1. Nausea & Vomiting Brian H. Black D.O.

2.  Review the importance of Nausea & Vomiting in both acute and palliative settings  Discuss and review key anatomic considerations  Discuss receptors important for appropriate medication selection and treatment  Describe a mechanistic approach

3.  nau·se·a  ˈ nôzēə,-ZHə  noun  a feeling of sickness with an inclination to vomit  synonyms: sickness, biliousness, queasiness, “swimmy”, lothing, gagging, sea/air/car sickness

4.  re·gurge  ˈ rə ˈ gərj, rē ˈ -, -gəj, -gəij  Verb  Passive retrograde movement of ingested material, usually before it has reached the stomach  synonyms: dry heave, retch, drive the bus, “puke in my own mouth”, “barf a little”, boff, or “be sick”

5.  vom·it  ˈ vämət/  Verb or present participle  eject matter from the stomach through the mouth  synonyms: heave, retch, get sick, throw up, puke, purge, hurl, barf, upchuck, bark, spew, ralph, or “be sick”

6.  Progressive Failsafe Measures are plenty in the human body which help prevent toxic absorption  Examples include:  Appearance  Smell  Taste  GI receptor stimulation  AND… VOMITING

8.  Nausea & Vomiting is common  cc in 2%  a component in > 20%  Only 25% of pts with symptoms visit a physician  Thus stats likely significantly under-represent the problem  It is more common in those 15-24 yo as a single presenting complaint, but nausea is a major component of morbidity  Cost estimates - over 4 billion/yr in U.S.  Complications include hypokalemia and metabolic acidosis which can lead to serious illness or death

9.  A 46 yo obese female presents with nausea s/p cholecysectomy three days ago. She has dysuria. She notes worsening symptoms after she eats at which point she occasionally vomits. She is taking the IR morphine as prescribed for pain on a regular basis and pain is a 4/10.  What pathway is involved this pts nausea?  A.) Vagal & splanchnic mechanoreceptor firing d/t stretch d/t Ileus  B.) SE of Morphine acting on the chemoreceptor trigger zone  C.) Urinary infection s/p unnecessary cath placement  D.) Substance P and histamine release from pain and inflammation  E.) Any or all of the above

10.  A 46 yo obese female presents with nausea s/p cholecysectomy 4 days ago. She has dysuria. She notes worsening symptoms after she eats at which point she occasionally vomits. She is taking the IR morphine as prescribed for pain on a regular basis and pain is tolerable  What pathway is involved in her nasuea?  A.) Vagal & splanchnic mechanoreceptor firing d/t stretch caused by Ileus  B.) SE of Morphine acting on the chemoreceptor trigger zone  C.) Urinary infection s/p unnecessary cath placement  D.) Substance P and histamine release from pain and inflammation  E.) Any or all of the above

11.  Nausea is caused by many disease states and is often multi-factorial.  Some medications are more effective than others for different causes.  What are the common pathways?  How do we approach treatment?

14.  Muscarinic / Acetylcholine (M1)  Histamine (H1)  Serotonin aka 5- HydroxyTryptamine (5-HT3 / 4)  Dopamine (D2)  Neurokinin 1 (NK1)  Gamma-aminobutyric acid (GABA)

18.  The right Rx at the right time  Leveraging of S.E.  Limitation of testing  Consideration for cost  Multi-drug strategies  Non-pharmaceutical options

19. The Art of War “It is said that if you know your enemies and know yourself, you will not be imperiled in a hundred battles…” Sun Tzu

20. VOMIT(c)  Vestibular  cOnstipation (and other Enteric Dysfunction)  Metabolic Derangement  Infection / Inflammation  Toxins  Cortical / Central

21.  An 72 yo WF presents to the Emergency room stating she has severe nausea of sudden onset. She was reaching down to get the trash and suddenly noted ringing in her ears and dizziness. She denies vision changes or difficult swallowing. She has had this before and has several meds at home. She calls you because she is now confused which one to take.  Which of the following treatments are likely to act on the main neurotransmitters involved?  A.) Haldol  B.) Gabapentin  C.) Benadryl  D.) Ondansetron  E.) Vitamin B6

22.  An 72 yo WF presents to the Emergency room stating she has severe nausea of sudden onset. She was reaching down to get the trash and suddenly noted ringing in her ears and dizziness. She denies vision changes or difficult swallowing. She has had this before and has several meds at home. She calls you because she is now confused which one to take.  Which of the following treatments are likely to act on the main neurotransmitters involved?  A.) Haldol  B.) Gabapentin  C.) Benadryl  D.) Ondansetron  E.) Vitamin B6

24. V OMIT(c)  Peripheral Vestibular (VIIIth nerve)  Sudden onset  Head movement triggers  More likely to have auditory symptoms (ringing)  Does not require an extensive workup  Central Vestibular  Likely involve posterior circulation brainstem symptoms “the D’s” including Diplopia, Dysphagia, Dysarthria  Can indicate more serious disease  Often vague symptoms and history  Imaging of the brain may be helpful in these cases

25. V OMIT(c)  Peripheral Vestibular  Receptors involved: Cholinergic & Histaminic  Scopolamine patch 1.5mg sq q3 days  can also be given via IV, or SubQ injection  Meclizine 25mg po tid  Promethzaine 25mg po q4-6 hrs prn

26. V OMIT(c) Vestibular cautions and considerations:  Cholinergic/Histaminic blockade can lead to:  Dry mouth  Sedation  Vision changes  Fall risks  May exacerbate poor gut motility  Non-rational treatment with H1 / M1 blockade leads to these side effects WITHOUT IMPROVEMENT OF THE NAUSEA!  Anti-cholinergic symptoms are especially concerning in the elderly

27.  A 52 yo male presents with metastatic lung cancer presents to the clinic with abdominal fullness, nausea, and intermittent vomiting. His sx previously were managed on Ondansetron (zofran), but have become refractory to escalating doses…  What is the next best step?  A.) Stop Ondansetron  B.) Change Chemo Regimen  C.) Add Dexamethethasone  D.) Do a Rectal Exam  E.) Add Haldol

28.  A 52 yo male presents with metastatic lung cancer presents to the clinic with abdominal fullness, nausea, and intermittent vomiting. His sx previously were managed on Ondansetron (zofran), but have become refractory to escalating doses…  What is the next best step?  A.) Stop Ondansetron  B.) Change Chemo Regimen  C.) Add Dexamethethasone  D.) Do a Rectal Exam  E.) Add Haldol

30. V O MIT(c)  cOnstipation (and other enteric dysfunction)  O in this case does not count for a frank obstruction of the bowel, but instead “obstruction” via constipation and also movement problems of the bowel leading to nausea  Cholinergic, Histaminic, and 5-HT3, 5-HT4 receptors helpful targets  Stimulation of the myenteric plexus (senna) can relieve “obstruction” of the bowel due to constipation  Bowel dysmOtility  Loss of bowel movement which impairs food and waste transit  Can occur as a result of DM or other dz  Prokinetics can be helpful (Metoclopramide stimulates 5HT4 receptors)

31. V O MIT(c)  Laxative therapy can be burdensome & unpredictable  Methylnaltrexone  Action: selectively inhibits the Mu receptors of the GI tract  Does not affect analgesia  10mg SubQ qod usually effective  Rapidly response when effective  May be cost prohibitive in some settings

32. V O MIT(c) cOnstipation (& other enteric dysfunction) cautions and considerations:  Stimulant laxative overuse can lead to …  Beware of Prokinetic agents (Meta… Reglan) for use in frank obstruction! They are contraindicated  To prevent constipation you should consider starting a stool softener with all Narcotic prescriptions… they go together like peas and carrots…

33. Frank and Complete Obstruction of the Bowel  Common in ovarian & colon CA  Hernias or post-op adhesions can cause partial or complete obstruction too  Definitive treatment is not pharmaceutical, but surgical  Options include: IV fluids and NG tubes, surgical correction, venting gastrostomy tube, and placing stents across the obstruction  Poor surgical candidates can be approached with endoscopic methods

34. Frank and Complete Obstruction of the Bowel  Opiates and Dopamine antagonists are key  Somatostatin analogues like Octreotide (Sandostatin)  used to inhibit secretion of GH, TSH, ACTH, prolactin, and decrease the release of gastrin, CCK, insulin, glucagon, gastric acid and pancreatic enzymes.  All leading to decreased peristalsis & splanchnic blood flow

36. VO M IT(c)  Metabolic Derangement  Correction of the abnormality is key  Not all cases of nausea need lab testing  Consider a metabolic profile in refractory cases  Check a metabolic profile: Ca/Na/K. Cause & Effect  Adrenal disorders  Parathyroid disorders  Uremia  Many others exist. These causes should be considered in resistant cases and in patients who exhibit signs and symptoms of disease

38. VOM I T(c)  Receptors involved: Cholinergic, Histaminic, 5HT-3, & Neurokinin 1  Infection  Tx of infection (Sepsis, Pyleonephritis, Pneumonia)  Inflammation  Of the Gut  stimulation of NK1 receptors  Corticosteroids may have a role but the evidence is limited  Useful Medications  Promethazine (eg. Labrinthitis)  Prochlorperazine (Sepsis)  Coating Agents like Bismuth or Sulcralfate

40. A 69yo diabetic pt with hx of heart failure is seen at the ECF. On review of symptoms she has complaints of nausea. You note she is on 12 medications, and recently started a new anti-depressant.  Which of the following is true regarding medication induced Nausea?  A.) Nausea is an uncommon SE of medication  B.) The mechanism involved in most causes of nausea are poorly defined  C.) Medication induced nausea is typically associated with brief periods of symptoms immediately after administration  D.) Medication induced nausea occurs early in use and exhibits a consistent course over time

41. A 69yo diabetic pt with hx of heart failure is seen at the ECF. On review of symptoms she has complaints of nausea. You note she is on 12 medications, and has recently started a new anti-depressant.  Which of the following is true regarding medication induced Nausea?  A.) Nausea is an uncommon SE of medication  B.) The mechanism involved in most causes of nausea are poorly defined  C.) Medication induced nausea is typically associated with brief periods of symptoms immediately after administration  D.) Medication induced nausea occurs early in use and exhibits a consistent course over time

43. Toxins  Receptors involved usually include Dopamine and 5-HT3  Useful classes: Anti-dopaminergic & 5-HT3 antagonists  Many toxins cause nausea due to stimulation of the chemreceptor trigger-zone  Chemotherapy  Medications  Opiates (Morphine)  Digoxin  Clonadine  Polypharmacy  NSAIDs  local irritation

44.  Chemotherapy Risk Factors  Multi-day  Dose-dense  IV (vs po)  Short infusion time  Chemotherapy induced nausea and vomiting can be limited by judicious use of treatment  Medication rotation may be helpful

45. VOMIT( C )  Cortical / Central  CNS disease (brain mets)  Dexamethasone 40mg daily  PO, IV, or SubQ  Decrease swelling  Anxiety  Tx c Benzo’s can be helpful  Ativan 1mg po q4 hrs

46. Cortical / Central / Chemo cautions… considerations … and other c’s:  Anxiolytics  Can cause over-sedation  Not helpful for the tx of nausea  Can help decrease anxiety associated with poor sx control  5HT3 drugs – expensive & not always needed  Corticosteroids – can cause S.E.

47. Special Cases:  Carcinomatosis  Prokinetics Agents are usually agents of choice  Steroids as anti-inflammatories can be very useful as well  Examples include Metoclopramide & Decadron combos  Treatment resistant cases  D2 Blockage can be very effective via central action  Haloperidol 1mg q4 hours (po, IV, or SubQ)  Prochlorperazine 5mg po q6 hrs or 25mg PR BID

48. A 15 year old with recent mood swings pt presents with complaint of vague symptoms of nausea. She is also complaining of some mild dysuria & fatigue. Which of the following is true:  A.) Empiric antibiotics and sx recheck is adequate  B.) Lab testing is essential for the dx  C.) A med acting at the serotonin receptor (5-HT3) will be the best anti-emetic for treatment  D.) These cases are generally self limited, but NSAIDs or corticosteroids can be helpful  E.) The diagnosis is likely to be psychogenic

49. A 15 year old with recent mood swings pt presents with complaint of vague symptoms of nausea. She is also complaining of some mild dysuria & fatigue. Which of the following is true:  A.) Empiric antibiotics and sx recheck is adequate  B.) Lab testing is essential for the dx  C.) A med acting at the serotonin receptor (5-HT3) will be the best anti-emetic for treatment  D.) These cases are generally self limited, but NSAIDs or corticosteroids can be helpful  E.) The diagnosis is likely to be psychogenic

50.  Nausea Gravidarum ( aka morning sickness)  Affects more than half of all pregnant patients.  Usually worse in the early AM hours, but can occur anytime of day  Usually abates on its own around the 12 th week of pregnancy  Felt to be multi-factoral and related to increased estrogen & progesterone levels, increase in salivation, low blood sugar, as well as the hormone BHCG’s effects.  Women with uncomplicated “morning sickness” have a LOWER risk of miscarriage, preterm delivery, low birth wt, & mortality  Consider alternative causes in a pregnant women if worsening sx or if onset AFTER 9 weeks gestation

51.  Timing?  New Medications could be the culprit  Lifestyle changes could lead to anxiety & psychosocial distress  Vomiting occurs earlier and in larger amounts in proximal obstructions (as compared to colorectal obstruction)  Location?  Sometimes asking “Where is the nausea” can be helpful to elucidate symptoms of dizziness, pain, or infection  Others with same illness? Travel?  Cases of food poisoning or infection can be shared with others, but this is not always volunteered by the patient in a nurses intake

52.  Nausea + Heartburn  likely GERD  Vomiting + Abd pain  likely organic etiology  Early Morning Vomiting  Pregnancy  Feculent Vomiting  Consider gastrocolic fistula  Vertigo / Nystagmus  Likely Vestibular sx  Nausea+Diarrhea+HA+Myalgias  Viral Gastroenteritis

53.  Nausea + dental /parotid gland changes  Bulemia  Nausea + “the D’s”  Neurogenic vomiting  Nausea + THC use daily  Cannabinoid Hyperemesis  Nausea + Bilious Vomiting  Small bowel obstruction  Abd pain, then nausea  Appendicitis  Symptoms > 1 months  Chronic Nausea & Vomiting

54.  Vitals & Volume  Dehydration (tachycardia & skin tenting with dry mm)  Abdominal exam (including rectal)  Nausea, Pain, and Distension  Obstruction  Hypo or Hyperactive bowel sounds?  Masses?  Ascites?  Tenderness?  Hard stool in rectal vault?  Neuro exam  Nystagmus

55.  CMP (Comprehensive Metabolic Profile)  To review: Renal Function, Liver Function, e- levels (Ca / Na)  Urine: UA & BHCG  Other testing is done as suggested by Hx & PE  CBC  TSH  Stool Guiac  Amylase/Lipase  H Pylori testing  Stool cultures *** Labs and testing should only be done as needed to dx problem & assist identification of appropriate management strategy. If it wont change your treatment, then don’t do it!

56.  MRI / CT of brain (CT if acute  Ultrasound  “Obstruction series”  Other GI studies  For pts with significant dysphasia or sx of GERD with failure to resolve with tx trial  EGD  Manometry can be done to eval LES pressure and mm contractions if EGD normal  Gastric emptying study is recommended if gastroparesis is suspected.

58.  Nausea/Vomiting >48 hours  Hematochezia or Melena  Sustained High Fever  Weakness or Altered (focal neuro change)  No urination in > 8hrs / or other dehydration signs  Diarrhea or severe abd pain  Lack of charting  “return if worsening or new symptoms” Rick Bukata

59.  Aprepitant (NK-1 blocker mainly for use in CINV)  Decadron 10mg po/IV (Anti-inflammatory Corticosteroid)  Haldol 1mg po, im, subq q4 hrs prn (D2 Blockade)  Lorazepam 1mg po q4hrs prn (Benzodiazepine Anxiolytic)  Meclizine 25mg po tid (Antihistamine)  Methylnaltrexone 10mg SQ qod (Mu Receptor Antagonist)

60.  Metoclopramide 10mg po/iv ac&hs (Dopamine agonist & Prokinetic agent)  Ondansetron 4mg po/sl/iv q4 hr prn (5HT3 blockade)  Prochlorperazine 5mg po qid (D2 blockade)  Prochlorperazine 25mg pr bid (D2 blockade)  Scopolamine patch (1.5 mg patch) (Anticholinergic)  Senekot S 1-2 tabs po tid (Stimulant Laxative)

61.  Frequent small meals  Removal of all unpleasant and strong scents  AVOID ALL PERFUMES  LIMIT HARSH CLEANERS  Removal triggering visual stimuli  Coke syrup, B12, Ginger, Cinnamon, Marijuana (dronabaniol)  Accupressure / Accupuncture (Sea Bands on anterior wrist)

63.  Accupuncture  Accupressure  Sea Bands  Herbs  Clove  Cinnamon  Cumin  Ginger  Mint  Cold Compress  Avoiding Spicy Foods and offending foods  Alka-Seltzer  Avoid due to the fact it contains ASA and can irritate stomach lining

65.  Promethazine & Prochlorperazine  Sound similar but are very different drugs  Promethazine (Phenergan)  MOA: Strong Antihistamine with weak anti-dopaminergic effects  most useful for vertigo and gastroenteritis due to infections and inflammation  Prochlorperazine (Compazine)  MOA: Antidopaminergic  preferred agent for opioid related nausea  Can be given 5-10mg po qid  Very helpful PR at 25mg PR BID!!!  Both meds: Are commonly used to treat nausea and especially OINV (Opiate induced Nasusea & Vomiting), but no trials (that I know) have compared them head-to-head…

66.  There is NO EVIDENCE for the use of anxiolytics as isolated agents in the treatment of nausea  Anxiolytics ARE useful for tx of anxiety as associated with severe nausea & vomiting. SE can include sedation, fall risk, and aspiration  Constipation is a frequent SE of narcotics (and multiple other meds)  Consider starting laxatives when starting opiates and other meds that are associated with constipation

67.  Nausea & Vomiting is common  Control can dramatically improve quality of life  A rational symptomatic approach can yield improved control & minimize side effects  All approaches should:  Identify the etiology of disease  Correct the complications  Target the receptor for therapy

68.  Several animals do not vomit:  Rats  Horses  Rabbits  Guiena pigs  Japanese quail  But Pandas apparently do vomit and there is an entire subculture of artists capturing the thought… and vision… in rainbows…

70.  Glare P, et al. Systemic review of the efficacy of antiemetics in the treatment of nausea in patients with far-advanced cancer. Support Care Cancer. 2004; 12:432-440  Hallenbeck J. Palliative Care Perspectives. New York, NY: Oxford University Press; 2003: pp75-86  Vol. 8, No. 1, January/February 2009 issue of ASHA's Access Audiology.  Clark K, Smith JM, Currow DC. The prevalence of bowel problems reported in a palliative care population. J Pain Symptom Manage 2012;43:993-1000.  Basch E, Prestrud AA, Hesketh PJ, et al. American Society of Clinical Oncology. Antiemetics: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol 2011;29:4189-98.  Maceira E, Lesar TS, Smith H. Medication related nausea and vomiting in palliative medicine. Ann Palliat Med 2012;1(2):161-176. DOI: 10.3978/ j.issn.2224-5820.2012.07.11  Keith Scorza, MD, et al., Dewitt Army Community Hospital Family Medicine Residency, Fort Belvoir, Virginia. Am Fam Physician. 2007 Jul 1;76(1):76-84  William D. Anderson, MD, et al, University of South Carolina School of Medicine, Columbia, South Carolina, Am Fam Physician. 2013 Sept 15; 99(6): 371-379