Nauseated and Breathless: Nobody’s Preferred Way to Die Annie Massart, MD [email protected] Twitter: @Annie_Massart_ Disclosures

• None Objectives

• Describe the prevalence of dyspnea in advanced COPD and lung • Identify therapeutic options for managing dyspnea • Name the mechanisms of action for common • Tailor regimens to triggers

Case 1

• 37.6, HR 95, BP 130/80, RR 20, O2 sat 94% on RA. • Normal work of breathing, decreased air movement throughout, no wheezes. While speaking, some pursed lip breathing and has to pause intermittently to breathe. • Normal bowel sounds, LLQ TTP, no rebound/guarding

• CT abdomen: uncomplicated diverticulitis • CXR: stable emphysema, no infiltrate Case 1

How would you address his breathing concerns? A. Start supplemental oxygen and monitor response B. Treat for COPD exacerbation with steroids and nebulized bronchodilators C. Start him on Morphine Extended Release 30 mg po q12h and monitor response D. Provide him with a hand-held fan and monitor response E. Remind him he’s here for diverticulitis and you’ll refer him to pulmonary clinic Kamal, A.H., et al. J Palliat Med. 2011 Oct;14(10):1167-72 Dyspnea

• 50-80% of patients with advanced cancer • 90-95% of patients with advanced COPD • Dyspnea and distress both higher in COPD than lung cancer Dyspnea

• Decreased activity level • Deconditioned patients become dyspneic more easily

• Increased dependence on their caregivers

• Decreased quality of life Assessing Dyspnea

O’Donnell, D.E., et al. Can Respir J. 2007 Sep;14 Suppl B:5B-32B. Management Options

• Disease optimization

• Oxygen

• Non-pharmacologic therapies

• Pharmacologic therapies Disease Optimization

Tailored to patient • Endobronchial lesion→ Bronch with tumor destruction vs stent • Lesion compressing airway → XRT • Emphysema with large bullae → Surgery • Malignant effusion → Thoracentesis

Case courtesy of Dr Mohammad Osama Yonso, Radiopaedia.org, rID: 25128 Oxygen Oxygen Helps Hypoxemic Patients

Continuous oxygen

Nocturnal oxygen

Continuous or nocturnal oxygen therapy in hypoxemic chronic obstructive lung disease: a clinical trial. Nocturnal Oxygen Therapy Trial Group. Ann Intern Med.1980 Sep;93(3). Oxygen for Dyspnea

Abernathy, A.P., et al. Lancet. 2010 Sep 4;376(9743):784-93. Too Much is Harmful

Chu, D.K., et al. Lancet. 2018 Apr 28;391(10131):1693-1705. Non-pharmacologic Therapies Kako, J., et al. J Pain Symptom Manage 2018 Oct;56(4):493-500. Favors usual care Favors pulm rehab Pharmacologic Therapies Dyspnea Improves with

A-L Jennings et al. Thorax 2002;57:939-944 -Naive Opioid-Tolerant

Mild Dyspnea Severe Dyspnea

Morphine 5 mg po q4h Increase baseline Hydrocodone 5 opioid dose 25-50% mg q4h Oxycodone 5 mg po q4h

Hydromorphone 1 mg po q4h

Titrate 50-100% every 24 hours as needed *In severe lung disease, start at 50% of above, titrate <25% per 24 hours

Thomas, J., von Guten. C.. Lancet Oncol. 2002 Apr;3(4):223-8.

• Not 1st line therapy • 2nd line if opioids alone insufficient

• Don’t relieve dyspnea, but associated with dyspnea Dyspnea Summary

• Dyspnea is highly prevalent in COPD and advanced cancer patients • Impacts QOL and functional status • First line management is nonpharmacologic • Opioids are an option for those with persistent dyspnea • Supplemental oxygen only benefits hypoxemic patients

The Emetogenic Pathway

Harris, D.G. British Medical Bulletin, Volume 96, Issue 1, 30 September 2010, Pages 175–185 site affinities of commonly used antiemetics

Glare, P., et al. Treating nausea and in : a review. Clinical interventions in aging. , 2011, Vol.6, p.243-259 Nausea and Vomiting

• 1. Investigate! Nausea and Vomiting

Relevant history: • Colicky abdominal pain, nausea better after voluminous emesis→ obstruction • Bloating, nausea improves with small volume emesis → gastric stasis • Vertigo, worsening of nausea with movement → Vestibular problem • Morning nausea and headaches → Increased ICP • Associated with anxiety → Cortex • New medications, opioids, polypharmacy → med activation of CTZ • Radiation treatment? Nausea and Vomiting

• 1. Investigate! • 2. Choose antiemetic based on involved pathway Receptor site affinities of commonly used antiemetics

Glare, P., et al. Treating nausea and vomiting in palliative care: a review. Clinical interventions in aging. , 2011, Vol.6, p.243-259 Nausea and Vomiting

• 1. Investigate! • 2. Choose antiemetic based on involved pathway • 3. Schedule and titrate up • 4. If no improvement, ADD another medication with a different mechanism

QTc is 510 msec Case 1

What do you do? A. Order 4 mg IV x 1. B. Order ondansetron 4 mg IV x 1 and telemetry. C. Provide the patient with isopropyl alcohol wipes. D. Repeat the EKG and hope the QTc is better.

Medication Studied Dose(s) Impact on QTc 15 mg/day po +7.1 msec ~34 mg/day IV +41 msec 20 mg/day po +1.7 msec 1.25-10 mg IV +11 msec 25 mg IV +20-25 msec Ondansetron 4 mg IV x 1 +16-20 msec 0.25-2.25 mg po No significant effect* 200 mg IV No significant effect

*Palonosetron has not demonstrated QTc prolongation in CINV. Two studies in PONV demonstrated QTc prolongation but this may have been related to anesthesia. Inhaled Alcohol vs IV Ondansetron

Nausea reported on a 0-10 scale, 0 for no nausea and 10 indicating worst nausea

imaginable. Winston, A.W., et al. AANA journal. , 2003, Vol.71(2), p.127-132 Inhaled Alcohol vs Oral Ondansetron

April, M.D., et al. Annals of Emergency Medicine : Journal of the American College of Emergency Physicians. , 2018, Vol.72(2), p.184-193

Case courtesy of Dr Ian Bickle, Radiopaedia.org, rID: 50327 Case 2

Does she need prophylactic anti-emetics? A. I don’t know, I’ll have the fellow call you. B. She’s not nauseated now, but I can throw on some ondansetron prn to be safe. C. If she is receiving moderately or highly nauseating chemo, she definitely needs scheduled antiemetics. D. It’s probably not a big deal, let’s see how she does without them. Induced Nausea and Vomiting (CINV) • 83% of patients in 1979 → 35% of patients in Emetogenic Risk of 2004 Chemotherapy Category Risk • Huge impact on quality of life! High >90%

• 2014: Antiemetics listed as one of the top 5 Moderate 30-90% advances in over the last 50 years Low 10-30%

• Untreated CINV can be a trigger for future nausea Minimal <10% Navari RM, Aapro M. N Engl J Med 2016;374:1356-1367. Navari RM, Aapro M. N Engl J Med 2016;374:1356-1367. Navari RM, Aapro M. N Engl J Med 2016;374:1356-1367. Acute CINV

Delayed CINV Olanzapine Works on multiple receptors - Dopamine: D1, D2, D3, D4 - : 5-HT2a, 5-HT2c, 5-HT3, 5-HT6 - Acetylcholine: Muscarinic receptors - Histamine: H1 Olanzapine for the Prevention of CINV

Navari RM et al. N Engl J Med 2016;375:134-142. Trigger Mechanism of Typical 1st Line Nausea/Vomiting Antiemetics Opioid-induced Stimulation of CTZ , (D2),Gastroparesis (D2) haloperidol, and Constipation (H1, AchM), Sensitization of labyrinth (H1,AchM) Malignant bowel Stimulation of CTZ (D2), Stimulation Metoclopramide (if obstruction of peripheral pathways (H1, AchM) partial), haloperidol, and

Impaired GI Gastroparesis (D2) Metoclopramide motility of advanced cancer Wood, G. J., et al. JAMA 2007, Vol.298(10), p.1196-1207 Trigger Mechanism of Nausea/Vomiting Typical 1st Line Antiemetics Radiation- 5HT3 released in gut, vagal nerve 5HT3 antagonists induced activates vomiting center

Brain tumor ↑ ICP or meningeal irritation activate Dexamethasone meningeal mechanoreceptors which stimulate the vomiting center.

Motion- Stimulation of vestibulocochlear , associated nerve (H1, AchM). promethazine,

Wood, G. J., et al. JAMA 2007, Vol.298(10), p.1196-1207 Nausea and Vomiting Summary

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