Review Board; CCK, cholecystokinin.
Journal compilation Ó 2006 Blackwell Publishing Ltd prokinetic actions of the drug and that antiemetic to double-blind continuation of domperidone vs with- mechanisms may be important for clinical effic- drawal on placebo. Those maintained on domperidone acy.22,23 One additional possible mechanism of action reported significantly greater persistence of symptom of metoclopramide is to normalize gastric slow wave benefit compared with those withdrawn from active drug regardless of the results of gastric emptying Metoclopramide is generally begun at a oral dose of testing. In a small study of six patients with diabetic 5–10 mg 30 min before meals and at bedtime, which gastroparesis, symptom improvement on domperidone can be increased to 20 mg four times daily if necessary was associated with resolution of gastric slow wave and if there are no side-effects. For patients who may dysrhythmias suggestive of a possible gastric antidys- not efficiently empty pills from the stomach for absorption, metoclopramide is available in a liquid Domperidone is generally started at 10 mg four times formulation. An orally disintegrating preparation may a day. If symptoms persist, the dose is increased to 20– soon be available. For individuals with more refractory 30 mg four times daily. A trial of 80–120 mg day)1 for nausea and vomiting and unable to retain oral medi- up to 1 month is considered the time needed to assess cations, subcutaneous injections of metoclopramide its efficacy. Because it does not cross the blood–brain have shown symptomatic efficacy in patients.25 Final- barrier, domperidone has a more favourable side-effect ly, i.v. metoclopramide is often used in inpatient care profile compared with metoclopramide. Dystonias and other movement disorders are exceedingly uncommon Most of the severe side-effects of metoclopramide with this agent. Domperidone is often used in patients result from its ability to easily cross the blood–brain whom have had side-effects to metoclopramide. Dom- barrier. Up to 30% of patients cannot tolerate meto- peridone is especially useful in gastroparetic patients clopramide due either to drowsiness and fatigue or to with Parkinson’s disease in whom it can improve restlessness and irritability. Acute dystonic reactions gastric emptying without blocking the central dopam- develop in approximately 1% of patients, often within inergic actions of treatment for Parkinson’s disease.31 24–48 h of initiating treatment. Prolonged treatment The anterior pituitary lies outside of the blood–brain infrequently may produce Parkinsonian-like symp- barrier; hyperprolactinaemic effects represent the major toms. Tardive dyskinesia, characterized by involuntary adverse effects of domperidone therapy. An i.v. form of movement of the face, tongue, or extremities, is an domperidone was withdrawn in the 1980s due to rare infrequent adverse effect of prolonged use of meto- reports of fatal cardiac dysrhythmias.
clopramide that may not reverse upon discontinuing In the United States, domperidone is not approved by the medication. The prevalence of tardive dyskinesia the Food and Drug Administration (FDA) and cannot be ranges from 1% to 10% when taking metoclopramide obtained by routine prescription or covered by health- for at least 3 months.26,27 Doctors should discuss the care plans. Traditionally, domperidone has been obtain- risk of tardive dyskinesia with their patients and able from other countries, from Internet websites, or document this discussion in their medical record. Some from compounding pharmacies within the USA. These clinicians have patients sign an informed consent to practices have been discouraged by the FDA. Domperi- document communicating the risks of metoclopra- done can be obtained through a FDA investigational mide. Other common side-effects of metoclopramide new drug application (IND) with local Institutional relate to its actions to stimulate prolactin secretion Review Board (IRB) approval. Using this mechanism, from the pituitary and include breast tenderness, patients sign an informed consent document and pur- galactorrhoea and menstrual irregularities.
chase domperidone from an FDA-approved pharmacy.
Domperidone, a peripheral dopamine receptor ant- Other dopamine receptor antagonists are in develop- agonist, has been studied most extensively in diabetic ment. Itopride, an agent with dopamine antagonist and gastroparesis. The drug stimulates both liquid- and acetylcholinesterase inhibitory properties, accelerates solid-phase gastric emptying; however, the symptom gastric emptying in patients with diabetic gastroparesis benefits of domperidone do not clearly relate to its and is used in Asia as a therapy for functional motor stimulatory actions but may instead stem from dyspepsia.32,33 In North America, itopride is currently its antiemetic properties.28 In a trial of diabetics with symptoms suggestive of gastroparesis, 260 patientsinitially received domperidone at 20 mg four times a day for 4 weeks.29 Eighty percentage of these individ-uals responded to therapy, defined as more than 30% Motilin, an endogenous peptide hormone released by reduction in symptoms. Responders were randomized the duodenal mucosa, elicits antroduodenal contrac- Ó 2006 The AuthorsJournal compilation Ó 2006 Blackwell Publishing Ltd tions via activation of smooth muscle L-type calcium- channels after occupation of motilin receptors on enteric neurones and smooth muscle tissue.34 A num- Cisapride is the best characterized 5-HT4-receptor ber of macrolide antibiotics act as motilin receptor agonist with prokinetic properties in the GI tract.
agonists to promote upper gut transit, including eryth- Cisapride activation of 5-HT4-receptors facilitates romycin, clarithromycin and azithromycin.35,36 When release of acetylcholine from myenteric cholinergic given i.v., erythromycin is the most potent stimulant nerves throughout the gut. The functional conse- of gastric emptying among the available prokinetic quences of this action are to stimulate antral contrac- drugs.37 The regional actions of erythromycin include stimulation of cholinergic nerves in the antrum which accelerate gastric emptying.49,50 Cisapride initially elicit co-ordinated phasic contractions and activation was approved by the FDA for treatment of nocturnal of inhibitory nerves in the pylorus which promote heartburn in patients with gastro-oesophageal reflux disease. Studies demonstrated symptom benefits in A number of controlled and open trials have reported patients with gastroparesis which lasted for at least clinical benefits of erythromycin therapy in patients 1 year.51 As a result, cisapride became a drug of choice with gastroparesis. Symptom improvement has been for management of gastroparesis. In prolonged post- noted in 43% of patients treated with oral erythro- marketing surveillance, a number of cases of sudden mycin.41 However, the utility of chronic oral erythro- death from cardiac dysrhythmias were attributed to mycin therapy may be limited by development of cisapride use.52 Subsequent investigations implicated a tachyphylaxis as a consequence of motilin receptor direct action of cisapride on cardiac potassium-chan- downregulation which can develop within days of nels, which promoted QT interval prolongation and initiating treatment.42 When given chronically, eryth- predisposed patients to development of ventricular romycin is usually started in low doses (125 mg two to dysrhythmias including Torsades de pointes. Patients four times daily) in liquid form to facilitate its with underlying cardiac disease, especially of the absorption. Dosing can be titrated as needed for conduction system, and those on medications known clinical effect. Side-effects of erythromycin therapy to prolong the QT interval are the main groups at risk.
are common and include nausea, vomiting and abdom- Because of this adverse effect, cisapride was withdrawn inal pain that may occur more prominently at higher from the USA market in 2000. Currently, the drug is doses. Recently, a review of a large Medicaid cohort available in the United States through a compassionate observed approximately a twofold increased risk of use/limited-access programme through Janssen Phar- sudden cardiac death in individuals on erythromycin maceutica (Titusville, NJ, USA) with strict patient therapy.43 This risk was further increased by concom- monitoring.52 Cisapride also can be obtained from itant use of cytochrome P-450 (CYP-3A) inhibitors Internet websites and in various geographic sites such as verapamil or diltiazam. Azithromycin does worldwide. However, its use is discouraged by the not have the cardiac risk and has been proposed as an alternative, although long-term data are not Tegaserod, a 5-HT4-receptor agonist, is approved for treatment of constipation-predominant irritable bowel A recent focus of pharmaceutical investigation has syndrome and chronic constipation. Although its been the development of motilin receptor agonists prokinetic actions appear to be greatest in the small exhibiting prokinetic capabilities but without antimi- intestine and proximal colon, tegaserod given at a crobial properties. An early motilin agonist, ABT-229, dose of 6 mg twice daily accelerates gastric emptying actually worsened symptoms in diabetics with nausea in healthy volunteers.53,54 In an abstract publication and vomiting compared with placebo and showed no of 163 patients with gastroparesis, tegaserod was benefits in functional dyspepsia.44,45 A newer agent, shown to accelerate solid-phase gastric emptying mitemcinal, exhibits potent prokinetic action in which was most pronounced at doses higher than the stomach and early results in diabetic gastroparesis those commonly used to treat constipation (6 mg show good effects.46 Ghrelin, a neurohumoral trans- three times daily and 12 mg twice daily).55 The mitter secreted by the stomach, is believed to play effect of tegaserod on symptoms was not reported.
a physiological role as a stimulant of food intake.
Because of this prokinetic effect, tegaserod has been Recent preliminary investigations show a prokinetic used on an off-label basis for the treatment of gastroparesis. Studies are ongoing to determine if the emptying in patients with diabetic and idiopathic prokinetic actions of tegaserod produce clinically meaningful symptom improvements in diabetics with Journal compilation Ó 2006 Blackwell Publishing Ltd gastroparesis. Tegaserod has no effects on the cardiac such as nizatidine, exhibit anticholinesterase activity and stimulate gastric emptying but their efficacy in Other 5-HT4-receptor agonists have been developed long-term treatment of gastroparesis is unknown.64,65 and show efficacy in gastroparesis. Mosapride acceler- The a-adrenoceptor receptor agonist clonidine was ates gastric emptying in healthy volunteers and reported to accelerate gastric emptying in a small patients with diabetic gastroparesis.57,58 Furthermore, study of patients with diabetic gastroparesis, but the drug may improve glycaemic control in diabetics delayed gastric emptying in another trial.66,67 Chole- with delayed gastric emptying.58 In contrast to cisa- cystokinin receptor antagonists accelerate gastric pride, mosapride has little effect on potassium-channel emptying in some studies. The utility of such agents activity and appears to exhibit a significantly lesser in gastroparesis remains to be determined.
cardiac dysrhythmogenic potential.59 Renzapride is acombined 5-HT4-receptor agonist and 5-HT3-receptor antagonist. Future studies are needed to determine ifrenzapride exhibits efficacy in gastroparesis.
As stated above, it is likely that a component of theclinical benefits observed with some of the availableprokinetic drugs, such as metoclopramide and dom- peridone, stem from antiemetic actions on brainstem Other agents have been proposed as motor stimulatory nuclei (Table 3). Use of antiemetic medications with- treatments in gastroparesis. The cholinergic muscarinic out prokinetic potential to reduce nausea and vomiting receptor agonist bethanechol increases phasic antral associated with gastroparesis is common clinical prac- motor activity; however, the elicited contractions are tice. However, there is very limited literature on the not peristaltic and do not facilitate gastric empty- use of antiemetic agents in gastroparesis. Indeed, a ing.60–62 Bethanechol also produces significant side- careful Medline search revealed only a single case effects including flushing, diaphoresis, nausea and study reporting on the use of the non-prokinetic abdominal discomfort. As a consequence, bethanechol dopamine receptor antagonist thiethylperazine in is rarely used alone for treating gastroparesis. Some gastroparesis.68 Most of the standard antiemetic agents clinicians employ the medication in low doses in have no effect on gastric motor function; some may combination with other prokinetic agents; however, delay stomach emptying. It is the consensus opinion of this practice has not been subjected to a clinical trial.
the authors that use of antiemetic medications may be Acetylcholinesterase inhibitors, such as physostig- beneficial in cases in which prokinetic drug therapy is mine and neostigmine, stimulate gut motor activity ineffective or produces unacceptable toxicity. Indeed, it by increasing acetylcholine levels with subsequent is possible that some cases of gastroparesis may show muscarinic receptor activation. As with bethanechol, anticholinesterase agents do not improve antroduo- patients of gastroparesis (grade 3), both prokinetics denal co-ordination and have inconsistent effects on and antiemetics are often used in combination to gastric emptying.63 Some H2-receptor antagonists, address control of symptoms. Although pharmacoge- Desipramine, nortriptyline, amitriptyline The H1, D2 and M1 receptor antagonists have overlap. The classification reflects thepredominant activity.
Ó 2006 The AuthorsJournal compilation Ó 2006 Blackwell Publishing Ltd nomics related to phase I reactions are relevant to the prophylaxis and treatment of chemotherapy-evoked combination of prokinetics and antiemetics, there is nausea and vomiting.81,82 The utility of these agents no evidence to suggests that adding an antiemetic in reducing symptoms in patients with gastroparesis agent adversely affects the clinical course of patients.
must be subjected to controlled investigation.
Antiemetic medications reduce vomiting by action One group of medications with antiemetic proper- on a diverse range of receptor subtypes in the peripheral ties, the tricyclic antidepressant agents, may warrant and central nervous systems (Table 3). When consider- special attention as a potential therapy for certain ing antiemetic drug use in gastroparesis, the clinician patients with gastroparesis. Low-dose tricyclic drugs should take into account factors such as side-effects, are commonly prescribed by gastroenterologists for interactions with other medications, development of refractory functional bowel diseases such as irritable tolerance and cost. The most commonly prescribed bowel syndrome. In a recent retrospective evaluation, traditional antiemetic drugs are the phenothiazines, tricyclic drugs given for a mean of 5 months produced which act as both dopamine and cholinergic receptor moderate to complete symptom reductions in the antagonists. These agents include prochlorperazine and majority of patients with functional vomiting.83 In a thiethylperazine, which are believed to act primarily in preliminary abstract on the retrospective analysis of the area postrema. Cholinergic muscarinic M1-receptor 24 diabetics with nausea and vomiting unresponsive to antagonists are commonly employed for disorders prokinetic drugs, 88% experienced symptom reduc- involving vestibular pathways, including motion sick- tions on tricyclic medications at a median dose of ness. Transdermal scopolamine is occasionally used to 50 mg day)1 and one-third of patients reported symp- treat nausea and vomiting in gastroparesis,69 although tom remission.84 Nearly one-third of patients had a there is no published data to support this practice.
pre-existing delay in gastric emptying, suggesting that Muscarinic antagonists such as hyoscyamine and tricyclics may be effective in some cases of gastropa- clidinium delay gastric emptying.70,71 Histamine resis even though this drug class traditionally has been H1-receptor antagonists exhibit the greatest benefit in considered to delay gastric emptying. Future prospect- conditions that activate vestibular pathways, such as ive controlled trials will define the role of this group of motion sickness and labyrinthitis, and some cases of medications in the management of gastroparesis.
postoperative emesis.72,73 Pure H1 antagonists include Complementary and alternative medicine therapies dimenhydrinate and meclizine, whereas promethazine often are given for treatment of nausea and vomiting.
has mixed actions on other receptor subtypes. Many of Ginger, a traditional Chinese antiemetic agent, exhib- these agents have a mild inhibitory effect on gastric its weak 5-HT3-receptor antagonist properties and has emptying.74 The serotonin 5-HT3-receptor antagonists gastric slow wave antidysrhythmic effects in hu- have efficacy in chemotherapy-induced emesis, post- mans.85,86 Acupressure and electrical acustimulation operative emesis and radiation therapy-induced vomit- on the P6 acupuncture point (the Relief Band) have ing. An abstract reported that ondansetron produced shown variable success for postoperative emesis, small but statistically significant reductions in nausea, chemotherapy-induced vomiting and nausea of preg- vomiting and abdominal pain in 17 patients with nancy.87 One study has reported benefits of acupunc- refractory unexplained nausea and vomiting.75 On- dansetron has no effect on gastric emptying in healthyvolunteers although one investigation observed inhibition of gas-tric activity with tropesitron.78 Cannabinoids exhibit In some patients with gastroparesis, pain represents a potency equal to or slightly greater than dopamine prominent symptom and can produce significant mor- receptor antagonist antiemetic drugs in chemotherapy- bidity and utilization of healthcare resources.2,5 The induced emesis, and may have additional appetite pathogenesis of pain in gastroparesis is poorly under- stimulatory effects.79 Benzodiazepines are useful in stood and treatments for this symptom largely are the management of anticipatory nausea and vomiting unsatisfactory. In diabetics with gastroparesis, pain has prior to chemotherapy administration, in large part been considered to be a consequence of autonomic because of their anxiolytic and tranquilizing effects.
neuropathy. However, one small study found that Benzodiazepines do not affect gastric emptying and more severe forms of visceral afferent neuropathy were may be useful in i.v. form for inpatients with gastro- associated with fewer rather than more symptoms.89 paresis by virtue of their sedating actions.80 The most To date, there have been no studies to specifically recently introduced antiemetics are the neurokinin address the effectiveness of any therapy of abdominal NK1-receptor antagonists, which are available for pain in patients with gastroparesis.
Journal compilation Ó 2006 Blackwell Publishing Ltd The approach to dealing with pain in these patients produce fewer side-effects.100 Longer acting compounds begins with an empathetic understanding by the doctor such as methadone or continuous release preparations with recognition that pain is a valid component of the such as transdermal fentanyl may elicit less constipa- gastroparesis symptom complex. The role of pharmac- tion than other narcotics.101,102 A current area of drug otherapy in the management of pain with gastroparesis development is the generation of peripheral opioid is complicated by potential drug toxicities and drug receptor antagonists which block peripheral effects of properties, which can delay emptying and/or worsen narcotic drugs but preserve the central analgesic symptoms thereby counteracting the benefits of pro- effects.103,104 However, a study of the novel peripheral kinetic and antiemetic medications. Several medica- l-opiate receptor antagonist alvimopan observed rever- tion classes offer theoretical benefits for reducing pain sal of the inhibitory effects of codeine on the small in the gastroparesis patient. Non-steroidal anti-inflam- intestine and colon but not the stomach.105 matory agents ameliorate gastric slow wave dysrhyth-mias in several healthy human models.90 Furthermore, oral indomethacin and i.v. ketorolac have been repor-ted to resolve slow wave abnormalities in diabetics and Unrelenting nausea and vomiting, often with associ- patients with dyspeptic symptoms.91,92 However, non- ated pain, frequently combine to produce significant steroidal agents are potentially ulcerogenic and may psychological consequences. Virtually all studies worsen renal function in some diabetics. Thus, their examining psychological aspects of gastroparesis and routine use cannot be advocated by the authors of this functional dyspepsia show impaired quality of life and consensus document although selected patients can be increased levels of anxiety, depression and somatiza- considered for these drugs. In addition to their poten- tion.2,106,107 Furthermore, one study has reported that tial utility as antiemetics, tricyclic medications in low measures of psychological dysfunction correlated bet- doses may reduce pain associated with gastroparesis ter with gastropathic symptoms in diabetics than do much as they do in other forms of neuropathic pain.93 measures of neuropathy and gastric emptying.108 Other antidepressant classes including selective sero- Patients with gastroparesis need an empathetic doc- tonin reuptake inhibitors (SSRIs), selective noradren- tor who recognizes the emotional disruptions caused by aline reuptake inhibitors and combined serotonin/ their GI illness. Instilling hope, addressing pain and noradrenaline reuptake inhibitors (such as the novel increasing self-management of their chronic illness are agent, duloxetine, which was recently approved for important. Conceptualizing the psychophysiological diabetic neuropathy) may have benefits as well; how- aspects of the disease helps the patient focus on what ever, there are no data on their actions on visceral he/she can control and decreases viewing the disease as nerve function.94 Among SSRIs, paroxetine may selec- ÔpsychiatricÕ in nature.109 Management of severe gastro- tively accelerate small intestinal transit.95,96 Other paresis may be enhanced by the active participation of a agents with efficacy in peripheral neuropathic pain team of providers who communicate together and such as gabapentin and topiramate have unknown collaborate effectively.110 The clinical psychologist actions in patients with pain associated with gastrop- can be an important member of the Ôgastroparesis teamÕ aresis.97,98 The a-adrenoceptor receptor agonist cloni- to help the patient develop a game plan for coping with dine exhibits visceral antinociceptive effects, but its symptoms. Efforts to facilitate psychosocial support effects on pain with gastroparesis are uncertain.99 and rehabilitation, including encouraging education Unfortunately many patients with severe pain do not and the support of family and friends, are import- respond to more conservative therapies and are given ant.109,111 Psychotherapeutic interventions can be help- intermittent or chronic therapy with opiate agents for ful as adjunctive measures. Simple measures such as pain control. Although narcotic agents produce gener- relaxation techniques, cognitive restructuring and dis- alized analgesia, their efficacy in gastroparesis is traction help promote a sense of control on the part of unproved. Furthermore, opiates exert potent inhibitory the patient. Other techniques such as hypnosis and effects on GI transit inhibiting gastric emptying and biofeedback may benefit some patients.112 colonic transit.100 Finally, chronic narcotic use mayresult in tolerance to its analgesic effects, physical dependence and addiction. Thus, the routine use of opiate agents for the management of pain with gastro-paresis is not advocated by the authors. If narcotics are In tertiary care centres, up to 50% of patients with to be considered, milder agents such as tramadol, an long-standing (>5 years) type 1 (insulin-dependent) or opioid with less impact on l-opiate receptors, may type 2 (non-insulin-dependent) diabetes may have Ó 2006 The AuthorsJournal compilation Ó 2006 Blackwell Publishing Ltd delayed gastric emptying.113 The prevalence of GI glycaemia on gastric function to its impact on symp- symptoms in diabetics in the primary care setting toms is less clear. However, one study has observed a appears to be lower. A population-based survey repor- significant correlation between the degree of hypergly- ted that 18% of diabetics experience frequent dysmo- caemia and the severity of postprandial fullness in tility type, upper GI symptoms, a rate greater than in diabetic patients.124 All studies to date have examined non-diabetics.114 Moreover, this survey observed a the functional consequences of acute elevations in trend to an increase in frequency of symptoms in those blood glucose. The impact of chronic, long-term with poor glycaemic control. Conversely in a US hyperglycaemia on gastric dysfunction in persons with epidemiological study, the prevalence of most GI diabetes is less clear; there are no long-term controlled symptoms was similar in persons with or without studies confirming the importance of good glycaemic diabetes.115 The presence of impaired motor function control in reducing symptoms in diabetic gastroparesis.
of the stomach in patients with diabetes does not However, observations from physiological studies sug- always lead to development of gastric symptoms. In gest that high blood glucose levels can adversely affect one investigation, only 50% of diabetic patients with responses to therapy. In both type 1 diabetic patients delayed gastric emptying reported typical symptoms of and healthy volunteers, induction of acute hypergly- gastroparesis.116 Additionally, diabetics with normal caemia markedly attenuates the motor stimulatory gastric emptying may have a symptom constellation effects of the prokinetic drug erythromycin on the indistinguishable from those with delayed gastric emptying.117 It is a common clinical observation thatdiabetic patients with gastroparesis may also exhibit Glycaemic control in diabetic gastroparesis erratic postprandial blood sugar values. Indeed, loss ofgood glycaemic control in a previously well-regulated Because of the consistent observations from physiolo- diabetic should raise concern for gastroparesis. Gastric gical studies that high serum glucose levels adversely stasis impairs delivery of nutrients and oral hypoglyc- affect gastric function, it is the consensus opinion of aemic medications to the small intestine for absorp- the authors that intensification of therapies to correct tion. Postprandial hypoglycaemia or hyperglycaemia hyperglycaemia may facilitate the actions of and may develop depending on how the delivery of nutri- increase the benefits of other treatments in managing ents corresponds with the peak absorption of the the patient with diabetic gastroparesis. Measures that are likely to be effective include more aggressiveglucose monitoring with frequent dosing of short-acting insulin preparations to prevent profound post- prandial hyperglycaemia. Prevention of wide fluctua- A number of studies have demonstrated a relationship tions in serum glucose levels may be more important between blood glucose levels and parameters of gastric than maintenance of a given steady-state blood sugar function both in diabetic patients and in healthy value from a gastric emptying perspective.127 To this volunteers.118,119 In patients with type 1 diabetes, end, monitoring 2-h postprandial blood glucose levels acute hyperglycaemia to blood glucose levels of 288– may be useful. Conversely, there is little convincing 360 mg dL)1 elicits delays in both liquid and solid evidence to suggests that prokinetic treatment of gastric emptying.118 Other investigations in diabetics delayed gastric emptying can reliably improve glycae- have demonstrated hyperglycaemia-evoked impair- ment of postprandial phasic antral contractions and Glucose control in the type 2 diabetic patient with induction of tachygastria, providing possible mecha- gastroparesis can represent a significant challenge. In nisms for the retarding effects on gastric emptying of many type 2 diabetics, oral hypoglycaemic medica- high glucose levels.120 Conversely in some type 2 tions often are ineffective and can contribute to swings diabetics, liquid-phase gastric emptying may be accel- in blood glucose levels because of the temporal erated during hyperglycaemia.121 Investigations in mismatch between nutrient absorption and medica- healthy volunteers observe that acute increases in tion. The addition of basal insulin therapy to oral blood glucose can abolish phasic antral motor activity, therapy may be valuable in achieving glycaemic stimulate pyloric contractions, evoke tachygastria and control in the type 2 diabetic patient. Furthermore, enhance fundic compliance, indicating that the degree use of a long-acting insulin preparation with a 24 h of glycaemic control itself can influence gastric func- profile that mimics normal pancreatic basal secretion tion independently of the presence of underlying may improve overall regulation of blood glucose levels.
neuropathy.122,123 The relation of the actions of hyper- Newer insulin analogues such as insulin glargine limit Journal compilation Ó 2006 Blackwell Publishing Ltd the number and severity of isolated insulin peaks and are associated with fewer hypoglycaemic episodes.
Addition of basal insulin glargine or neutral protamine Determining the degree of nutritional compromise Hagedorn (NPH) to target a mean fasting plasma involves assessment of symptoms, diet history, body- glucose concentration of £100 mg dL)1 facilitates weight (bw) and disease course. The conventional attainment of glycosylated haemoglobin (HbA1c) val- nutritional laboratory assessments of serum albumin ues of <7% in patients who were inadequately and prealbumin levels are affected by a variety of controlled with oral hypoglycaemic agents.129 Patients factors in gastroparesis and may not be reliable meas- on insulin glargine are more likely to reach this goal ures of nutritional status. Unintentional weight loss without nocturnal hypoglycaemia compared with over time is probably the most important, non-invasive parameter for assessing the degree of malnutrition. A Patients with type 1 diabetes are especially prone to 10% loss of weight over 6 months is consistent with wide variations in blood glucose levels. The use of a current definitions of significant malnutrition.130 One premixed formulation with both short- and long- should compare the patient’s current actual weight to acting insulin requires relatively strict adherence to his or her usual bw as opposed to the ideal bw, which meal timing and composition, and assumes that can result in overestimation or underestimation of true nutrients will be available within a given time frame weight loss. The subset of diabetic patients with to avoid hypoglycaemia. Because of these restrictions, chronic renal failure requiring haemodialysis requires premixed insulin may be a poor choice for individuals careful scrutiny as progressive falls in weight may with delayed or unpredictable gastric emptying. For reflect either development of gastroparesis or excessive many type 1 diabetic patients, a long-acting prepar- fluid withdrawal during dialysis. Essential nutrient and ation such as insulin glargine may be administered mineral deficiencies, particularly those resulting in twice daily with preprandial injections of regular anaemia and metabolic bone disease, require ongoing insulin formulas. However, in those with gastropa- monitoring and supplementation if needed. Laboratory resis, postprandial hypoglycaemic episodes can occur studies should include: (i) electrolytes including mag- when the glucose-lowering effects of preprandial nesium, as hypokalaemia and hypomagnesaemia can short-acting insulin precede delivery of nutrients into exacerbate delay in gastric emptying; (ii) serum glucose the small intestine for digestion and absorption. As a and HbA1c in diabetic patients; (iii) iron and ferritin consequence, some persons with delayed emptying levels particularly for partial gastrectomy settings; (iv) may need regular insulin dosing during or even after vitamin B12 and (v) 25-OH vitamin D especially in meal ingestion. Postprandial administration also al- those with long-standing gastroparesis or gastroparesis lows the patient to reduce the insulin dose if vomiting occurring after partial gastrectomy.
prevented consumption of the entire meal. Somepatients benefit from use of improved insulin pumps which can be set to provide a constant basal insulininfusion 24 h a day. These individuals then adminis- Initiation of enteral feedings is indicated if oral nutri- ter bolus regular insulin injections prior to, during, or tion fails to meet the caloric and fluid needs of the after meals. In selected cases, jejunostomy feedings patient with gastroparesis. Enteral nutrition is prefer- may minimize extreme glycaemic fluctuations. Addi- able to total parenteral nutrition (TPN) in most tional insulin may be needed for those receiving individuals, because of issues related to infectious complications, thrombosis, i.v. access problems, hepa- additional calories and to prevent overnight hyper- tobiliary consequences, administration and cost. Fur- thermore, TPN rarely is necessary in the patient withgastroparesis unless there is profound dysmotility alsoinvolving the small intestine as in chronic intestinal pseudo-obstruction. However, some severely malnour- ished gastroparetic patients may benefit from a brief Patients with chronic symptoms of gastroparesis may course of TPN to provide supplemental caloric support develop dehydration, electrolyte abnormalities and/or and to gain glycaemic control. For these individuals, extreme malnutrition. Such individuals warrant care- 30–40 units of regular insulin may need to be added to ful nutritional assessment and consideration to initiate each litre of TPN, depending on the patient’s prior supplemental enteral nutrition, or as a last resort, insulin requirements and TPN contents (1 unit regular insulin per 5 g carbohydrate or 15 g protein).
Ó 2006 The AuthorsJournal compilation Ó 2006 Blackwell Publishing Ltd Criteria for initiation of enteral nutrition have been the decision to begin enteral feedings is made ration- proposed which relate to symptom severity, nutritional ally. Several options for enteral access and feeding are consequences of disease and complications of gastrop- available (Table 5). There are no data favouring one aresis (Table 4).131 The recommendation to place approach over another and the choice of access is often enteral access may not initially be accepted by the determined by the expertise of the individual centre.
patient. Management goals such as desired weight, However, infusion of liquid meals into the stomach via reductions in hospitalizations and improved glycaemic a nasogastric tube or gastrostomy is not advocated control should be discussed with the patient, such that because of the likelihood of symptom exacerbation andthe risk of pulmonary aspiration resulting from the Table 4 Criteria for initiation of enteral nutrition supple- impairment of gastric emptying. Short-term nasojejun- al feeding is often used to help determine if the patientwill tolerate chronic small bowel feedings through a Severe weight loss, e.g. unintentional weight loss >5–10% permanent enteral access. Jejunostomies are most commonly placed by laparotomy or laparoscopy. Direct Repeated hospitalizations for refractory gastroparesis percutaneous endoscopic jejunostomy placement is requiring i.v. hydration and/or i.v. medication performed in some centres. Jejunostomy extension Inability to meet weight goals set by doctor, dietician tubes can be passed through pre-existing gastrostomies Patient would benefit from gastric decompression for delivery of enteral feedings in patients who are not Patient would benefit from a way to absorb medications candidates for direct jejunostomy access or in whom everyday to gain therapeutic levels when vomiting such access is not desired for other reasons. In some individuals, a button device may improve quality of life Patient has maintained usual bodyweight, but experiences and personal appearance. Enteral feedings are usually initiated 24 h after jejunostomy tube placement. Stand- ard polymeric formulas with caloric density of 1.0– Overall poor quality of life due to gastroparesis symptoms 1.5 cal mL)1 (e.g. Jevity 1.5, Nutren 1.5 unflavoured,Promote, or Isosource HN) are begun at low infusion Used with permission from the University of Virginia HealthSystem Nutrition Support Traineeship Syllabus (87).
rates of 25–50 mL h)1 and advanced by 10–25 mL h)1 Table 5 Forms of enteral access for nutrition supplementation Large tube size often causes is comfortIs a poor choice for feeding due to Significant gastro-oesophageal reflux can occur Vomiting may expel the tube into the stomach May be acceptable if there are no other options May be used for venting of secretions to decrease Allows the patient to vent gastric secretions to Migration of the J-tube extension into stomach New PEG-Js have distal feeding ports to reduce Stable access for reliable jejunal nutrient delivery Avoids gastric penetration which would interfere with proper electrode placement for gastricelectrical stimulation Two sites – one for venting and one for Journal compilation Ó 2006 Blackwell Publishing Ltd every 4–12 h until the desired daily caloric intake is initial enthusiastic reports – and the average duration achieved. Liquid formulations of medications can be of response was 5 months.139 In an abstract report of 78 given though the jejunostomy followed by low volume patients, percentages of patients experiencing symp- water flushes.131 Individuals should avoid oral intake tom reductions after pyloric injection of botulinum during the initial 48–72 h after starting enteral infu- toxin were similar in patients with diabetic (55%), sions to facilitate determination of patient tolerance of tube feedings. When first administering enteral nutri- (44%).140 Prior response to botulinum injection predic- tion, jejunal feedings should be delivered continuously ted a favourable response to subsequent injection.
24 h a day. Over time, this can be converted to Higher doses of botulinum toxin (150–200 units) were nocturnal infusions to free up the daytime hours for more likely to produce reductions in nausea and optional oral intake and to participate in normal daily vomiting compared with doses £100 units.
activities. High calorie formulas (1.5–2.0 cal mL)1) can Results of these uncontrolled trials have served as reduce volumes and times of infusion; however, sup- the impetus for the conduct of placebo-controlled trials plemental hydration may be needed. In those with of pyloric injection of botulinum toxin in gastroparesis.
considerable weight loss, enteral feedings should be Preliminary results of one investigation reported an initiated more slowly to avoid refeeding problems such as respiratory failure and congestive heart failure.132 improvement.141 However, this preliminary report of Prevention of complications from jejunostomy tubes 12 patients was underpowered to detect an effect of the include regular flushing after use and routine skin care.
drug. Until appropriate studies are performed, the Some centres advocate tube replacements every 3– authors feel it is appropriate to consider pyloric 6 months to avoid problems such as tube decomposi- injection of botulinum toxin when other accepted tion and skin infection whereas other institutions medication therapies have failed or produce unaccept- recommend intervention only when adverse issues able side-effects. To date, few adverse effects have been reported with botulinum toxin injections thus themajor limiting factors relate to issues of insurancecoverage and the inconvenience of undergoing endo- Some patients with documented gastroparesis exhibit The therapeutic endoscopist also may offer other prolonged periods of increased phasic and tonic motor treatment options to individuals with refractory gastr- activity of the pylorus.12 This phenomenon, termed oparesis. Endoscopic placement of a venting gastrosto- pylorospasm, has been postulated to contribute to the my may allow the patient with severe postprandial delay in gastric emptying by producing a functional fullness or discomfort to release gas and fluid inter- gastric outlet obstruction.12 In theory, use of a therapy mittently to reduce symptoms.142,143 In theory, dila- to reduce pylorospasm might have beneficial actions in tion of the pylorus may produce similar benefits as gastroparesis. Botulinum toxin binds to presynaptic pyloric injection of botulinum toxin; however, no acetylcholine terminals and produces blockade at the studies have been performed to test this method.
level of the neuromuscular junction thereby preventingcholinergic transmission and promoting muscle relax- ation. Endoscopic injection of botulinum toxin into thepylorus has been shown to reduce fasting and post- Development of practical gastric electrical stimulation prandial phasic and tonic pyloric contractions in techniques for the treatment of gastroparesis have patients with gastroparesis.133,134 In several small been a focus of research over the past decade. Studies open-label series, acceleration of gastric emptying and using a gastric pacemaker that delivered high energy modest reductions in symptoms have been observed 1– depolarizing stimuli to the stomach just above the 3 months after pyloric injection of botulinum tox- physiological slow wave frequency (3.3 cpm) showed in.134–138 Doses have ranged from 80 to 200 units promise in promoting gastric emptying and reducing delivered in circumferential fashion at 4–5 sites into symptoms of gastroparesis.144 However, this system proved unwieldy because of the large external current More recent retrospective analyses of larger numbers source required to drive the stomach through pacing of patients have provided additional information on the electrodes that penetrated the abdominal wall and utility of pyloric botulinum toxin injection.139,140 In sewn to the gastric serosa. In 2000, the FDA-granted one study of 63 patients in clinical practice, the humanitarian device exemption approval for the response rate was 43% – lower than many of the Enterra gastric electrical stimulator (Medtronic, Inc.; Ó 2006 The AuthorsJournal compilation Ó 2006 Blackwell Publishing Ltd Shoreview, MN, USA) for patients with refractory stimulator has shown efficacy in reducing symptoms diabetic or idiopathic gastroparesis. This system con- in postsurgical gastroparesis – an unapproved indica- sists of a pair of electrodes sutured to the muscular tion.151,152 The most common complication of this layer of the anterior wall of the stomach, which are form of therapy is infection of the subcutaneous connected to a pulse generator implanted in a subcu- stimulator pocket, which occurs in 5–10% of patients taneous pocket in the abdominal wall. The pulse and nearly always requires surgical removal of the generator delivers low energy 0.1 s trains of pulses at a device. Other complications include wire breakage, frequency of 12 cycles per minute. Within each pulse electrode dislodgement or penetration of the stomach, train, individual pulses oscillate at a frequency of 14 and intestinal obstruction. Patients should not undergo magnetic resonance imaging and should avoid certainmetal detecting security devices after stimulatorimplantation.
While the results of these investigations are encour- Two multicentre trials have been conducted to evalu- aging, the clinical benefits of gastric electric stimula- ate the efficacy of the gastric electrical stimulator in tion have not been unequivocally demonstrated or the patients with diabetic and idiopathic gastroparesis. In site of action. A larger, longer duration, sham-stimu- an open-label study, 35 of 38 patients (mostly with lation controlled, multicentre trial of gastric electrical idiopathic gastroparesis) experienced >80% reductions stimulation is ongoing in patients with gastroparesis.
in nausea and vomiting which persisted for the Optimal pulse parameters need to be defined and duration of the observation period (3–15 months) asso- predictors of clinical improvement must be character- ciated with significant weight gain.145 Although many ized. Endoscopic placement may offer a much more individuals were able to discontinue enteral or paren- attractive lead placement method. A recently reported teral nutrition, one quarter of patients needed to method of temporary gastric electrical stimulation via undergo additional surgeries including subtotal gas- endoscopically placed electrodes offers a potential trectomy for symptom control and device removal for means to preoperatively predict potential response to complications. The second multicentre investigation represents the only sham-stimulation controlled studyto date.146 In this trial, 33 gastroparesis patients (16 idiopathic, 17 diabetic) were randomized to shamvs active stimulation for 1 month each in double-blind, The mechanism(s) underlying the clinical benefits of crossover fashion followed by an open-label stimula- the gastric electrical stimulator are not fully under- tion period to 12 months. During the blinded phase, stood. Most investigations observed only minimal vomiting frequencies were 14% lower when the device acceleration of gastric emptying.145,146,148,149 Those was ON compared with times when the device was studies reporting acceleration of emptying are com- deactivated – a difference reported to be statistically posed largely of patients with idiopathic gastroparesis, significant. Furthermore, patients preferred the ON a condition which can show progressive spontaneous period over the OFF period by a threefold margin.
improvement. Furthermore, this device does not However, the benefits of treatment were predomin- entrain slow waves or reverse underlying slow wave antly, if not exclusively, experienced by the diabetic dysrhythmias.154 Recent reports indicate that electrical group. During the open phase of the study, electrical stimulation can modulate gastric biomechanical prop- stimulation produced a 76% reduction in vomiting at erties, enhance postprandial proximal gastric accom- 12 months. Approximately 15% of patients required device explant or revision because of complications. In distension.155,156 An investigation employing cerebral other open-label, single centre studies, electrical sti- imaging methods suggests that gastric electrical sti- mulation has been reported to improve nutritional mulation has inhibitory actions on afferent pathways status, limit the need for prokinetic and antiemetic projecting to different regions in the brain.157 Others medications, reduce the need for supplemental nutri- have suggested that the benefits of the device may tion, decrease health-related costs and improve HbA1c stem from action on vagal pathways.147,154 However, if values in diabetics.110,147–149 In an abstract with long- the findings from case series reporting responses in term patient follow-up, investigators have observed patients with postvagotomy gastroparesis are repro- 26% and 44% reductions in nausea and vomiting, duced, mediation by vagal pathways cannot represent respectively, persisting for up to 10 years after device the sole mechanism of action of gastric electrical implantation.150 Most recently, the gastric electrical Journal compilation Ó 2006 Blackwell Publishing Ltd Because of the restrictions imposed by its humanitar- ian device status, the Enterra gastric electrical stimu- lator cannot be implanted at any given institution until its use has been approved by the local IRB.
Although patients with refractory symptoms have embraced the availability of this device, this special status has been used by some third party insurance carriers to deny coverage. Candidates for implantation of the gastric electrical stimulator include patientswith chronic diabetic or idiopathic gastroparesis with relentless nausea and vomiting who are not responding to appropriate diet and medication therapy. There is a special need in diabetics being considered for renal and/or pancreas transplantation where it is important that the immunosuppressive agents will be absorbed.
Conversely, individuals without nausea and vomiting but with other manifestations of gastroparesis (full- ness, early satiety, anorexia, pain) have not been shown to predictably respond to gastric stimulation.
Patients being considered for enteral or parenteral nutritional support may be given particular considera- tion for this treatment option. However, one group has reported in an abstract that aggressive medical therapy with combination drug therapy (antiemetics and pro- kinetics in adequate doses) and pyloric injections of botulinum toxin produces adequate symptom responses that avoid the need for surgery in up to two-thirds of patients referred for consideration of gastric electrical stimulation.158 Contraindications may include generalized dysmotility syndromes also involving the small bowel including chronic intestinal pseudo-obstruction and collagen vascular diseases such as scleroderma and prior gastric resections.
Although chronic narcotic analgesic use may reduce the symptomatic benefits of gastric electrical stimula- tion, the need for opiates should be evaluated on an individual basis and does not necessarily represent an exclusion criterion.159 Insertion of a jejunostomy tube during implantation of the gastric electrical stimulator should be considered in patients who may have difficulty meeting their nutritional and hydration In selected instances, other surgical procedures may be considered for control of refractory symptoms in patients with gastroparesis.143 The range of surgical options includes drainage procedures such as pyloro- myotomy or pyloroplasty and partial or total gastric resections to bypass a non-emptying stomach and Ó 2006 The AuthorsJournal compilation Ó 2006 Blackwell Publishing Ltd decrease symptoms. Most published studies are uncon- trolled and report disappointing responses to operative 1 Parkman HP, Hasler WL, Fisher RS. American Gast- resection.143 Of seven patients who underwent partial roenterological Association technical review on the (subtotal) gastrectomy with Roux-en-Y gastrojejunos- diagnosis and treatment of gastroparesis. Gastroenterol- tomy, six reported reduced vomiting.160 However, three individuals developed renal failure and two died 2 Soykan I, Sivri B, Sarosiek I, Kierran B, McCallum RW.
Demography, clinical characteristics, psychological pro- within 5 months of surgery. More impressive results files, treatment and long-term follow-up of patients with have been observed in some studies in which total gastroparesis. Dig Dis Sci 1998; 43: 2398–404.
(completion) gastric resection was performed for post- 3 Revicki DA, Rentz AM, Dubois D et al. Gastroparesis surgical gastroparesis.161–163 Results from these uncon- Cardinal Symptom Index (GCSI): development and trolled, retrospective case series observed symptom validation of a patient reported assessment of severityof gastroparesis symptoms. Qual Life Res 2004; 13: reductions in approximately two-thirds of patients after this drastic surgical option. However, a more 4 Farup CE, Williams GR, Leidy NK, Helbers L, Murray M, recent study of completion gastrectomy for severe Quigley EMM. Effect of domperidone on the health- postsurgical gastric stasis reported successful out- related quality of life of patients with symptoms of dia- comes in only 43% of patients.164 In diabetic patients, betic gastroparesis. Diabetes Care 1998; 21: 1699–706.
5 Hoogerwerf WA, Pasricha PJ, Kalloo AN, Schuster MM.
pancreatic transplantation has been shown to halt Pain: the overlooked symptom in gastroparesis. Am J progression or even partly reverse peripheral polyneur- opathy.165 However, no consistent benefits of pancreas 6 Talley NJ, Vakil NB, Moayyedi P. American Gast- transplantation on symptoms or gastric emptying have roenterological Association technical review on the been reported in patients with diabetic gastro- evaluation of dyspepsia. Gastroenterology 2005; 129:1756–80.
7 Horowitz M, Harding PE, Maddox AF et al. Gastric and oesophageal emptying in insulin-dependent diabetes mellitus. J Gastroenterol Hepatol 1986; 1: 97–113.
8 Jones KL, Russo A, Stevens JE, Wishart JM, Berry MK, The treatment of gastroparesis includes dietary mod- Horowitz M. Predictors of delayed gastric emptying indiabetes. Diabetes Care 2001; ifications, prokinetic and antiemetic medications, 9 Stanghellini V, Tosetti C, Paternico A et al. Risk indi- measures to control pain and address psychological cators of delayed gastric emptying of solids in patients issues, and endoscopic or surgical options in selected with functional dyspepsia. Gastroenterology 1996; 110: instances. Table 6 lists the consensus opinions of the authors of this document regarding the organized 10 Sarnelli G, Caenepeel P, Geypens B, Janssens J, Tack J.
Symptoms associated with impaired gastric emptying of approach to treating this challenging condition. The solids and liquids in functional dyspepsia. Am J Gast- different therapeutic modalities may be offered alone or in different combinations as dictated by the needs of 11 Delgado-Aros S, Camilleri M, Cremonini F, Ferber I, the individual patient. Goals of therapy include relief Stephens D, Burton DD. Contributions of gastric vol- of symptoms, normalization of nutrition and hydration umes and gastric emptying to meals size and postmealsymptoms in functional dyspepsia. Gastroenterology status, improvement of glycaemic control in diabetics, and improvement of gastric emptying when appropri- 12 Mearin F, Camilleri M, Malagelada JR. Pyloric dysfunc- ate. Effective management of the patient with gastrop- tion in diabetics with recurrent nausea and vomiting.
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The authors are appreciative of Jeanne Keith-Ferris of 15 Samsom M, Salet GAM, Roelofs JMM, Akkermans LM, the patient support group Gastroparesis and Dysmotil- Vanberge-Henegouwen GP, Smout AJ. Compliance of the ity Association (GPDA) who helped organize the proximal stomach and dyspeptic symptoms in patients conferences held to discuss the topics contained in with type 1 diabetes mellitus. Dig Dis Sci 1995; 40: 2037– this report of the American Motility Society Workshop 16 Bredenoord AJ, Chial HJ, Camilleri M, Mullan BP, on Consensus Guidelines for the Treatment of Gastro- Murray JA. Gastric accommodation and emptying in Journal compilation Ó 2006 Blackwell Publishing Ltd evaluation of patients with upper gastrointestinal symp- 33 Basque J-R, Noritake M, Mizogami H, Katsura Y. Efficacy toms. Clin Gastroenterol Hepatol 2003; 1: 264–72.
of itopride hydrochloride on gastric emptying in patients 17 Revicki DA, Rentz AM, Dubois D et al. Development with diabetic gastroparesis. Gastroenterology 2005; 128: and validation of a patient-assessed gastroparesis symp- toms severity measure: the Gastroparesis Cardinal 34 Farrugia G, Macielaq M, Peeters TL, Sarr MG, Galdes A, Symptom Index. Aliment Pharmacol Ther 2003; 18: 141– Szurszewski JH. Motilin and OHM-11526 activate a cal- cium current in human and canine jejunal circular 18 Parrish CR, Yoshida C. Nutrition intervention for the smooth muscle. Am J Physiol 1997; 36: G404–12.
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A obra O mulato não só inaugura o Naturalismo no Brasil, como é uma das principais expressões dessa corrente na literatura brasileira. Sua marca é a análise da sociedade e dos tipos huma-nos a partir de uma visão orgânica, pessimista, do próprio com-portamento das pessoas reduzido a seus instintos mais básicos. Neste caso, trata também da questão racial, da discriminação e da hip


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