IICBS Summaries

Nausea, Vomiting, and Indigestion by William Hasler

Nausea – subjective feeling of the need to vomit
Vomiting – the oral expulsion of GI contents due to contractions of the gut and thoracoabdominal wall musculature
Regurgitation – the effortless passage of gastric contents into the mouth
Rumination – the repeated regurgitation of food residue, which may be rechewed and reswallowed
Indigestion – term encompassing a range of complaints including nausea, vomiting, heartburn, regurgitation, and dyspepsia

Nausea
 Definied as “the unpleasant painless subjective feeling that one will imminently vomit”
 Common occurrence with diverse causes and a significant disease burden
 Considered to function as a protective mechanism, warning the organisms to avoid potential toxic ingestion
 Does not always exist on a temporal continuum with vomiting: there are situations where severe nausea may be
present without emesis, and emesis may be present without preceding nausea
 In population studies, more than 50% of adults reported at least one episode of nausea and more than 30% of adults
reported one episode of vomiting within the preceding 12 months, women > men

Mechanisms
The underlying mechanisms involved in nausea are complex and encompass psychological states, the CNS, autonomic
nervous system, gastric dysrhythmias, and the endocrine system.

Figure 1. Pathogenesis of Nausea. Central and peripheral pathways involved in the pathogenesis of nausea. Afferent
information from various stimuli are relayed to nucleus tractus solitarius via four pathways: vestibular and cerebellar,
cerebral cortex, and limbic system, area postrema, and gastrointestinal tract via the vagus nerve. Once any of these neural
pathways area activated, it culminates into sensation of nausea with or without vomiting. The efferent information from
nucleus tractus solitarius is also responsible for activation of ANS response via vagal pathwhays. Nausea is also
associated with gastric dysrhythmia and release of vasopressin. However, the cause-effect relationship of this triad is not
very well understood and warrants further studying.
Dynamic Threshold
 It is proposed that each individual has a threshold for nausea that changes minute by minute
 At any given moment, the threshold depends on the interaction of certain inherent factors of the individual with the
more changeable psychological states of anxiety, anticipation, expectation and adaptation
o Explains the inter- and intra-individual variability that is typically encountered in the face of nauseogenic
stimulus
 Stimuli giving rise to nausea and vomiting originate from visceral, vestibular, and chemoreceptor trigger zone
inputs which are mediated by serotonin/dopamine, histamine/acetylcholine, and serotonin/dopamine respectively.
These relationships serve as the basis on which current pharmacologic therapy for nausea and vomiting is
recommended
Central Nervous System
 Surprisingly little is known regarding the central mechanisms underlying this sensation
 Associated autonomic changes occurring during nausea and emesis (e. g. salivation and sweating) are coordinated
at the level of the medulla oblongata
o Chemosensitive receptors detect emetic agents in the blood and thus information is relayed via the area
postrema to the nucleus tractus solitarius
o Abdominal vagal afferents which detect gastric tone and contents also project to the NTS, which project
to a central pattern-generator which coordinates the various actions involved in the act of emesis in addition
to directly projecting to neurons in the ventral medulla and hypothalamus, from which higher brain areas
can be reached
 Cerebral cortex may also be involved in the pathways of nausea
o Medial prefrontal cortex and the pregenual anterior cingulate cortex areas of the brain involved in
higher cognitive function and emotional centers in modulating the parasympathetic to sympathetic shift
associated with nausea
o Nauseaogenic stimulus causes activation of the amygdala, putamen, and locus ceruleus which translates
into fear conditioning and emotional triggering, which ultimately leads to the sensation of strong nausea
o This is followed by continued, sustained activation in the cortical areas such as the insula, anterior
cingulated cortex, nucleus accumbens, orbitofrontal, somatosensory, and prefrontal cortex
 Involved in the interoceptive, limbic, somatosensory, and cognitive network which alerts the
suffering individual of the changes in interoceptive signaling so that appropriate autonomic and
motor responses are initiated in a timely manner
 Many of these (anterior cingulate cortex, insular cortex, nucleus accumbens, and amygdala) are
known to be involved in the processing of acute and chronic painful stimulus
 The medial prefrontal cortex is also known to be involved in chronic pain, thus it is possible that
the brain perceives peripheral stimuli through similar pathways
Autonomic Nervous System
 Characteristic physiological changes (sweating, pallor, salivation, increase in BP, tachycardia, cutaneous
vasoconstriction, decreased gastrointestinal motility) occurring before vomiting are mediated by the ANS and are
well described
o Afferent signaling arises from vagal inputs (mechanical or chemical stimuli)
o Increasing nausea perception is associated with decreased parasympathetic and increased sympathetic
modulation
 ANS outflow and CNS network controlling it could be determinant of overall nausea intensity
Endocrine
 Vasopressin, among other hormones, have been implicated in the pathogenesis of nausea
o Vasopressin increases in various emetogenic situations, not because of volume depletion or
hyperosmolarity
o There is a correlation between vasopressin level and nausea intensity, but the cause-effect relationship is
still unclear
Gastric Dysrhythmias
 The stomach is a neuromuscular organ, the myoelectrical activity of which can be measured by a number of
techniques including electrogastrography
o Normal gastric myoelectrical activity reflects the balance of the intrinsic pacemaker activity of the stomach,
smooth muscle, the enteric nervous system, the ANS and hormone levels
 Bradygastria: activity frequency slower than intrinsic rate
 Tachygastria: activity frequency faster than intrinsic rate
o Medications and interventions that promote normalization of myoelectrical activity decrease nausea and
conversely, stimuli that decrease normal myoelectrical activity and increase dysrhythmias promote the
sensation of nausea

Emesis
 Brainstem nuclei – including the nucleus tractus solitarius, dorsal vagal and phrenic nuclei, mexulary nuclei
regulating respiration, and nuclei that control pharyngeal, facial, and tongue movements – coordinate
initiation of emesis
o Neurokinin NK1, serotonin 5-HT3, and vasopressin pathways participate in this coordination
 Somatic and visceral muscles respond stereotypically during emesis
o Inspiratory thoracic and abdominal wall muscles contract, producing high intrathoracic and intraabdominal
pressures that evacuate the stomach
o The gastric cardia herniates above the diaphragm, and the larynx moves upward to propel the vomitus
o Distally migrating gut contractions are normally regulated by an electrical phenomenon, the slow wave,
which cycles at 3 cycles/min in the stomach and 11 cycles/min in the duodenum
o During emesis, the slow wave is abolished and is replaced by orally propagating spikes that evoke
retrograde contractions that assist in expulsion of gut contents
 Emetic stimuli act at several sites
o Emesis evoked by unpleasant thoughts or sells originate in the brain
o Cranial nerves mediate vomiting after gag reflex activation
o Motion sickness and inner ear disorders act on the labyrinthine system
 Stimulates muscarinic M1 and histaminergic H1 receptors
o Gastric irritants and cytotoxic agents like cisplatin stimulate gastroduodenal vagal afferent nerves
 Stimulates serotonin 5-HT3 receptors
o Nongastric afferents are activated by intestinal and colonic obstruction and mesenteric ischemia
o The area postrema in the medulla responds to bloodborne stimuli and is termed the chemoreceptor trigger
zone
 Stimulates 5-HT3, M1, H1, and dopamine D2 subtypes
 Cannabinoids CB1 pathways may participate in the cerebral cortex

Diagnosis
Table 1. Common Causes of Nausea
Medications and Toxic Disorders of the gut and CNS Causes and Miscellaneous Causes,
Etiologies peritoneum Psychiatric Disease Labyrinthine Disorders,
and Endocrine
Cancer Chemotherapy Mechanical obstruction Migraine Cardiac Disease
  Gastric outlet
obstruction
 Small bowel
obstruction
Analgesics Functional gastrointestinal Increased intracranial Myocardial Infarction
disorders pressure
 Functional dyspepsia  Malignancy
 Chronic idiopathic  Meningitis
nausea  Hemorrhage
 Cyclic Vomiting  Infarction
Sydrome  Abscess
 Idiopathic vomiting  Meningitis
 Non-ulcer dyspepsia
 Irritable bowel
syndrome
Cardiovascular Medications Organic gastrointestinal Congenital malformation Congestive Heart Failure
 Digoxin disorders
 Antiarrhythmics  Pancreatic adenoCA
 Antihypertensives  Peptic Ulcer Disease
o Beta-  Cholecystitis
blockers  Pancreatitis
o Calcium  Hepatitis
channel  Crohn’s Disease
antagonists
Hormonal Preparations and Neuromuscular Disorders of Hydrocephalus Radiofrequency Ablation
Therapies the gastrointestinal tract
 Oral antidiabetics  Gastroparesis
 Oral contraceptives  Post-op N and V
 Chronic intestinal
pseudo-obstruction
Antibiotics/Antivirals Pseudotumor cerebri Starvation
 Erythromycin
 Tetracycline
 Sulfonamides
 Antituberculous
drugs
 Acyclovir
Gastrointestinal Seizure disorder Motion sickness
Medications
 Sulfasalazine
 Azathioprine
Nicotine Demyelinating disorders Labyrinthitis
CNS Active Narcotics Psychogenic vomiting Tumors
Antiparkinsonian Drugs Anxiety disorders Meniere’s disease
Anticonvulsants Depression Iatrogenic
Radiation therapy Pain Pregnancy
Ethanol abuse Eating disorders Other endocrine and
metabolic
Infectious causes Uremia
 Gastroenteritis
 Otitis Media
Acute intermittent DKA
porphyria
 Hyper/hypoparathyroidism
Hyperthyroidism
Addison’s Disease

 Detailed history and physical exam forms the cornerstone of evaluating patients with the chief complaint of nausea
o Rule out non-gastrointestinal causes of nausea such as CNS, endocrinological and psychiatric diagnosis
 Mainstay of diagnostic evaluation
o Correcting any symptom consequences (electrolyte abnormalities, dehydration, malnutrition)
o Identifying the cause of the symptoms and initiating targeted therapy
o If no cause is found, initiating therapy directed at suppressing the symptoms
 Laboratory work
o Electrolytes
o Liver function tests
o Pancreatic enzymes
o Pregnancy test if applicable

Table 2. Causes of Nausea and Vomiting

 Differential Diagnosis can also be grouped based on how the disease affects the body: within the gut, outside the
gut, and drugs or circulating toxins
o Intraperitoneal Disorders: Visceral obstruction and inflammation of hollow and solid viscera may elicit
vomiting
 Gastric obstruction: ulcers and malignancy
  Small-bowel and colon blockage: adhesions, benign or malignant tumors, volvulus,
intussusception, or inflammatory disease like Crohn’s disease; Superior mesentery artery
syndrome (occurring after weight loss or prolonged bed rest) happens when the duodenum is
compressed by the overlying superior mesenteric artery
 Abdominal irradiation: impairs intestinal motor function and induces strictures
 Biliary colic: acts on local afferent nerves
 Visceral irritation and induction of ileus: caused by pancreatitis, cholecystitis, and appendicitis
 Enteric infections: such as norovirus or Staphylococcus aureus and Bacillus cereus can cause
vomiting; CMV and HSV can induce emesis in immunocompromised individuals
o Intraperitoneal Disorders: Gut sensorimotor dysfunction often causes nausea and vomiting
 Gastroparesis (symptoms of gastric retention with evidence of delayed gastric emptying which
occurs after vagotomy or with pancreatic carcinoma, mesenteric valvular insufficiency, or organic
diseases like diseases like diabetes, scleroderma, and amyloidosis)
 Idiopathic gastroparesis is the most common
 Intestinal pseudoobstruction: characterized by disrupted intestinal and colonic motor activity
with retention of food residue and secretions, bacterial overgrowth, nutrient malabsorption, and
symptoms of nausea, vomiting, bloating, pain, and altered defecation
 Idiopathic, familial, systemic, or occurs as a paraneoplastic consequence
 Gastroesophageal reflux
o Intraperitoneal disorders: Others
 Chronic idiopathic nausea: nausea without vomiting occurring several times a week
 Functional vomiting: one or more vomiting episodes weekly in the absence of an eating disorder
or psychiatric disease
 Cyclic vomiting syndrome: perioidic discrete episodes of relentless nausea and vomiting in
children and adults
 Associated with migraines, rapid gastric emptying
 Cannabinoid hyperemesis syndrome: cyclical vomiting with intervening well periods in
individuals who use large quantities of cannabis over many years and resolves with its
discontinuation
o Extraperitoneal disorders
 Myocardial infarction and congestive heart failure
 Postoperative emesis occurs after 25% of surgeries, most commonly laparotomy or orthopedic
surgery
 Increased intracranial pressure from tumors, bleeding, abscess, or blockage of CSF outflow:
vomiting with or without nausea
 Psychiatric illnesses including anorexia nervosa, bulimia nervosa, anxiety, depression
o Medications and Metabolic Disorders
 Drugs evoke vomiting by action on the stomach (analgesics, erythromycin) or area postrema
(opiates, anti-parkinsonian drugs)
 Others include antibiotics, cardiac antiarrhymics, antihypertensives, oral hypoglycemics,
antidepressants (SSRIs and SNRIs), smoking cessation drugs, contraceptives
 Cancer chemotherapy: acute (within hours such as cisplatin mediated by 5-HT3 pathways), delayed
(after 1 or more days), or anticipatory (use anxioyltics instead)
 Metabolic disorders: pregnancy (ost prevalent, affects 70% of women in the first trimester)
 Hyperemesis gravidarum causes significant blood loss and electrolyte disturbances
 Metabolic disorders uremia, ketoacidosis, adrenal insufficiency, and parathyroid and thyroid
disease
 Circulating toxins: endogenous toxins such as that in liver failure or exogenous enterotoxins,
ethanol intoxication
 If mechanical obstruction is suggested by clinical presentation
 o Radiologic examination such as an abdominal X-ray and abdominal CT scan are typically the first-line
investigators
 If mucosal diseases such as an ulcer or mass are suspected: esophagogastroduodenoscopy remains the most
sensitive and specific investigation
 Scintigraphic measures of solid phase gastric emptying are commonly used to evaluate gastric motor functions
in suspected gastroparesis
o Most would advocate an empirical trial of antiemetic or prokinetic medications prior to specialized testing,
however, many of these agents can alter gut motility
o Cutaneous electrogastrography and antroduodenal manometry is not widely available, expensive, and its
role in diagnosis is not known
 It aids in the diagnosis of motor disorders in such cases and helps rule out dysmotility as the cause
of nausea if normal
 If patient has unexplained chronic nausea even after thorough investigation and normal gastric emptying studies
o Rome III criteria for functional gastroduodenal disorders can be utilized to diagnose functional disorders
related to nausea and vomiting, including chronic idiopathic nausea, functional vomiting, cyclical vomiting
syndrome, and rumination syndrome

Approach to the patient with Nausea and Vomiting

History and Physical Examination
 History: defines the etiology of nausea and vomiting
o Drugs, toxins, infections
o Established illnesses
o Gastroparesis and pyloric obstruction: vomiting within hours after eating
o Emesis from intestinal blockage occurs later than this
o Vomiting occurring within minutes of food intake: rumination syndrome
o Hematemesis: ulcer, malignancy, Mallory-Weiss tear
o Feculent emesis: distal intestinal or colonic obstruction
o Bilious vomiting excludes gastric obstruction
o Zenker’s diverticulum or achalasia: emesis of undigested food
o Vomiting can relieve abdominal pain in obstruction, but does not relieve pancreatitis or cholecystitis
o Profound weight loss: malignancy, obstruction
o Fever: inflammation
o Intracranial source: headaches or visual field changes
o Vertigo or tinnitus indicates labyrinthine disease
 Physical examination complements the history
o Orthostatic hypotension and reduced skin turgor: IV fluid loss
o Pulmonary abnormalities: aspiration of vomitus
o Abdominal auscultation: absent bowel sounds, with ileus
o High-pitched rushes suggest bowel obstruction, whereas a succession splash upon abrupt lateral movement
of the patient is found with gastroparesis or pyloric obstruction
o Tenderness and involuntary guarding: inflammation
o Fecal blood: mucosal injury from ulcer, ischemia, tumor
o Neurologic disease: papilledema, visual field loss, focal neural abnormalities
o Neoplasm: palpation of masses or adenopathy

Diagnostic Testing
 For intractable symptoms or an elusive diagnosis, selected screening tests can direct clinical care
o Electrolyte replacement for hypokalemia or metabolic alkalosis
o Iron-deficiency anemia: search for mucosal injury
o Pancreaticobiliary disease: abnormal pancreatic or liver biochemistries
 o Endocrinologic, rheumatologic, or paraneoplastic etiologies are suggested by hormone or serologic
abnormalities
o If obstruction is suspected, supine and upright radiographs may show intestinal air-flulid levels with
reduced colinic air
 Ileus: diffusely dilated air-filled bowel loops
 Anatomic studies are indicated if initial testing is nondiagnostic
o Upper endoscopy: ulcers, malignancy, retained gastric food residue in gastropresis
o Small bowel barium radiography or CT diagnoses partial bowel obstruction
o Colonoscopy or contrast enema: colonic obstruction
o Ultrasound or CT: intraperitoneal inflammation
o CT and MRI enterography: inflammation in Crohn’s disease
o CT or MRI of the head: intracranial disease
o Mesenteric angiography, CT, or MRI for suspected ischemia
 Gastrointestinal motility testing may detect an underlying motor disorder when anatomic abnormalities are absent
o Gastroparesis: gastric scintigraphy
 Isotopic breath tests and wireless motility capsule methods are alternative tests
o Intestinal pseudo-obstruction: abnormal barium transit and luminal dilatation on small bowel contrast
radiography
o Small intestinal manometry can confirm diagnosis of delayed bowel transit
o These studies can remove need for biopsy
o Rumination: combined ambulatory esophageal pH/impedance testing and high resolution manometry

Treatment
General Principles
 The management of acute vs. chronic symptoms is different and response to therapeutics differ
 There is a paucity of evidence evaluating pharmacologic therapy of chronic, unexplained nausea
 Nausea is more difficult to treat than vomiting
 Therapy of vomiting is tailored to correcting remediable abnormalities if possible
o Hospitalization is considered for severe dehydration, especially if oral fluid replacement cannot be
sustained
o Once oral intake is tolerated, nutrients are restarted with low-fat liquids (lipid delays gastric emptying)
 Foods high in indigestible residue are avoided because these prolong gastric retention
o Controlling blood glucose in poorly controlled diabetics can reduce hospitalizations in gastroparesis
 Current medical therapy falls into two categories: agents directed at suppressing nausea and preventing vomiting
(antiemetic) which acts centrally, and agents modulating gastrointestinal motility (prokinetic)
Antiemetic Medications
 Antihistamines (e. g. dimenhydrinate and meclizine)
o Motion sickness and labrynthitis and exert their antiemetic action through central anticholinergic (M1
receptor) and antihistamine (H1 receptor) effects
o Suppress labyrinthine and vestibular stimulation and that of the chemoreceptor zone in the brainstem
o Meclizine 25-250 mg q24 orally, IM, or IV; watch out for drowsiness, confusion, blurred vision
o Diphenhydramine (Cinnarizine, Cyclizine, Hydroxyzine) 25-50mg q6-8 hours Orally
 Anticholinergics like scopolamine
o Acts centrally via the muscarinic receptors and blocks the pathway from the inner ear to the brainstem and
the vomiting center
o Scopolamine (0.3-0.6 mg q24 hours) watch out for tachycardia, confusion, dry mouth, constipation, urinary
retention, blurred vision SL, IV, IM, transdermal
 Most widely used anticholinergic agent and is administered as a transdermal patch for prophylaxis
and treatment of motion sickness
 Selective M3 and M5 antagonist (Zamifenacin) may be equally effective
  Dopamine D2 antagonists treat emesis evoked by area postrema stimuli and are used for medication, toxic, and
metabolic etiologies; they cross the BBB and cause anxiety, movement disorders, and hyperprolactinemic effects
o Phenothiazines are antidopaminergic agents which act via nonselective inhibition of mainly D2 and D3
receptors in the region of the area postrema, but also muscarinic and H1 receptors: demonstrate efficacy
in nausea related to migraine, motion sickness, and vertigo, as well as post-op and post-chemotherapy
nausea and vomiting
o Prochlorperazine 5-10mg q6-8 hours orally, IM, IV; watch out for extrapyramidal side effects, tardive
dyskinesia, neuroleptic malignant syndrome, QT prolongation
o Promethazine 12.5-25 mg q4-6 hours
 5-HT3 antagonists (e. g. ondansetron, granisetron) peripherally (intestinal vagal and spinal afferents) and centrally
(chemoreceptor trigger zone) can prevent postoperative vomiting, radiation therapy-induced symptoms, and cancer
chemotherapy-induced emesis
o Not superior to metoclopramide or promethazine in a double blinded RCT in controlling nausea symptoms
in adults visiting the emergency department
 Cannabinoids (Dronabinol, Nabilone): thought to act primarily via the cannabinoid receptor (CB1) in the vomiting
receptor of the medulla and the area subpostrema of the NTS, although potential to modulate 5-HT3 activation in
nodose ganglions and substance P release in the spinal cord could also contribute
o Not well established
 Benzodiazepines (Lorazepam, Alprazolam) are investigated as adjunctive therapy in post-operative nausea and
small reports have shown that its use reduces anticipatory nausea associated with chemotherapy
o Dopamine in the chemoreceptor trigger zone: acts via its sedative, anxiolytic, and amnestic properties in
reducing the anticipatory component of nausea
 Corticosteroids can be used with 5-HT3 antagonists for acute and delayed chemotherapy-induced nausea and
vomiting
o Most likely involves prostaglandin formation and inflammation
 Aprepitant, an NK1 antagonist, antagonizes the tachykinin receptor since substance P and other tachykinin peptides
may have a role in the vomiting reflex’
o FDA approved for prevention of both acute and delayed chemotherapy-induced nausea and vomiting and
has been showed to potentiate the effects of 5-HT3 receptor antagonists and corticosteroids
o Case reports demonstrate use of aprepitant in treatment of gastroparesis-associated nausea and vomiting
with no change in gastric emptying
Gastrointestinal Motor Stimulants
 Includes agents that act as a prokinetic versus those that have both prokinetic and antiemetic properties such as
metoclopramide
 First choice for delayed gastric emptying
 Metoclopramide (combined 5-HT4 agonist and D-antagonist) is effective in gastroparesis but has antidopaminergic
side effects such as dystonias and mood and sleep disturbances, so its use is limited
o Potent antiemetic and prokinetic properties via its central and peripheral action via the gut dopamine
receptor antagonist and the 5-HT4 receptor agonist activity
o Efficacious in post-chemotherpay vomiting and gastroparesis
 Erythromycin increases gastroduodenal motility by action on receptors for motilin (endogenous stimulant of fasting
motor activity)
o IV is useful for inpatients with refractory gastroparesis, but oral forms have some utility
o Activation of motilin receptors present on gut smooth muscle, possibly leading to modulation of vagal
nerve pathways involved in emesis
o Efficacious in low disease of 50-100mg before meals in patients with delayed gastric emptying; it causes
nausea in higher antibiotic doses by contracting the gastric fundus and thus inducing gastric dysrhythmias
and prolonged, nonpropulsive hypermotility of the antrum
 Domperidone, a D2 antagonist, exhibits prokinetic and antiemetic effects but does not cross into the brain region,
unlike metoclopramide: anxiety and dystonic reactions are rare
 o Major side effects: induction of hyperprolactinemia
 Somatostatin analogue octreotide: for intestinal pseudo-obstruction  effects by inducing propagative
small0intestinal motor complexes
 Acetylcholinesterase inhibitors such as pyridostigmine can benefit some pages with small bowel dysmotility
Novel Therapies
 TCAs can provide symptomatic benefit in patients with chronic idiopathic nausea and functional vomiting as well
as in long-standing patients with nausea and vomiting
o Moderate symptom reduction in patients with chronic nausea and vomiting including cyclical vomiting
syndrome
o Lak of good prospective studies  only used in severe or refractory symptoms
o Amitriptyline has been shone to have some benefit in functional upper GI symptoms like painful dyspepsia
o First line for chronic nausea, along with olanzapine, gabapentin, cannabinoids, benzodiazepines
 Gabapentin, a gamma-aminobutyric acid analog has been shown to be efficacious in preventing post-operative
nausea and vomiting in multiple RCTs
o Acute and delayed chemotherapy-associated nausea and vomiting, hyperemesis gravidarum, life-
threatening refractory emesis
o MOA involves mitigation of calcium currents in areas such as area postrema
 Mirtazapine and olanzapine may exhibit antiemetic effects
o Dopamine and serotonin receptor antagonist
o Efficacy in acute and delayed chemotherapy0induced nausea and voiting
 Gastric electrical stimulation: for refractory gastroparesis
o Activation of vagal afferent pathways to influence CNS control mechanisms for nausea and vomiting
o GES with short pulses can improve gastroparesis syndromes
 Ginger has been shown to have some efficacy in small studies to reduce severity of post-operative nausea and
vomiting, morning sickness, and motion sickness
o Improvements in gastric motility, anti-5-hydroxytryptamine activity, and central antiemetic effects
 Hypnosis, acupressure and acupuncture
o P6 acupoint stimulation significantly reduced nausea, vomiting, and the need for rescue medications
o P6 acupoint stimulation was superior to metoclopramide in achieving complete recovery rate
o Hypnosis in preventing chemotherapy-induced anticipatory nausea and vomiting

Resources
1. Singh, Prashant, Sonia S. Yoon, and Braden Kuo. “Nausea: A Review of Pathophysiology and
Therapeutics.” Therapeutic Advances in Gastroenterology9.1 (2016): 98–112. PMC. Web. 14 Apr. 2018.
2. Kasper, Dennis, et al. "Harrison's principles of internal medicine, 19e." (2015).

Fever by Charles A. Dinarello, Reuven Porat

 Body temperature is controlled by the hypothalamus
o Normal temperature is considered to be 37 degrees Celsius, but may vary by up to 1 degree in healthy
individuals
 Elevated core temperature is a common finding in the intensive care, affecting 70% of patients
 American College of Critical Care Medicine, the ISCD, and IDSA defines fever as a core temperature of 38.3
degrees Celsius or higher, irrespective of the cause
o In Latin, fever simply means heat, and pyrexia means fire or fever
o Pyrexia may be used interchangeably or fever, but some prefer to preserve fever to mean raised temperature
caused by the action of thermoregulatory pyyrogens on the hypothalamus
 Hyperthermia has no agreed definition: may be greater than 38.2 degrees, or increase in body’s temperature above
that set by the hypothalamus, etc., not due to pyrogens e. g. classical and exertional heatstroke, drug-related illnesses
like malignant hyperthermia and neuroleptic syndrome
Generation of Fever
 Sepsis accounts for up to 74% of fever in hospitalized patients
o The remainder: malignancy, tissue ischaemia, drug reactions, neurogenic fever, endocrinopathy fevers

Sepsis

Figure 2. Proposed mechanisms for the generation of fever in sepsis. Stimulation of sentinel cells by exogenous
pyrogens produce endogenous pyrogens which stimulate fever production in the POA of the hypothalamus by second
messengers PGE2 and ceramide. PGE2 is also produced from Kupffer cells in the liver in response to stimulation from
LPS which additionaly stimulates the POA via the vagus nerve.

 Pyrogenic fever is a common response to sepsis in critically ill patients, and the generation of fever occurs through
several mechanisms
o Interaction of exogenous pyrogens (microorganisms) or endogenous pyrogens (IL-1, IL-6, TNF-alpha)
with the organum vasculosum of the lamina terminalis leads to the production of fever
o OVLT is one of seven predominantly cellular structures in the anterior hypothalamus wthin the lamina
terminalis, located in the optic recess at the anteroventral end of the third ventricle
 Highly vascular and lacks a BBB, permitting it to be stimulated by pyrogenic substance
 Its stimulation leads to increased synthesis of prostanoids including PGE2, which acts in the pre-
optic nucleus of the hypothalamus slowing the firing rate of the warm sensitive neurons and
resulting in increased body temperature
o Ceramide, which has proapoptotic and cell-signaling roles, may act as a second messenger independent of
PGE2, and may have significance in early stages of fever
o LPS from gram-negative bacteria may stimulate peripheral production of PGE2 from hepatic Kupffer cells
 LPS may also be neutrally mediated, and may account for rapid onset of fever, with cytokine
production responsible for the maintenance, rather than the initiation of ever
o Toll-like cascade may also generate fever, which may be independent of the cytokine cascade
 Figure 4. Chronology of events required for the induction of fver.

 Febrile response is well preserved across the animal kingdom, and may be beneficial to infections by several
mechanisms
o Human infective pathogens often demonstrate optimal replication at temperatures below 37 degrees Celcius
o Increasing the temperature in vitro from 35 to 41.5 degrees Celsius increases the antimicrobial activity of
many classes of antibiotics
o Thirdly, a rise in temperature may also be associated with microbial destruction
 However at temperatures above 40 degrees there is further mortality increase (signifying deleterious effects of
hyperthermia on organ and cellular function outweighing any benefit conferred from hyperpyrexia in acute sepsis)
 A non-pyrogenic fever is not of any perceived teleological benefit, and trends towards worse outcomes in the ICU
especially whengreater than 38.5 degrees Celsius

Fever Associated with Inflammation

 In critically ill patients, inflammation is commonly observed to aid repair after traumatic or infective insults
 Fever is a ubiquitous component of inflammation and enhances host response
o A large number of both cell-derived and plasma-derived inflammatory mediators are pyrogenic
 Chronic inflammation is deleterious (e. g. compensatory anti-inflammatory response syndrome restores
homeostasis)
 Fever in patients with malignancy is reported to be sepsis-related in 2/3 of cases; the tumor is the cause 10% of the
time, but most of the time its tumor necrosis and production of pyrogenic cytokines
 Regulated autoimmunity is considered to be a natural physiological reaction, however, pathological autoimmunity
occurs because of higher titres of antigen-specific antibodies
 Autoinflammatory conditions (also known as periodic fever syndromes), are different from autoimmune diseases
o Familial Mediterrranean fever and some arthropathies

Drug-induced fever
Class Examples of Causes
Antimicrobial Agents Beta-lactam antibiotics (piperacillin, cefotaxime), Sulphonamides
Malignant hyperthermia Suxamethonium, Volatile anesthetic agents
Neuroleptic malignant Dopamine antagonists like chlorpromazine, haloperidol
syndrome Atypical agents like olanzapine, risperidone, paliperidone, quetiapine
Serotonin syndrome Antidepressants, (MAOs, TCAs, SSRIs, SNRIs, bupropion)
 Propofol infusion syndrome Propofol
Anticholinergic agents Anticholinergics like atropine and glycopyrrolate, Antihistamines like chlorpheniramine,
Antipsychotics such as olanzapine and quetiapine, Antispasmodics like oxybutynin,
Cyclic antidepressants (amitriptyline, doxepin), Mydriatics (tropicaminde)
Sympathomimetic agents Prescription drugs (e. g. bronchodilators), non-prescription drugs (e. g. ephedrine), Illegal
street drugs like cocaine, amphetamines, methamphetamines, mephedrone, dietary
supplements
Piperazine compounds Antiemetics (cyclizine), Antihelminths, Legal club drugs (legal X, legal E, frenzy)
Synthetic cathinones Street drugs (mephedrone, meow meow), Buproprion

 Cause of drug-induced fever are shown in Table 1

 Pharmacologic agents may cause fever by a number of pathophysiological mechanisms
o Interference with the physiological means of heat loss from the peripheries, interference with central
temperature regulation
o Direct damage to tissues
o Stimulation of an immune response
o Pyrogenic properties of the drug
 A common mechanism in many of these drugs is considered to be stimulation of non-shivering thermogenesis
(brown adipose tissue and skeletal muscle)
o ANST uncouples proton movement from this pathway, allowing the energy to be dissipated as heat, under
the control of uncoupling proteins, ultimately influenced by thyroid hormones and catecholamines.
o A number of agents, including sympathomimetics, and those which act via the serotonin pathway, are
though to cause fever by modifying the NST pathway at a central, peripheral, or cellular level

Fever after brain injury

 Fever after acute brain damage, from trauma or a vascular event, is common and independently associated with
worse outcome
 Multifactorial
o Hypothalamic lesions suggest dysregulation
o Alterations in cellular metabolism, a shift to anaerobic metabolism, ischaemic-reperfusion injury are
associated with thermogenesis
o Cerebral production of a large number of inflammatory and pyrogenic cytokines is increased acutely
o IL-6 is particularly associated with fever production after a stroke, with a worse outcome
o Hemorrhage  blood and degradation products are associated with fever
 Brain injury following cardiac arrest is well recognized, but pathology is complex
o Cell death, excitotoxicity, cell signaling changes, cellular metabolism changes, ischemia reperfusion
injuries, etc.

Endocrine Fever
 Hyperthyroidism is associated with hyperthermia: patients with thyroid storm have an average body temperature
of 38 degrees Celsius
o Metabolism of peripheral tissues increases through a peripherally mediated pathway
o Thyroid hormones may also act centrally to increase the hypothalamic set point, and this centrally driven
neurogenic activation of uncoupling protein-1 acting on brown adipose tissue may be responsible for
thermogenesis
 Adrenal insufficiency is rarely associated with fever, but may be related

Approach to the Patient with Fever

Physical Exam
 Chronology of events preceding fever (exposures) should be ascertained
  Electronic devices for measuring oral, tympanic membrane, or rectal temperatures are reliable, but the same site
should be used consistently
 Newborns, elderly patients, patients with chronic liver or renal failure and patients taking glucocorticoids or being
treated with an anticytokine may have active infection in the absence of fever due to a blunted fever response

Laboratory Tests
 Should include CBC, differential count to identify juvenile or band forms, toxic granulations, and Dohle bodies
suggestive of bacterial infection
 Cytokine measurement is not helpful
 CRP and ESR may be helpful in low grade fever

Fever in patients receiving anticytokine therapy

 Lowered host defense against infection
o Active TB can develop even if tests are negative
o Opportunistic infections
o Fever is among the presenting signs: even low grade fever is of considerable concern

Mechanisms of Damage in Fever

Figure 4. Diagrammatic representation of the mechanisms of damage from hyperthermia

Direct cellular damage

 Hyperthermia is directly cytotoxic, affecting membrane stability and transmembrane transport protein function
 Ionic transport is disrupted leading to intracellular sodium and calcium increase with decreased intracellular
potassium concentration
o DNA and protein synthesis is disrupted  nuclear damage leads to direct cell death at around 41 degrees
Celsius, with rate of cell death increasing markedly with even modest further increases in temperature
 Cells in mitosis are more thermosensitive than cells in other phases of replication

Local effects (stimulation of cytokines and inflammatory response)

 Effect of cytokines and the inflammatory response
o Rise in IL=6 and duration of increased expression is correlated with mortality
o Antagonism of IL-1 improves survival
o Cytokine profile of classical and exertional heatstroke show similarities, also with endotoxemia
o Development of other hyperthermic states may be associated with inflammatory mediators
 NMS is at least partly driven by an acute phase response; IL-6 and TNF-alpha have been shown to
be increased in NMS and MH
 Protection by heat shock proteins
o Offer protection against a variety of insults, including heat
 o Intracellular HSPs have a protective role of correcting misfolded proteins, preventing protein aggregation,
transport of proteins, and supporting antigen processing and presentation, as well as limiting apoptosis
 Vascular changes
o Changes occur after onset of hyperthermia: capillary dilatation, vascular stasis, extravasation

Systemic effects (e. g. gut bacterial translocation)

 Gastrointestinal bacterial and endotoxin translocation
o Increases gut bacterial translocation and BBB and GI tract appears to be more permeable to toxins
o Implicated in the development of multi-organ dysfunction in non-pyrogenic hyperthermia

Treatment of Patient with Fever

Decision to treat fever
 Mostly self-limited
o Use of antipyretics is not contraindicated in these infections
 In bacterial infections, withholding of antipyretic therapy can be helpful in evaluating the effectiveness of an
antibiotic
o Routine antipyretic can mask an inadequately treated bacterial infection
 Withholding antipyretics may facilitate diagnosis of unusual febrile disease
o Temperature-pulse dissociation (relative bradycardia) occurs in typhoid fever, brucellosis, leptospirosis,
some drug-induced fevers, and factitious fever
 Some infections may have characteristic patterns
o Plasmodium vivax: every third day, but every fourth day with P. malariae
o Borrelia infection with days of fever followed by several afebrile days and then a relapse into additional
days of fever
o Pel Ebstein Fever (classic for Hodgkin’s disease and other lymphomoas): fever lasting 3-10 days followed
by afebrile periods of 3-10 days

Anticytokine therapy to reduce fever in autoimmune and autoinflammatory diseases

 Recurrent fever is documented at some point in most autoimmune and autoinflammatory disaeses
 Fevers associated with these illnesses are dramatically decreased by blocking of IL-1Beta activity
o Anticytokines therefore reduce fever in autoimmune and autoinflammatory disaeses
o Patients may also respond to antipyretics

Mechanisms of Antipyretic Agents

 Reduction of fever by lowering of the elevated hypothalamic set point is a direct function of reduction of the PGE2
level in the thermoregulatory center
o Synthesis of PGE2 level depends on the constitutively expressed enzyme cyclooxygenase
 Substrate is arachidonic acid released form the cell membrane and this release is the rate-limiting
step in the synthesis of PGE2
 Inhibitors of COX are potent antipyretics, and antipyretic potency of various drugs is directly correlated with the
inhibition of the brain COX
o Acetaminophen is oxidized by the p450 cytochrome system, and the oxidized form inhibits cyclooxygenase
activity.
 In the brain, the in inhibition of COX-3 by acetaminophen may account for the antipyretic effect
of this agent
o Oral aspirin is equally effective
o NSAIDs such as ibuprofen and specific inhibitors of COX-2 are also excellent antipyretics
o As antipyretics, glucocorticoids act on two levels
 Reduces PGE2 synthesis by inhibiting the activity of phospholipase A2, needed to release AA from
cell membrane
  Second, glucocorticoids block the transcription of mRNA for pyrogenic cytokines
 Goal: Reduce the elevated hypothalamic setpoint, then facilitate heat loss
o Also reduces systemic symptoms of headache, myalgia, and arthralgia
o Oral aspirin and NSAIDS are effective but can adversely affect platelets and the GI tract
o Therefore, acetaminophen is preferred as the antipyretic
o In children, acetaminophen and ibuprofen must be used because aspirin increases risk for Reye’s syndrome
o Treatment of fever in some patients is highly recommended
 Increases demand for oxygen (1 degree increase over 37 degrees Celsius = 13% increase in oxygen
consumption, which may aggravate other conditions)
 Febrile seizure history warrants aggressive treatment to reduce fever
 Hyperpyrexia: use of cooling blankets facilitates the reduction of temperature, but should not be
used without oral antipyretics

Anemia and Polycythemia

Hematopoiesis and the Physiologic Basis of Red Cell Production
 Hematopoiesis: the process by which formed elements of the blood are produced
o Stem cells are capable of producing all classes of cells of the immune and hematopoietic system, but the
molecular mechanism is yet to be defined
o Influenced by growth factors and hormones
o EPO is the primary regulatory hormone for red cell production
 IN it’s absence, the erythroid progenitor cells undergo apoptosis

 In the bone marrow: pronormoblast

o Increased EPO production  increased number of erythrocytes
 The red cell
o O2 is transported via hemoglobin
o Mature red cell is 8 micrometers in diameter, anucleate, discoid, and pliable, traits needed to traverse the
microcirculation successfully
o Membrane integrity is maintained by intracellular ATP generation
o 0.8-1% is replaced daily, since the average red cell lives 100-120 days
 o Erythron: the organ responsible for red cell production; a dynamic organ made up of a rapidly proliferating
pool of marrow erythroid precursor cells and a large mass of mature circulating red blood cells
 Size of red cell mass: reflects balance of red cell production and destruction
 EPO: the glycoprotein physiologic regulator of red cell production
o Produced and released by peritubular capillary lining cells
o Fundamental stimulus: availability of O2 for tissue metabolic needs
 HIF-1alpha is hydroxylated in the presence of oxygen at proline, allowing it to be ubiquiinated and
degraded
 If limiting O2, HIF-1 alpha upgrades the expression of EPO gene
 Impaired O2 delivery to the kidney can result from the ff.
o A decreased red cell mass (anemia)
o Impaired O2 loading of the hemoglobin molecule
o High O2 affinity mutant hemoglobin (hypoxemia)
o Rarely, impaired blood flow to the kidney (renal artery stenosis)
 EPO can be measured in the plasma by sensitive immunoassays  normal level is 10-25U/L
o If hemoglobin falls below 100-120 g/L (10-12 g/dL), plasma EPO levels increase in proportion to the
severity of the anemia
o EPO has a half clearance time of 6-9h in circulation
o EPO acts by binding to specific receptors on the surface of marrow erythroid precursors, inducing them to
proliferate and to mature  red cell production can increase four to five fold within a 1-2 week period but
onlyl in the presence of adequate nutrients, especially iron
o Functional capacity of the erythron: requires normal renal prducion of EPO, a functioning erythroid
marrow, and an adequate supply of substrates for hemoglobin synthesis
 Any defect here can lead to anemia
 Anemia
o Recognized in the laboratory when hemoglobin level or hematocrit is reduced below an expected value
o Mean hematocrit value
 For males: 47% with SD: 7%
 For females: 42% with SD: 5%
 A hematocrit of less than 39% in an adult male has about 25% chance of being normal
o Hematocrit levels are less useful than hemoglobin levels in assessing anemia because they are calculated
rather than measured directly
 Anemia is defined as <130 g/L in men and <120 g/L in women
 Critical elements of erythropoiesis are used for the initial classification of anemia
o EPO Production
o Iron Availability
o Proliferative Capacity of the Bone Marrow
o Effective Maturation of Red Cell Precursors

Anemia
Clinical Presentation of Anemia
Signs and Symptoms
 Most often is recognized by abnormal screening laboratory tests
 Acute anemia is due to blood loss or hemolysis
o Mild blood loss: enhanced O2 delivery through the Bohr effect (changes in O2-hemoglobin dissociation
curve)
o Acute blood loss: hypovolemia dominates the clinical picture
 Remember that hematocrit and hemoglobin does not reflect volume of blood lost
 Signs of vascular instability appear with 10-15% loss of acute blood volume: hypotension and
decreased organ perfusion
  > 30% loss: unable to compensate with vascular contraction and changes in regional blood flow:
postural hypotension and tachycardia
 >40%: signs of hypovolemic shock include confusion, dyspnea, diaphoresis, hypotension, and
tachycardia
o Acute hemolysis: signs and symptoms depend on the mechanism that leads to red cell destruction
 Intravascular hemolysis with release of free hemoglobin: acute back pain, free hemoglobin in
plasma and urine, renal failure
 Chronic or progressive anemia: depends on the patient’s age and adequacy of blood supply to critical organs
o Moderate anemia: fatigue, loss of stamina, breathlessness and tachycardia
o Signs and symptoms will present in young adults only with severe anemia (<70-80 g/L)
o When anemia develops over a period of days to weeks: total blood volume is normal to slightly increased,
and changes in cardiac output and regional blood flow help compensate for overall loss in O 2-carrying
capacity
 However, this only works in a 20-30 g/L deficit in hemoglobin concentration
 Disorders associated with anemia
o Chronic inflammatory states (infection, RA, arthritis, CA): mild to moderate anemia
o Lymphoproliferative disorders (CLL, B cell neoplasms) may be associated with autoimmune hemolysis

Approach to Patient with Anemia

 History
o Nutritional History: drugs or alcohol intake, family history of anemia
o Geographical backgrounds and ethnic origins: increased likelihood of inherited disorders of hemoglobin or
intermediary metabolism
o G6PD deficiency and hemoglobinopathies in those of ME or African origin
o Exposure to toxic agents or drugs
o Symptoms related to other disorders associated with anemia
 Bleeding, fatigue, malaise, fever, weight loss, night sweats, other systemic symptoms
 PE
o Infection, Blood in the stool, lymphadenopathy, splenomegaly, petechiae
o Splenomegaly + Lymphadenopathy: Lymphoproliferative disease (petechiae presents platelet dysfunction)
o Past laboratory measurements are helpful to determine a time of onset
o Forceful heartbeat, strong peripheral pulses, a systolic flow murmur
o Skin and mucous membranes may be pale if hemoglobin is < 80-100 g/L
 Mucous membranes, nail beds, palmar crease
 If palmar crease is lighter in color: <80 g/L
 Laboratory Evaluation
o Complete Blood Count (affected by age, sex, pregnancy, smoking, and altitude)
 Red Blood Cell Count: Hemoglobin, Hematocrit, Reticulocyte Count
 Reticulocyte count: identified by staining with a supravital dye that precipitates a
ribosomal RNA
o Counted manually or by fluorescent emission of dyes that bind to RNA
o Metabolized over the first 24-36 hours of the reticulocyte’s life span in circulation
o Reticulocyte count is compared with expected: if moderate anemia, 2-3 times
normal reticulocyte response
o First correction: adjust reticulocyte count based on reduced number of circulating
red cells (reticulocyte percentage is multiplied to ratio of hemoglobin to
hematocrit for the age and sex)
o Second correction as an index of marrow production peripheral blood smear is
examined to see if there are polychromatophilic macrocytes (shift cells)
 Red Blood Cell Indices: MCV, MCH, MCHC, RDW
  MCV: represents the peak of the distribution curve; is insensitive to the appearance of
small populations of macrocytes or microcytes; microcytosis (<80) or macrocytosis (>100)
 MCH and MCHC: defects in hemoglobin synthesis (hypochromia)
 ARDW: described by automated cell counters
 White Blood Cell Count: Cell differential, Nuclear segmentation of neutrophils
 Platelet Count
 Cell Morphology: Cell size, Hemoglobin content, Anisocytosis, Poikilocytosis, Polychromasia
 Provides important information about defects in red cell production
 Variations in size (anisocytosis, correlates with increases in RDW) and shape
(poikilocytosis, suggests defect in maturation of red cell precursors in the bone marrow or
fragmentation of circulating red cells)
 Polychromasia (red cells slightly larger than normal and grayish blue in color on the
Wright-Giemsa stain)  reticulocytes that have been prematurely released from the bone
marrow; appear in response to EPO stimulation or architectural damage of the bone
marrow (as in fibrosis, infiltration of the bone marrow by malignant cells, etc.) resulting
in their disordered release
 Nucleated red cells, Howell-Jolly bodies, target cells, sickle cells, others
o Iron Supply Studies: reflects availability of iron for hemoglobin synthesis
 Serum Iron: ranges from 9-27 micromol/L, whereas te normal TIBC is 54-6 micromol/L
 Total Iron-binding capacity
 Serum ferritin: 10-15 micrograms/L indicates depletion of body stores
 Percent transferrin saturation is derived by dividing the serum iron level (x100) by the TIBC
 Normal range: 25-50%
o Marrow Examination (in patients with severe anemia and abnormalities in red blood cell morphology)
 Can diagnose primary marrow disorders (myelofibrosis, a red cell maturation defect, infiltrative
defect)
 Increase or decrease of one cell lineage: differential count of nucleated cells in the bone marrow
smear
 Aspirate: M/E Ratio, Cell Morphology, Iron Stain
 Biopsy: Cellularity, Morphology
Definition and Classification of Anemia
Initial Classification of Anemia

 Marrow Production Defects (hypoproliferation)

o Typically seen with a low reticulocyte production index together with little or no change in red cell
morphology
o 75% of all cases of anemia are Hypoproliferative anemia: absolute or relative marrow failure
o Majority: due to mild or moderate iron deficiency or inflammation
o Can result from the ff.:
 Marrow damage
 Iron deficiency
 Inadequate EPO stimulation (may reflect impaired renal function, suppression by inflammatory
cytokines like IL-1, or reduced tissue needs such as hypothyroidism)
o Normocytic, normochromic red cells, though hypochromic and microcytic cells may be observed with mild
iron deficiency or long-standing chronic inflammatory disease
o Laboratory tests
 Serum iron and iron binding capacity, evaluation of renal and thyroid function, marrow biopsy or
aspirate, and serum ferritin
 Red cell maturation defects (ineffective erythropoiesis)
o Slight to moderately elevated reticulocyte production index accompanied by either macrocytic or
microcytic red cell indices
 Low reticulocyte count: reflection of ineffective erythropoiesis that results from the destruction
within the marrow of developing erythroblasts
o Divided into two categories:
 Nuclear maturation defects: macrocytosis
  Cytoplasmic maturation defects: microcytosis and hypochromia usually from defects in
hemoglobin synthesis
o Bone marrow exam: erythroid hyperplasia
o Nuclear maturation defects: vitamin B12 or folic acid deficiency, drug damage, myelodysplasia,
methotrexate or alkylating agents which interfere with cellular DNA synthesis
o Cytoplasmic maturation defects: severe iron deficiency, abnormalities in globin or heme synthesis
 Decreased red cell survival (blood loss, hemolysis)
o Increase in reticulocyte production index to at least three times normal (provided that iron is available)
o Increased number of polychromatophilic macrocytes: marrow examination is rarely indicated if
reticulocyte production index is increased appropriately
o Hemolytic disease is dramatic but least common
 Extravascular hemolysis: iron is recycled
 Intravascular hemolysis: loss of iron may limit the marrow response
o Hemoglobinopathies: show a mixed picture
o Differential Diagnosis of acute or chronic hemolytic event
 Family History, Pattern of Clinical Presentation, Careful examination of peripheral blood smear

Treatment
 Initiate treatment of mild to moderate anemia only when a specific diagnosis is made
 Selection of appropriate treatment is determined by the documented cause of anemia
 Therapeutic options
o Blood component therapy
o Recombinant EPO
o Targeted gene therapy

Bowel Movement Changes

GI Physiology
Overview
 Learning Guide
o Know the major functions of the GI system
o You will be able to explain the phases of digestion
o You will be able to identify and explain the function of the GI signaling molecules
 Neurocrines, Paracrines, GI hormones
 Fundamental functions of GI tract
o Absorption: from the lumen of the GI body
o Digestion: you eat food in complex types, which should be broken down
o Excretion: Food we don’t need
o Motility
o Storage: Deliver a particular foodstuff at the right place at the right time
o Secretion: put a number of substances for the food to be digested
 GI Overview: Approaches
o Anatomic Viewpoint
 Pharynx  Esophagus Etc.  Rectum
o Engineering Tube Viewpoint
 Detergent Supplier: Liver and Gallbladder
 Chopper: Mouth and Teeth (large particles  small particles for higher surface area)
 Hydrolyzer and Lubricator: Salivary glands
 Blender, Acid, Sterilizer, Reservoir: Stomach
 Enzyme supplier and Neutralizer: Pancreas
  Catalytic and Absorptive Surface: Small intestine
 Residue combustor, desiccator and pelleter: Large intestine
 Emission Control Device: Rectum

 Phases of Digestion
o Cephalic Phase: Chemoreceptors and mechanoreceptors in the oral and nasal cavity  stimulated by
tasting, chewing, swallowing, and smelling of food as well as the thought of food or eating, engaging
primarily neural responses
 Food  Vagal center of medulla  Parasympathetic innervation excites pepsin and acid
production
o Gastric Phase: Begins when foodstuff enters the stomach and is linked to distention of the stomach and
contents (AAs and peptides), engaging neural and hormonal responses
 Local nervous secretory reflexes  Vagal reflexes  Gastrin-histamine stimulation (increases
acid production)
o Intestinal Phase: Foodstuff enters the duodenu m and is linked to digested constituents of proteins and
fats, as well as H+, engaging hormonal but also paracrine and neural responses
 Nervous and hormonal mechanisms
 Parasympathetic Nervous System: Typical Functions
o Relax and digest
o Increase secretions, motility, decrease constriction of sphincters, increase blood flow

 Sympathetic Nervous System

o Light or Aggressive Conflict Mediation
o Decreases secretions, motility, increased constriction of sphincters, decrease blood flow
o Superior cervical ganglion, celiac ganglion, superior and inferior mesenteric ganglion
 Regulation of Blood Flow
o Parasympathetic: uses ACh and VIP (Vasoactive intestinal peptides) to increase diameter of blood vessels
o Sympathetic: NE and ATP
o Local reflexes: ACh and VIP from IPAN
o Sensory Afferent: More conscious in nature; CGRP and SP (small amount of vasodilation)
 Feeling of fullness or distention

 Neural Signaling Molecules

o Acetylcholine: Released by the PSNS, acts on the glands, Sm, muscle, blood vessels  Increase motility,
secretions, blood flow
o ATP: Released by SNS  blood vessels to increase blood flow
o CGRP: Afferents  Blood vessels to increase blood flow
o Enkephalins: ENS  Smooth muscle to constrict sphincters
o GRP: PSNS and ENS  Glands to increase gastrin secretions
o Norepinephrine: SNS  Glands, Sm, muscle, blood vessels to decrease motility, secretions, blood flow
o Neuropeptide Y: ENS and SNS  Sm. Muscle to decrease motility
o Substance P: Afferets and PSNS  Blood vessels and glands to increase blood flow
o VIP: PSNS and ENS  Glands, Sm. Muscle, blood vessels, increases motility and blood flow
 GI Hormones
o CCK: Released by I cells  on exocrine pancreas, gallbladder, stomach  increase enzyme secretion,
contracts gallbladder, decreases gastric emptying
o Gastrin: G cells  Stomach to increase acid secretion
o GIP: K cells  stomach and endocrine pancreas to inhibit acid secretion and release insulin
o Motilin: M cells  Sm. Muscle to increase contraction and MMC
o Secretin: S cells  Pancreas and stomach to increase bicarbonate secretion and peptide secretion
 o Location of Release along the GI Tract

 Paracrine Signaling Molecules

o Histamine: Released by enterochromaffin-like cells, mast cells  acts on the stomach to increase acid
secretion
o Nitric Oxide: Released by numerous types  Acts on sm. Muscle and blood vessels to relax the smooth
muscle and increase blood flow
o Prostaglandins: Released by numerous types  Acts on the mucosa to increase mucus and bicarbonate
secretion
o Somatostatin: Released by D cells  Acts on the stomach and pancreas to decrease secretion

Upper GI System
 Learning Goals
o The constituents and mechanisms of salivary secretions and salivary glands
o Constituents of gastric secretions
o Understand the mechanisms of hydrogen ion secretions, parietal cell control and regulation
 Salivary Secretions
o Primary Function: Protection of the oral cavity, lubrication, digestions
o Parotid Gland: Watery secretions which helps hydrolyze food
o Submandibular and sublingual glands: mucus secretions and serous secretions  lubrication
o Constituents
 K+: Lost to absorb Na+ and H2O
 HCO3- buffer acid
 Salivary amylase: starch digestion
 Lingual lipase: partial lipid digestion
 Muramidase: a lysozyme
 Lactoferrin: Fe-binding protein which prevents bacterial growth
 IgA: immune mediator
o Salivary Glands
 Lower flow rates help reabsorption of Na+
 Potassium is secreted because it is higher in concentration in the plasma
 Bicarbonates are secreted because it’s above the level of the pasma
 Transporters
o Acinar cells (where secretion occurs) and ductal cells (where reabsorption occurs)
o Chloride, Sodium is reabsorbed in the ductal cells
o Bicarbonate and Potassium is secreted
o No net water movement
 o Acinar Cells: Na, K-ATPase increases sodium concentration in the interstitial space, allowing a gradient to
form for sodium to go back into the lumen through the paracellular route. Water follows sodium. By
secondary active cotransport, sodium and chloride enter the cells, then sodium is transported along with
hydrogen back into the interstitial space, leaving chloride, which cotransports with bicarbonate out into the
lumen
o Ductal Cells: Sodium and Hydrogen is reabsorbed, then sodium is moved into the interstitial change in
exchange for potassium using the Na-K ATPase. The potassium that is brought into the cells is co-
transported with hydrogen out of the cells. Hydrogen ions are simply reabsorbed. Potassium is secreted.
Bicarbonate is produced by metabolism through the carbonic anyhydrase action. Hydrogen ion is removed
from the cell by countertransport with sodium, which is used by Na-K ATPase to move potassium into the
cell and sodium out into the interstitial space. Chloride then exchanges with chloride, thus getting a
secretion of bicarbonate and a reabsorption of chloride.

 Control and Regulation of Salivary Glands

o Cephalic Phase Involvement
 Parasympathetic: ACh and VIP
 Sympathetic: NE
 Gastric Secretions
o Primary Functions: Protection (Acidic environment), Storage (reservoir for foodstuff for a while then
gradually releases it, Absorption of lipophilic substances, Prepares chime for digestion in the small intestine
(releasing acid and pepsinogen which converts into pepsin to digest protein)
o Gastric pits are lined by epithelial tissue, mucous neck cells (provides protection for the endothelial layer
so that it isn’t eaten by the acid) and oxyntic or parietal cells
o Gastric Oxyntic Gland: Decreases pH and activates enzymes
 H+ is quite difficult to do; takes a lot of energy, needs a hydrogen pump
o Intrinsic Factor: Vitamin B12 absorption
o Pepsinogen from chief cells: Endopeptidase for protein digestion
o Secretion Constituents
 Sodium is reabsorbed in a flow dependent manner: faster flow rates increase its reabsorption
 Potassium is being secreted
 Chloride is also being secreted
 Hydrogen is secreted in high amounts
 Structures and Functions
 o Mucous neck cells: protection
o G cells: gastrin
o D cells: Somatostatin
o Chief Cells: Pepsin
o Parietal Cells: Intrinsic Factor, HCl
 Metabolism  CO2 which combines with water to form carbonic acid  bicarbonate and hydrogen
ion; bicarbonate is exchanged with chloride to leave the cell, then the hydrogen ion is kicked out
in the stomach lumen via ATP in exchange with potassium. Potassium is secreted again by
facilitated diffusion. Chloride also.

 Control and Regulation: Oxyntic Gland

o Cephalic Phase accounts for 40%
 Parasympathetic Nervous System is involved
 Vagus Nerve Ach stimulates acid production and engages ECL cells to release histamine
 ACh engages G cells to produce gastrin, which stimulates hydrogen ion production
o Gastric Phase accounts for 50%
 Vasovagal reflex response
 Proteins and peptides, especially amino acids, stimulate G cells to release gastrin
 H+ stimulates D cells to produce somatostatin
o Intestinal Phase accounts for 10%
 Protein digestion in the intestine
o Direct Pathway
 Cranial Nerve Number 10  ACh stimulates muscarinic receptors on the parietal cell; ACh may
also stimulate ECL cells, releasing histamine in interstitial space, which binds to histamine
receptors in the lumen; ACh may also stimulate G cells to release Gastrin to stimulate ECL and
lumen cells
  Muscarinic receptors  Gq  PLC  IP3 and DAG from PIP 2; IP3 stimulates ER to produce
calcium release while DAG phosphorylates PKC; PKC and Calcium stimulates the H-K pump
 Gastrin works through CCK receptors and also works in the same Gq as muscarinic receptors
 Histamine: works through an alternate mechanism: histamine receptors  Gs  AC  CAMP 
PKA  H-K pump
 They can potentiate each other; both stimulated together leads to more acid production
 Somatostatin stops CAMP  Gi stops adenylate cyclase
 Prostaglandins work in the same pathway
 Targeted pharmacologically

Lower GI System
 Learning Goals
o You will know the constituents and mechanisms of pancreatic secretions and how these glands are
controlled and regulated
o You will know the constituents of biliary secretions, storage, and bile release
o You will understand the functions of the cystic fibrosis transmembrane regulator
 Pancreatic Secretions
o Dumps into small intestine via the pancreatic duct
o Made of two different endocrine glands and exocrine glands
 Digestive enzymes, water, bicarbonate
o Primary Function: digestion of carbohydrates, fats, and proteins
 Carbohydrates: Amylase
 Fats: Lipase, Phospholipase A2, Cholesterol Esterase
 Proteins: Chymotrypsin, Trypsin, Elastase, Carboxypeptidase
 Nucleotides: Ribonuclease and deoxyribonuclease
 Ions and Water: HCO3-
 We secreted a lot of hydrogen ions in the stomach, so we need a buffer or else the acidity
will eat up the small intestine
o Secretion Constituents of Exocrine Pancreas
 Sodium, Potassium
 Chloride decreases in concentration with flow rate (reabsorption)
 Bicarbonate (Increases in concentration with flow rate)
o Structure and Function
 Endoplasmic reticulum and golgi apparatus  release of enzymes into the lumen
 Carbon dioxide goes into the cells, converted into bicarbonate and hydrogen ions. Hydrogen ions
are exchanged with sodium from he interstitial space, and bicarbonate is exchanged with chloride
 into the lumen. Chloride passively goes out. Sodium is extruded with an ATP-ase into the
interstitial space.. Sodium pulls water back from the interstitial space into the lumen
o Control and Regulation
 Cephalic Phase (25%): Vagus Nerve
 Gastric Phase (10%) Via Vago-Vagal Reflexes
 Intestinal Phase (5%): Secretin and Cholecystokinin
 Sequence of events: acid releases secretin from the walls of the duodenum; fats and amino acids
causes release of CCK. Secretin and CCK are delivered to the pancreas via the blood stream, while
the vagus stimulates release of enzymes into the acini lumen. Both of these causes copious
secretions of pancreatic fluid and bicarbonate.
 Cellular: CCK, ACh, GRP increases intracellular calcium  phosphorylation of structural and
regulation proteins  fusion of granules with apical membranes. VIP and Secretin stimulate
CAMP, then phosphorylates.

 Intestinal Secretions: mucus form goblet cells, endothelial cells and Paneth cells
o Primary function: increase fluid and mucus for protective effect on the walls
 Biliary Secretions
o Gallbladder is the storehouse for biliary secretions
o From the hepatic ducts, bile is stored from the liver to the gall bladder.
o It will eventually be released through the bile duct into the small intestine
o Primary Function: Fat emulsification like detergents
o Constituents
 Bile Salts, Cholesterol, Lecithin, Bilirubin, Ions
 Concentration (5-20%) occurs in the gallbladder via dehydration
o Hepatocytes  Canaliculi  terminal bile ducts -> perilobular  interlobular –> Bile flow
o Structure and Function
 Cystic duct  Combines with right and left hepatic ducts from the liver  Common hepatic duct
 Common bile duct  Sphincter of Oddi (one of the primary regulatory spots)  Duodenum
 Mechanisms of Biliary Concentration: Dehydration occurs first by the reabsorption of sodium in
exchange for hydrogen  Sodium is exchanged out by sodium potassium ATPase, then potassium
moves out via a channel; chloride is exchanged into the lumen for bicarbonate, then chloride moves
out of the cell; osmotic gradient is created for water to follow

o Bile is constantly produced by the liver and transported to the gallbladder

 o CCK is the primary mediator of release that is stored from the gallbladder by first overcoming somatostatin
and NE
 Bile acids via blood stimulate parenchyma secretion; CCK contracts the gallbladder and relaxes
the sphincter of Oddi
 Vagal stimulation causes weak contraction of gallbladder
 CFTR
o A mutated CFTR can cause problems in the pancreas, gallbladder, and elsewhere
o From a sweat gland, CFTR moves Chloride into the cells then eventually out in the basolateral membrane
into the interstitial fluid
o Without normal function of the CFTR, both Cl- and Na+ remain in the lumen
 If chloride is left in the luminal portion, it prevents sodium from being reabsorbed via an ENaC
channel
 Increase in sweat solutions
o CFTR needs ATP for it to function properly
o Quantitative Pilocarpine Iontophoresis Test for Cystic Fibrosis
 Pilocarpine is a cholinergic agonist and uses the current to pass the drug across the skin, causing
sweating to occur
 Low chloride (<4 mmol/L) not diseased
 Diagnostic if > 60 mmol/L

Digestion and Absorption

 Learning Objectives
o Understanding the digestion of carbohydrates, fats, and proteins and the primary enzymes
o Basics of absorption of macronutrients, ions, and water
o Aspects of the splanchnic circulation

Digestion
 Carbohydrate Digestion
o Amylase: breaks down the bonds of starch
 Starch has Amylose (1-4), and Amylopectin (1-6)
 Amylase works on alpha 1-4 bonds and is found in salivary and pancreatic juice
 Dietary fiber cannot be digested (Cellulose, lignin, gums, pectin)
o Brush border disaccharidases (Glucoamylase, Isomaltase, Lactase, Sucrase)
 Lactose  Glucose and Galactose  through SGLT1 in exchange for sodium
 Protein Digestion
o Neutral: Chymotrypsin, Elastase  Carboxypeptidase A breaks them down into neutral AAs and short
peptides
 o Basic: Trypsin  Carboxypeptidase B into short and basic amino acids
o Proteins
 Chymotrypsinogen  Chymotrypsin by Endopeptidase
 Pepsinogen  Pepsin by Endopeptidase via low pH; secreted by chief cells
 ProCarboxypeptidase A and B  Carboxypeptidase A and B by exopeptidases
 Proelastase and Trypsinogen  Elastase and Trypsin by Endopeptidases
 Trypsinogen  activates brush border peptidases; activated by low pH
 Fat digestions
o Triglycerides  Breakdown by lipases into fatty acids and monoglyceride backbone
o Cholesterol  Cholesterol and Fatty acid by cholesterol ester hydrolase
o Phospholipid  Lysolecithin and FAs by Phospholipase A2
o Helped out by bile salts (emulsification), colipase (binding with lipase)
Absorption
 Monosaccharides
o Enzymes in lumen and brush border reduce CHO to monosaccharides
o Apical SGLT1 transports: 2 Na+ cotransport for either glucose or galactose
 Set up by basolateral Na-K ATPase as the diving force
 Water is moved across
o Fructose is moved via GLUT 5
o All monosaccharides are moved into the interstitial tissue by GLUT2
 Peptides
o Normally hydrolyzed to AAs and short peptides
o Apical transport
 Limited phagocytosis
 Amino acid and small peptide utilizes a apical Na and H exchanger mechanisms
 PepT1
o Basolateral transport
 Neutral, Acidic, and Basic
 Fat Absorption in the Small Intestine
o Short and Medium Chain FAs are lipophilic and so can easily cross the apical membrane and traverse an
enterocyte without special assistance  Portal system
o Larger amounts are processed first
 Mixed micelles  Small pH change starts digestive process  Absorbed as long chain FAs,
cholesterol, lysolecithins, and monoglycerols, then are incorporated into triacylglycerides,
phospholipids, and cholesterol esters
 They are repackaged into chylomicrons, which cross the basolateral membrane by exocytosis into
the lymphatic circulation  liver
 Large intestine
o Short chain fatty acid transporter (SMCT1)  aids also in water transport
 Sodium cotransport mechanism
 Summary
o Most of absorption occurs in the duodenum
o Jejunum and ileum also participate
o Ions, Iron, Calcium, Folate are primarily absorbed in the duodenum, but calcium throughout
o Bile Acids are absorbed primarily in the ileum
o Cobalamin is absorbed in the ileum
 Calcium and Iron Absorption
o Calcium transporters (which can be increased by vitamin D3 along with apical and basolateral transporters)
 Calcium is transported across then bound to calbindin (to prevent cytotoxicity) to transport to the
basolateral membrane to transport it out
 o Iron
 Specialized transporters (DMT cotransports with H+ after it is oxidized by Dcytb)  Mobiferrin
binding protein  Released via FP1 then reduced by Hephaestin
 Heme can be reabsorbed the iron can be released
o Cobalamin
 Bound to proteins in food so it needs to be liberated
 Acid pH and pepsin release  cobalamin is disassociated
 Haptocorin binds to cobalamin
 Parietal cells secrete IF
 Proteases are released from the pancreas and bicarbonate, causing CBL to be released then it binds
to IF. It only gets absorbed in the lower part of the small intestine via an endosome.
 Water balance
o Balance of intake and secretions vs. absorption
o Small intestine is the major player (absorbs 80% of water, large intestine absorbs 20%)
o Large intestine is regulated
Splanchnic Circulation
 Celiac Artery  Spleen, Stomach, and Liver
 SMA  Pancreas, Small Intestine
 IMA  Colon
 All are linked to the liver via the hepatic circulation
 Tissue flow pattern
o 75% Blood flow to the mucosa
o 25% in muscularis
o Oxygen is decreased as you move into the microvilli
 Can be ischemic with vasoconstriction  can cause problems like allowing bacteria to cross

Gastrointestinal Motility
 Learning Goals
o Mechanisms of GI motility
o Understand how swallowing is both initiated and controlled
o Explain gastric emptying and how it is regulated and controlled
 GI Motility Overview

o Peristalsis: ACh is released where contraction is necessary, NO and VIP where release is necessary
 Both controlled by PSNS and ENS
 Enkephalins mediate constriction of sphincters (tonic constriction)
 VIP often mediates relaxation
o Mixing and Grinding (Stomach)
o Swallowing
 Voluntary Initiation
 Involuntary Reflex once mechanoreceptors are stimulated
  Pharynx  Stomach
 UES
 LES: acid reflux or regurgitation, Barrett’s Esophagus
 Striated muscle in the upper 1/3, Smooth muscle in the lower 2/3
 Swallowing Center: coordinates striated and smooth muscle
 Glossopharyngeal feedback  Nerves directly stimulate striated muscle to contract.
Autonomic nerves regulate via reflexes
 Primary Peristalsis  Second peristalsis to begin the process  Stomach has to be relaxed (VIP)
and receptive relaxation of cardia region by stomach (VIP)
 Gastric Motility
o LES and Cardia: Food entry, regulation of belching
o Fundus and Body: Pacemaker (ICC) and reservoir
o Antrum and Pylorus: mixing, grinding, regulation of emptying;
o Stomach Contents Affect Gastric Emptying
 Glucose faster than Protein faster than fats
 Liquid > Solid
 High osmolality: delayed gastric emptying (high sodium concentration)
 Intestinal Motility
o Segmentation contractions (involves mixing movements) to move food in both directions
o Fed state: peristalsis
o Fasting: migrating motor complex (for house cleaning)
 What controls these movements?
o Interstitial cells of Cajal
o Stomach: 3-5
o Small Intestine: 12-20
o Large intestine: 6-8
o Slow waves: higher amplitude, greater the contraction
 Upper slope: Calcium
 Lower slope: Potassium channel

Definition of Chronic Diarrhea

 Diarrhea: Loose stools, increased stool frequency, urgency
 Chronic diarrhea: Duration of greater than 4 weeks
 Frequent defecation with normal consistency: pseudodiarrhea; thus, abnormal stool form should be the basis

Differential Diagnosis
 Consider comorbid symptoms and epidemiologic clues when constructing a differential diagnosis
o Functional Category
 Irritable bowel syndrome (abdominal pain accompanies diarrhea)
 Rome IV: recurrent abdominal pain at least 3 days per month in the last 3 months,
associated with stool frequency and form change, and improvement with defecation
 Functional diarrhea (absent abdominal pain):similar stool changes without prominent pain
o Inflammatory cause: significant abdominal pain, fever, GI bleeding
o Carbohydrate malabsorption: gas and bloating
o Substantial weight loss  malabsorption, maldigestion, malignancy (older)
o Lymphoma  fatigue and night sweats
o Anemia or change in stool caliber  colorectal malignancy
 Characteristics of Stool
o Small, frequent bowel movements with tenesmus and bleeding  Proctitis
o Large volume, less frequent stools  Small bowel source of diarrhea
o Steatorrhea  fat maldigestion of malabsorption
 Epidemiologic Associations
o Travelers: bacterial, protozoal, tropical sprue
o Epidemics and outbreaks: infection, epidemic idiopathic secretory diarrhea, protozoal, viral
o Diabetic patients: altered motility, associated diseases (CD, pancreatic exocrine insufficiency, SIBO),
drugs (acarbose, metformin)
o Patients with acquired immunodeficiency syndrome (drug side effects, lymphoma, opportunistic
infections)
o Institutionalized and hospitalized patients (Clostridium difficile, drug side effects, fecal impaction,
ischemic colitis)
 By Stool Characteristics
o Osmotic Diarrhea
 Carbohydrate malabsorption, Osmotic laxatives
o Secretory diarrhea
 Bacterial toxins, BAM, IBD, Lymphocytic colitis, Medications and toxins, disordered motility
 Endocrinopathies
 Addison’s disease, Hyperthyroidism, Neuroendocrine tumors, Medullary carcinoa of the
thyroid
 Idiopathic secretory diarrhea
 Stimulant laxative abuse
 Neoplasia
 Colon CA, Adenoma, Laxactives
 Vascultitis
o Inflammatory Diarrhea
 Diverticulits, IDS, bacterial or parasitic infections, pseudomembranous colitis, ulcerating viral
infections, IBD (Crohn’s or Ulcerative Colitis)
 Ischemic Colitis, Neoplacia, Radiation Colitis
o Fatty Diarrhea
 Malabsorption Syndromes (ischemia, mucosal diseases, SBS, SIBO)
 Maldigestion (pancreatic exocrine insufficiency, inadequate luminal bile acid concentration)_
Pathogenesis of Chronic Diarrhea
 Specific foods and diets are often incriminated
o Substances that in sufficient quantities can cause diarrhea e. g. fructose
o Foods that cause diarrhea because of an underlying condition (lactose intolerance)
o Gut alterations that limit digestion or absorption (short bowel pancreatic insufficiency)
o Idiosyncratic food intolerances
o Food allergy is rare
 CD: based on on symptoms, serology, intestinal histology
 Medications
o 700 drugs have been implicated
o Factitious: laxatives  secretory diarrhea
 Chronic Diarrhea Therapies
o Radiation therapy such as radiation enteritis
 Risk factors: low BMI, prior abdominal surgery, comorbidities, technique, etc.
o Abdominal surgery: intentional or inadvertent vagotomy, SIBO, BAM, and short bowel syndrome
 Vagotomy: rapid gastric emptying of liquids and diarrhea
 Bacterial overgrowth: small intestine bacterial overgrowth causes diarrhea by bile acid
deconjugation, interfering with enzymatic action and damage to the mucosa
 Bile acid malabsorption: stimulates fluid secretion and motility in the colon, resulting in diarrhea
 Short bowel syndrome: occurs after resection of a large portion of the small intestine
Causes

Management
 Diagnostics must be rationally directed by a careful history, including medications, and a physical examination
o If this is unrevealing, simple triage tests are warranted to direct the choice of more complex investigation
  History and Physical Exaxm should attempt to characterize the mechanisms of diarrhea, identitfy diagnostically
helpful aociations, and assess the patient’s fluid/electrolyte and nutritional status
 Therapeutic Trial is often appropriate, definitive, and highly cost-effective when a specific diagnosis is suggested
on the initial physician encounter
o IBS should be initiated with a flexible sigmoidoscopy with colorectal biopsy to exclude IBD, or particularly
microscopic colitis
 Further evaluation of osmotic diarrhea: lactose intolerance and magnesium ingestion
o Low fecal pH: carbohydrate malabsorption, can be confirmed by breatth testing or empirical trial of lactose
exclusion
 Fatty diarrhea: endoscopyp with small bowel biopsy should be performed. If unrevealing, small-bowel radiograph
is the next step.

Treatment
 Depends on the specific etiology: May be curative, suppressive, or empirical
o If can be eradicated: curative
o Controlled by suppression of the underlying mechanism
 If evades diagnosis, empirical therapy may be beneficial
 Avoid antimotility agents with IBD to avoid toxic megacolon
 Clonidine for diabetic diarrhea: poorly tolerated because of postural hypertension

Dyspnea
Dyspnea General Principles
 Definition: A subjective experience of breathing discomfort that consists of qualitatively distinct sensations that
vary in intensity

Mechanisms
 Respiratory sensations: consequence of interactions between efferent (outgoing) motor output from the brain to the
ventilatory muscles and the afferent (incoming) sensory input from the receptors throughout the body
o Integrative processing of this information, most probably in the brain
  Holistic, like hunger or thirst
Motor Efferent
 Disorders of the ventilatory pump
o Most commonly increased airway resistance or stiffness of the respiratory system
o Associated with increased work of breathing or a sense of an increased effort to breathe
 Muscle fatigue  greater effort to breath
 Increased neural output from motor context is sensed via a corollary discharge  sent to the sensory cortex at the
same time as motor output is directed to ventilatory muscles
Sensory Afferents
 Chemoreceptors in the carotid bodies and medulla are activated by hypoxemia, hypercapnia, and acidemia
o Stimulation leads to an increase in ventilation producing a sensation of air hunger
 Mechanoreceptors in the lungs, when stimulated by bronchospasm  chest tightness
o J receptors, sensitive to interstitial edema, and pulmonary vascular receptors, activated by acute changes
in pulmonary artery pressure  contributes to air hunger
o Hyperinflation  sensation of increased work of breathing, an inability to take a deep breath, or an
unsatisfying breath
 Metaboreceptors, located in skeletal muscle, are activated by changes in local biochemical milieu of tissue active
during exercise  breathing discomfort
Integration: Efferent-Reafferent Mismatch
 Mismatch between feed-forward message to the ventilatory muscles and the feedback from receptors that monitor
response of ventilatory pump  increases intensity of dyspnea
o COPD or asthma
Contribution of Emotional or Affective Factors in Dyspnea
 Acute anxiety or fear  increases the severity of dyspnea by altering the interpretation of sensory data or by leading
to patterns of breathing that heighten physiologic abnormalities in the respiratory system
 Expiratory flow limitation  hyperinflation, increased work and effort of breathing, and sensation of unsatisfying
breath

Assessing Dyspnea

 Quality of Sensation: for patients who have difficulty describing their breathing sensations
 Sensory Intensity: A modified Borg scale or VAS can be utilized to measure dyspnea at rest, after exercise, or recall
of a reproducible physical task
o Alternative: what activities of the patient are possible
o Baseline Dyspnea Index or Chronic Respiratory Disease Questionnaire
 Affective Dimension: To be reported, a symptom must be unpleasant or abnormal
o Air hunger evokes a stronger affective response than increased effort or work of breathing
o Pulmonary rehabilitation may reduce breathing discomfort

Differential Diagnosis
Respiratory System Dyspnea
Diseases of the Airways
 Asthma and COPD (most common obstructive lung disease)
o Expiratory airflow obstruction leading to dynamic hyperinflation of the lungs and chest wall
o Moderate to severe disease  increased resistive and elastic loads on the ventilatory muscles and
experience increased work of breathing
 Patients with acute bronchoconstriction  tightness (even when lung function is within normal range)
 Tachypneic  hyperinflation and reduced respiratory system compliance and limitation of tidal volume
 Chest tightness and tachypnea: stimulation of pulmonary receptors
 COPD and asthma  hypoxemia and hypercapnia from VQ mismatch
 Emphysema  Diffuse limitation during exercise with emphysema
o Hypoxemia is more common than hypercapnia as a consequence of different ways in which oxygen and
carbon dioxide bind to hemoglobin
Diseases of the Chest Wall
 Stiffening of the chest wall (e. g. kyphoscoliosis) or weakened ventilatory muscles (myasthenia gravis, Guillain-
Barré Syndrome) are associated with an increased effort to breathe
 Large pleural effusions  increased work of breathing and stimulation of pulmonary receptors if with atelectasis
Diseases of the lung Parenchyma
 Interstitial lung diseases
o Arise from infections, occupational exposures, autoimmune disorders
o Associated with increased stiffness of the lung and increased work of breathing
o V/Q mismatch and destruction or thickening of alveolar-capillary interface  leads to hypoxemia and an
increased desire to breathe

Cardiovascular System Dyspnea

Disease of the Left Heart
 Coronary artery disease and non-ischemic cardiomyopathies  greater LV end diastolic volume and an elevation
of LV end diastolic and pulmonary capillary pressure
o Interstitial edema and stimulation of pulmonary receptors
o V/Q mismatch  breathlessness
 Diastolic dysfunction (very stiff left ventricle) leads to severe dyspnea with relatively mild degrees of physical
activity (particularly if associated with MR)
Diseases of the Pulmonary Vasculature
 Pulmonary thromboembolic disease and primary diseases of the pulmonary circulation  causes dyspnea via
increased pulmonary-artery pressure and stimulation of pulmonary receptors
 Hyperventilation is common, and hypoxemia may be present
Diseases of the Pericardium
 Constrictive pericarditis and cardiac tamponade  increased intracardiac and pulmonary vascular pressures 
likely the cause of dyspnea
 Metaboreceptors may be stimulated if CO is compromised to the degree that lactic acidosis develops

Dyspnea with Normal Respiratory and Cardiovascular Systems

 Mild to moderate anemia  associated with breathing discomfort due to exercise
o Related to stimulation of metaboreceptors
 Obesity
o High cardiac output, impaired ventilatory pump function
 Cardiovascular deconditioning (poor fitness)
 o Characterized by early development of anaerobic metabolism and stimulation of chemoreceptors and
metaboreceptors

Approach to the Patient with Dyspnea

History
 Describe what the discomfort feels like
 Effect of position, infections, environmental stimuli
o Orthopnea is a common indicator of CHF
 It can also be due to mechanical impairment of the diaphragm associated with obesity, or asthma
triggered by esophageal reflux
o Nocturnal dyspnea suggests CHF or asthma
o Acute, intermittent episodes  MI, bronchospasm, pulmonary embolism
o Chronic, persistent  COPD, ILD, chronic thromboembolic disease
 Risk factors should be elicited
 If platypnea (dyspnea while standing and relieved by supine position)  left atrial myxoma or hepatopulmonary
syndrome

Physical Examination
 Begins during the interview of the patient
  Inability of the patient to speak in full sentences before stopping to get a deep breath
o Condition that leads to stimulation of the controller or impairment of ventilatory pump with reduced vital
capacity
 Evidence of increased work of breathing (supraclavicular retractions, use of accessory muscles of ventilation, tripod
position)
o Indicative of increased airway resistance or stiffness of the lungs and the chest wall
 RR and pulsus paradoxus
o If systolic pressure decreases by > 10 mmHg, presence of COPD, asthma, or pericardial disease is
considered
 Signs of anemia, cyanosis, cirrhosis (spider angiomata, gynecomastia)
 Chest: Symmetry of movement, dullness in percussion, auscultation for wheezes, rhonchi, prolonged expiratory
phase, diminished breath sounds  disease of the airway
o Rales  interstitial edema or fibrosis
 Cardiac Examination:
o Elevated right heart pressure (jugular venous distention, edema, accentuated pulmonic component to the
second heart sound)
o LV dysfunction (S3 and S4) and valvular disease (murmurs)
 Abdomen
o Paradoxical movement of the abdomen (diaphragmatic weakness)
o Rounding of the abdomen during exhalation: pulmonary edema
 Extremities
o Clubbing in the digits  interstitial pulmonary fibrosis
o Joint swelling or deformation and Raynaud’s disease  collagen vascular process associated with
pulmonary edema
 Exertional dyspnea  asked to wallk under observation
o Examined during and at the end of the exercise
Chest Imaging
 Chest radiograph should be obtained
 Lung volumes should be obtained
o Hyperinflation: obstructive lung diseae
o Low lung volume: interstitial edema or fibrosis, diaphragmatic dysfunction, impaired chest wall motion
 Pulmonary parenchyma: interstitial disease and emphysema
 Prominent pulmonary vasculature in the upper zone: pulmonary venous hypertension
 Enlarged central pulmonary arteries: pulmonary arterial hypertension
 Enlarged cardiac silhouette: cardiomyopathy or valvular disease
 Bilateral pleural effusion: CHF, collagen-vascular disease
 Unilateral effusion: specter of carcinoma and pulmonary embolism; may also occur in heart failure
 CT if further evaluation is needed (ILD or PE)
Distinguishing CVS from Respiratory System Dyspnea
 Cardiopulmonary exercise test if patient has signs of both pulmonary and cardiac disease
o If reaches predicted maximal ventilation at peak exercisedead space or hpoxemiia, bronchospasm 
lung disease
o Heart rate > 85% of predicted maximum, anaerobic threshold is early, blood pressure is excessively high,
decreases during exercise, O2 pulse falls, ischemic changes in ECG  CVS

Treatment
 First goal: Correct the underlying problem responsible for the symptom
 If first goal isn’t met, Effort is made to lessen intensity of the symptom and its effect on patient’s quality of life
  Supplemental O2 should be administered if resting O2 saturation is less than or equal to 89% or if it drops to these
levels with activity
 For patients with COPD: pulmonary rehab programs
 Anxiolytics and antidepressants not well studied

1. Appraising Directness
a. How well the PEO in the study corresponds with our own PEO
2. Appraising validity
a. Were patients randomly assigned to treatment groups?
b. Was allocation concealed?
c. Were baseline characteristics similar at the start of the trial?
d. Were patients blinded to treatment assigned
e. Were caregivers blinded to treatment assignment
f. Were outcome assessors blinded to treatment assignment
g. Were all patients analyzed in the groups to which they were originally randomized
h. Was follow-up rate adequate?
3. Appraising the results
a. How large was the treatment effect?
b. How precise was the estimate of the treatment?
4. Assessing applicability
a. Sex
b. Comorbidities
c. Race
d. Age
e. Pathology
f. Socioeconomic factors
5. Individualizing the results

1 and 2: Trisha and Jolo

3: James
4 and 5: Raymond and Bea