GI Dysmotility in CC. Whitehead. 2016. JVECC Flashcards
1
Q
What are established risk factors for GIDM in critically ill people:
A
- mechanical ventilation
- sepsis, shock, trauma, systemic inflammatory response syndrome [SIRS], and multiple organ failure
2
Q
Name substances that excite the motor neurons in the GI wall:
A
- acetylcholine (Ach),
- tachykinins (particularly substance P and neurokinin A)
- serotonin (5-hydroxytryptamine [5-HT])
3
Q
Name substances that inhibit the motor neurons in the GI wall:
A
- vasoactive intestinal peptide (VIP),
- somatostatin
- nitric oxide (NO)
- gamma-amino butyric acid (GABA)
4
Q
What is the primary neurotransmitter of the GI tract promoting GI motility and what nerves supply it?
A
- Acetylcholine (Ach)
- Parasympathetic innervation mainly via the vagus and pelvic nerves + other preganglionic parasympathetic fibers (including ENS)
5
Q
What is the primary neurotransmitter of the GI tract inhibiting GI motility and where does it work?
A
- Norepinephrine
- acts indirectly on neurons of the enteric system (ENS) and directly on muscles and glands
6
Q
Explain the interdigestive motility complex. What is its function, how is it generated and regulated?
A
- Alternate form of motility clearing indigestible materials (“housekeeping” function)
- Involves the migrating motor complex (MMC) in dogs: pyloric relaxation, strong antral wave of peristalsis, moves indigestible material into the duodenum
- MMCs are regulated by the enteric nervous system (ENS) and modulated directly by regulatory peptides including somatostatin, motilin, and pancreatic polypeptide.
- MMCs occur at a rate of 15 to 20 per minute
- Ingestion of a meal will interrupt the interdigestive motility and digestive motility pattern starts
7
Q
What is the difference between canine and feline interdigestive motility?
A
- Interdigestive motility in dogs involves the migrating motor complex (MMC) and giant migrating complexes in cats
8
Q
How do the muscle fibers differ between the feline and canine esophagus?
A
- Canine esophagus is entirely made of striated muscle fibers
- Feline esophagus has a distal portion of smooth muscle fibers
9
Q
How are the different muscle fibers regulated?
A
- Striated muscles of the esophagus are regulated through the vagus nerve
- Smooth muscle fibers are innervated through the ENS, and indirectly through the autonomic nervous system
10
Q
What substances have been shown to affect esophageal motility?
A
- NO
- Somatostatin
- Motilin
11
Q
Explain adaptive and receptive relaxation of the stomach
A
Receptive relaxation
- induced by chewing and swallowing
- regulated through a vago-vagal reflex
Adaptive relaxation
- relaxation of muscles when food enters the stomach
- inhibitory vagal fibers à Ach release à activation of inhibitory enteric pathways à release of NO, VIP, ATP à muscle relaxation
12
Q
What are the steps of gastric emptying?
A
- Relaxation of the fundal portion of the stomach
- Antral Peristalsis
- Opening of the pyloric diameter
- Relaxation of the duodenum
- Contraction of the duodenum
13
Q
Describe the enterogastric reflex. What is it stimulated by?
A
- Inhibits further gastric emptying into the duodenum when the duodenum is “full”
- inhibits the vagal nuclei of the medulla and local reflexes while activating sympathetic fibers à cause the pyloric sphincter to tighten, delaying gastric emptying.
- activated by a low pH, high osmolality, and the presence of high lipid content. (+ distention of the duodenum?)
14
Q
What are the 5 main contractile patterns of the small intestines?
A
- peristaltic waves
- stationary segmenting contractions
- giant contractions (aboral)
- stationary or migrating clusters of contractions
- MMCs
15
Q
What is the average small intestinal transit times in dogs versus cats?
A
- 3-5 hours in dogs
- 2-3 hours in cats
16
Q
What are the types of colonic contraction?
A
- short duration phasic contractions amidst a background state of persistent colonic tone.
17
Q
How does mechanical ventilation affect esophageal motility?
A
- Shown to reduce the frequency, amplitude, and percentage of propulsive contractions of the esophagus
- Gastroesophageal reflux from relaxation of the lower esophageal sphincter
- Inhibition of esophageal motor activity from medications such as benzodiazepines, opioids, ketamine
18
Q
The pathophysiology of delayed gastric emptying in critically ill animals and people is not fully understood. Describe the two most important theories?
A
“pump failure”
- Primary motor dysfunction
- Decreased antral motility and display of the fasting motility pattern during feeding.
“excessive feedback” theory
- disproportionate activation of an inhibitory feedback pathway originating in the proximal small intestine or duodenum
- based on the nutrient release of neuroendocrine peptides such as cholecystokinin (CCK) and 5-HT (via 5-HT3 receptors), which subsequently inhibit vagal and spinal afferent neurons and result in delayed gastric emptying
19
Q
GI inflammation is an implicated cause for functional ileus of the small intestines. What is the presumed pathophysiology?
A
- During GI inflammation, leukocytes (particularly neutrophils) à releasing proteolytic enzymes and cytokines à damage the muscle layer of the GI tract directly
- inflammatory mediators à release of NO à paralysis of the muscular cells à propagation of intestinal dilation.
20
Q
Explain how migrating motor complex disturbances may lead to bacterial overgrowth and translocation
A
- people: increase in quiescent period (phase I), decrease in intermittent contractions (phase II), increase in high amplitude regular contractions (phase III) but these are retrograde
- reduce expelling of the luminal contents, including bacteria and food particles, into the colon
21
Q
Is megacolon in cats associated with critical illness?
A
Not usually, megacolon is considered an end-stage condition of a chronic disease process rather than an acute critical illness
22
Q
What is Ogilvie’s syndrome?
A
- affiliated with an autonomic imbalance, an impaired pelvic parasympathetic innervation, and a predominance of inhibitory sympathetic tone.
- acute colonic pseudo-obstruction
- has been associated with gut ischemia, systemic or local inflammation, and sepsis.
23
Q
What conditions have been shown to secondarily cause GIDM?
A
- Acute stress (e.g., noise stress, TBI)
- Inflammation of the viscera (e.g., pancreatitis, mesenteritis, peritonitis)
- Electrolyte derangements (hypokalemia, hypermagnesemia, and hyper- or hypocalcemia)
- Metabolic disturbances (e.g., acidosis, hypoadrenocorticism, hepatic encephalopathy, uremia)
- Drugs (opioids, dopamine, alpha-2-adrenergic agonist)
- diabetic gastro-neuropathy
- splanchnic hypoperfusion
- hypoxemia
- obesity
- SIRS or sepsis
- Neoplasia
24
Q
How do opioids lead to GIDM?
A
- have been shown to inhibit GI transit by reducing Ach release and altering neuronal excitability (Ach main neurotransmitter for GI motility!)
- may also increase smooth muscle activity → BUT inhibit coordinated propulsive peristalsis à disordered nonpropulsive contractile activity
25
Explain the pathophysiology of GIDM in diabetes mellitus.
may include **diabetes-associated neuropathy**, **hypoglycemic and hyperglycemic** effects on GI motor function, and **insulin’**s effect on GI motility
* autonomic neuropathies and vagal nerve dysfunction
* Hyperglycemia has been shown to reduce gastric antral contractions, suppress interdigestive phase III activity, and impair gall bladder emptying
26
Name 3 mediators shown to cause GIDM in patients with MODS and sepsis
1. Tumor necrosis factor
2. VIP (vasoactive intestinal peptide)
3. NO
27
What are proposed reasons for post-surgical GIDM
* mechanical manipulation of the bowel
* inflammation → GI inflammation may affect increased sympathetic efferent activity via the splanchnic nerves, resulting in an overall shift toward decreased gut motility in postoperative ileus
* pain
* hormonal factors (eg, substance P, VIP, NO)
* concurrent medications (especially opioid medications)
* electrolyte disturbances.
28
List consequences associated with GIDM
* gastroesophageal reflux
* esophagitis
* aspiration
* bacterial overgrowth
* bloating or distension of the GI tract leading to increased IAP
* fluid sequestration and hypovolemia
* delay of nutritional delivery
29
List clinical signs associated with GI dysmotility
* anorexia
* abdominal pain
* abdominal distension
* nausea, vomiting
* increased volume of gastric residual volumes (GRVs)
30
Explain the self-exacerbating cycle of GI dysmotility and hypovolemia
* GI dysmotility \> gastrointestinal distention \> rise in intraabdominal pressure \> compromises intestinal perfusion and microcirculation \> fluid sequestration into the intestinal wall and lumen \> hypovolemia and further microcirculatory impairment \> more dysmotility
* Dysmotility \> unabsorbed nutrients in the intestinal lumen \> osmotic diarrhea \> further fluid loss \> …
* \> hypovolemia and further microcirculatory impairment
* Inflammation of the intestines \> fluid loss into the lumen
31
List the limitations of radiography to assess for GIDM
* inability to identify subtle motility disorders
* administering food with barium or barium to anorectic patients
* risk of aspiration of food and barium
32
List the limitations of ultrasonography to assess for GIDM
* inherent **subjectivity**
* no published/established **reference ranges** for normal motility on ultrasonography
33
Discuss how well Gastric residual volume measurements can be used to guide treatment strategies of patients with GIDM
* one study on dogs found no direct association between GRV, the occurrence of vomiting or regurgitation, or incidences of aspiration
* Therefore, the use of GRV to guide treatment strategies should be approached with caution until additional studies have been conducted.
34
Lists specialized tests that may be utilized to assess GI motility
* Radioscintigraphy
* C-breath test (C-acetate validated in dogs)
* Lactulose breath test
* Manometry
* Tracer studies
* MRI
35
List the mainstay of treatment for GIDM
* Identify and treat the predisposing illness
* Early nutritional intervention
* Judicious fluid therapy
* Early ambulation
* Correction of metabolic derangements
* Maintenance of normothermia
* Multimodal pain management
* Pharmacologic intervention
36
What are the proposed mechanisms supporting early enteral feeding in critically ill patients?
* improving **blood flow** to the gut
* protecting the **GI mucosa**
* reducing the **risk of translocation** of intestinal bacteria
* **stimulating** motility
* promoting **secretion** of various gut hormones and growth factors
37
38
In a study of critically ill and mechanically ventilated patients, how was early enteral nutrition associated with survival?
* EN within 48 hours was associated with a 20% decrease in mortality in ICU patients and 25% for hospital mortality
39
What are the detrimental effects of fluid therapy on GI integrity?
* Rat studies showed that GI edema induced by fluid therapy led to increased transit time, increased intestinal permeability to macromolecules, and decreased tissue resistance
40
What is the proposed cellular mechanism of gut edema leading to GIDM?
Incompletely understood
**nuclear factor _kappa B_ \>**
* trigger a gene regulation program leading to **decreased myosin light-chain phosphorylation** and \> **decreased intestinal contractile activity**
increased expression of **inducible _NO synthase_ and subsequent NO production**
* upregulates smooth muscle **cyclic guanosine monophosphate** (cGMP) \> impeding myosin light chain phosphorylation and actin/myosin cross-linking \> deterring smooth muscle contractility
41
what is the evidence supporting early ambulation to reduce ileus in veterinary patients?
* There are no veterinary studies supporting early ambulation postoperatively to prevent or treat ileus
* Human studies have not found a difference in occurrence of ileus, but early ambulation is still recommended, more so due to shown decrease of risk for postoperative respiratory and thrombotic complications
42
What is the difference between morphine and fentanyl on their effect on GI motility?
* Morphine requires much lower concentrations to cause GI ileus whereas fentanyl requires similar concentrations for analgesic effects and ileus
43
Study results on the effect of vasopressin on GI motility are conflicting. What are the proposed mechanisms?
* motility modulating effects could have resulted from vasopressin-mediated stimulation of **sodium chloride and water absorption, as well as inhibition of chloride secretion**
* may act as a neuromodulator of enteric cholinergic neurons inducing excitatory effects on the contractility **via V1a receptors.**
44
By what mechanism do _both_ metoclopramide and domperidone increase GI motility. Explain this mechanism and its pathways. Discuss the efficacy of this pathway for prokinetic effects.
* Dopaminergic receptor (D2) antagonism (both)
* D2 receptors of the post-ganglionic cholinergic neurons in the myenteric plexus (s. picture)
* When activated \> these cholinergic neurons will reduce Ach release \> decreased peristalsis
* When deactivated (D2 antagonisms) \> increased release of Ach à increased peristalsis
* Controversial whether dopaminergic effects contribute to GI contractility
45
Besides dopaminergic antagonism, what pathway contributes to domperidone’s prokinetic effect. Compared to dopaminergic antagonism, how effective is this pathway.
* **Alpha2 and beta2** adrenergic antagonism (domperidone)
* **Decreased sympathetic tone** will **lead to increase in Ach**
* Alpha2 and beta2 agonism directly inhibits GI motility \> decrease inhibition à increased motility
* Prokinetic effects likely owing more to adrenergic antagonism than dopaminergic antagonism
46
How well is domperidone established as a prokinetic agent?
* Effect on motility controversial
* Shown to actually dyscoordinate motility
* Does not work on LES, will not help with gastroesophageal reflux
* No documented small intestinal effects on transit
47
Besides prokinetic effects, what does domperidone work well for? How does it compare to metoclopramide?
* Antiemetic effect
* Works better than metoclopramide for antiemetic effects (12-25 times stronger)
48
Explain how the pathway of serotonin-receptor agonists increase GI motility
* Mainly implicated in increasing GI motility: 5HT-4 (secreted by GI mucosa)
* 5HT-4 receptor agonists will increase its presynaptic activity \> stimulates Ach release from postganglionic cholinergic neurons \> smooth-muscle contraction
* 5HT-1 and -3 receptors also implicated in having effects on GI motility
49
What are the common veterinary serotonin-receptor agonists used to increase GI motility?
* Metoclopramide
* Cisapride
50
What serotonin receptors are commonly targeted to decrease vomiting and nausea. Is this via antagonism or agonism and what common veterinary medications have this effect?
* 5HT-1 and -3 receptor **antagonism** reduces nausea and vomiting
* Ondansetron, Dolasetron, Erythromycin, Cisapride, Metoclopramide
51
List the locations of the GI tract where Cisapride has shown to increase motility
* Esophagus in animals with smooth muscles in the esophagus (cats, not dogs)
* Gastroesophageal sphincter pressure
* Stomach
* Antropyloroduodenal coordination
* Jejunum
* Colon
52
What complications of Cisapride lead to its withdrawal from the human market, and have been shown in induced canine models, but not small animal veterinary patients?
* QT interval prolongation and slowing of cardiac repolarization via a **blockade of the rapid component of the delayed rectifier potassium channel**
53
Through what mechanism of action does metoclopramide act as an antiemetic
* Through dopaminergic and 5HT-3 receptor antagonism \> prevents stimulation of the chemoreceptor trigger zone
54
Through what mechanism of action does metoclopramide act an a prokinetic?
* 5HT-4 receptor agonism \> increased presynaptic activity \> stimulates Ach release from postganglionic cholinergic neurons \> smooth-muscle contraction
* Dopaminergic receptor antagonism \> unclear whether this works, likely more reliant on 5HT-4 pathway
55
List the locations of the GI tract where Metoclopramide has shown to increase motility. Where does metoclopramide not work?
* Lower esophagus (cats, not dogs)
* Stomach (gastric emptying)
* Antropyloroduodenal coordination
* Not documented to work in the distal small intestines or colon
56
What are the main side effects of metoclopramide and how are they treated?
* “Extrapyramidal signs” \> motor restlessness, involuntary muscle spasms, inappropriate aggression
* Treat symptomatically with antihistamines, benzodiazepines, beta-adrenergic antagonists, dopamine agonists
57
What are the main veterinary drugs used for their motilin receptor agonism?
* Erythromycin and Azithromycin
58
Explain how motilin stimulates GI motility
* Motilin is a peptide synthesized by endocrine cells of small intestinal mucosa
* Motilin receptors are located on cholinergic nerves, and they have been isolated from the smooth muscle of the GI tract
* Regulates interdigestive MMCs \> phase III
59
Through which receptors does erythromycin act to increase GI motility in dogs versus cats?
* In both animals erythromycin mimics the effects of motilin on the upper GI tract and increases motility
* In dogs this happens indirectly through 5HT-3 cholinergic pathways
* In cats this happens directly through stimulation of motilin smooth muscle receptors
60
List the locations of the GI tract where erythromycin has shown to increase motility.
Upper GI tract
* Esophagus (cats)
* Stomach
* Small intestines
61
Explain whether you can use Erythromycin in the same animal for both its antimicrobial and prokinetic effects.
* Cannot be used for both effects in the same animal:
* Prokinetic effects are achieved at lower dosages, which are microbially ineffective
* Larger, antimicrobial dosages have shown to cause retrograde peristalsis
62
What are the side effects of erythromycin? Are these more commonly seen when used as a prokinetic or as an antimicrobial?
* Q-T prolongation, nausea, inappetence \> at higher dosages (antimicrobial)
* Low dose (prokinetic) well tolerated
63
How are histamine receptors supposedly involved in GI motility? What is the current therapeutic target?
* Histamine 1 receptor activation causes contraction by increasing Ca-availability
* Histamine 2 receptor **antagonism** inhibits acetylcholine esterase \> more Ach available \> enhances and prolongs effects of Ach on smooth muscle contractions \> increased motility
* Drugs used include ranitidine and nazitidine
64
What locations of the GI tract have ranitidine and nazitidine shown to work?
* Stomach
* Ileus
* Colon
65
Explain potential strategies to reduce the effects of opioids on GI motility. Why is this commonly not achievable/feasible?
* Mu-antagonists, e.g., naloxone, alvimopan
* Oral naloxone has only limited bioavailability
* Alvimopan à antagonize the inhibitor effects of opioids on gut motility but do not cross the blood-brain barrier and therefore do not antagonize the analgesic effects
* BUT very expensive! (1000 $ per treatment)
