- Esophageal and Gastric Dysmotilities are Associated with Altered Glucose Homeostasis and Plasma Levels of Incretins and Leptin. [Journal Article]
- Rev Diabet Stud 2016; 13(1):79-90.
Gastrointestinal complications in diabetes may affect glucose and endocrine homeostasis. Glucose-dependent insulinotropic peptide (GIP), glucagon-like peptide-1 (GLP-1), and leptin regulate glucose homeostasis, food intake, and gastric emptying.The aim was to investigate associations between diabetes complications and glucose homeostasis and plasma levels of GIP, GLP-1, and leptin.Sixteen diabetes patients (seven men) were examined with gastric emptying scintigraphy and 72-h continuous subcutaneous glucose monitoring, 14 with the deep-breathing test, and 12 with esophageal manometry. A fiber-rich breakfast was given during the second day of glucose registration. Blood samples were taken 10 min and right before a fat-rich breakfast, as well as 10, 20, 30, 45, 60, 90, 120, 150, and 180 min afterwards. 20 healthy volunteers acted as controls. Plasma was analyzed regarding GIP, GLP-1, and leptin by Luminex.Gastroparesis lowered maximal concentration (c-max) (p = 0.003) and total area under the curve (tAUC) (p = 0.019) of glucose levels as well as d-min (p = 0.043) of leptin levels. It tended to lower baseline (p = 0.073), c-max (p = 0.066), change from baseline (d-max) (p = 0.073), and tAUC (p = 0.093) of GLP-1 concentrations. Esophageal dysmotility tended to lower tAUC of glucose levels (p = 0.063), and c-min (p = 0.065) and tAUC (p = 0.063) of leptin levels. Diabetes patients had a higher baseline concentration of glucose (p = 0.013), GIP (p = 0.023), and leptin (p = 0.019) compared with healthy subjects.Gastric and esophageal dysmotility are associated with both lesser increases in postprandial glucose elevations and decreased postprandial changes in GLP-1 and leptin.
- EUS-guided intrapyloric injection of botulinum toxin to treat diabetic gastroparesis. [LETTER]
- Dig Endosc 2016 Aug 24.
- Peroral endoscopic pyloromyotomy accelerates gastric emptying in healthy pigs: proof of concept. [Journal Article]
- Endosc Int Open 2016 Jul; 4(7):E796-9.
Gastroparesis, or delayed gastric emptying, can be diagnosed with gastric emptying scintigraphy. Manometric studies of patients with gastroparesis show increased pyloric tone (pylorospasm). Among the recent endoscopic therapies for pylorospasm is peroral endoscopic pylorotomy (POP). In this study, we explored the effect of POP on gastric emptying in healthy pigs.Four mini-pigs underwent POP following general anaesthesia. The mucosal entrance was situated 5 cm above the pylorus. POP was performed through a submucosal tunnel dissection. The duration of gastric emptying was assessed by scintigraphy before and after the procedure. The pigs were then euthanised for necropsy and pathologic assessment of the pylorus.The mean duration of the procedure was 55 (± 4 SD) min. All surgeries were performed in their entirety with 100 % feasibility. There were no cases of bleeding. The one case of perforation had no clinical significance. The duration of gastric emptying was 2.22-fold shorter after POP compared with before POP (T½ post-POP = 84.5 [± 35.7 SD] min vs. T½ pre-POP = 188.4 [± 87.3 SD] min; P = 0.029). In agreement with the endoscopic observations, sectioning of the pyloric muscle in each pig was histologically complete.The efficacy of the procedure provides indirect proof of the involvement of the pyloric ring in delayed gastric emptying and suggests new therapies for patients with gastroparesis. Our protocol combining gastric emptying scintigraphy and POP validated the use of anaesthetised mini-pigs as a learning and training model for POP or other endoscopic/surgical procedures related to gastric emptying.
- Methodologic considerations for studies of chronic nausea and vomiting in adults and children. [REVIEW, JOURNAL ARTICLE]
- Auton Neurosci 2016 Aug 3.
Methods to characterize and quantify severity of chronic nausea and vomiting and to elucidate their underlying mechanisms have received significant attention for both adult and pediatric patients. Validated dyspepsia symptom surveys include measures of nausea and vomiting intensity in relation to other upper gut symptoms. Visual analog scales quantify nausea intensity in real-time in physiologic studies and have been employed as enrollment criteria in clinical trial settings. A new nausea and vomiting survey has been administered to gastroparesis patients to provide insight into timing, triggers, and autonomic and psychological correlates of these symptoms. Several gastric sensorimotor and extragastric abnormalities are proposed to contribute to nausea and vomiting pathogenesis, but their relations to symptom severity are either limited or uninvestigated. Gastric emptying delays are prevalent in patients with chronic nausea and vomiting, as are blunting of fundic accommodation, aberrant gastric slow wave rhythms, and heightened perception of noxious and physiologic luminal stimulation. Potential extragastric correlates of nausea and vomiting include transit delays distal to the stomach, autonomic abnormalities, altered central nervous system activation, metabolic dysregulation, and psychological dysfunction. One goal of novel survey development will be to relate these physiologic correlates to specific symptom presentations to gain insight into mechanisms of nausea in different clinical conditions. Pediatric patients represent special challenges because of the different disorders that cause nausea and vomiting in children and differences in understanding disease manifestations, the ability to communicate symptom intensity and characteristics, and immature coping mechanisms compared to adults.
- Treating an oft-unrecognized and troublesome entity: using gastric electrical stimulation to reduce symptoms of malignancy-associated gastroparesis. [JOURNAL ARTICLE]
- Support Care Cancer 2016 Aug 17.
Malignancy-associated gastroparesis (MAG) is a cause of morbidity in cancer patients but therapies are lacking. Gastric electrical stimulation (GES) is a novel treatment for MAG. Here, we describe 19 patients with MAG who underwent temporary GES placement.Nineteen patients (6 males, 13 females) with various malignancies were reviewed for symptom scores and physiologic measures at baseline and after temporary GES placement. Symptoms were scored by three variables: nausea (N), vomiting (V), and GI total symptom score (TSS). Physiologic profiles were measured by solid and liquid phase gastric emptying scans (GET) at 1, 2, and 4 h and cutaneous electrogastrogram (EGG) and mucosal electrogram (EG) frequencies. Symptoms were measured for 5 days after temporary endoscopic GES placement, and measures were repeated post GES placement.Baseline GET results displayed delayed gastric emptying in 16 of 19 patients (mean solid retention 21.7 % at 4 h, normal <10 %; mean liquid retention 10.4 % at 4 h, normal <5 %). Cutaneous EGG (mean frequency 5.5 cpm) and EG (mean proximal frequency 5.1 cpm; mean distal frequency 5.1 cpm) showed evidence of neuromuscular dysfunction (normal 2.5-3.3 cpm). Symptom scores in N, V, and TSS showed statistically significant reduction after GES placement.A small sample of patients with MAG and receiving temporary GES experienced symptom improvement, with less change on gastric emptying time or gastric electrical amplitude or frequency. GES may provide a potential therapeutic option for symptomatic management of MAG and evaluation of these MAG patients after permanent GES placement is ongoing. Prospective studies of MAG using temporary and permanent GES may be warranted.
- Domperidone to Treat Symptoms of Gastroparesis: Benefits and Side Effects from a Large Single-Center Cohort. [JOURNAL ARTICLE]
- Dig Dis Sci 2016 Aug 16.
There is increased awareness about risks and benefits of using domperidone to treat gastroparesis.To describe the outcome of treating patients with refractory gastroparesis symptoms with domperidone.Domperidone 10 mg QID or TID was prescribed to patients with refractory gastroparesis symptoms; follow-up obtained at 2-3 months assessing symptoms and side effects. Patients filled out Patient Assessment of Upper GI Symptoms prior to treatment and at follow-up along with Clinical Patient Grading Assessment Scale (CPGAS, +7 = completely better; 0 = no change).Of 125 patients initially prescribed domperidone, 7 did not take this medication and 3 were lost to follow-up. Of the 115 known patients treated with domperidone, 88 had idiopathic, 16 diabetic, and 9 postsurgical gastroparesis. Side effects were reported by 44 patients (most common-headache, tachycardia/palpitations, diarrhea); 14 patients stopped treatment. Hundred and one patients were seen at follow-up taking domperidone (2.4 ± 2.7 months, average dose 36 ± 13 mg/day). CPGAS averaged 2.7 ± 2.7 (p < 0.01) with 69 patients reporting symptom improvement and 45 patients at least moderately improved with CPGAS ≥ 4. Improvements were seen in most symptoms, especially postprandial fullness, nausea, vomiting, and stomach fullness.In this large single-center study of patients treated with domperidone, side effects necessitating discontinuing treatment occurred in 12 %. The majority of patients remaining on treatment experienced an improvement in symptoms of gastroparesis, particularly postprandial fullness, nausea, vomiting, and stomach fullness. Thus, domperidone treatment is beneficial for many patients with symptoms of gastroparesis. This study provides needed benefit and risk information concerning treating patients with domperidone. FDA IND Number: 71,089.
- Integrative Control of Gastrointestinal Motility by Nitric Oxide. [JOURNAL ARTICLE]
- Curr Med Chem 2016 Aug 12.
In the gastrointestinal (GI) tract, nitric oxide (NO) has been shown over the last 25 years to exert a prominent function as inhibitory neurotransmitter. Apart from the regulation of secretion and resorption, NO from nitrergic neurons has been demonstrated to be crucial for GI smooth muscle relaxation and motility. In fact, several human diseases such as achalasia, gastroparesis, slow transit constipation or Hirschsprung's disease may involve dysfunctional nitrergic signaling. Most of NO's effects as neurotransmitter are mediated by NO-sensitive guanylyl cyclase (NO-GC) and further transduced by cGMP-dependent mechanisms. In contrast to the vascular system where NO from the endothelium induces relaxation by acting on NO-GC solely in smooth muscle cells, GI tissues contain several different NO-GC-expressing cell types that include smooth muscle cells, interstitial cells of Cajal and fibroblast-like cells. Based on this diverse localization of the NO receptor, the exact pathway(s) leading to NO-induced relaxation are still unknown. Global and cell-specific knockout mouse strains have been generated that lack enzymes participating in nitrergic signaling. These animals have been helpful in examining the role of NO in smooth muscle of the GI tract. Here, we discuss the current knowledge on NO-mediated mechanisms in the relaxation of GI smooth muscle in stomach, small and large intestine including sphincters. Special focus is placed on the integration of nitrergic signals by specialized cell types within the gut smooth muscle layers.
- The efficacy and safety of prokinetic agents in critically ill patients receiving enteral nutrition: a systematic review and meta-analysis of randomized trials. [Journal Article]
- Crit Care 2016; 20(1):259.
Intolerance to enteral nutrition is common in critically ill adults, and may result in significant morbidity including ileus, abdominal distension, vomiting and potential aspiration events. Prokinetic agents are prescribed to improve gastric emptying. However, the efficacy and safety of these agents in critically ill patients is not well-defined. Therefore, we conducted a systematic review and meta-analysis to determine the efficacy and safety of prokinetic agents in critically ill patients.We searched MEDLINE, EMBASE, and Cochrane Library from inception up to January 2016. Eligible studies included randomized controlled trials (RCTs) of critically ill adults assigned to receive a prokinetic agent or placebo, and that reported relevant clinical outcomes. Two independent reviewers screened potentially eligible articles, selected eligible studies, and abstracted pertinent data. We calculated pooled relative risk (RR) for dichotomous outcomes and mean difference for continuous outcomes, with the corresponding 95 % confidence interval (CI). We assessed risk of bias using Cochrane risk of bias tool, and the quality of evidence using grading of recommendations assessment, development, and evaluation (GRADE) methodology.Thirteen RCTs (enrolling 1341 patients) met our inclusion criteria. Prokinetic agents significantly reduced feeding intolerance (RR 0.73, 95 % CI 0.55, 0.97; P = 0.03; moderate certainty), which translated to 17.3 % (95 % CI 5, 26.8 %) absolute reduction in feeding intolerance. Prokinetics also reduced the risk of developing high gastric residual volumes (RR 0.69; 95 % CI 0.52, 0.91; P = 0.009; moderate quality) and increased the success of post-pyloric feeding tube placement (RR 1.60, 95 % CI 1.17, 2.21; P = 0.004; moderate quality). There was no significant improvement in the risk of vomiting, diarrhea, intensive care unit (ICU) length of stay or mortality. Prokinetic agents also did not significantly increase the rate of diarrhea.There is moderate-quality evidence that prokinetic agents reduce feeding intolerance in critically ill patients compared to placebo or no intervention. However, the impact on other clinical outcomes such as pneumonia, mortality, and ICU length of stay is unclear.
- Gastric per-oral endoscopic myotomy with antro-pyloro-myotomy in the treatment of refractory gastroparesis: clinical experience with follow-up and scintigraphic evaluation (with video). [JOURNAL ARTICLE]
- Gastrointest Endosc 2016 Jul 28.
Gastroparesis is a chronic, debilitating condition. We report an experience conducting G-POEM with objectives to assess clinical efficacy, gastric emptying evolution and procedural adverse events.Clinical pilot series on 12 consecutive patients who underwent G-POEM for refractory gastroparesis in our tertiary center between February 2014 and August 2015 Patients included had severe disease as defined by elevated GCSI score and delayed gastric emptying scintigraphy (GES). G-POEM was performed by mucosal incision upstream the pylorus followed by submucosal tunnel and antropyloromyotomy with subsequent access closure. Efficacy was assessed at 5 days, 1 month, and 3 months, based on GCSI score, and individualizing (Lickert scale) the main symptoms (nausea, vomiting, abdominal pain, early satiety and anorexia). GES was performed 2 months after the procedure.G-POEM was successfully performed in all 12 patients yielding a technical success rate of 100%. Significant improvements in GCSI were observed: 3.5 ± 0.8 vs 0.9 ± 0.9 (1 month), and 1.1 ± 1.5 (3 months), respectively (p<0.001), as well as the severity of main symptoms at 3 months. Clinical efficacy was 85% (10/12). GES normalized in 75% of cases, with improvement of half emptying time (222 ± 90 min vs 133 ± 90; p=0.03) and retention at 2 hours (76 ± 20 % vs 44 ± 26 %; p=0.009). There were no adverse events related to the procedure.We report a single-center study evaluating G-POEM for refractory gastroparesis, demonstrating its feasibility, reproducibility, and safety with promising clinical and scintigraphic efficacy.
- The effect of camicinal (GSK962040), a motilin agonist, on gastric emptying and glucose absorption in feed-intolerant critically ill patients: a randomized, blinded, placebo-controlled, clinical trial. [Journal Article]
- Crit Care 2016; 20(1):232.
The promotility agents currently available to treat gastroparesis and feed intolerance in the critically ill are limited by adverse effects. The aim of this study was to assess the pharmacodynamic effects and pharmacokinetics of single doses of the novel gastric promotility agent motilin agonist camicinal (GSK962040) in critically ill feed-intolerant patients.A prospective, randomized, double-blind, parallel-group, placebo-controlled, study was performed in mechanically ventilated feed-intolerant patients [median age 55 (19-84), 73 % male, APACHE II score 18 (5-37) with a gastric residual volume ≥200 mL]. Gastric emptying and glucose absorption were measured both pre- and post-treatment after intragastric administration of 50 mg (n = 15) camicinal and placebo (n = 8) using the (13)C-octanoic acid breath test (BTt1/2), acetaminophen concentrations, and 3-O-methyl glucose concentrations respectively.Following 50 mg enteral camicinal, there was a trend to accelerated gastric emptying [adjusted geometric means: pre-treatment BTt1/2 117 minutes vs. post- treatment 76 minutes; 95 % confidence intervals (CI; 0.39, 1.08) and increased glucose absorption (AUC240min pre-treatment: 28.63 mmol.min/L vs. post-treatment: 71.63 mmol.min/L; 95 % CI (1.68, 3.72)]. When two patients who did not have detectable plasma concentrations of camicinal were excluded from analysis, camicinal accelerated gastric emptying (adjusted geometric means: pre-treatment BTt1/2 121 minutes vs. post-treatment 65 minutes 95 % CI (0.32, 0.91) and increased glucose absorption (AUC240min pre-treatment: 33.04 mmol.min/L vs. post-treatment: 74.59 mmol.min/L; 95 % CI (1.478, 3.449). In those patients receiving placebo gastric emptying was similar pre- and post-treatment.When absorbed, a single enteral dose of camicinal (50 mg) accelerates gastric emptying and increases glucose absorption in feed-intolerant critically ill patients.The study protocol was registered with the US NIH clinicaltrials.gov on 23 December 2009 (Identifier NCT01039805 ).